Sollas&Notes&2015&

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Sollas!
Pharmacology!II!/!MADNESS!
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Sollas&Notes&2015&

TOPIC!1! 4&
1.1!ANTIEPILEPTICS! ERROR!&BOOKMARK&NOT&DEFINED.&
1.2!PRINCIPLES!OF!ANTIBACTERIAL!AND!ANTINEOPLASTIC!CHEMOTHERAPY.!CLASSIFICATION!OF!THE!
CHEMOTHERAPEUTIC!DRUGS! 9&
1.3!PHARMACOTHERAPY!OF!ASTHMA!BRONCHIALE! 12&

TOPIC!2! 15&
2.1!SEDATIVE/HYPNOTIC!DRUGS;!BARBITUATES!AND!OTHER!NON/BENZODIAZEPINE!SEDATOHYPNOTICS! 15&
2.2!PROBLEMS!WITH!CHEMOTHERAPEUTIC!DRUGS:!RESISTANCE! 17&
2.3!DRUGS!USED!IN!THE!TREATMENT!OF!HYPERLIPIDEMIAS! 18&

TOPIC!3! 21&
3.1!SEDATIVE/HYPNOTIC!DRUGS!ACTING!ON!BENZODIAZEPINE!RECEPTOR! 21&
1.2& BETA/LACTAM!ANTIBIOTICS!I:!PENICILLINS! 23&
3.3!TREATMENT!OF!ACUTE!MYOCARDIAL!INFARCTION! 25&

TOPIC!4! 27&
4.1!MECHANISM!OF!NEURONAL!DEATH.!PHARMACOTHERAPY!OF!ALZHEIMERS!DISEASE! 27&
4.2!BETA/LACTAM!ANTIBIOTICS!II.!CEPHALOSPORINS!AND!OTHER!CELL!WALL!SYNTHESIS!INHIBITORS! 29&
4.3!AGENTS!USED!IN!ANEMIAS!AND!OTHER!CYTOPENIAS! 32&

TOPIC!5! 34&
5.1!PHARMACOLOGICAL!MANAGEMENT!OF!PARKINSONS!DISEASE! 34&
5.2!AMINOGLYCOSIDES!AND!SPECTINOMYCIN! 39&
5.3!DRUGS!USED!IN!DISORDERS!OF!COAGULATION! 41&

TOPIC!6! 44&
6.1!ANTIPSYCHOTICS!AND!LITHIUM! 44&
6.2.!CHLORAMPHENICOL!&!TETRACYCLINES! 48&
6.3!THE!EXOCRINE!PANCREAS.!PHARMACOLOGY!OF!THE!LIVER.!DRUGS!THAT!INHIBIT!THE!FORMATION!OF!
GALLSTONES! 50&

TOPIC!7! 55&
7.1!GENERAL!ANESTHESIA! 55&
7.2!MACROLIDES,!CLINDAMYCIN,!STREPTOGRAMIN! 59&
7.3!PHARMACOLOGY!OF!VASOACTIVE!AGENTS! 61&

TOPIC!8! 64&
8.1!PERIPHERALLY!ACTING!SKELETAL!MUSCLE!RELAXANTS! 64&
8.2!QUINOLONES!AND!FLUOROQUINOLONES.!SULFONAMIDES!&!TRIMETHOPRIM! 66&
8.3!ANTI/OBESITY!DRUGS! 68&

TOPIC!9! 69&
9.1!ANTIDEPRESSIVE!AGENTS! 69&
9.2!ANTIFUNGAL!AGENTS! 72&
9.3!POSITIVE!INOTROPIC!DRUGS! 76&

TOPIC!10! 78&
10.1!OPIOID!ANALGESICS:!NATURALLY!OCCURRING!OPIOIDS! 78&
10.2!ANTIVIRAL!AGENTS!I!!ANTIRETROVIRAL!AGENTS! 82&
10.3!DRUGS!THAT!PROMOTE!UPPER!GI!MOTILITY! 85&

TOPIC!11! 86&

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Sollas&Notes&2015&

11.1!OPIOID!ANALGESIC:!SEMISYNTHETIC!AND!SYNTHETIC!DERIVATIVES! 86&
11.2!ANTIVIRALS!II:!ALL!EXCEPT!FOR!ANTIRETROVIRALS! 89&
11.3!DRUGS!USED!IN!THE!TREATMENT!OF!INFLAMMATORY!BOWEL!DISEASE! 93&

TOPIC!12! 94&
12.1!OPIOIDS!AS!ABUSED!DRUGS.!TREATMENT!OF!MORPHINE!&!HEROIN!DEPENDENCE! 94&
12.2!ANTIMALARIAL!AGENTS! 95&
12.3!LAXATIVES,!GLP/1!ANALOGS,!DPP/4!INHIBITORS!AND!SGLT/2!INHIBITORS!IN!THE!TREATMENT!OF!
DIABETES! 97&

TOPIC!13! 98&
13.1!DRUGS!OF!ABUSE! 98&
13.2!INDIRECTLY!ACTING!PARASYMPATHOMIMETICS! 101&
13.3!ANTI/DIARRHEAL!DRUGS.!ANTIHELMINTHIC!DRUGS! 103&

TOPIC!14! 107&
14.1!PHARMACOLOGY!OF!ALCOHOLS! 107&
14.2!SEROTONIN!AND!DRUGS!ACTING!ON!SEROTONIN!RECEPTORS! 110&
14.3!ANTITUBERCULOTICS! 112&

TOPIC!15! 115&
15.1!LOCAL!ANESTHETICS! 115&
15.2!HISTAMINE!AND!ANTIHISTAMINE! 117&
15.3!DRUGS!ACTING!ON!THE!RENIN!ANGIOTENSIN!SYSTEM! 119&

TOPIC!16! 122&
16.1!HYPOTHALAMIC!AND!PITUITARY!HORMONES! 122&
16.2.!ERGOT!ALKALOIDS!AND!PHARMACOTREATMENT!OF!MIGRAINE! 125&
16.3!ANTIANGINAL!DRUGS! 126&

TOPIC!17! 129&
17.1!THYROID!AND!ANTITHYROID!DRUGS! 129&
17.2!PHARMACOLOGICAL!TREATMENT!OF!INFLAMMATION! 131&
17.3!ANTIARRHYTHMIC!DRUGS! 133&

TOPIC!18! 136&
18.1!ADRENOCORTICOSTEROIDS!AND!ADRENOCORTICAL!ANTAGONISTS! 136&
18.2!NON!STEROIDAL!ANTI/INFLAMMATORY!DRUGS!(NSAIDS)! 139&
18.3!PHARMACOTHERAPY!OF!CONGESTIVE!HEART!FAILURE! 143&

TOPIC!19! 146&
19.1!THE!ENDOCRINE!PANCREAS.!INSULIN!PREPARATIONS!AND!THE!TREATMENT!OF!INSULIN!RESISTANCE146&
19.2!DRUGS!USED!IN!THE!TREATMENT!OF!GOUT! 148&
19.3!BETA!SYMPATHOLYTICS! 150&

TOPIC!20! 152&
20.1!ORAL!ANTIDIABETIC!AGENTS! 152&
20.2!ALPHA!SYMPATHOLYTICS! 154&
20.3!DISEASE!MODIFYING!ANTIRHEUMATIC!DRUGS!(DMARDS)! 156&

TOPIC!21! 158&
21.1!GONADAL!HORMONES!AND!INHIBITORS! 158&
21.2!PHARMACODYNAMIC!DRUG!INTERACTIONS! 163&
21.3!DRUGS!USED!IN!ACID/PEPTIC!DISEASE! 164&

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Sollas&Notes&2015&

TOPIC!22! 166&
22.1!ALKYLATING!AGENTS!AND!ANTIMETABOLITES!IN!THE!TREATMENT!OF!NEOPLASTIC!DX.! 166&
22.2!PHARMACOKINETIC!DRUG!INTERACTIONS! 170&
22.3!BOTANICAL!(HERBAL)!MEDICATIONS! 172&

TOPIC!23! 174&
23.1!DRUGS!THAT!EFFECT!BONE!MINERAL!HOMEOSTASIS! 174&
23.2!SELECTIVE!COX/2!INHIBITORS! 178&
23.3!CALCIUM!ANTAGONISTS! 178&

TOPIC!24! 180&
24.1!PLANT!ALKALOIDS,!ANTIBIOTICS,!HORMONAL!&!MISCELLANEOUS!ANTICANCER!AGENTS! 180&
24.2!EMETICS!AND!ANTI/EMETICS! 183&
24.3!CHOLINOMIMETIC!DRUGS! 184&

TOPIC!25! 187&
25.1!IMMUNOPHARMACOLOGY! 187&
25.2!ADH!ANTAGONISTS! 192&
25.3!ANTIHYPERTENSIVE!DRUGS! 193&

TOPIC!26! 195&
26.1!INTRODUCTION!TO!TOXICOLOGY.!MANAGEMENT!OF!THE!POISONED!PATIENT! 195&
26.2!DIURETICS! 199&
26.3!CHOLINOLYTICS!AND!CHOLINESTERASE!REACTIVATORS! 205&

TOPIC!27! 207&
27.1!PHARMACOLOGY!OF!NICOTINE! 207&
27.2!BIOPHARMACEUTICALS,!BIOLOGICAL!THERAPY!(MONOCLONAL!ANTIBODIES,!INTERLEUKINS!ETC.)! 210&
27.3!NO!DONORS!AND!INHIBITORS! 214&

TOPIC!28! 217&
28.1!CENTRALLY!ACTING!MUSCLE!RELAXANT! 217&
28.2!DRUGS!ACTING!ON!UTERUS!AND!SMOOTH!MUSCLES! 219&
28.3!EXPECTORANS!AND!ANTITUSSIVES! 224&
&&
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These&topics&were&made&from&the&10th&edition&of&Pharmacology&Examination&&&Board&
review&by&Katzung&&&Trevor,&Color&atlas&of&pharmacology,&lecture&slides,&Kaplan&videos&
and&of&course&the&internet.&My&wonderful&friends&Neil!Bharkhada!and!Anupam!Seth&
also&helped&to&contribute&to&this&madness!&Where&would&I&be&without&you&guys?&&
GOOD&LUCK&PEOPLE!&

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 Sollas&Notes&2015&

Topic&1&
1.1 Antiepileptics&&
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Epilepsy(comprises(a(group(of(chronic(syndromes(that(involve(the(recurrence(of(
seizures((abnormal(discharge(of(cerebral(neurons).(Effective(antiseizure(drugs(
have(selective(depressant(actions(on(such(abnormal(neuronal(activity.(They(vary(in(
the(mechanism(of(action(and(degree(of(effectiveness(in(specific(seizure(disorders.(
&
Antiepileptics!(antiseizure)!drugs!groups:!
&
Tonic/clonic!&!partial! Absence! Myoclonic! Back/up!&!adjunctive!drugs!
seizures! seizures! seizures!
!
Carbamazepine(( Clonazepam( Clonazepam( Felbamate(
Lamotrigine( Ethosuximide( Lamotrigine( Gabapentin(
Phenytoin( Valproic(acid( Valproic(acid( Lamotrigine(
Valproic(acid( Levetiracetam(
( Phenobarbital(
Tiagabine(
Topiramate(
Vigabatrin(
Zonisamide(
&
Antiseizure&drugs&are&commonly&used&for&long&periods&of&time&and&therefore&its&
important&to&take&into&consideration&their&pharmacokinetic&properties&to&avoid&
toxicity&and&harmful&drug&interactions.&Determination&of&plasma&levels&and&
clearance&in&individual&patients&is&also&commonly&needed&to&reach&optimum&
therapeutic&dose&(drugs&like&phenytoin)&
&
In&general&for&antiseizure&drugs:&
Well&absorbed&orally&
Have&good&bioavailability&
Most&are&metabolized&by&hepatic&enzymes&
o Except:&gabapentin,&,vigabatrin&
o Some(drugs(are(prodrugs(that(become(active(in(the(liver((
Pharmacokinetic&drug&interactions&are&common&&
o Some&drugs&inhibit&antiseizure&drug&metabolism&or&displace&
anticonvulants&from&plasma&protein&binding&sites&that&will&result&in&
toxic&levels&in&the&plasma&
o Inhibitory&drug&interactions&(e.g.&Rifampin)&may&result&in&
inadequate&seizure&control&
Resistance&to&antiseizure&drugs&may&involve&increased&expression&of&drug&
transporters&at&the&level&of&the&blood]brain]barrier&(BBB)&
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!
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Sollas&Notes&2015&

Phenytoin:!
Is&variable&in&its&bioavailability&due&to&individual&differences&in&the&first]
pass&metabolism!
o Rapid]onset&and&extended]release&forms&exists!
Metabolism&is&non]linear&&&elimination&kinetics&shift&from&first]order&to&
zero]order&at&moderate&to&high&dose&levels!
High&binding&capacity&to&plasma&proteins&(97]98%)!
o Free&(unbound)&phenytoin&levels&in&plasma&are&increased&
transiently&by&drugs&that&compete&for&binding:!
! &Carbamazepine,,sulfonamide,,valproic,acid!
Metabolism&is.!
o Enhanced&in&the&presence&of&liver&enzyme&inducers&!
! Rifampin,and,phenobarbital!
o Inhibited&in&the&presence&of&liver&enzyme&inhibitors!
! Cimetidine,and,isoniazid!
The&drug&itself&induces&hepatic&drug&metabolism&and&by&that&it&decreases&
effects&of&other&antiseizure&drugs&such&as:!
o Carbamazepine,,clonazepam,and,lamotrigine!
Water]soluble&prodrug&form&is&available&and&is&given&parenterally!
o Fosphenytoin!
!
Carbamazepine:!
Induces&formation&of&liver&drug]metabolizing&enzymes&that&increases&the&
metabolism&of&the&drug&itself&and&may&increase&clearance&of&many&other&
anticonvulsant&drugs&such&as:!
o Clonazepam,,lamotrigine,and,valproic,acid!
Valproic!acid:!
Competes&with&phenytoin&for&plasma&protein&binding&site!
Inhibits&metabolism&of&carbamazepine,&ethosuximide,&phenytoin,&
phenobarbital&and&lamotrigine!
Hepatic&biotransformation&leads&to&formation&of&a&toxic&metabolite&that&is&
hepatotoxic!
Other!drugs:!
Gabapentin,&pregabalin,&levetiracetam&and&vigabatrin&are&unusual&in&that&
they&are&eliminated&by&the&kidney&(largely&in&unchanged&form)!
o These&drugs&have&virtually&no&drug]drug&interactions!
Tiagabine,&topiramate&and&zonisamide&undergo&both&hepatic&metabolism&
and&renal&elimination&of&an&intact&drug!
Lamotrigine&is&eliminated&via&hepatic&glucuronidation&!
!
Mechanism!of!action:!
Main&aim&is&to&suppress&repetitive&action&potentials&in&epileptic&foci&in&the&
brain&&many&different&mechanisms&are&involved&in&trying&to&achieve&this&
effect,&and&in&some&cases&several&mechanisms&may&contribute&to&the&effect!
o Sodium&channel&blockade&(voltage&gated&sodium&channels)!
! Phenytoin,,carbamazepine,,lamotrigine,,zonisamide!
! Phenobarbital,&,valproic,acid,at&high&levels!

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Sollas&Notes&2015&

! Rate]dependent&action&(dep.&on&the&frequency&of&neuronal&
discharge)&that&results&in&prolongation&of&the&inactivated&
state&of&the&Na+&channel&and&the&refractory&period!
o GABA]related&targets!
! Phenobarbital,enhances&the&inhibitory&actions&of&GABA&by&
interacting&with&receptor&sites&on&Cl]&channels&resulting&in&
increased&duration&of&its&opening!
! Vigabatrin,irreversibly&inactivates&the&GABA&
aminotransaminase&(GABA]T)&that&normally&results&in&
termination&of&the&action&of&GABA!
Phenytoin,at&high&doses&can&inhibit&GABA]T!
! Tiagabine,inhibits&GABA&transporter&(GAT]1)&in&neurons&
and&glial&cells&and&by&that&prolongs&the&action&of&GABA!
! Gabapentin,is&a&structural&analog&of&GABA&but&doesnt&
activate&GABA]receptors&directly!
o Calcium&channel&blockade!
! Ethosuximide,inhibits&low]threshold&(T]type)&Ca2+&
currents,&mainly&in&the&thalamic&neurons&that&act&as&
pacemakers&to&generate&rhythmic&cortical&discharge!
! Valproic,acid,,gabapentin,and,pregabalin&have&similar&
actions&as&ethosuzimide!
o Other&additional&mechanisms&of&some&drugs!
! Neuronal&membrane&hyperpolarization&by&enhancing&K+&
channel&permeability!
Valproic,acid!
! Antagonistic&effects&at&some&glutamate&receptors!
Phenobarbital,!
! Blockade&of&glutamate&NMDA&receptors!
Felbamate!
Clinical!uses:!
Its&very&important&to&diagnose&the&specific&seizure&type&properly&to&be&
able&to&prescribe&the&most&appropriate&antiseizure&drug&(or&combo)!
Drug&of&choice&is&found&by&taking&into&consideration:!
o Established&efficacy&in&the&specific&seizure&type!
o Prior&responsiveness&of&the&patient!
o Anticipated&toxicity&of&the&drug!
Treatment&may&involve&drug&combinations&and&follows&the&principle&of&
adding&an&unknown&effective&agents&if&the&preceding&drugs&are&not&
sufficient&enough&!
Generalized!Tonic/clonic!(grand!mal)!seizures!
DOC&(drugs&of&choice):&Valproic,acid,,carbamazepine,and,phenytoin&!
Alternative&in&adults:&Phenobarbital,(or,primidone)!
DOC&in&infants:&Phenobarbital!
Others:&Lamotrigine,and,topiramate!
Partial!seizures:!
DOC:&Carbamazepine,(or,oxcarbazepine),,lamotrigine,or,phenytoin!
Alternative:&Felbamate,,phenobarbital,,topiramate,and,valproic,acid!
Adjunctively:&Gabapentin,,pregabalin!

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Sollas&Notes&2015&

Absence!seizures!
DOC,&since&they&cause&min.&sedation:&Ethosuximide,or,valproic,acid!
Uncomplicated&seizures&if&patient&can&handle&GI&side&effect:&Ethosuximide!
Alternative:&Lamotrigine,,levetiracetam,and,zonisamide!
Myoclonic!and!atypical!absence!syndromes!
Myoclonic&seizures:&Valproic,acid,,lamotrigine,(monotherapy&or&combo)!
Alternatives:&Levetiracetam,,topiramite,,zonisamide!
Status!epilepticus!
DOC&in&terminating&attacks&and&providing&short&term&control:&!
o Intravenous&diazepam,or,lorazepam!
Prolonged&therapy&DOC:&intravenous&phenytoin!
o Possibly&causes&cardiotoxicity!
o Fosphenytoin&is&a&safer&choice&!
In&children:&phenobarbital!
In&extreme&cases&"&general&anesthesia&may&be&needed!
Other!uses:!
Some&antiseizure&drugs&are&used&in&manangement&of&bipolar&disorder&and&
mania:&mainly&Valproic,acid,but&also&carbamazepine,and,lamotrigine!
Trigeminal&neuralgia&has&been&treated&with&carbamazepine!
Pain&of&neuropathic&origin&has&been&treated&with&gabapentin!
Migrane&has&been&treated&with&phenytoin,and,topiramate!
!
Toxicity:!
!
Benzodiazepine& Sedation,&tolerance,&dependence&
Carbamazepine& Diplopia,&cognitive&dysfunction,&drowsiness,&ataxia,&Stevens]
Johnsons&syndrome,&teratogenic&
Phenytoin& Nystagmus,&diplopia,&sedation,&gingival&hyperplasia,&
hirsutism,&anemia,&peripheral&neuropathy,&osteoporosis,&
induction&of&hepatic&drug&metabolism&
Valproic&acid& Drowsiness,&nausea,&hair&loss,&weight&gain,&hepatotoxic&
(infants),&inhibition&of&hepatic&drug&metabolism,&teratogenic&
Phenobarbital& Sedation,&cognitive&dysfunction,&tolerance,&induction&of&
hepatic&drug&metabolism&
Ethosuximide& GI&distress,&lethargy,&headache,&behavioral&changes&
Lamotrigine& Dizziness,&ataxia,&nausea,&rash,&rarely&Stevens]Johnsons&
syndrome&
!
Overdosage:!
CNS&depressants&and&respiratory&depression&and&management&is&
primarily&supportive&(mechanical&ventilation)!
Flumazenil,is&used&in&benzodiazepine&overdose!
Fatal&hepatotoxity&has&occurred&with&valproic&acid&(mainly&in&kids&<2yrs)!
!
!
!
!

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Sollas&Notes&2015&

1.2&Principles&of&antibacterial&and&antineoplastic&chemotherapy.&
Classification&of&the&chemotherapeutic&drugs&
&
Antimicrobial&therapy&in&established&infections&is&guided&by&several&principles:&
&
Susceptibility&testing&
o Establishes&drug&sensitivity&of&the&organism&
o Predicts&the&minimum&inhibitory&concentration&(MIC)&of&a&drug&for&
comparison&with&anticipated&blood&or&tissue&level&
o Two&most&common&methods&of&susceptibility&testing&are:&
! Kirby]Bauer&disk&diffusion&
! Broth&dilution&
o Beta]lactamase&test&is&used&in&case&of&more&severe&infections&
Drug&concentration&in&blood&
o Needed&to&measure&when&using&agents&with&low&therapeutic&index&
(eg.&Aminoglycosides,&vancomycin)&
o Needed&to&check&for&reason&of&poor&clinical&response&to&the&drug&
Serum&bactericidal&titers&
o In&certain&infections&in&which&the&host&defense&contributes&
minimally&to&the&cure&its&important&to&know&titers&to&choose&
appropriate&drug&and&dosage&
o Serial&dilutions&of&serum&are&incubated&with&standardized&
quantities&of&the&pathogen&isolated&from&the&patient&
! Killing&at&a&dilution&of&1:8&is&satisfactory&
Route&of&administration&&
o Parenteral&therapy&is&preferred&in&most&serious&cases&
o Chloramphenicol,&fluoroquinolones&and&trimethoprim]
sulfamethozaxole&(TMP]SMZ)&is&effective&orally&
Monitoring&therapeutic&response&
o Clinical&and&microbiological&monitoring&to&check&for&responses&to&
the&drug&therapy&&to&detect&the&development&of&resistance&or&
superinfections&
o Duration&of&treatment&depends&on&the&pathogen& &
! Longer&treatment&for&mycobacteria&or&fungi&
o Site&of&action&decides&the&length&of&treatment&
! Endocarditis,&osteomyelitis&requires&long&antibiotic&treatm.&
o Immunocompromised&patients&require&longer&treatment&
Clinical&feature&of&antimicrobial&therapy&
o Inadequate&clinical&or&microbial&response&can&result&from&&
! Laboratory&testing&errors&
! Problems&with&the&drug&
Incorrect&choice,&poor&tissue&penetration,&inad.dose&
! Problems&with&patient&
Poor&host&defenses,&undrained&abscess&
! Pathogen&
Resistance,&superinfections&
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Sollas&Notes&2015&

Cancer(chemotherapy(produces(high(rates(of(cure(of(diseases,(which,(without(therapy,(
results(in(extremely(high(mortality(rates.(On(the(other(hand,(some(types(of(cancer(are(
barely(affected(by(currently(available(drugs.(Furthermore,(as(a(group,(the(anticancer(drugs(
are(more(toxic(than(any(other(pharmaceutic(agents,(and(thus(their(benefit(must(be(
weighed(against(their(risks.(Many(of(the(available(drugs(are(cytotoxic(agents(that(act(on(
all(dividing(cells.(The(ultimate(goal(in(cancer(chemotherapy(is(to(use(advances(in(cell(
biology(to(develop(drugs(that(selectively(target(specific(cancer(cells.(Few(of(those(agents(
are(used(in(the(clinical(practice(and(many(more(are(continuously(being(developed.(
(
Decision&to&use&antineoplastic&chemotherapy&depends&on:&
Type&of&tumor&&&stage&of&malignancy&
Condition&of&the&patient&&&financial&constraints&
&
Antineoplastic&chemotherapy&is&used&in&three&main&clinical&settings:&
Primary&induction&chemotherapy&
o Used&as&a&primary&treatment&for&many&hematologic&cancers&and&for&
advanced&solid&tumors&for&which&no&alternative&treatment&exists&
o Can&be&curative&in&small&number&of&patients&presenting&with&
advanced&metastatic&disease&(e.g.&lymphoma,&acute&myelogenous&
leukemia,&germ&cell&cancers,&choriocarcinoma&and&several&
childhood&cancers)&
o In&many&cases&the&goal&of&therapy&is:&
! Palliation&of&cancer&symptoms&
! Improved&quality&of&life&
! Increased&time&to&tumor&progression&
Neoadjuvant&chemotherapy&
o Therapy&in&patients&who&present&with&localized&cancer&for&which&
alternative&local&therapy&&such&as&surgery&or&irradiation&
o Administered&before&the&surgery&or&irradiation&
o Goal&is&to&render&the&local&therapy&more&effective&by&possibly:&
! Decreasing&tumor&size&
! Stage&of&malignancy&
! Presence&of&micro]metastatic&lesions&
Adjuvant&chemotherapy&
o Used&in&treatment&of&many&solid&tumors&as&an&important&adjuvant&
to&local&treatment&procedures&such&as&surgery&or&radiation&
o Administered&immediately&after&or&before&the&primary&treatment&
o Goal&is&to&reduce&risk&of&local&and&systemic&recurrence&and&to&
improve&disease]free&and&overall&survival&
&
Combination&therapy:&
Usually&increases&the&log]kill&markedly&and&can&be&synergistic&
Often&cytotoxic&to&heterogenous&population&of&cancer&cells&and&may&
prevent&development&of&resistant&clones&
Follows&principles:&
o Each&drug&should&be&active&when&used&alone&against&cancer&
o Drugs&should&have&different&mechanism&of&action&
o Cross]resistance&between&two&drugs&should&be&minimal&
o The&drugs&should&have&different&toxic&effects&

& 10&
 Sollas&Notes&2015&

Classification&of&the&chemotherapeutic&drugs:&
&
&
Anticancer&drugs:&
&
Alkylating&agents& Antimetabolites& Natural&products& Antitumor& Miscellaneous& Hormonal&
antibiotics&
Cyclophosphamide& 5]fluoruracil& Etoposide& Bleomycin& Imatinib& Predisone&
Cisplantin& Methotrexate& Paclitaxel& Doxorubicin& Cetuximab& Tamoxifen&
Gemcitabine& Vincristine& Mitomycin&
6]mercaptopurine&
&
&
&
Alkylating&agents:&
Directly&damage&DNA&to&prevent&the&cancer&cell&from&reproducing&
Not&phase]specific&(hence&they&work&on&all&phases&of&cell&cycle)&
Used&to&treat&many&different&cancers&such&as:&
o Leukemia,&lymphoma,&Hodgkins,&multiple&myeloma,&sarcoma&as&
well&as&lung,&breast&and&ovarian&cancers&
They&can&cause&long&term&damage&to&the&bone&marrow&&
o Rare&cases&lead&to&acute&leukemia&
! Dose]dependent&
! Most&commonly&occurs&5]10&yrs&post&treatment&
Antimetabolites:&
Interfere&with&DNA&&&RNA&growth&by&substituting&for&the&normal&building&
blocks&of&RNA&&&DNA&&work&in&the&S]phase&of&the&cell&cycle&
Commonly&used&to&treat&leukemias,&breast,&GI&&&ovarian&cancers&
&
Natural&products:&
Topoisomerase&inhibitors&(etoposide)&
o Interfere&with&topoisomerase&enzymes,&which&help&separate&the&
strands&of&DNA&so&they&can&be&copied&
o Commonly&used&to&treat&certain&leukemias,&lung,&ovarian&&&cancers&
Mitotic&inhibitors&(paclitaxel)&
o Often&plant&alkaloids&
o Can&stop&mitosis&or&inhibit&enzymes&from&making&proteins&needed&
for&cell&reproduction&&work&in&the&M]phase&of&the&cell&cycle&
o Commonly&used&to&treat&breast&&&lung&cancers&along&with&
myelomas,&lymphomas&and&leukemias&
o Can&possibly&cause&peripheral&nerve&damage&&dose]limiting&
Hormonal:&
Steroids&are&useful&in&treating&some&types&of&cancer&(e.g.&lymphoma,&
leukemias&and&myelomas)&in&addition&to&other&diseases&
They&kill&cancer&cells&or&slow&their&growth&
Also&commonly&used&as&anti]emetics&to&help&preventing&nausea&and&
vomiting&caused&by&the&chemotherapy&as&well&as&allergic&reactions&to&the&
drugs&(hypersensitivity)&&not&a&chemotherapeutical&factor&of&steroids&

& 11&
Sollas&Notes&2015&

1.3&Pharmacotherapy&of&asthma&bronchiale&
&
Asthma(is(a(dx(characterized(by(airway(inflammation(and(episodic(reversible(
bronchospasms.(Drugs(that(are(useful(in(the(treatment(of(asthma(include(
bronchodilators((smooth(muscle(relaxants)(and(antiLinflammatory(drugs.(
Bronchodilators(include(sympathomimetics((mainly(2Lselective(agonists,(
muscarinic(antagonists,(methylzanthines(and(leukotriene(receptor(blockers).(AntiL
inflammatory(drugs(used(in(asthma(are(corticosteroids,(mast(cell(stabilizers(and(
anti(IgE(antibodies.(Leukotriene(antagonists(play(a(dual(role.(
(
Pathophysiology&of&asthma:&
Release&of&several&mediators&from&IgE]sensitized&mast&cells&and&other&
cells&of&the&immune&system:&
o LTC4,&LTD4,&LTB4&&attract&inflammatory&cells&to&the&airways&
o Cytokines&that&mediate&chronic&inflammation&
! Chronic&inflammation&leads&to&marked&bronchial&
hyperactivity&to&various&inhaled&substances&;&
Cold&air,&antigens,&histamine,&muscarinic&agonists&
and&irritants&such&as&sulfur&dioxide&(SO2)&
o Also&mediated&by&vagal&responses&&
Strategy&of&therapy:&
Reliever&drugs&&2]agonists,&muscarinic&antagonists&and&theophylline&
Controller&drugs&&corticosteroids,&long&acting&2]agonists,&IgE&Abs&
Leukotriene&antagonists&are&both&relievers&and&controllers&
o Used&as&prophylaxis&
&
2]agonists:&
First&line&therapy&in&acute&asthma&
Directly&acting&and&selective&are&the&best&to&reverse&an&attack&
o Albuterol,,terbutaline,and,metaproterenol&
! All&short&acting&and&common&in&US&
4hrs&and&not&used&for&prophylaxis&
Life]saving&
! Good&for&acute&episodes&of&bronchospasms&
o Salmeterol,,formoterol,and,indacaterol,(only(for(COPD)&
! All&long&acting&&
12hrs&&used&for&prophylaxis&
! Used&alone&they&increase&mortality&&
! Used&in&combo&with&corticosteroids&&improve&control&
Given&by&inhalation&in&aerosol&canisters&or&nebulizer&
o Decreases&the&systemic&dose&(+adverse&effects)&
o Effective&dose&is&locally&administered&
o 12]24hrs&duration&
Stimulate&AC&via&Gs&to&increase&cAMP&in&smooth&muscle&cells&
o Increased&cAMP&will&result&in&powerful&bronchodilatory&effect&
Adverse&effects:&
o Skeletal&muscle&tremor&
o At&high&doses&&Tachycardia&

& 12&
Sollas&Notes&2015&

o Loss&of&responsiveness&(tolerance&and&tachyphylaxis)&
! Excessive&use&of&short]acting&
! More&common&in&COPD&patients&
Methylxanthine:&
Purine&derivative&
o Caffeine,&theophylline&(tea)&and&theobromine&(cocoa)&
Theophylline&is&the&only&one&that&is&used&in&the&treatment&of&asthma&
o Orally&active,&slow&&&fast&acting&categories&&
o Eliminated&by&cytP450&
o Clearance&varies&with&age,&smoking&status&and&drug&interactions:&
! Highest&clearance&in&young&adolescence&&&smokers&
Inhibits&phosphodiesterase&(PDE)&
o Enzyme&that&degrades&cAMP&to&AMP&&
o Maintains&high&IC&levels&of&cAMP&
o Needs&high&cc.&of&the&drug&to&work&properly&
o Causes&bronchodilation&
o Increases&strength&of&diaphragm&(in&some&cases)&
Aminophylline,&,pentoxifylline&
Adverse&effects:&
o GI&distress,&tremor,&insomnia&
o Severe&nausea,&vomiting&
o Large&overdose&causes&arrhythmias&and&seizures&
! Beta]blockers&are&useful&in&this&case&
&
Muscarinic&antagonists:&
Ipratropium,&,tiotropium,&
o Quaternary&compound&that&are&similar&to&atropine&but&less&harmful&
o Aerosoles&that&competitively&block&muscarinic&receptors&in&the&
airways&and&effectively&prevent&bronchoconstriction&that&is&
mediated&by&vagal&discharge&
Commonly&used&in&children&and&COPD&patients&
o &to&&of&patients&benefit&from&the&use&of&these&drugs&
Have&no&effect&on&the&chronic&inflammatory&aspects&of&asthma&
]blockers&are&preferred&in&bronchial&asthma&but&muscarinic&antagonists&
seem&to&be&more&effective&against&the&acute&bronchospasms&of&COPD&
patients&
Adverse&effects:&
o Slim&to&none&since&they&act&very&locally&
o No&tremor&nor&arrhythmias&
&
Cromolyn&&&nedocromil:&
Given&as&aerosols&for&asthma&but&are&rarely&used&now&
Poorly&understood&but&are&thought&to&decrease&leukotrienes&and&
histamines&&highly&insoluble&so&their&systemic&effects&are&almost&none!&
o Local&effects&ONLY&
No&bronchodilator&effects&but&seem&to&prevent&bronchoconstriction&
caused&by&allergic&responses&&
Was&commonly&used&in&children&

& 13&
Sollas&Notes&2015&

Corticosteroids:&
Beneficial&anti]inflammatory&agents&that&are&used&for&severe&asthma&
Systemic&(oral)&corticosteroids&&prednisone&
o Toxic&and&are&only&used&as&a&prolonged&treatment&when&all&
other&drugs&have&failed&to&manage&the&asthma&
Local&(aerosols)&corticosteroids&&beclomethasone,,budesonide,,
dexamethasone,,flunicolide,,fluticasone,and,mometasone&
o Surface&active&&&relatively&safe&&
o 1st&line&treatment&for&moderate&to&severe&asthma&
IV&corticosteroids&are&used&in&acute&severe&asthma&(status&
asthmaticus)&&prednisolone,&,hydrocortisone&
Corticosteroids&reduce&synthesis&of&arachidonic&acid&by&PLA2&and&
inhibit&expression&of&COX]2&
o Bind&to&IC&receptors&and&activate&glucose&response&element&
! Results&in&prevention&of&inflammation&an&allergic&
responses&that&are&mediated&by&various&cytokines&and&
LT&
Child&treatment&with&aerosol&corticosteroids&are&thought&to&prevent&
the&severe,&progressive&inflammatory&changes&that&are&the&
characteristics&of&long]standing&asthma&
Adverse&effects&of&aerosols:&
o Oral&candidiasis,&small&degree&of&adrenal&suppression&&
o Mild&growth&retardation&in&children&that&is&usually&reversible&as&
they&grow&into&adults&
&
Leukotriene&antagonists:&
Drugs&that&interfere&with&synthesis&or&action&of&the&leukotrienes&
Not&as&effective&as&corticosteroids&in&severe&asthma&
Zafirlukast,&,montelukast&
o Antagonists&of&LTD4&
o Orally&active&and&effective&in&
prevention&of&exercise],&
antigen]&and&aspirin]induced&
bronchospasms&
o Not&recommended&for&acute&
episodes&of&asthma&
Adverse&effects:&
o Very&rarely&Churg]Strauss&
syndrome&&&allergic&
granulomatous&angiitis&occur&
&but&no&connection&has&been&
found&yet&
o Toxicity&is&generally&very&low&
&
&
&
&
&
&

& 14&
Sollas&Notes&2015&

Topic&2&
2.1&Sedative?hypnotic&drugs;&barbituates&and&other&non?benzodiazepine&
sedatohypnotics&&
&
Sedative/hypnotic/anxiolytic!drugs:!
Benzodiazepines&(BPZs)!
Barbiturates!
Alcohols&!
(
The(sedativeLhypnotic(drugs(belong(to(a(chemically(
heterogenous(class(of(drugs(that(cause(doseL
dependent(CNSLdepression(that(extends(from(sedation(
to(anesthesia(to(respiratory(depression(and(death.((
(
Benzodiazepines!reach!a!plateau!in!CNS!
depression!while!barbiturates!and!
alcohol!does!not!
Non]linear&relationship&
&
Paradoxical&disinhibition&(first&stage&of&the&diagram&above):&
Stimulation&of&GABA&receptor&on&a&GABAergic&neuron&will&result&in&
disinhibiton&of&the&action&potential&that&will&actually&result&in&stimulation&
o First&stage&is&therefore&more&related&to&excitation&due&to&this&
paradoxical&loss&of&inhibition&
! Take&for&example&alcohol&consumption,&the&first&drinks&after&
we&start&drinking&will&make&us&happy,&more&social&and&even&
more&excited/agitated&
This&is&due&to&this&mechanism&
CNS&Depression&&main&hallmark&of&these&drugs:&
Inhibition&of&receptors&results&in&decreased&glutamate&release&from&
excitatory&neurons&in&the&CNS&
o Sedation,&anxiolysis,&possible&anticonvulsants&&&muscle]relaxation&
o Hypnosis&&
o Anesthesia&from&here&and&upwards&in&the&diagram&we&need&to&
administer&mechanical&ventilation&
o Medullary&depression&(here&is&were&the&BZDs&stop&in&effects)&
o Coma&&&death&(effects&of&very&high&levels&of&ethanol&barbiturates)&
GABAA&receptor&(VG&Cl]&ion&channel):&
Activation&of&receptor&results&in&hyperpolarization&
5&subunits&(types)&&&&&&&1&million&variants&
o ]subunit&"&binding&of&GABA&
! Commonly!2!!subunits&
! Two&GABA&molecules&to&open&the&
channel&
o ]subunit&"&binding&of&important&
component&of&Benzodiazepines&
o ]subunit&"&binding&of&important&
components&of&Barbiturates&

& 15&
Sollas&Notes&2015&

The&subunits&and&other&specific&binding&sites&overlap&each&others&
o Alcohol&also&has&its&own&binding&site&on&the&receptor&
Allosteric&regulated&receptor&on&GABA&binding&
GABAB&is&a&G]protein&coupled&receptor&"&increased&K+&efflux&
o Baclofen&is&the&only&drug&that&we&know&to&work&here&
! Centrally&acting&muscle&relaxant&used&in&spasticity&
Barbiturates:!
Prolonged&GABA&activity&"&increased&duration&Cl]&channel&opening!
Have&GABA&mimetic&activity&at&high&doses!
o Distinguishes&them&from&benzodiazepines!
o This&means&that&at&high&enough&cc.&barbiturates&ALONE&will&open&
the&channel&without&GABA&"&increased!hyperpolarization!!
! Risk&of&this&is&COMA&and&DEATH!
Act&through&their&own&receptors&(binding&sites)&on&the&GABAA&receptor!
o Flumazenil&"&DOES&NOT&WORK&AS&AN&ANTIDOTE!!!!!
! Only&works&on&benzodiazepines!
Pharmacokinetics:!
Liver&metabolized,&sometimes&to&active&compounds!
General&inducers&of&CYP&enzymes&!
o Increased&gene&expression,&number&of&enzymes&and&increased&VMax&!
Contraindicated&in&porphyrias!
o Induces&D]ALA&synthase&&#&rate&limiting&step&of&heme&synthesis!
Uses!of!barbiturates:!
Phenobarbital&&anticonvulsant&(good&for&children&and&in&pregnancy)!
Thiopental&&induction&of&anesthesia!
Toxicity:!
Tolerance&and&dependence&!
o Chronic&uses&lead&to&tolerance!
o Psychological&(craving)&and&physiological&(abstinence&syndrome)!
Withdrawal&signs&"&anxiety,&agitation,&life]threatening&seizures!
! Status&epilepticus&!
Use&lorezepam,and,diazepam!
Drug&interactions!
o Additive&CNS&depression&!
! Antihistamines,&other&sedative]hypnotics,&alcohol,&opioids,&
]blockers,&reserpine,&anesthetics&etc.!
! Resulting&in&life]threating&respiratory&depression&!
Non/benzodiazepine!drugs:!
Zolpidem,,zaleplon,,eszopiclone!
o BZ1&receptor&agonists&used&in&sleep&disorders!
o Less&tolerance&and&abuse&liability&than&BZD&and&barbiturates!
o Overdose&can&be&reversed&with&flumazenil!
Buspirone!
o NO&effect&on&GABA!
o 5]HT1A&partial&agonist&used&to&treat&anxiety&disorders!
o Non&sedative&and&takes&around&1]2&weeks&to&start&working!
!
!

& 16&
Sollas&Notes&2015&

2.2&Problems&with&chemotherapeutic&drugs:&resistance&
&
Drug&resistance&is&a&major&problem&in&cancer&chemotherapy.&&
&
Mechanism&of&resistance&includes&the&following:&
Increased&DNA&repair&
o Can&be&responsible&for&resistance&
o Particularly&important&for&alkylating&agents&and&cisplantin&
Formation&of&trapping&agents&
o Some&tumor&cells&increase&their&production&of&thiol&trapping&
agents&(e.g.&glutathione)&
o These&trapping&agents&interact&with&anticancer&drugs&that&form&
reactive&electrophilic&species&
o Seen&in&bleomycin,&cisplantin&and&in&anthracyclines&
Changes&in&target&enzymes&
o Changes&in&drug&sensitivity&of&a&target&enzyme,&dihydrofolate&
reductase&along&with&increased&synthesis&of&the&enzyme&are&
mechanisms&of&resistance&of&tumor&cells&to&methotrexate&
Decreased&activation&of&prodrugs&
o Resistance&to&purine&antimetabolites&(mercaptopurine,,
thioguaninie)&
o Resistance&to&pyrimidine&antimetabolites&(cytarabine,,
fluorouracil)&
o Resistance&can&be&the&result&of&decreased&activity&of&the&tumor&cell&
enzymes&needed&to&convert&these&prodrugs&to&their&cytotoxic&
metabolites&
Inactivation&of&anticancer&drugs&
o Increased&activity&of&enzymes&capable&of&inactivating&anticancer&
drugs&is&a&mechanism&of&tumor&cell&resistance&to&most&of&the&purine&
and&pyrimidine&antimetabolites&
Decreased&drug&accumulation&
o This&form&of&multidrug&resistance&involves&increased&expression&of&
normal&gene&(MDR1)&for&cell&surface&glycoprotein&(P]glycoprotein)&
o This&transport&molecule&is&involved&in&the&accelerated&efflux&of&
many&anticancer&drugs&in&resistant&cells&
&
&
&
&
&
&
&
&
&
&
&
&
&

& 17&
Sollas&Notes&2015&

2.3&Drugs&used&in&the&treatment&of&hyperlipidemias&
&
Atherosclerosis(is(the(leading(cause(of(death(in(the(Western(world.(Drugs(discussed(
in(this(chapter(prevent(the(consequences(of(atherosclerosis((MI,(angina,(peripheral(
artery(disease(and(ischemic(stroke)(and(decrease(mortality(in(patients(with(a(
history(of(cardiovascular(diseases(and(hyperlipidemia.(Although(the(drugs(are(
generally(safe(and(effective((they(can(cause(problems,(including(drugLdrug(
interactions(and(toxic(reactions(in(skeletal(muscle(and(the(liver.(
(
LipidLlowering(drug(categories:(
HMGLCoA(reductase(inhibitors((e.g.(lovastatin)(
Resins(
Ezetimibe(
Niacin((
Fibrates((e.g.(gemfibrozil)(
(
Pathogenesis:&
Premature/accelerated&development&of&atherosclerosis&is&due&to:&
Increased&LDL&
Decreased&HDL&
Some&genetic&factors&influencing&this&&
o Hypertriglyceridemia&
o Chylomicronemia&(chylomicrons&in&serum&while&fasting)&
! Recessive&and&results&in&acute&pancreatits&
Regulation&of&plasma&lipoprotein&levels&involves&a&complex&interplay&of&dietary&
fat&intake,&hepatic&processing&and&utilization&in&peripheral&tissues.&&
Primary&disturbances&in&regulation&occurs&in&number&of&genetic&conditions:&
Mutation&in&apolipoproteins,&their&receptors,&transport&mechanisms&and&
lipid]metabolizing&enzymes&
Secondary&disturbances&are&associated&with:&
Western&diet,&many&endocrine&conditions&and&liver/kidney&diseases&
&
Treatment:&Goal&is&to&$LDL&and&atheroma&plaque&formation&
&
Diet:&
Reduced&intake&of&cholesterol&and&saturated&fats&
Reduced&intake&of&alcohol&
o Since&it&raises&triglyceride&and&VLDL&levels&
o Should&be&avoided&in&patients&with&hypertriglyceridemia&
Drugs:&
Choice(of(drug(is(based(on(individual(lipid(abnormality(
&
HMG]CoA&reductase&inhibitors&]&statins:&
HMG]CoA&(hydroxymethylglutaryl&CoA)&
Inhibits&the&rate]limiting&step&in&hepatic&cholesterol&synthesis&
o The&convertion&of&HMG]CoA&to&mevalonate&by&HMG&reductase&
Statins&are&structural&analogs&of&HMG]CoA&&&completely&inhibit&the&ezyme&
Prodrugs:&Lovastatin,and,simvastatin&

& 18&
Sollas&Notes&2015&

Active&as&given:&Atorvastatin,,fluvastatin,,pravastatin,&,rosuvastatin&
The&inhibition&of&hepatic&cholesterol&synthesis&contributes&only&a&small&
amount&to&the&total&serum&cholesterol]lowering&effects&of&these&drugs.&
However&their&much&greater&effect&is&related&to&the&hepatic&pool&of&
cholesterol,&which&is&tightly&regulated&
o The&liver&starts&to&compensate&by&increasing&the&number&of&LDL]
receptors,&that&will&consequently&clear&the&LDL&and&VLDL&from&the&
blood&
HMG]CoA&reductase&inhibitors&also&have&a&direct&anti]atherosclerotic&
effects&and&have&been&shown&to&prevent&bone&loss&
Actions:&
Lower&LDL&cholesterol&levels&dramatically&(and&even&greater&in&combo&
with&other&lipid]lowering&drugs)&
Used&commonly&are&effective&and&well&tolerated&
o Reduce&mortality&from&ischemic&heart&dx&and&stroke&
Rosuvastatin,(atorvastatin(and(simvastatin(have&greater&maximal&efficacy&
then&the&other&in&addition&to&being&able&to&reduce&triglycerides&and&
increase&HDL&
Toxicity:&
Mild&elevations&of&serum&aminotransferase&(not&due&to&hepatic&damage)&
Increased&creatine&kinase&(from&sk.muscles)&&10%&&
o Very&few&feel&muscle&pain&and&rhabdomyolysis&
Eating&food&that&inhibits&cytochrome&P450&can&increase&the&risk&of&
hepatotoxicity&and&myopathy&
o Since&the&drugs&are&metabolized&by&the&enzyme&&
Have&possible&teratogenic&effects&and&are&therefor&not&used&in&pregnancy&
&
Resins:&
Bile]acid&binding&resins&(cholestyramine,,coletipol,and,colesevelam)&&
o Large&non]absorbable&polymers&that&bind&bile&acids&and&similar&
steroids&in&the&intestine&to&prevent&their&absorption&
o By&preventing&recycling&of&bile&acids,&resins&divert&hepatic&
cholesterol&synthesis&to&the&synthesis&of&new&bile]acids&&
! Thereby&reducing&the&amount&of&cholesterol&in&the&hepatic&
pool&&which&will&have&the&same&effects&as&the&statins&
Cause&a&modest&reduction&in&LDL&but&have&little&effects&on&HDL&and&Trigly.&
Used&in&patients&with&hypercholesterolemia&and&have&also&been&used&to&
reduce&pruritus&(itching)&in&patients&with&cholestasis&and&bile&salt&
accumulation&
Adverse&affects&&bloating,&constipation,&gritty&taste&along&with&decreased&
absorption&of&fat]soluble&vitamins&and&folates&
o Also&decreased&absorption&of&drugs&
! Thiazides,&warfarin,&pravastatin&and&fluvastatin&
Exetimibe:&
Prodrug&that&is&converted&into&active&(glucuronide)&in&the&liver&
Inhibits&a&transporter&that&mediates&GI&uptake&of&cholesterol&and&
phytosterols&&this&reduces&the&cholesterol&in&the&hepatic&pool&
Reduces&cholesterol&by&about&18%&]&more&effective&with&HMG]CoA&inhib.&

& 19&
Sollas&Notes&2015&

Niacin&(nicotinic&acid):&
Reduces&LDL,&cholesterol,&triglycerides&and&VLDL&in&addition&to&often&
increase&HDL&
In&the&liver&&reduces&VLDL&synthesis&that&reduces&LDL&levels&
In&adipose&&activates&a&signaling&pathway&that&reduces&hormone&
sensitive&lipase&(HSL)&activity&and&thus&decreases&plasma&FA&and&TAG&
o Consequently&reduces&LDL&formation&
Increased&clearance&of&VLDL&by&lipoprotein&lipase&&
Reduces&catabolic&rate&for&HDL&
Decreases&circulating&fibrinogen&&increases&tissue]plasminogen&activator&
Widely&used&in&treatment&of&hypercholesterolemia,&hypertriglyceridemia&
and&in&low&levels&of&HDL&
Adverse&effects:&
o Cutaneous&flushing&(prevented&with&aspirin&or&NSAIDs)&
! Probably&due&to&prostaglandins&
! Tolerance&develops&in&few&days&
o Dose]dependent&nausea&and&abdominal&problems&
o Pruritus&and&other&skin&causes&
o Moderate&increase&in&liver&enzymes&&
o Severe&hepatotoxicity&
o Hyperuricemia&&20%&
o Impaired&carbohydrate&tolerance&
Fibric&acid&derivatives&(gemfibrozil,,fenofibrate):&
Ligands&for&peroxisome&proliferator]activated&receptor]alpha&(PPAR])&
o Receptor&that&regulates&transcriptions&of&genes&involved&in&lipid&
metabolism&
o Interaction&with&PPAR]&results&in&increased&synthesis&by&adipose&
tissue&of&lipoprotein&lipase&
! Enhanced&clearance&of&TAG]rich&lipoproteins&&endothel.cell&
! Stimulation&of&fatty&acid&oxidation&in&liver&
Limits&supply&of&TAG&and&decreases&VLDL&synt.&
! Can&increase&LDL&in&patients&with&familial&combined&
hyperlipoproteinemias&(increase&in&VLDL&and&LDL)&
Used&to&treat&hypertriglyceridemia&and&are&often&combined&with&other&
cholesterol]lowering&drugs&for&better&results&on&LDL&and&VLDL&
Adverse&effects:&
o Nausea&&very&common&
o Skin&rashes&&gemfibrozil&
o Decrease&in&white&blood&count&and&hematocrit&
o Increased&risk&of&cholesterol&gallstones&
o In&combo&with&reductase&inhibitors&the&fibrate&increase&risk&of&
myopathy&
Combination&therapy:&
All&patients&are&treated&first&and&foremost&with&modification&of&their&diet&
Combinations&of&drugs&are&often&needed&to&achieve&optimal&effects&
&
&
&

& 20&
Sollas&Notes&2015&

Topic&3&&
&

3.1&Sedative?hypnotic&drugs&acting&on&benzodiazepine&receptor&
&
Benzodiazepines(are(a(class(of(psychoactive(drugs(whose(core(chemical(structure(is(
the(fusion(of(a(benzene(ring(and(a(diazepine(ring.(They(enhance(the(effects(of(GABA(
at(the(GABAA(receptor((resulting(in(sedative,(hypnotic,(anxiolytic,(anticonvulsant(
and(muscle(relaxant(properties.(High(doses(of(many(BZD(may(also(cause(
anterograde(amnesia(and(dissociation.(BZD(are(categorized(as(short,(intermediate(
or(long(acting.(
(
Remember!the!structure!of!the!GABAA!receptor!from!topic!3.1!and!talk!
about!it!in!relation!to!the!benzodiazepines!!
&
Structure:!
Basic&benzene&ring&+&diazepine&ring!
o &Diazepam,,chlordiazepocide,,clonazepam,,midazolam!
Basic&rings&+&Triazole&ring!
o Triazolam!
Basic&rings&+&oxazole&rings!
o Alprazolam,,clozaxolam!
!
Benzodiazepines:!
Potentiate&GABA&(left&shift&on&a&dose/response&curve)&&means&that&we&
need&less&GABA&to&result&in&normal&or&greater&response!
Increases&the&frequency&of&Cl]&channel&opening!
o This&gives&the&specific&plateau&of&BZDs&that&distinguishes&them&
from&barbiturates&and&alcohols&and&prohibits&them&to&cause&
significant&medullary&depression&that&can&potentially&result&in&
coma&or&death!
Act&via&BZD&receptors&(specific&components&on&the&GABAA&receptor)!
o BZ1&receptors&"&sedation!
o BZ2&receptors&"&antianxiety&&&impaired&cognitive&function!
! Anterograde&amnesia&(from&time&taken&and&until&finish)!
o Flumazenil,is&an&antagonist&of&both&types&of&BZ&receptors!
! IV&drug&with&short&half]life!
! Reverses!an!overdose!of!BENZODIAZEPINES!
!
Pharmacokinetics:!
! Many&of&the&benzodiazepines&are&converted&initially&to&active&metabolites&
with&long&half&lives&!
o Diazepam&(T:&8hrs)&is&metabolized&to&nordiazepam&(active&&T:&
60hrs)&that&will&then&be&metabolized&to&oxazepam&(T:&6hrs)!
! This&results&in&accumulation&of&the&drug!!!!
Good&for&anxiety&but&not&for&insomnia!
o For&insomnia&we&like&a&shorter&acting&BZD!
o Lorazepam,,temazepam,and,oxazepam&undergo&extrahepatic&
conjugation&and&do&not&form&active&metabolites&

& 21&
Sollas&Notes&2015&

Clinical!use!of!BZD:!
! Relief&of&anxiety&(alprazolam,,diazepam,,lorazepam)!
o Generalized&anxiety&disorders,&phobias&and&OCD!
! Insomnia&(temazepam,,oxazepam)!
! Sedation&and&amnesia&before&and&during&medical&and&surgical&treatments!
o Lorazepam,,midazolam&(ultra&short&acting)!
o Main&component&of&balanced&anesthesia&(IV)!
! Treatment&of&epilepsy,&status&epilepticus&(IV,lorazepam,&,diazepam)!
! Control&of&ethanol&or&other&sed.]hyp.&withdrawal&states&(diazepam)!
!
!

&
&
&
&
&
&

& 22&
Sollas&Notes&2015&

1.2 Beta?lactam&antibiotics&I:&Penicillins&
&
Penicillins(and(cephalosporins(are(the(main(antibiotics(that(inhibit(bacterial(cell(
wall(synthesis.(They(are(called(betaLlactam(because(of(their(usual(4Lmember(ring(
that(is(common(in(all(its(members.(They(are(some(of(the(most(effective,(widely(used,(
and(wellLtolerated(agents(available(for(the(treatment(of(microbial(infections.((
(
Penicillins!
! All&are&derivatives&of&6]aminopenicillanic&acid!
! Contain&a&beta]lactam&ring&structure&&main&antibacterial&activity&site!
! Penicillin&have&subclasses&for&the&differences&in&antimicrobial&activity,&
susceptibility&to&acid&and&enzymatic&hydrolysis,&and&biodisposition!
!
Pharmacokinetics!
! Oral&bioavailability&is&varies&(depends&on&resistance&to&gastric&acid)&!
o Procaine,and,benzathine&(types&of&Penicillin&G)&are&IM&injection!
! Longer&half]lives&than&orally&administered!
! Polar&compounds&that&are&not&metabolized&extensively&and&excreted&
unchanged&in&the&urine&via&glomerular&filtration&and&tubular&secretion!
o Probenecid&can&inhibit&the&tubular&secretion!
o Nafcillin&is&excreted&mainly&in&the&bile!
o Ampicillin&undergoes&enterohepatic&cycling&!
! Most&have&short&half]lives&(3min&to&1hr)!
! Most&penicillin&can&cross&the&BBB&(only&when&the&meninges&are&inflamed)&!
Mechanisms!of!action!and!resistance!
! Beta]&lactam&antibiotics&are&bactericidal&!
! They&inhibit&cell&wall&synthesis&by&the&following&steps:!
o The&drug&binds&to&penicillin]binding&proteins&(PBPs)&located&in&the&
bacterial&cytoplasmic&membrane&!
o Cause&inhibition&of&the&transpeptidation&reaction&that&cross]links&
the&linear&peptidoglycan&chain&of&the&cell&wall!
o Activation&of&autolytic&enzymes&"&damage&to&bacteria&cell&wall!
! The&formation&of&beta/lactamases&(penicillinases)&by&most&staphylococci&
and&many&gram]negative&organisms&is&a&major&mechanism&of&bacterial&
resistance!
o To&overcome&this&resistance,&penicillin&are&used&in&combo&with&
clavulanic,acid,,sulbactam,,and,tazobactam,&this&is&prevent&
penicillin&inactivation!
o Structural&change&in&the&target&PBPs&is&another&mechanism&of&
bacterial&resistance,&and&is&responsible&for&methicillin&resistance&in&
staphylococci&and&for&resistance&to&penicillin&G&in&pneumococci&and&
enterococci!
o In&Psuedomonas(aeruginosa&changes&in&the&porin&structure&on&the&
other&cell&wall&may&contribute&to&resistance,&by&not&allowing&access&
of&the&penicillin&to&the&PBPs&!
Clinical!uses!
! Narrow/spectrum!penicillinase/susceptible!agents!
o Penicillin,G&is&a&prototype&!
! Infections&caused&by&common&streptococci,&meningococci,&

& 23&
Sollas&Notes&2015&

gram&positive&bacilli,&and&spirochetes!
o Many&strains&of&pneumococci&are&resistant&to&penicillins&!
o Many&Staphylococcus(aureus&and&Neisseria(gonorrhoeae&are&
resistant&via&the&production&of&beta]lactamases&!
o Penicillin,G&is&no&longer&suitable&for&treatment&of&gonorrhea!
o Penicillin,G&is&the&drug&of&choice&for&syphilis!
o Penicillin,V&is&used&mainly&for&oropharyngeal&infections&!
!
! Very!narrow!spectrum:!penicillinase/resistant!drugs!
o Methicillin,,nafcillin,,and(oxacillin,
o Staphylococcal&infections!
o Methicillin&resistant&(MR)&staphylococci&(S(aureus([MRSA]&
and&S(epidermidis([MRSE])&are&resistant&to&all&penicillins&!
!
! Wider/spectrum!penicillinase/susceptible!drugs!
o Ampicillin,and,amocillin!
o Wide&spectrtum&that&still&remains&susceptible&to&penicillinases!
o Their&clinical&uses&include&infections&from&enterococci,&Listeria(
monocytognes,(E.(coli,(haemophilus(influenza!
o When&used&in&combo&with&inhibitors&of&penicillinases&(e.g.&
clavulanic&acid)&their&antibacterial&activity&enhances&!
o In&enterococcal&and&listerial&infections,&ampicillin&is&synergistic&
with&aminoglycosides!
!
o Piperacillin,and,ticarcillin!
o Active&against&several&gram&neg.&rods,&including&Pseudomonas,(
Enterobacter,&and&in&some&Klebsiella(species!
o Synergistic&action&when&used&with&aminoglycosides&!
o Susceptible&to&penicillinases&and&are&used&in&combo&with&
penicillinases&inhibitors&(e.g.&tazobactam&and&clavulanic&
acid)&to&enhance&their&activity!
Toxicity!
! Allergic&reaction&include&urticarial,&severe&pruritus,&fever,&joint&swelling,&
hemolytic&anemia,&nephritis,&and&anaphylaxis!
! Methicillin&causes&interstitial&nephritis,&and&nafcillin&is&associated&with&
neutropenia!
! Ampicillin,frequently&causes&maculopapular&skin&rash&that&doesnt&appear&
to&be&an&allergic&reaction!
!
Gastrointestinal!disturbances!
! Nausea&and&diarrhea&may&occur&with&oral&penicillin,&mainly&ampicillin!
! Ampicillin&has&been&shown&to&cause&pseudomembranous&colitis!
! GI&upsets&may&be&cause&by&direct&irritation&or&by&the&overgrowth&of&gram]
positive&organisms&or&yeast!
&
&
&
&

& 24&
Sollas&Notes&2015&

3.3&Treatment&of&acute&myocardial&infarction&&
&
An(acute(myocardial(infarction(requires(immediate(medical(attention.(Treatment(
attempts(to(save(as(much(viable(heart(muscle(as(possible(and(to(prevent(further(
complications.(
(
STEMI!(ST/Elevation!Myocardial!Infarction):!
! Current&definitive&treatment&modalities&for&STEMI&include:!
o Thrombolysis&!
o Percutaneous&coronary&intervention!
! Thrombolysis&is&aimed&to&destroy&the&blood&clot&causing&the&AMI!
o Streptokinase&(synthesized&by&streptococci)!
o Artificial&forms&of&human&tissue,plasminogen,activator,(tPA)!
! Alteplase,,reteplase,&,tenecteplase!
o All&are&given&intravenously&and&turn&plasminogen&into&plasmin&and&
by&that&degrade&clots&
o Uses:&
! Alternative&drug&for&percutaneous&coronary&angioplasty&&
! Emergency&treatment&of&coronary&artery&thrombosis&
! Contraindicated&in&patients&with&cerebral&hemorrhage&
! Used&in&acute&pulmonary&embolism&treatment&
! Streptokinase&can&evoke&the&production&of&antibodies&that&cause&it&to&lose&
its&effectiveness&or&induce&severe&allergic&reactions&&
o So&streptokinase&can&only&be&used&once&during&whole&lifetime&
! If&thrombolysis&does&not&improve&the&patients&symptoms&significantly&or&if&
there&is&<50%&improvement&in&ST]elevation&on&the&ECG!
o Emergency&percutaneous&coronary&intervention&(PCI)&is&done!
! Primary&PCI&is&the&treatment&of&choice&for&STEMI&if&it&can&be&performed&in&
a&hospital&in&a&timely&manner!
o If&it&cannot&be&perfomed&within&90]120&minutes&then&thrombolysis,&
preferably&within&30&min&of&arrivel&to&hospital,&is&recommended!
o After&PCI&patients&are&given&dual&antiplately&therapy&for&at&least&a&
year&(aspirin,&,clopidogrel)!
! Those&patients&who&have&had&cardiac&arrest&may&benefit&from&targeted&
temperature&management&with&evaluation&for&implementation&of&
hypothermia&protocols!
NSTEMI!(Non!ST/Elevation!Myocardial!Infarction):!
! Formal&diagnosis&is&delayed&until&a&blood&test&for&biomarkers&!
o Troponin&and&CK]MB!
! Initial&treatment&is&aspirin,(1st),&clopidogrel,(2nd),&&LMW,heparin,(3rd)!
! Nitroglycerin,or,opioids&are&used&to&alleiviate&the&chest&pain!
! Supplimental&oxygen&should&only&be&used&in&patients&with&low&oxygen&
levels&and&shortness&of&breath!
! NSTEMI&is&very&similar&to&unstable&angina&and&therefore&here&would&be&
good&to&take&a&closer&look&at&topic&16.3!
!
When!the!occlusion!of!the!coronaries!is!to!extensive!the!only!possible!mode!
of!treatment!might!be!that!of!a!CABG!surgery!(coronary!artery!bypass!
grafting).!

& 25&
Sollas&Notes&2015&

Secondary!prevention:!
! After&an&episode&of&STEMI&or&NSTEMI&a&lifestyle&change&is&needed!
o Starting&to&eat&more&Mediterranean]type&diet!
o Proper&alcohol&intake,&cessation&of&smoking&!
o Exercise&20]30&min&daily&within&limits!
! Proper&medical&preventive&therapy&post&an&AMI&episode&is&done&to&
prevent&the&possibility&of&developing&another&MI,&congestive&heart&failure&
or&stroke:!
o Aspirin,and,clopidogrel,(dual&antiplatelet&therapy)!
! Continued&for&12&months!
! Aspirin&should&be&life]long!
! Warfarin,is&commonly&added&in&high]risk&cases!
Such&as&atrial&fibrillation!
! See&all&details&on&these&drugs&in&topic&5.3!
o Pblockers,(Metaprolol,,carvedilol,ect.)!
! Recommended&to&start&<24&hrs&of&an&MI!
Provided&there&is&no&acute&heart&failure&or&block!
! More&info&about&beta&blockers&are&in&topic&19.3!
o ACEi,(captopril,,enalapril),or,ARBi,(losartan,,candesartan),!
! Should&be&started&when&the&patient&is&stable!
! Continue&indefinitely&at&highest&possible&dose!
! More&on&info&on&these&drugs&are&in&topic&15.3!
o Statins,(atorvastatin,,rosuvastatin,etc.)!
! Reduces&both&mortality&and&morbidity!
! Protective&effects&are&due&to&the&lowering&of&LDL!
! More&on&statins&in&topic&2.3!
o Aldosterone,antagonists,(spironolactone,or,eplerenone)!
! May&be&usd&if&there&is&evidence&of&LV&dysfunction!
! Should&be&administered&2nd&to&an&ACE/ARB&inhibitor!
! More&on&aldosterone&antagonists&in&topic&26.2!

&

& 26&
Sollas&Notes&2015&

Topic&4&
&
4.1&Mechanism&of&neuronal&death.&Pharmacotherapy&of&Alzheimers&disease&
&
Alzheimers(disease(is(a(common(ageLrelated(dementia(and(is(very(distinct(from(vascular(dementia(
that(is(associated(with(brain(infarction(damages.(The(main(pathological(features(of(Alzheimers(
comprise(amyloid,plaques,,neurofibrillary,tangles,and,loss,of,neurons((particularly(the(
cholinergic(neurons(of(the(basal(forbrain).(Amyloid(plaques(consist(of(aggregates(of(the(A,
fragment,of,amyloid,precursor,protein,(APP),(a(normal(neuronal(membrane(protein,(produced(
by(the(action(of(L(and(Lsecretases.(Alzheimers(is(associated(with(excessive(A(formation(that(
ultimately(results(in(neurotoxicity(and(neuronal(death.(
Familial(Alzheimers((rare)(results(from(mutations(in(the(APP(gene,(or(in(presenilin(genes((that(are(
involved(in(Lsecretate(function),(both(of(which(cause(increased(A(formation.(Neurofibrillary(
tangles(comprise(intracellular(aggregates(of(a(highly(phosphorylated(form(of(a(normal(neuronal(
protein((Tau).(The(relationship(of(these(structures(to(neurodegeneration(is(not(known.(Loss(of(
cholinergic(neurons(is(believed(to(account(for(much(of(the(learning(and(memory(deficit(in(
Alzheimers.(
(
Stages!of!Alzheimers:!
! Early&stage:!
o Considered&as&a&mild/early&stage!
o Duration&period&is&2]4&years!
o Characterized&by:!
! Frequent&recent&memory&loss,&problems&in&expressing&and&
understanding&language&]&Writing&&&using&objects&difficult!
! Depression&&&drastic&personality&changes&!
! Patients&needs&reminders&for&daily&activities&!
! Second&stage:!
o Considered&as&middle/moderate&stage!
o Duration&period&is&2]10&years!
o Characterized&by:!
! Patients&can&no&longer&cover&up&their&problems!
! Pervasive&and&persistent&memory&loss&in&all&aspects&of&life!
! Rambling&speech,&unusual&reasoning,&confusion&!
! Become&lost&in&familiar&settings,&sleep&disturbances&and&mood&or&
behavioral&symptoms&accelerate!
! Slowness,&rigidity,&tremors&and&gait&problems&impact&mobility&and&
coordination!
! Moderate&stage:!
o Increased&memory&loss&and&confusion,&problems&in&recognizing&family&and&
friends&and&inability&to&learn&new&things!
o Difficulties&carrying&out&tasks&that&involve&multiple&steps&(such&as&getting&
dressed)&and&problems&coping&with&new&situations!
o Delusions&and&paranoia,&impulsive&behavior!
o Damages&to&areas&of&the&brain&that&control&language,&reasoning,&sensory&
processing&and&conscious&thoughts!
! Last&stage:!
o Considered&as&a&severe&stage&and&duration&is&1]3&years!
o Confusion&about&past&and&present&]Severe&to&total&loss&of&verbal&skills!
o Frequent&falls&and&immobility&]&Problems&with&swallowing&&&incontinence!
o Extreme&mood,&hallucinations&and&delirium&&&patients&!
o Patients&often&die&from&infections&or&pneumonia!
Diagnosis!of!Alzheimers:!
! Clinically&from&patients&history,&collateral&history&from&relatives&and&clinical&
observations,&based&on&the&presence&of&characteristic&neurological&and&
neuropsycological&features&and&the&absence&of&alternative&conditions!
! Advanced&medical&imaging&with&CT&or&MRI&and&SPECT&or&PET&!

& 27&
Sollas&Notes&2015&

Drugs!used!in!treatment!of!Alzheimers:!
! Tacrine!
o Centrally&acting&anti]cholinesterase&and&indirect&cholinergic&agonist&
(parasympathomimetic)!
! Also&acts&as&a&histamine&N]methyltransferase&inhibitor!
! First&centrally&acting&cholinesterase&inhibitor&approved&for&the&
treatment&of&Alzheimers!
o Trial&showed&modest&improvements&in&tests&of&memory&and&cognition&in&about&
40%&of&patients!
! But&no&improvement&on&other&functional&measures&that&effect&quality&of&
life!
o Side&effects:!
! Cholinergic&effects&such&as&nausea,&abdominal&cramps,&hepatotoxicity&in&
some&patients&+&many&more!!!!
Antidote&for&overdose&is&atropine&!
o Later&compounds&similar&have&been&shown&to&be&more&effective&in&improving&
quality&of&life&(donepezil,,rivastigmine,,galantamine)!
! Aricept,(donepezil)!
o Loses&its&effects&over&time!
o Used&in&mild,&moderate&and&severe&Alzheimers!
o Does&not&prevent&or&cure&the&disease&slows&symptoms!
! Celexa,(citalopram)!
o Used&to&reduce&depression&and&anxiety!
o Sometimes&used&also&for&patients&to&be&able&to&sleep!
! Depakote,(sodium,valproate)!
o Used&to&treat&severe&aggression&&&used&to&treat&epilepsy!
! Exelon,(Rivastigmine)!
o Used&to&delay&or&slow&the&symptoms&!
o Used&for&mild&to&moderate&disease&]&Does&not&prevent&or&cure&!
Drugs!under!development:!
! Rasagiline!
o Irreversible&inhibitor&of&MAO!
o Used&as&a&monotherapy&in&early&Parkinsons&dx&or&as&an&adjunct&therapy&in&more&
advanced&cases!
o Its&14&times&more&selective&for&MAOB&than&MAOA!
! Ladostigil!
o Novel&neuroprotective&agent&that&is&under&investigation&for&the&treatment&of&
Alzheimers,&Lewy&body&dementia&and&Parkinsons!
o Reversible&acetylcholinesterase&&&butytylcholinesterase&inhibitor&!
o Irreversible&MAOB&inhibitor!
o Combines&older&drugs&like&rivastigmine&and&rasagiline&into&1&drug!
! Cymserine!
o Related&to&physiostigmine&(a&reversible&cholinesterase&inhibitor)&with&moderate&
selectivity&for&butyrylcholinesterase!
o Could&be&used&to&treat&Alzheimers&without&the&side&effects&(tremors,&
lacrimation,&salivation)&that&are&seen&in&older&non]selective&cholinesterase&
inhibitors&(donepezil)!
! Bifemelane,P,Nootropic&(neuro,&cognitive&and&memory&enhancers),&!
! Latrepirdine,&antihistamine&drug!
! Semagacestat,&worse&results&than&a&placebo&so&trials&were&stopped!
o Was&supposed&to&block&the&]secretase!
! Mementine,(NMDA,receptor,blocker)!
o Acts&on&glutamatergic&system&by&blocking&NMDA&receptors!
o Has&modest&effects&in&moderate]severe&Alzheimers!
! BetaPgamma,secretase,inhibitors!
!

& 28&
Sollas&Notes&2015&

4.2&Beta?lactam&antibiotics&II.&Cephalosporins&and&other&cell&wall&synthesis&
inhibitors&
&
Cephalosporins:!
! Derivatives&of&7]aminocephalosporanic&acid&containing&a&beta]lactam&ring!
! Most&of&the&cephalosporins&are&perenterally&administered,&but&some&are&
given&orally&as&well!
! They&bind&to&PBPs&in&bacterial&cell&membranes&to&inhibit&the&bacterial&cell&
wall&synthesis&&in&a&mechanism&similar&to&penicillins!
! Bactericidal&against&susceptible&organisms!
! Less&susceptible&against&penicillinases&produced&by&staphylococci!
o Due&to&structural&differences&from&penicillins!
! Resistance&can&develop&if&the&bacteria:!
o Has&beta]lactamases&!
o Decreased&membrane&permeability&of&the&drugs!
o Changes&in&PBPs!
o MRSA&are&also&resistant&to&cephalosporins!
! Major&mode&of&excretion&is&via&active&tubular&secretion&in&the&kidneys!
o Cefoperaxone,and,ceftriaxone,are&eliminated&via&bile!
!
! Many&members&of&this&category&and&they&are&divided&into:!
o 1st&Generation&"&Cefaxolin,(parenteral)(cephalexin,(oral)!
! Active&against&gram&pos.&staphylococci&&&common&
streptococci,&many&strains&of&E.coli(and&K.pneumoniae!
! Used&to&treat&infections&by&these&organisms&and&as&a&
surgical&prophylaxis&in&selected&conditions&!
o 2 &Generation&"&Cefotetan,,cefoxitin,,cefamandole,,cefuroxime!
nd

! Usually&slightly&less&active&against&gram&pos.!
! But&have&more&gram&neg.&properties!
! Infections&caused&by&the&anaerobe&Bacteroides(fragilis!
Treated&with&cefotetan,&,cefoxitin!
! Sinus,&ear,&respiratiory&infections&caused&by&H.influenzae(or(
M.(catarrhalis!
Treated&with&cefamandole,,cefuroxime!
o 3rd&Generation&"ceftazidime,,cefoperazone,,cefotaxime,,cefixime!
! Increased&activity&against&gram&neg.&organisms&resistant&to&
other&beta]lactam&drugs&and&have&ability&to&penetrate&BBB!
Except&for&cefotaxime,,cefixime!
! Most&are&active&agains&Providencia,(Serratia(marcescens,(
strains&of&Neisseria(and(H.influenzae!
! Less&active&against&Enterobacter!
! Ceftriaxone,&,cefotaxime&are&currently&best&for&penicillin]
resistant&pneumococci&strains&(PRSP)!
! 3rd&generation&drugs&should&be&reserved&for&treatment&with&
serious&infections!
Exceptions&are&ceftriaxone,(par.)&&&cefixime,(oral)!
o Drugs&of&choice&(DOC)&in&gonorrhea!
Ceftriaxone,is&also&used&as&a&single&dose&in&acute&
otitis&media&!

& 29&
Sollas&Notes&2015&

o 4th&Generation&"&Cefepime,,ceftaroline!
! More&resistant&to&beta]lactamases&in&gram&neg.!
Enterobacter,(Haempophilus,(Neisseria!
! Combines&the&1st&generation&to&the&3rd&generation&!
! Ceftaroline,is&new&and&is&effective&against&MRSA!
! Toxicity!
o Allergy&(rashes&to&anaphylactic&shock)!
! Less&pronounced&than&in&case&of&penicillins!
o Pain&at&IM&injection&point&&&phlebitis&after&IV&injection!
o May&increase&the&nephrotoxicity&of&aminoglycosides&when&
administered&together!
o Hyperprothrombinemia&and&disulfiram]like&reactions&!
! Cefmandole,,cefoperazone,,cefotetan!
!
Other!beta/lactam!drugs:!
! Aztreonam,(monobactam)!
o Resistant&to&beta]lactamases&of&certain&species&such&as&Klebsiella,(
Pseudomonas(and(Serratia!
o No&effect&on&gram&pos.&or&anaerobes!
o Binds&to&PBP3&to&inhibit&the&cell&wall&synthesis!
o Administered&IV&and&eliminated&via&renal&tubular&secretion!
o Toxic&effects&!
! GI&disturbance&with&possible&superinfection!
! Vertigo,&headache,&hepatotoxicity&(very&rare)!
! Skin&rashes!
! Imipenem,,doripenem,,meropenem,,ertapenem,(carbopenems)!
o Chemically&different&from&penicillins&but&have&a&b]lactam&ring!
o Have&low&susceptibility&to&beta]lactamases!
o Wide&activity&agains&gram&pos.&cocci,&gram&neg.&rods&and&anaerobes!
! P.aeruginosa,(Acinetobacter!
! MRSA&is&resistant!
o Administration&is&parenterally!
o Imipenem,+,cilastatin!
! Combo&that&increases&the&half]live&of&imipenem&!
! Inhibits&the&formation&of&a&potentially&nephrotoxic&metab.!
! Adverse&effects&&GI&distress,&skin&rash,&CNS&toxicity&(at&very&
high&levels)!
! Clavulanic,acid,,sulbactam,&,tazobactam,(b]lactamase&inhibitors)!
o Used&in&fixed&combos&with&certain&hydrolysable&penicillins!
o Most&active&against&gonococci,&streptococci,&E.coli,&H.influenzae!
!
Other!cell!wall!or!membrane!active!agents!
! Vancomycin,(bactericidal)!/!teicoplanin,and,telavancin,(similar)!
o Glycoprotein&that&binds&to&the&D]ALa]D]ALa&terminal&of&the&
paptidiglycan&pentapeptide&side&chain&to&inhibit&transglycosylation!
o Vancomycin]resistant&enterococci&(VRE)&and&vancomycin]resistant&
staphylococcus&aureus&(VRSA)&!
! Occurs&due&to&decreased&affinity&for&vancomycin&due&to&a&
replacement&of&D]Ala&with&D]lactate!

& 30&
Sollas&Notes&2015&

o Narrow&spectrum&antibiotic&!
! Used&in&serious&infections&caused&by&drug]resistant&gram&
pos.&organisms&and&MRSA&(methicillin&resistant&S.(Aureus)!
! Also&used&in&treatment&for&strains&that&are&penicillin]
resistant&pneumococci&(then&in&a&combo&with&3rd&gen&ceph.)!
! Given&parenternally&usually&!
Penetrates&most&tissues&and&excreted&unchanged&
from&the&kidneys!
! Orally&its&not&taken&up&by&the&GI&but&treats&enterocolitis!
! Toxicity:!
Chills,&fever,&phlebitis,&oto]&and&nephrotoxicity!
o Needs&to&be&monitored&for&these&sakes!
! Fosfomycin!
o Antimetabolite&inhibitor&of&cytosolic&enolpyruvate&transferase!
! Inhibiting&the&formation&of&N]acetylmuramic&acid&that&is&
essential&in&the&formation&of&a&peptidoglycan&chains!
o Excreted&by&the&kidney!
! Urinary&levels&exceed&the&minimal&inhibitory&cc.&for&many&
urinary&pathogens!
o Used&in&treatment&of&many&urological&infections&!
! However&fluoroquinolones&are&DOC!
! Bacitracin!
o Gram&pos.&organisms!
o Limited&to&topical&use&&due&to&its&high&nephrotoxicity&!
o Usually&used&in&treatment&of&eye&infections!
! Cyclosterin!
o Only&used&to&treat&TB&caused&by&organisms&that&are&resistant&to&the&
primary&DOC!
o Potentially&neurotoxic&(tremors,&seizures,&psychosis)!
! Daptomycin!
o Similar&to&vancomycin&but&works&against&VRE&&&VRSA!
o Eliminated&via&the&kidney!
o May&cause&myopathy!
!
!
!
!
!
!
!
!
!
!
!
!
!
!

& 31&
 Sollas&Notes&2015&

4.3&Agents&used&in&anemias&and&other&cytopenias&
&
Blood(cells(play(essential(role(in(oxygenation(of(tissues,(coagulation,(protection(
against(infectious(agents(and(tissue(repair.(Blood(cell(deficiency(is(a(relatively(
common(problem(all(over(the(world(that(can(have(some(serious(consequences.(Most(
common(cause(of(anemia(is(insufficient(supply(of(iron,(vitamin(B12(or(folic(acid((all(
of(these(being(required(for(normal(production(of(erythrocytes.(Pharmacological(
treatment(of(these(types(of(anemia(hence(usually(involves(replacement(of(these(
missing(substances.(An(alternative(treatment(for(certain(types(of(anemia(and(
deficiency(in(other(components(of(the(blood(is(administration(of(recombinant(
hematopoietic(growth(factors((that(stimulate(production(of(various(lineages(of(
blood(cells(and(regulate(blood(cell(function(
(
Hematopoietic&factors&
&
&

&
&
Erythrocyte&factors& & &&&&&&&&&Platelet&factor& & &&&&&Granulocyte&factors&
&
&
&
& Oprelvekin&&
B12,&folate& Erythropoiesis& (IL]11)&
Iron& stimulating& Filgrastim& Sargramostim&
agent&(ESAs,& (G]CSF)& (GM]CSF)&
&
erythropoietin)&
&
&
Iron:&
Essential&component&of&heme&
Most&body&iron&is&contained&in&hemoglobin&
o Rest&is&found&bound&to&transferrin&(transport)&or&ferritin&(storage)&
Deficiency&occurs&mainly&in&&
o Women&]&since&they&loose&blood&monthly&during&menstruation&
o Vegetarians&or&malnourished&persons&
o Children&and&pregnant&women&&increased&requirements&
Excessive&amounts&are&highly&toxic&
o Thats&why&there&is&a&strict&complex&system&of&absorption,&transport,&and&
storage&of&free&iron&
o Regulation&is&done&via&absorption&since&there&is&no&effective&mechanism&
of&excretion&
Clinical&uses:&
o To&prevent&iron&deficiency&anemia&(the&most&common&anemia)&
! Microcytic&cells&with&diminished&hemoglobin&concentration&
o Treatment&is&done&by&dietary&ferrous&iron&supplementation&with:&
! Ferrous,sulfate,,ferrous,gluconate,and,ferrous,fumarate&
! Parenteral&iron&preparations&such&as&colloid,with,iron,
oxyhydroxide,surrounded,by,a,core,of,carbohydrate&
Iron,dextran,,sodium,ferric,gluconate,complex,and,
iron,sucrose&

& 32&
Sollas&Notes&2015&

o Contraindicated&in&hemolytic&anemia&]&iron&stores&are&increased&
Iron&toxicity:&
o Most&common&in&kids&and&is&due&to&accidental&intake&of&iron&supplement&
tablets&
o Can&result&in:&
! Necrotizing&gastroenteritis,&shock,&metabolic&acidosis,&coma&and&
death&
! Hemochromatosis&&chronic&overload&of&iron&
Damaged&liver,&heart&and&pancreas&
Usually&inherited&abnormality&of&iron&absorption&and&in&
those&that&receive&frequent&blood&transfusions&
o Treatment&of&acute&toxicity:&
! Removal&of&tablets&from&the&gut,&correction&of&acid]base&and&
electrolytes&abnormalities&
! Deferozamine,&chelates&circulating&free&iron&
o Treatment&of&chronic&toxicity:&
! Phlebotomy&(removal&of&blood&via&venipuncture)&
Used&in&hemochromatosis&
! Deferozamine,and,defrasirox,(both&are&chelators)&
&
Vitamin&B12:&
Along&with&folate&acid&its&necessary&for&the&synthesis&of&DNA&
o Affects&all&cells&but&is&most&obvious&on&the&RBCs&since&those&are&
continuously&produced&every&120&days&&
! Macrocytic&megaloblastic&anemia&
! Neurologic&defects&that&can&become&irreversible&&
Vitamin&B12&is&produced&by&bacteria&only&&&is&absorbed&through&the&GI&tract&via&
help&from&intrinsic&factor&(produced&by&parietal&cells&of&stomach)&
o Stored&in&the&liver&in&huge&amounts&&so&deficiency&is&quite&rare&
! Stores&are&usually&enough&for&5&years&
Treatment&of&deficiency:&
o Cyanocobalamin,and,hydroxocobalamin,(supplements)&
o Used&also&in&the&treatment&of&pernicious&anemia&following&gastric&
resection&(loss&of&intrinsic&factor)&
Folic&acid:&
Same&as&B12&&needed&for&normal&DNA&synthesis&&
Deficiency&results&in&megaloblastic&anemia&and&increased&risk&of&neural&tube&
defects&&deficiency&takes&only&around&3&months&to&appear&
Treatment&is&done&with&supplementary&intake&of&folate&
o Recommended&before/during&pregnancy&&
Hematopoietic&growth&factors:&
Erythropoiesis&stimulating&agents&are&used&in&the&anemia&that&can&follow&renal&
failure,&post]chemo/radio&treatments&or&nephrotomy&
o Darbepoetin,alfa,(glycosylated&form&of&EPO)&has&longer&half]life&
o Methoxy,polyethylene,glycolPepoetin,beta,long&lasting&(injected&1]2&x&
month)&
Most&common&complication&is&HTN&and&thrombosis&
Myeloid&growth&factors:&
Filgrastim,&,sargramostim,stimulate&production&and&function&of&neutrophils&
Used&primarily&to&restore&the&components&of&the&blood&post&chemo&and&other&
types&of&neutropenia&
Megakaryocyte&growth&factors:&
Oprelvekin,(ILP11)&increases&the&amount&of&peripheral&platelets&

& 33&
Sollas&Notes&2015&

Topic&5&
&

5.1&Pharmacological&management&of&Parkinsons&disease&
&
Parkinsons(disease((PD)(is(a(degenerative(disorder(of(the(CNS.(The(motor(
symptoms(of(PD(result(from(the(death(of(dopamineLgenerating(cells(in(the(pars(
compacta(of(the(substancia(nigra((located(in(the(midbrain).(The(cause(of(cell(death(
is(still(unknown.(This(results(in(akinetic/hypokinetic(rigid(movements(that(are(the(
characteristic(signs(of(Parkinsons.(The(disease(is(most(common(in(elderly(and(
starts(to(be(more(evident(around(50L60.(
(
Etiology:!
! As&the&cells&of&the&pars&compacta&of&substancia&nigra&start&to&die&we&can&
see&imbalances&in&the&nigrostriatal&dopaminergic&pathway&!
o This&pathway&is&associated&with&the&striatum&of&the&basal&ganglia&
system&of&in&the&deep&cerebral&cortex!
o Imbalance&in&the&ratio&of&dopamine&to&acetylcholine!
o This&results&in&uncontrolled&functions&of&GABAergic&neurons&and&
imbalances&in&the&striatum&(caudate,&putamen),&substancia&nigra,&
globus&pallidus&and&cerebral&cortex!
! Causes&are&mainly&unknown,&but&some&factor&seem&to&be&of&importance:!
o Exogenous!
! MPTP&(meperidine&derivative)&"&MPP+&(selective&
destruction)!
! Drugs:&usually&causing&reversible&parkinsonism!
Dopamine&receptor&antagonists!
o Antipsychotics&(butyrophenone,,
phenothiazine)!
o Reserpine,(depletes&the&dopamine&stores)!
Heroin&induced&Parkinsonism!
o Endogenous!
! Neurotoxins!
! Mutation&of&]synuclein,&LRRK2!
Symptoms:!
! Most&common&symptoms&in&early&disease&are&movement&related:!
o Tremors,&rigidity&(rigor),&slowness&of&movement,&difficulties&in&
walking,&altered&gait,&mogigraphia&(writers&cramps)!
o Hypokinasia&and&bradykinesia!
! Starting&hesitations&and&muscle&freezing!
! Later&in&the&course&of&the&disease:!
o Impaired&cognitive&functions,&dementia,&depression,&sleeping&
problems&and&emotional&changes!
o Aphasia&(speaking&difficulties)!
o Autonomic&symptoms:!
! Hypersalivation,&obstipation&(severe&constipation),&
hypotension!
!
!

& 34&
Sollas&Notes&2015&

Treatment!regiments:!
! Dopamine&substitution&&Levodopa!
! Dopamine&receptor&antagonists&!
o Bromocriptin,,pergolide,,pramipexol,(ropinirole),,
apomorphine,,rotigotine!
! MAO/COMT&inhibition:!
o Selegilin,,tolacapone,(entacapone)!
! Acetylcholine&blocking&drugs!
o Benztropine,mesylate,,biperiden!
!
Levodopa:!
! Metabolic&precursor&of&dopamine&!
o Dopamine&cannot&cross&the&BBB&and&has&very&low&bioavailability!
! Turned&into&active&form&of,dopamine&in&the&CNS&by&DOPA&decarboxylase!
o Only&3%&of&the&absorbed&levodopa&reaches&the&CNS!
! Taken&up&by&L]amino&acid&transporter&(LAT)!
! Due&to&intense&fast&pass&metabolism&and&peripheral&
decarboxylation!
! Rapidly&absorbed&from&the&small&intestine!
! Half]life:&1]3hrs!
! Peripheral&DOPA&decarboxylase&inhibitors&can&reduce&the&intense&
peripheral&decarboxylation&and&hence&more&drug&will&reach&the&CNS!
o Carbidopa,and,benserazid!
! These&drugs&increase&half]life;&ultimately&reducing&the&
effective&dose&of&levodopa&and&the&peripheral&side&effect!
! Effects:!
o Alleviation&of&the&signs&of&parkinsonism,&mainly&the&bradykinesia!
o Doesnt&cure&the&disease&but&improves&the&mortality&rate!
! Responsiveness&to&the&drug&fluctuates&and&ultimately&
decreases&with&time!
Sometimes,&completely&unrelated&to&the&dosing&and&
timing&of&the&drug&administration,&the&patients&
experience&off]periods&of&akinesia&that&alternates&
over&period&of&few&hours&with&on]periods&of&
improved&motility&but&often&with&dyskineasia!
o On]off&phenomena!
! Clinical&doses:!
o Levodopa&(100mg)&+&carbidopa/benserazid&!
o Levodopa+carbidopa+COMT&inhibitor!
o Tolerance&is&usually&achieved&after&around&3]4&years!
o Important&to&decrease&gradually&as&abrupt&cessation&may&cause&
akinetic&state)!
! Adverse&effects:!
o Vomiting,&nausea&(due&to&D2&receptors&in&the&area&postrema)!
o Cardiac&arrhythmias&(tachycardias&and&ventricular&extrasystoles)!
o Hypotension!
o Dyskinesias&(involuntary&choreic&movements)!
o Hallucinations,&nightmares,&euphoria!
Contraindicated!in!psychotic!patients!and!patients!on!MAOA!inhibitors!

& 35&
Sollas&Notes&2015&

Dopamine!receptor!agonists:!
! Bromocriptine!
o Ergot&alkaloid&that&is&a&partial&agonist&at&the&D2&receptor&in&brain!
o The&drug&increases&the&functional&activity&of&dopamine&pathways!
! Including&the&ones&ass.&with&the&extrapyramidal&functions!
o &Used&alone&or&in&combination&with&levodopa&(and&anticholinergic&
drugs)&+&alone&when&patients&cannot&tolerate&levodopa!
o Clinical&use&"&treatment&of&akinetic&crisis&&&hyperprolactinaemia!
o Adverse&effects:& !
! Anorexia,&nausea&&&vomiting,&dyskineasia&and&orthostatic&
hypotension,&behavioral&effects&(confusions,&hallucinations&
&&delusions)!
! Ergot&related&effects&can&be&erythromelagia&and&pulmonary&
infiltrates!
! Pergolide!
o Ergot&alkaloid&that&works&as&an&agonist&on&D1&and&D2&receptors!
o More&effective&than&bromcriptine!
o Adverse&effects:!
! &Cardiac&valvulopathy&and&arrhythmias!
! Pramipexole,&,ropinirole!
o Non]ergot&drugs&that&have&high&affinities&for&D3&and&D2&respectively!
o Effective&in&monotherapy&in&mild&parkinsonism!
o Sometimes&coupled&with&levodopa&in&more&advanced&disease&to&
smooth&out&response&fluctuations!
o Usually&given&3&times&a&day!
o Adverse&effects:!
! Anorexia,&nausea,&vomiting,&orth.hypotension,&dyskinesia!
! Mental&disturbances&(more&commonly&then&in&levodopa)!
! Uncontrollable&tendency&to&fall&asleep&(rare)!
o Pramipexole,is&contraindicated&in&patients&with&an&active&peptic&
ulcer&disease,&psychotic&illness&or&recent&MI!
! The&drug&is&thought&to&be&neuroprotective&because&of&its&
scavenger&effects&for&hydrogen&peroxide!
o Ropinirole&is&metabolized&by&CYP1A2&and&therefore&caffeine&and&
warfarin&may&reduce&its&clearance!
! Apomorphine!
o Potent&D2&receptor&agonist!
o Injected&subcutaneously&to&rapidly&(<10min)&relieve&the&off&
phenomenon&of&akinesia&in&patients&on&optimized&dopaminergic&
therapy&(this&effects&only&work&temporarily&(1]2hrs))!
o Adverse&effects&include&severe&nausea!
! So&the&administration&of&the&drug&is&done&after&a&
prophylactic&pretreatment&(3days)&of&antiemetics!
o Other&adverse&effects:!
! Dyskinesia,&hypotension,&drowsiness&and&sweating!
! &Rotigotine!
o Non]ergot&alkaloid!
o Skin&patch&(24&hrs)&that&is&used&in&the&early&treatment&of&PD!
!

& 36&
Sollas&Notes&2015&

Monoamine!oxidase!inhibitors!(MAO):!
! Selegiline,&,rasagiline(
o Irreversible&inhibitors&of&MAOB(
o At&high&doses&they&can&also&inhibit&MAOA!
o Selegiline,has&minimal&efficacy&in&PD&when&used&alone&but&can&be&
used&adjunctively&with&levodopa!
! Prolongs&effects/reduces&doses&of&levodopa!
! Reduces&on/off&phenomenon!
o Rasagiline&is&much&more&potent&and&can&be&used&alone&for&PD&or&
can&also&be&used&in&advanced&PD&in&combo&with&levodopa!
o Adverse&effects:!
! Insomnia,&mood&changes,&dyskinesia,&GI&distress,&hypoten.!
! Combination&with&meperidine,have&resulted&in&agitation,&
delirium&and&mortality!
o Contraindicated&in&serotonin&syndrome&when&used&with&serotonin&
selective&reuptake&inhibitors&(SSRI)&and&tricyclic&antidepressants!
Catechol/O/methyltransferase!(COMT)!inhibitors:!
o COMT&is&an&enzyme&in&both&CNS&and&peripheral&tissues&that&converts&
levodopa&to&3]O]methyldopa&(3]OMD)!
o Increased&levels&of&3]OMD&are&associated&with&poor&response&to&
levodopa&partly&because&the&compound&competes&with&levodopa&
for&active&transport&in&the&BBB&and&intestinal&mucosa!
o Tolcapone,and,entacapone!
o Selective&COMT&inhibitors&that&are&rapidly&absorbed&!
o Half]life&of&2&hrs!
o Entacapone&only&works&in&the&peripheral&tissues!
o Clinical&uses:!
! Used&as&adjunctive&therapy&to&levodopa]carbidopa!
Decreases&fluctuations,&prolongs&on]phenom&and&
improves&responses!
! Reduces&levodopa&doses!
o Tolcapone,is&given&3/day&and&entacapone&5/day!
o Adverse&effects:!
! Dyskinesia,&GI&distress,&orthostatic&hypotension!
! Sleep&disturbances&and&orange&colored&urine!
! Tolcapone&increases&liver&enzymes&and&is&therefore&
hepatotoxic&(acute&hepatic&failure)!
Amantadine:!
o Antiviral&agent&that&enhances&dopaminergic&neurotransmission&by&
unknown&mechanisms!
o May&facilitate&dopamine&synthesis&or&release!
o May&increase&inhibition&of&dopamine&reuptake!
! A2A&receptor&antagonism!
o Blocks&NMDA&(glutamate)&receptors&and&has&anticholinergic&
properties!
o Clinical&uses&"&Acute&application:&improve&bradykinesia,&rigidity,&tremors!
o Adverse&effects&"&depression,&irritability,&insomnia,&agitation,&confusion,&
acute&toxic&psychosis,&livedo&reticularis&(derm.&probl.),&ortho.hypo,&edema!
o Contraindicated&in&seizures&and&heart&failure&!

& 37&
Sollas&Notes&2015&

Acetylcholine!blocking!drugs:!
o The&drugs&decrease&the&excitatory&actions&of&cholinergic&neurons&on&cells&
in&the&striatum&by&blocking&muscarinic&receptors!
o Clinical&use:!
o Improvement&of&tremors&and&rigidity!
o Little&effect&on&bradykinesia!
o Used&adjunctively&in&PD&and&also&to&alleviate&the&reversible&
extrapyramidal&symptoms&caused&by&antipsycotics!
o Drugs&(centrally&acting&antimuscarinic)!
o Block&M1R&and&M3R!
o Benztropine,mesylate!
o Biperiden!
o Orphenadrine!
o Procyclidine!
o Trihexyphenidyl!
o Adverse&effects:!
o Tachycardia,&mydriasis,&dry&mouth/skin,&obstipation,&agitation,&
aggression!
!
Akinetic!crisis:!
o Akinesis,&insufficient&swallowing&and&respiration&+&Exsiccosis!
o Treatment:!
o Bromocriptine,,pergolide!
o Amantadine,infusion,in&mild&cases!
o Apomorphine,infusion&in&severe&cases!
o Supportive&therapy:!
o Antibiotics!
o Anticoagulants!
o Fluid/electrolyte&supplementation!
!
!
!
!
!
!
&
&
&
&
&
&
&
&
&
&
&
&
(

& 38&
Sollas&Notes&2015&

5.2&Aminoglycosides&and&spectinomycin&
&
The(traditional(mode(of(action(of(antibiotics(is(via(multiple(daily(dosage(regimens(
that(have(been(designed(to(maintain(serum(concentrations(above(the(minimal(
inhibitory(concentration((MIC)(for(as(long(as(possible.(This(is(called(timeP
dependent,killing.(
However,(the(in(vivo(effectiveness(of(some(antibiotics,(including(aminoglycosides,(
result(from(a(concentrationPdependent,killing(action.(
As(plasma(level(rises(above(MIC((more(bacteria(die(at(faster(rate(
Aminoglycosides(are(also(capable(of(exerting(a(postantibiotic,effect(
o Meaning(that(the(killing(action(continues(even(after(the(plasma(level(
of(the(drugs(have(declined(below(measurable(levels(
Toxicity(of(aminoglycosides(depends(on(critical(plasma(concentration(and(
time(that(level(is(exceeded(
(
Due&to&the&above&listed&properties&of&aminoglycosides&the&best&method&of&
treatment&administration&is&a!single!large!dose!once!a!day!
This&reduces&the&probability&of&toxicity&and&increases&their&efficacy&
&
Pharmacokinetics!of!aminoglycosides:!
Structurally&related&amino&sugars&attached&by&glycosidic&linkages&
Polar&compounds&that&are&not&absorbed&after&oral&administration&
o Given&intramuscularly&or&intravenously&for&systemic&effects&
Limited&tissue&penetration&and&dont&cross&BBB&easily&
Mainly&excreted&via&the&kidneys&and&is&directly&proportional&to&creatinine&
clearance&&so&the&excretion&is&greatly&dependent&on&kidney&function&
o Normally&kidney&excretes&the&drugs&in&2]3hrs&(elim.&half]life)&
Mechanism!of!action:!
Aminoglycosides&are&bactericidal&inhibitors&of&protein&synthesis&
Partly&oxygen]dependent&and&work&poorly&for&anaerobes&
Bind&to&the&30S&ribosomal&subunit&and&interfere&with&pro.synthesis:&
o Block&formation&of&the&initiation&complex&
o Cause&misreading&of&the&code&on&the&mRNA&template&
o Inhibit&translocation&
Mechanism!of!resistance:!
Streptococci&and&enterococci&are&relatively&resistant&to&aminoglycosides&
due&to&the&failure&of&the&drug&to&enter&the&cell&
Group&transferase&enzymes&catalyze&the&acetylation&of&amine&functions&
and&the&transfer&of&phosphoryl&or&adenylyl&groups&to&the&oxygen&of&
hydroxyl&groups&on&the&aminoglycosides&
Clinical!uses:!
Effective&mainly&against&gramPneg.rods&
Gentamicin,!tobramycin!&!amikacin&
o Important&in&treatment&of&serious&infections&by&aerobic&gram]neg.&
bacteria&such&as&E.coli,(Enterobacter,(Klebsiella,(Proteus,(
Pseudomonas,(Serritia,(H.influenzae((some(ssp.),(Moraxella(and(
Shigella(ssp.&

& 39&
Sollas&Notes&2015&

Antibacterial&synergy&may&occur&when&aminoglycosides&are&used&with&cell&
wall&synthesis&inhibitors&(e.g.&penicillins)&
o Effective&against&gram]pos.&cocci&&
Streptomycin!+!penicillin&
o Good&in&the&treatment&of&enterococcal&carditis,&TB,&plague&and&
tularemia&
Netilmicin!is&used&in&treatment&of&serious&infections&that&are&not&
responding&to&other&aminoglycosides&&not&used&in&USA&
Specinomycin&
o Aminocyclitol&related&to&aminoglycosides&
o Used&as&a&backup&drug&&given&IM&as&a&single&dose&
o Used&in&treatment&of&gonorrhea&in&patients&that&are&allergic&to&
beta]lactams&
Toxicity!of!aminoglycosides:!
Ototoxicity&(damage&to&CN&VIII):&
o Can&be&irreversible&
o Auditory&part:&Damaged&with&amikicin&and&kanamycin&
o Vestibular&part:&Damaged&with&gentamicin&and&tobramycin&
o Risk&is&proportional&with&plasma&cc.&levels&and&is&increased&in&case&
of&renal&damage&or&co]administration&of&loop&diuretics&
o Contraindicated&(unless&pros&are&more&than&cons)&in&pregnancy&
since&they&have&been&shown&to&be&ototoxic&to&the&fetus&&
Nephrotoxicity:&
o Usually&takes&the&form&of&acute&tubular&necrosis&(ATN)&
o Often&reversible&
o Gentamicin&and&tobramycin&are&most&toxic&
Neuromuscular&blockage&
o Very&rare&curare]like&block&may&occur&at&high&doses&
o Can&cause&respiratory&paralysis&
o Usually&reversible&with&administration&of&Ca2+&and&neostigmine&
o Ventilator&support&might&be&needed&
Skin&
o Allergic&reactions&at&injection&sites&
&
&
&
&

&
&

&
&
&
&
&

& 40&
Sollas&Notes&2015&

5.3&Drugs&used&in&disorders&of&coagulation&
(
Drugs(used(in(clotting(and(bleeding(disorders(fall(into(two(major(groups:(
Drugs(used(to(decrease(clotting(or(dissolve(clots(already(present(in(patients(
at(risk(for(vascular(occlusions(
o AntiLclotting(drugs(
! Used(in(treatment(&(prevention(of(MI,(ACS,(ALfib,(ischemic(
stroke(and(DVT(
Drugs(used(to(increase(clotting(in(patients(with(clotting(deficiencies(
o Drugs(that(facilitate(clotting(
(
Drugs!used!in!clotting!disorders!
&
Anticoagulants!
Inhibit&the&formation&of&fibrin&clots&
Three&major&categories&
o Heparin&and&related&product&
! Used&parenterally&
o Direct&thrombin&and&factor&X&inhibitors&
! Used&parenterally&or&orally&
o Coumarin&derivative&(Warfarin)&
! Used&orally&
Heparin:&
o Large&sulfated&polysaccharide&polymer&obtained&from&animals&
o Slightly&acidic&and&can&therefore&be&neutralized&by&basic&molecules&
! Protamine&
o Given&IV&or&subcutaneously&&
o Each&batch&contains&molecules&of&varying&size&
! Average&molecular&weight&of&15.000]20.000&
LMWH&(low&molecular&weight&heparin)&
o Enoxaparin,&
o 2000]6000&Dalton&
o Great&bioavailability&and&long&lasting&
o More&selective&since&they&only&bind&to&AT]III&
Unfractionated&heparin&
o Shorter&action&&given&more&often&during&day&
o Binds&to&AT]III&as&well&as&thrombin&
o Heparin]ATIII&complex&combines&with&and&irreversibly&inactivates&
thrombin&and&several&other&factors&(mainly&factor&Xa)&
o LMWH]ATIII&complex&have&same&effects&but&are&more&selective&
o Activated&partial&thromboplastin&time&(aPTT)&is&used&to&monitor&
the&actions&of&heparin&
! Better&to&evaluate&unfractionated&heparin&
! Worse&to&evaluate&LMWH&
o Usage:&
! Used&when&anticoagulation&is&needed&immediately&
Treatment&of&DVT,&pulmonary&embolism,&AMI&
! Used&in&combo&with&thrombolytics&for&revascularization&

& 41&
Sollas&Notes&2015&

! Used&in&combo&with&GP&IIb/IIIa&inhibitors&during&
angioplasty&and&placements&of&coronary&stents&
! Does&not&cross&the&BPB&so&its&save&during&pregnancy&
o Toxicity:&
! Increased&bleeding&that&can&result&in&hemorrhagic&stroke&
! Unfractionated&heparin&causes&moderate&transient&
thrombocytopenia&in&many&patients&and&severe&
thrombocytopenia&and&thrombosis&in&small&percentage&
Heparin]induced&thrombocytopenia&(HIT)&
Antibodies&that&bind&to&a&complex&of&heparin&and&
platelet&factor&4&
! Unfractionated&heparin&for&longer&time&has&shown&
osteoporosis&
&
Direct!thrombin!inhibitors:!
Based&on&proteins&made&by&Hirudo(medicinalis((medicinal&leech)&
o Lepirudin,,desirudin,,bivalirudin,,argatroban&
! All&these&are&given&parenterally&
o Dabigatran&
! Orally&active&
Used&as&alternatives&in&HIT&
Bivalirudin&is&used&in&combo&with&asprin&during&percutaneous&coronary&
angioplasty&
Direct!oral!factor!Xa!inhibitors:!
Rivaroxaban,&,apixaban&
Rapid&onset&of&action&and&shorter&half]lives&than&warfarin&
&
Warfarin&and&other&coumarin&anticoagulants:&
Small,&lipid]soluble&molecules&that&are&readily&absorbed&after&oral&
administration&
Warfarin&is&highly&bound&to&plasma&proteins&(>99%)&&
Elimination&depends&on&metabolism&by&cytochrome&P450&
Warfarin&interferes&with&the&normal&post]translational&modification&of&
clotting&factors&in&the&liver&(a&process&that&
depends&on&an&adequate&supply&of&
reduced&vitamin&K)&
o Inhibits&vitamin&K&epoxide&
reductase&(VKOR)&that&normally&
converts&vitamin&K&epoxide&to&
reduced&vitamin&K&
o Actions&can&be&reversed&with&
vitamin&K&but&recovery&requires&
synthesis&of&new&clotting&factors&
and&hence&the&process&is&slow&
! Rapid&reversal&can&be&done&
by&injecting&fresh&or&frozen&
plasma&that&contains&
normal&clotting&factors&

& 42&
Sollas&Notes&2015&

Warfarin&is&monitored&by&prothrombin&test&(PT)&and&INR&values&
Uses:&
o Chronic&anticoagulation&in&all&of&the&clinical&situations&described&
before&for&heparin&&
! However&warfarin&is&NEVER&used&during&pregnancy&
o Narrow&therapeutic&window&&needs&to&be&monitored&tightly&since&
bleeding&tendencies&are&very&common&
&
Thrombolytic&agents:&
Endogenous&tissue&plasminogen&activator&(alteplase,,tenecteplase)&or&
protein&synthesized&by&streptococci&(streptokinase)&
All&are&given&intravenously&and&turn&plasminogen&into&plasmin&and&by&
that&degrade&clots&
Uses:&
o Alternative&drug&for&percutaneous&coronary&angioplasty&&
o Emergency&treatment&of&coronary&artery&thrombosis&
o Contraindicated&in&patients&with&cerebral&hemorrhage&
o Used&in&acute&pulmonary&embolism&treatment&
Streptokinase&can&evoke&the&production&of&antibodies&that&cause&it&to&lose&
its&effectiveness&or&induce&severe&allergic&reactions&&
o So&streptokinase&can&only&be&used&once&during&whole&lifetime&
&
Antiplatelet&drugs:&
Aspirin,&NSAIDs,&GP&IIb/IIIa&receptor&inhibitors&(abciximab,,tirofiban,,
eptifibatide),&antagonists&of&ADP&receptors&(clopidogrel,&,ticlopidine),&
inhibitors&of&phosphodiesterase&3&(dipyridamole,&,cilostazol)&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&

& 43&
Sollas&Notes&2015&

Topic&6&
6.1&Antipsychotics&and&lithium&
(
Antipsychotic(drugs((neuroleptics)(are(used(in(schizophrenia(other(psychoses(and(
agitated(states.(Although(schizophrenia(is(not(cured(by(drug(therapy,(the(symptoms(
can(be(reduced.(Unfortunately(during(prolonged(therapy(the(drugs(may(result(in(
severe(toxicity.(In(bipolar(affective(disorder(lithium(has(been(the(drug(of(choice(for(
many(years,(however(use(of(newer(antipsychotics(and(several(antiseizure(drugs(is(
increasing.((
(
Drugs:!
Antipsychotics:(
o Classic&drugs&(D2&&receptor&affinity)(
! Chlorpromazine,,fluphenazine,,haloperidol,,thioridazine,,
trifluoperazine(
o Newer&agents&(5HT2&&receptor&affinity)(
! Clozapine,,olanzapine,,quetiapine,,risperidone,,
ziprasidone(
Bipolar!drugs:(
o Classic&drugs&"&Lithium(
o Newer&agents(
! Carbamazepine,,clonazepam,,olanzapine,,valproic,acid(
(
Antipsychotics:!
Major&chemical&subgroups&are:!
o Phenothiazines&(chlorpromazine,,thioridazone,,fluphenaznine)!
o Thioxanthines&(thiothixine)!
o Butyrophenones&(haloperidol)!
o Heterocyclic&structure&(2nd&generation&drugs)!
! Clozapine,,olanzapine,,quetiapine,,risperidone,,
ziprasidone,and,aripiprazole(
Somewhat&more&effective&and&less&toxic&than&1st&gen.(
More&expensive(
Pharmacokinetics:(
o Well&absorbed&when&given&orally,&lipid&soluble&(cross&BBB)(
o Many&are&bound&extensively&to&plasma&proteins(
o Long&half]life&and&CYP&enzyme&metabolism&in&liver(
o Once&a&day&daily&dose(
o Parenteral&forms&are&available&for&rapid&initiation&of&therapy(
! Haloperidol,and,fluphenazine(
Mechanism&of&action:(
o Most&of&the&older&antipsychotic&drugs&act&on&the&dopamine&
receptors&(since&schizophrenia&is&thought&to&be&related&to&excess&
amount&of&the&neurotransmitter&dopamine&in&various&regions&of&
the&brain)!
o 5&different&dopamine&receptors&(D1]D5)&have&been&characterized!
! D1:&Gs&(putamen,&cortex,&nucleus&accumbens)!
! D2:&Gi&(putamen,&n.&accumbens,&cortex,&hypothalamus)!

& 44&
Sollas&Notes&2015&

! D3:&Gi&&(frontal&cortex,&medulla,&mesencephalon)!
! D4:&Gi&(cortex)!
! D5:&Gs&(hippocampus,&hypothalamus)!

!
Schizophrenia:!
Psychiatric(disease(characterized(by(abnormal(social(behavior(and(failure(to(
recognize(what(is(real.(The(etiology(of(the(disease(is(related(to:(
Dopamine&hypothesis!
o Hyperfunction&of&mesolimbic]mesocortical&dopaminergic&pathway!
o Based&on&several&observations:!
! D2&receptor&antagonists&reduce&psychotic&symptoms!
! D2&receptor&agonists&increase&psychosis!
! Increased&density&of&D2&receptor&in&the&midbrain&is&seen&on&
autopsies&!
! Increased&levels&of&dopamine&in&putamen,&n.accumbens!
Serotonin&!
o Indole&hallucinogens&(LSD),&mescalin&provoke&symptoms!
! Agonists&of&&5HT2A&receptor&!
o Inverse&agonist&of&5HT2A&receptor&reduce&symptoms!
! Clozapine,,queitapine!
Glutamate&hypothesis!
o Hypofunction&of&NMDA&receptor&located&on&GABAergic&neurons&
provoke&schizophrenic&symptoms!
Symptoms:!
o Positive!
! Illusions/delusions&!
! Auditory&and&visual&hallucinations!
! Thinking&disorders!
! Agitation,&aggressive&behavior!
o Negative!
! Blunted&effect&and&emotion!
! Alogia&(poverty&of&speech)!

& 45&
Sollas&Notes&2015&

! Inability&to&experience&pleasure&and&lack&of&motivation!
! Lack&of&social&relationships!
! Apathia&and&agonia!
Older&drugs&(D2&receptor&antagonists):!
o Anticholinergic&effects&(obstipation)!
o Anti&adrenergic&effects&(orthostatic&hypotension)!
o Reduction&of&positive&symptoms&of&schizophrenia!
o Broad&side&effect&profile!
! Extrapyramidal&symptoms&!
Due&to&dopamine&depletion&of&nigrostriatal&pathway!
Acute:!
o Achatisia&(uncontrolled&restlessness)!
o Acute&dystonic&reactions&!
! Spastic&retrocollis/torticollis!
Chronic:!
o Pseudoparkinsonism!
o Perioral&tremor&(rabbit&syndrome)!
o Tardive&dyskinesia&(choreo&movem.)!
o Malignant&neuroleptic&syndrome&(MNS)!
! Endocrine&effects!
Due&to&dopamine&depletion&of&tuberoinfund.&pathw.!
o Hyperprolactinaemia!
o Galactorrhea,&amenorrhea!
o Gynecomastia,&impotence!
! Anti]emetic&effects!
D2&receptor&blockade&of&area&postrema!
Promethazine!
! Cardiac&toxicity!
Thioridazine!
Prolonged&QT&interval&and&arrhythmias&(torsade)!
Newer&drugs:!
o Expanded&receptor&profile&!
o Reduction&of&both&positive&and&negative&symptoms!
o Reduced&side&effect&profile!
! Clozapine!
D4>D2&=&5HT2A&>&D1&!
Central&adrenergic&effects&!
Mesolimbic&selectivity!
Side&effects:!
o Obesity,&insulin&resistance,&agranulocytosis,&
myocarditis!
! Olanzapine!
5HT2A&>&H1&>&D4&>&D2!
Mesolimbic&selectivity!
Side&effects:!
o Obesity&and&insulin&resistance!
! Risperidone!
D2&>&5HT2A&>&H1&!

& 46&
Sollas&Notes&2015&

Mesolimbic&selectivity!
Side&effects!
o Extrapyramidal&symptoms,&
hyperprolactinemia,&sedation,&headache,&MNS!
! Sertindole!
D2&>&5HT2A&>&1!
Side&effects&"&QT&prolongation&!
Lithium:!
Effective&in&the&treatment&of&the&manic&phase&of&bipolar&disorder,&acute]
phase&illness&and&for&prevention&of&recurrent&manic&and&depressive&states!
Monovalent&cation&that&is&absorbed&rapidly&and&completely&from&gut!
o Distributed&via&body&water&and&cleared&by&the&kidneys!
o Half]life&is&approx.&20hrs!
o Plasma&levels&should&be&closely&monitored&to&establish&save&and&
effective&dosage&regimen!
! Acute&symptoms&"&0,8]1,2&mEq/L&(target&plasma&cc.)!
! Maintenance&"&0,4]0,7&mEq/L&(target&plasma&cc.)!
! Plasma&levels&may&vary&due&to&conditions&of&body&water!
Dehydration,&treatment&with&NSAIDS,&ACEIs&and&
loop&diuretics&may&result&in&toxic&levels&in&plasma!
Caffeine&and&theophylline&may&increase&renal&clear.!
Mechanism&is&not&well&defined!
o The&drug&inhibits&several&enzymes&involved&in&the&recycling&if&
neuronal&membrane&phosphoinositides!
! Resulting&in&depletion&of&PIP2&that&will&result&in&decrease&in&
IP3&and&DAG!
All&these&messengers&are&important&in&amine&
neurotransmission&&(central&adrenoreceptors&and&
muscarinic&receptors)!
Clinical&use:!
o Treatment&of&bipolar&dx&(manic]depressive&disease)!
! Drugs&like&valproic,acid,and,carbamazepine&also&good!
o Maintenance&therapy&with&lithium&decreases&manic&behavior&and&
reduces&both&the&frequency&and&magnitude&of&mood&swings!
o Slow&onset&of&action&so&benzodiazepines&or&antipsychotics&are&
usually&used&in&initial&treatment!
o Often&used&in&combo&therapy&with&antidepressants&!
! To&control&suicide&and&self]harm&tendencies!
Monotherapy&with&antidepressants&can&precipitate&
mania&in&bipolar&patients!
Toxicity:!
o Tremor,&sedation,&ataxia,&aphasia,&thyroid&enlargement!
o Reversible&nephrogenic&diabetes&insipidus&occurs&commonly!
o Edema,&acne,&leukocytosis&(always)!
o Increased&incidence&of&congenital&cardiac&anomalies&(Ebsteins)&
when&lithium&is&taken&during&preganancy!
o Teratogenicity&is&low&but&neonates&have&low&Apgar&scores!
!
!

& 47&
Sollas&Notes&2015&

6.2.&Chloramphenicol&&&tetracyclines&
&
Chloramphenicol:&
50S&ribosomal&subunit&inhibitor&
Inhibits&transpeptidaton&by&blocking&the&binding&of&the&aminoacetyl&
moiety&of&the&charged&tRNA&molecule&to&the&acceptor&site&on&the&mRNA&
o Thus&the&peptide&at&the&donor&site&cannot&be&transferred&to&its&
amino&acid&acceptor&site&
It&has&a&simple&and&distinctive&structure&(only&drug&in&its&class)&
o Effective&orally&as&well&as&parenterally&
o Widely&distributed&and&readily&crosses&placenta&and&BBB&
o Enterohepatic&cycling&&&&small&fraction&is&excreted&in&urine&
o Most&of&the&drug&is&inactivated&by&hepatic&glucuronosyltransferase&
Wide&spectrum&antibiotic&&usually&bacteriostatic!&
o Good&for&Haemophilus(influenza,(N.(meningitides(and(Bacteroides&
! Here&the&drug&mainly&works&as&bactericidal&agent&
o Not&effective&against&Chlamydia(ssp.&
o Resistance&is&plasmid]mediated&formation&of&acetyltransferase&that&
inactivates&the&drug&
Clinical&use:&
o Not&often&used&systematically&due&to&its&toxicity&
o Backup&drug&for&severe&Salmonella(infections&
o Treatment&of&pneumococcal&and&meningococcal&infections&in&ppl&
that&have&beta]lactam&sensitivity&
o Commonly&used&as&a&topical&antimicrobial&agent&
Toxicity:&
o GI&distubances,&inhibition&of&RBC&maturation&that&leads&to&anemia&
(dose]dep.&and&reversible)&
o Aplastic&anemia&is&a&rare&individualistic&reaction&that&occurs&in&1&
case&of&25.000]40.000&patients&
! Usually&irreversible&and&may&be&fatal&
o Gray&baby&syndrome&
! Occurs&in&infants&and&due&to&anemia,&cyanosis&and&
cardiovascular&collapse&
o Inhibition&of&hepatic&drug&metabolic&enzymes&and&thus&increasing&
the&elimination&half]lives&of&phenytoin,&tolbutamide&and&warfarin&
&
Tetracyclins:&
Bind&to&the&30S&ribosomal&subunit&and&prevent&the&binding&of&amino&acid]
charged&tRNA&to&the&acceptor&site&of&the&mRNA&complex&
Broad&spectrum!bacteriostatic!antibiotics&&
Variable&oral&absorption&that&can&be&impaired&by&foods&and&multivalent&
cations&(calcium,&iron&and&aluminum)&
Wide&tissue&distribution&and&crosses&the&placental&barrier&
Enteroheptatic&cycling&
o Doxycycline!is&excreted&mainly&in&the&feces&
o Others!are&excreted&via&urine&&
Clinical&uses:&

& 48&
Sollas&Notes&2015&

o Primary&uses:&
! Treatment&of&Mycoplasma(pneumonia,(chlamydiae,(
rickettsiae,(vibrios,(some(spirochetes&
! Doxycycline!is&alternative&to&macrolides&in&the&initial&
treatment&of&community]acquired&pneumonia&
Prevention&of&malaria&and&treatment&of&amebiasis&
o Secondary&uses:&
! Alternative&drugs&in&treatment&of&syphilis&
! Prophylaxis&in&case&of&chronic&bronchitis&
! Treatment&of&leptospirosis&and&acne&
o Selective&uses:&
! Treatment&of&ulcers&due&to&H.pylori((tetracycline)&
! Treatment&of&Lyme&dx.&(Doxycycline)&
! Meningococcal&carrier&state&(minocycline)&
! Treatment&of&ADH]secreting&tumors&to&inhibit&the&renal&
actions&of&ADH&(demeclocycline)&
Tigecycline&
o Is&used&in&case&of&tetracycline&resistance&strains&
! Gram]pos.&cocci&resistant&to&methicillin&(MRSA&strains)&and&
vancomycin&(VRE&strains),&beta]lactamase&producing&gram]
neg.&bacteria,&anaerobes,&chlamydia&and&mycobacteria&
Toxicity&of&tetracyclines:&
o GI&disturbances,&teeth&enamel&dysplasia&in&infants&&&young&kids&
(due&to&fetal&exposure&or&administrations&to&young&ones),&
irregularity&in&bone&growth&(fetal&exposure),&hepatotoxicity&
(tetracyclines&in&predisposed&patients&such&as&with&liver&dx&or&
pregnant&&result&in&hepatic&necrosis),&renal&toxicity&(outdated&
tetracyclines&can&cause&Falconis&syndrome&renal&tubular&
acidosis),&photosensitivity,&vestibular&toxicity&that&is&dose]
dependent&
&
&
&
&
&

&
&
&

&
(
(
&

&&
&
&

& 49&
Sollas&Notes&2015&

6.3&The&exocrine&pancreas.&Pharmacology&of&the&liver.&Drugs&that&inhibit&the&
formation&of&gallstones&
&
Pancreatic enzyme replacements:

The exocrine pancreas can get damaged due to various diseases. The most prevalent
disease injuring the parenchyma of the pancreas is the chronic pancreatitis. In most
cases there will be a dysfunction of the exocrine pancreas resulting in maldigestion,
steatorrhea, vitamin malabsorption and weight decrease. This condition can be
relieved by oral administration of pancreatic lipase (pancreatin or pancrelipase)
obtained from pigs. These agents are inactivated at a pH <4.0 and should be taken as
enteric coated capsules unless the pH is raised with antacids or drugs that reduce
acid secretion. They are administered with each meal and snack without no
significant adverse effects

Drugs that inhibit the formation of gallstones:

Several drugs can inhibit formation of cholesterol gallstones, although none are
dramatically effective
These agents include the bile acid derivatives: chenodiol and ursodiol.
o Chenodiol - a bile acid, works by preventing the production of
cholesterol in the liver, and its helps dissolve cholesterol in the biliary
system.
! Used for dissolution of small cholesterol gallstones, prevention
of gallstones in obese patients undergoing rapid weight loss and
in treatment of early stage primary biliary cirrhosis
!
Pharmacology!of!the!liver:!
(
The(liver(serves(as(the(main(detoxifier(of(the(body.(All(nutrients,(waste(products(and(
drugs(are(delivered(as(one(point(or(another(to(the(liver.(Given(this,(there(are(many(
drugs(that(can(influence(the(liver(and(even(be(harmful(to(its(parenchyma.(First(lets(
talk(about(hepatotoxicity.(
(
Hepatotoxicity:&
Chemical]driven&liver&damage&(hepatotoxins)&
o Related&to&overdose&of&a&drug&
o Related&to&drug&use&within&the&therapeutic&range&
! Some&other&underlying&problems&such&as&polymorphism&of&
CYP&enzymes&or&previously&damaged&liver&parenchyma&
o Related&to&natural&chemicals&
! Aflatoxins,&microcystins&
o Related&to&herbal&remedies&
More&than&900&drugs&have&been&implicated&in&causing&liver&injury&and&its&
the&most&common&reason&for&a&drug&to&be&withdrawn&from&the&market&
Chemicals&often&cause&subclinical&injury&to&the&liver&&
o Manifests&in&abnormal&liver&enzyme&tests&but&no&symptoms&
Drug]induced&liver&injury&is&responsible&for&5%&of&all&hospital&admissions&
and&50%&of&all&acute&liver&failures&
&

& 50&
Sollas&Notes&2015&

Drug!metabolism!in!the!liver:!
Phase&1&]&Usually&prepares&a&drug&for&phase&2&(some&drugs&go&to&phase&2&directly)&
Oxidation,&reduction,&hydrolysis,&hydration&are&the&main&reactions&
o These&processes&tend&to&increase&water&solubility&of&the&drug&&
o Can&generate&metabolites&that&are&more&chemically&active&and&
potentially&toxic&
This&process&takes&place&in&the&sER&
o Via&CYP&enzymes&
Phase&2&&most&take&place&in&the&cytosol&&
Conjugation&with&endogenous&compounds&via&transferase&enzymes&
Chemically&active&phase&1&products&are&rendered&relatively&inert&and&
suitable&for&elimination&by&this&step&
&
CYP/enzymes:!
Cytochrome&P450&is&a&superfamily&of&~&50&isoenzymes&(CYP)&that&are&
located&in&the&sER&of&the&liver&hepatocyte&
6&of&them&metabolize&90%&of&all&drugs&and&hence&are&the&most&important&&
Three&important&characteristic&of&the&P450&system&have&role&in&drug]
induced&toxicity:&
o Genetic&diversity&(polymorphism)&
! Each&of&the&P450&is&unique&and&accounts&(to&some&extent)&
for&the&variations&in&drug&metabolism&between&individuals&
! Polymorphism&should&always&be&considered&when&patients&
exhibits&unusual&sensitivity&or&resistance&drug&drug&effects&
ate&normal&doses&&
Poor&metabolizers&(unusually&sensitive&or&slow)&
Extensive&metabolizers&(metabolize&really&fast)&
! Polymorphism&is&responsible&for&variable&drug&responses&
amongst&patients&of&different&ethnic&backgrounds&
o Change&in&enzyme&activity:&
! Many&substances&can&influence&the&CYP&enzymes&
! Drugs&that&modify&CYPs&are&referred&to&as&
Inhibitors&
o Block&metabolic&activity&of&one&or&several&CYP&
o Immediate&effect&
Inducers&
o Increase&the&activity&(synthesis)&of&CYP&
o Progressive&increase&in&enzyme&effects&& &
! Depends&on&the&inducer&drugs&half]life&
o Competitive&inhibition:&
! Some&drugs&may&share&the&same&P450&specificity&and&thus&
competitively&block&their&biotransformation&
! This&may&lead&to&accumulation&of&drugs&metabolized&by&the&
enzyme&
! This&may&also&lead&to&reduced&rate&of&generation&of&toxic&
substrates&&
&
&
&

& 51&
Sollas&Notes&2015&

Mechanism!of!liver!damage:!
Many&chemicals&damage&the&mitochondria&that&will&result&in&increased&
release&of&oxidnats&that&injure&the&hepatocytes&
Activations&of&some&enzymes&in&the&cytP450&system&such&as&CYP2E1&can&
lead&to&oxidative&stress&
Injury&to&hepatocytes&and&bile&duct&cells&(cholangial&cells)&lead&to&
accumulation&of&bile&acids&inside&the&liver&&promoting&further&damage&
Kupffer&cells,&fat&storing&stellate&cells&and&leukocytes&also&have&a&role&in&
the&damaging&mechanism&
Pharmacological&(type&A)&hepatotoxicity&accounts&for&80%&of&the&toxins&
o Predictable&dose]response&curve&(higher&dose=more&damage)&
o Well&characterized&mechanism&of&toxicity&
Idiosyncratic&(type&B)&injury&occurs&without&warning&&
o Non]predictable&hepatotoxicity&in&susceptible&individuals&
o Not&related&to&dose&and&has&a&variable&latency&period&
&
Patterns!of!injury:!
Biochemical&markers&(e.g.&alanine&transferase&(ALT),&alkaline&phosphatase&
(ALP)&and&bilirubin)&are&often&used&to&indicate&liver&damage&
Hepatocellular&(predom.&ALT&elevation)&or&cholestatic&(predom.&ALP&#)&
o Mixed&injury&is&very&common&
&

Type of injury: Hepatocellular Cholestatic Mixed

ALT Twofold rise Normal Twofold rise

ALP Normal Twofold rise Twofold rise

ALT: ALP ratio High, 5 Low, 2 2-5

Acetaminophen Anabolic steroid Amitriptyline,

Allopurinol Chlorpromazine Enalapril
Examples[18] Amiodarone Clopidogrel Carbamazepine
HAART Erythromycin Sulfonamide
NSAID Hormonal contraception Phenytoin

Zonal&necrosis&(centrilobular):
o Most&common&type&of&drug]induced&liver&cell&necrosis
o Very&high&levels&of&ALP&leading&to&acute&liver&failure
o Caused&by:
! Paracetamol,(acetaminophen) Carbon,tetrachloride
Heptatitis:
o Hepatocellular&necrosis&is&associated&with&infiltration&of&
inflammatory&cells
o Three&types&of&hepatitis
! Viral&form&most&common&&similar&to&viral&hepatitis
Phenytoin,,isoniazide,,halothane

& 52&
Sollas&Notes&2015&

! Focal&form&&scattered&foci&of&necrosis&with&lymphocytes
Aspirin,
! Chronic&from&&similar&to&autoimmune&hepatitis
Methyldopa,,diclofenac
Cholestasis:
o Leads&to&itching&and&jaundice,&biliary&cirrhosis
o Three&forms:&
! Bland:&oral,contraceptives,,anabolic,steroids,,androgens
! Inflammatory:&allopurinol,,coPamoxiclav,,carbamazepine
! Ductal:&Chlorpromazine,,flucloxacillin
Steatosis:
o TAG&accumulation&that&leads&to&accumulation&of&fatty&droplets&
within&the&hepatocytes
o Accumulation&of&phospholipics&(similar&to&Tay]Sachs)
o Types:
! Microvesicular:&aspirin,(Reyes,syndrome,in,children),,
ketoprofen,,tetracycline
! Macrovesicular:&acetaminophen,,methotrexate
! Phospholipidsosis:&amiodarone,,total,parenteral,
nutrition
Granuloma:
o Drug&induced&hepatic&granuloma&are&usually&associated&with&
granulomas&in&other&tissues&and&patients&tend&to&have&systemic&
vasculitis&and&hypersensitivity
o Cause:
! Allopurinol,,phenytoin,,isoniazid,,penicillin
Vascular&lesions:
o Due&to&injury&to&the&vascular&endothelium
o Venoocclusive:&Chemodrugs,and,bush,tea
o Peliosis&hepatitis:&Anabolic,steroids
o Hepatic&vein&thrombosis:&Oral,contraceptives
Neoplasms:
o Have&been&described&with&prolonged&exposure&to&some&meds&or&
toxins&
o Hepatocellular&carcinoma,&angiosarcoma&and&liver&adenomas
o Causes:
! Vinyl,chloride,,combined,oral,contraceptive,pill,,anabolic,
steroid,,arsenic,,aflatoxin
Enteroheptatic&system&for&drugs:&
If&the&drug&gets&stuck&in&the&enterohepatic&circulation&for&longer&time&it&
might&start&accumulating&in&the&liver&
After&some&time&this&could&result&in&that&a&normally&harmless&drug&has&
accumulated&into&dangerously&high&levels&with&in&this&system&and&by&that&
turning&into&a&hepatotoxin&
&
&
&
&
&

& 53&
Sollas&Notes&2015&

Liver!protective!drug:!
!
Silymarin,
! Standardized&extract&of&the&milk&thristle&seeds,
! Contains&a&mixture&of&flavonolignans&consisting&of&silibinin&and&others,
! Protects&hepatocytes&against&toxins,
! Clinical&indications:,
o Chronic&hepatitis,&cirrhosis,&chronic&alcoholic&liver&and&mushroom&
poisoning,
Antibiotics,(mainly,neomycin),
! Typically&used&topically&but&can&be&given&orally&to&kill&bacteria&in&the&GI&
tract&lumen&(since&the&drug&is&not&absorbed&orally),
o By&this&it&keeps&ammonia&levels&low&and&prevents&hepatic&
encephalopathy&(especially&before&GI&surgery),
Lactulose,
! Clinically&used&in&treatment&of&constipation&and&hepatic&encephalitis,
o Decompensates&bacteria,&increases&carboxyl&acid&and&decreases&
absorption&from&gut&"&results&in&diahrrea&,
Thiocitc,acid,(alpha,lipoic,acid,,ALA),,
! Clinically&used&in&treatment&of&mushroom&poisoning&(Amanita(phalloides),&
alcoholic&liver&and&hepatitis,
! To&high&levels&can&be&hepatotoxic,
Choline,and,methionine,
! Needed&in&normal&levels&and&protects&against&steatosis&,
! To&high&levels&can&be&hepatotoxic,
,
,
&
&
&
&
&
&
&
&
&

&

&
&
&
&
&
&

& 54&
Sollas&Notes&2015&

Topic&7&
7.1&General&anesthesia&&
&
General(anesthesia(is(a(state(characterized(by(unconsciousness,(analgesia,(amnesia,(
skeletal(muscle(relaxation(and(loss(of(reflexes.(Drugs(that(are(used(here(are(CNS(
depressants(with(actions(that(can(be(induced(and(terminated(more(rapidly(than(
those(of(conventional(sedativeLhypnotics.(
(
Drugs:!
Inhaled!
o Gas&"&nitrous,oxide!
o Volatile&liquids&"&halothane,,sevofluran,,nefluran,,isofluran!
Intravenous!
o Barbiturates&"&thiopental!
o Dissociative&"&ketamine!
o Miscellaneous&"&etomidate,,propofol!
o Opioids&"&fentanyl,,sufentanyl,,morphine,,meperidine,!
o Benzodiazepines&"&midazolam!
Stages!of!anesthesia:!
Stage!1:!Analgesia!
o Patient&has&decreased&awareness&of&pain&(sometimes&amnesia)!
o Consciousness&may&be&impaired&but&is&not&lost!
Stage!2:!Disinhibition!
o Patient&appears&delirious&and&excited,&amnesia&occurs!
o Reflexes&are&enhanced&and&respiration&typically&irregular!
o Retching&and&incontinence&may&occur!
Stage!3:!Surgical!anesthesia!
o Patient&is&unconscious&and&has&no&pain&reflexes!
o Respiration&is&very&regular&and&BP&is&maintained!
o Look&out&for&asphyxia&due&to&loss&of&reflexes!
Stage!4:!Medullary!depression!
o Patient&develops&severe&respiratory&and&cardiovascular&depression!
o Requirement&for&mechanical&and&pharmacologic&support!
Main!periods/phases!of!anesthesia:!
Premedication!
Anesthesia&induction!
Anesthesia&maintenance!
Recovery!
Postoperative!
Mechanism!of!action:!
Blockage&of&voltage&gated&Na+&channels!
o General&and&local&anesthetics!
o No&IV&application&of&lidocaine,,novocain!
T]&&&L]type&Ca2+&cannels&blocking&!
NMDA&receptor&blocking&(glutamate&gated&cation&channels)!
GABAA&receptor&agonist!
o Inhaled&&&intravenous&narcotics&(benzodiazepines,,barbituates)!

& 55&
Sollas&Notes&2015&

mAChr&blockers!
o Halothane,,isoflurane,,sevoflurane!
Inhaled!anesthetics:!
Administered&as&gases!
o Their&partial&pressure,&or&tension,&in&the&inhaled&air&or&in&the&
blood&or&other&tissue&is&a&measurement&of&their&cc.!
o Standard&pressure&of&the&total&inhaled&mixture&is&atmospheric&
pressure&(760mmHg&at&sea&level)!
! Can&be&expressed&as&a&percentage!
! 50%&nitrous&oxide&in&the&inhaled&air&would&have&partial&
pressure&of&380mmHg!
Speed&of&induction&of&anesthetic&effects&depends&on&several&factors!
o Solubility!
! The&more&rapidly&a&drug&equilibrates&with&the&blood&the&
more&quickly&the&drug&passes&into&the&brain&to&cause&effects!
! Drugs&with&low&blood:gas&partition&coeff.&(nitrous,oxide)!
More&rapid!
! Drugs&with&high&blood:gas&partition&coeff.&(halothane)!
Slower!
o Inspired&gas&partial&pressure!
! High&partial&pressure&of&gas&in&the&lungs&results&in&more&
rapid&achievement&of&anesthesic&levels&in&the&blood!
! Initial&administration&of&gas&cc.&is&higher&than&those&
required&for&maintenance&dose!
o Ventilation&rate!
! Greater&ventilation&=&more&rapid&rise&of&drug&in&blood!
! Good&in&the&initiation&of&anesthesia!
o Pulmonary&blood&flow!
! At&high&flow&=&gas&partial&pressure&rises&at&a&slower&!
Speed&of&onset&of&anesthesia&is&reduced!
! At&low&flow&=&onset&is&faster!
In&circulatory&shock&this&contributes&to&the&rapid&rate&
of&onset&of&anesthesia!
o Arteriovenous&concentration&gradient!
! Uptake&of&soluble&anesthetics&into&highly&perfused&tissues&
may&decrease&gas&tension&in&mixed&venous&blood!
Can&influence&rate&of&onset!
Equilibrium&is&dependent&on&the&difference&in&
anesthetic&tension&btw&arterial&and&venous&blood!
Elimination&of&anesthesia&occurs&when&the&drug&is&redistributed&from&the&
brain&back&to&the&blood&and&finally&eliminated&back&out&from&the&lungs!
o Elimination&of&drugs&with&low&blood:gas&partition&coeff.&=&fast!
o Elimination&of&drugs&with&high&blood:gas&partition&coeff.&=&slow!
Halothane,&,methylflurane&are&metabolized&by&the&liver&enzymes!
o Plays&a&role&in&the&potential&toxicity&of&these&drugs!
Minimum!alveolar!anesthetic!concentration!(MAC):!
Best&measurement&of&potency!
Defined&as:& !

& 56&
Sollas&Notes&2015&

o Alveolar&concentration&required&to&eliminate&the&response&to&a&
standardized&painful&stimulus&in&50%&of&patients!
Each&anesthesia&has&a&defined&MAC!
o Value&varies&amongst&patients&due&to&age,&cardiovascular&status&
and&use&of&adjuvant&drugs!
! Lower&in&infants&and&elderly!
! Higher&in&adolescents&and&young&adults!
Estimations&of&MAC&value&suggest&a&relatively&steep&dose]response&
relationship&for&inhaled&anesthetics!
MAC&values&are&additive&when&multiple&agents&are&used&simultaneously!
!
Effects!of!inhaled!anesthetics:!
CNS&effects:!
o Decreased&brain&metabolic&rate!
o Reduced&vascular&resistance&resulting&in&#&cerebral&blood&flow!
! Can&lead&to&increased&ICP!
o High&cc.&of&enflurane&may&cause&spike]&and&wave&activity&and&
muscle&twitching!
! Effects&that&are&unique&to&this&drug!
o Nitrous,oxide&!
! Low&anesthetic&potency&(high&MAC)!
! Great&analgesic&and&amnestic&actions!
Cardiovascular&effects:!
o Moderate&decreased&in&blood&pressure&!
o Enflurane,&,halothane&are&myocardial&depressants&=&$&CO!
o Isoflurane,,desflurane,&,sevoflurane&cause&peripheral&vasodil.!
o Blood&flow&to&liver&and&kidneys&is&decreased!
o Halothane,(and&to&lesser&extent&isoflurane)&may&sensitize&the&
myocardium&to&the&arrhythmogenic&effects&of&catecholamines!
Respiratory&effects:!
o Rate&of&respiration&may&be&increased!
! But&all&inhaled&anesthetics&cause&a&$&in&tidal&volume&and&
minute&ventilation&"&leading&to&#&arterial&CO2&tension!
o Decreased&ventilatory&response&to&hypoxia!
o Nitrous,oxide&has&smallest&effects&on&respiration!
o Most&of&the&drugs&are&bronchodilators!
! Except&for&,desflurane&that&can&cause&bronchospasms!
Toxicity:!
o Postoperative&hepatitis&(rare)&after&halothane!
! Mainly&in&patients&in&hypovolemic&shock&or&other&stress!
! Unclear&mechanism&but&may&involved&reactive&metabolites&
that&cause&direct&toxicity&or&initiate&immune&responses!
o Fluoride&released&by&the&metabolism&of&methylflurane,(and&
possibly&enflurane,&,sevoflurane)&may&cause&renal&insufficiency&!
o Prolonged&exposure&to&nitrous,oxide&decreases&methionine&
synthase&activity&and&may&lead&to&megaloblastic&anemia!
o Malignant&hyperthermia&may&develop&in&susceptible&patients!
! When&anesthetics&are&used&with&neuromuscular&blockers!

& 57&
Sollas&Notes&2015&

! Thought&to&be&due&to&mutations&on&ryanodine&receptor&or&
genes&coding&for&L]type&Ca2+&channels!
! Uncontrolled&release&of&calcium&from&the&sarcoplasmic&
reticulum&leads&to&muscle&spasms,&hyperthermia&and&
autonomic&lability!
! This&condition&is&treated&with&dantrolene,and&support!
!
Intravenous!anesthetics:!
Barbiturates!
o Thiopental,&,methohexital&have&high&lipid&solubility&(enter&BBB)!
! Rapid&and&result&in&surgical&anesthesia&in&<1min!
! Used&for&induction&of&anesthesia&and&short&procedures!
! Respiratory&and&circulatory&depressants!
! Can&increase&ICP!
Benzodiazepines!
o Midazolam&is&widely&used&with&inhaled&anesthetics&and&IV&opioids!
! Slower&onset&than&the&barbiturates&but&longer&activity!
! Severe&postop&respiratory&suppression&(rare)!
Ketamine!
o Produces&state&of&dissociative&anesthesia!
! Patient&is&conscious&but&has&marked&catatonia&(neurogenic&
motor&immobilization&and&behavioral&changes),&analgesia&
and&amnesia!
! Chemical&congener&of&psychotomimetic&agent&PCP!
! CV&stimulant&and&may&lead&to&#&ICP!
! Emergence&reactions,&disorientation,&excitation&and&
hallucinations&can&occur&during&recovery&!
Reduced&by&benzos!
Opioids!
o Morphine,and,fentanyl,are&used&with&other&CNS&depressants&such&
as&nitrous&oxide&and&benzos&in&anesthesia&regimens&!
! Especially&valuable&in&high]risk&patients&that&might&not&
survive&full&general&anesthesia&!
o May&impair&ventilation&(can&be&controlled&with&naloxone)!
o Neuroleptanesthesia!
! State&of&analgesia&and&amnesia&that&occurs&when&fentanyl&is&
used&with&droperidol,&,nitrous,oxide,
o Alfentanil,and,remifentanil&are&newer&drugs&that&have&been&used&
for&the&induction&of&anesthesia,
Propofol,
o Produces&anesthesia&rapidly&and&recovery&is&rapid,
o Antiemetic&effects&&&recovery&is&not&delayed&after&prolonged&treat.,
o Commonly&used&as&a&component&of&balanced&anesthesia&and&as&an&
anesthetic&in&outpatient&surgery,
o Causes&marked&hypotension&during&the&induction&process&via&the&
decreased&resistance,
Other&drugs&include&etomidate,and,dexmedetomidine,

& 58&
Sollas&Notes&2015&

7.2&Macrolides,&clindamycin,&streptogramin&
&
The(macrolide(antibiotics(are(large(cyclic(lactone(ring(structures(with(attached(
sugars.(The(drugs(have(generally(good(bioavailability((azithromycin(absorption(is(
impeded(by(food).(
(
Macrolides:!
Erythromycin,,roxithromycin,,clarithromycin,,azithromycin,,
telithromycin!
!
Distribution:!
Wide&distribution&to&tissues&but&not&CNS!
Accumulation&in&the&liver!
Azithromycin&concentrates&in&macrophages&"&long&half&life!
Elimination:!
Metabolism&!
o Erythromycin&and&telithromycin&are&metabolized&by&CYP!
! Drug&interactions!
o Clarithromycin&has&an&active&metabolite!
Excretion!
o Erythromycin&mainly&eliminated&via&the&bile!
o Others&are&via&bile&and&urine!
Half]life!
o Short&"&erythromycin&=&administration&at&6hrs&interval!
o Long&"&other&drugs&=&twice&a&day&administration!
o Azithromycin&has&a&half]life&of&2]4&days!
! Once&a&day&or&single&high&dose!
o Telithromycin&"&once&a&day!
Mechanism:!
Bind&to&the&50S&subunit&and&inhibit&translocation&and&transpeptidation!
Bacteriostatic(and&bactericidal!at&high&doses!
!
Effects:!
Erythromycin&has&similar&spectrum&as&penicillin&G!
Clarithromycin!
o Similar&to&erythromycin&but&also&works&on&H.influenzae!
o Good&for&IC&pathogens&such&as&!
! Clamydia,(Legionella(&(Moxarella!
o Helicobacter(pylori!
Azithromycin!
o Less&active&for&streptococci&and&staphylococci!
o Good&for&respiratory&pathogens!
o Preferred&for&chlamydia!
Adverse!effects:!
GI]distress,&cholestatic&jaundice&(mainly&erythromycin)!
Ototoxicity&(erythromycin)!
!
!

& 59&
Sollas&Notes&2015&

Clindamycin!
Derivative&of&lincomycin&!
Absorbed&orally&and&IV&(3]4&times&a&day)!
Distributed&to&body&tissues&(not&CNS)&&good&for&abscesses&!
Metabolized&in&the&liver&and&excreted&by&urine&and&bile!
Works&on&the&50S&ribosomal&subunit!
o Mechanism&of&resistance&includes&methylation&of&the&binding&site&
on&the&50S&subunit&and&enzymatic&inactivation!
Cross&resistance&btw&clindamycin&and&macrolides&is&common!
Clinical&uses&(spectrum):!
o Treatment&of&severe&infections&caused&by&anaerobes&(Bacteroides)!
! Skin&and&soft&tissue&infections!
! Dental&and&valvular&heart&diseases&(endocarditis&prophyl.)!
o Used&as&a&backup&drug&against&gram&pos.&cocci&(MRSA)!
! Does&not&work&on&enterococci&and&gram&neg.!
Adverse&effects:!
o Diarrhea&and&increased&risk&of&pseudomembranous&colitis,&Rashes!
Streptogramins:!
QuinupristinPdalfopristin,&combo&(30:70)&is&bactericidal!
Administrated&IV&(3&times&daily)&and&half]life&is&short!
Metabolized&in&the&liver&via&phase&II&conjugation!
o Inhibitors&of&CYP3A4&&"&increases&plasma&levels&of&many&drugs!
! Cisaprode,,cyclosporine,,diazepam,,NNRTI,and,warfarin!
Excretion&is&predominantly&via&the&bile!
Binds&to&the&50S&subunit&and&works&similar&to&erythromycin!
Antibacterial&spectrum:!
o Gram&pos.&cocci!
! MRSA,&VRSA,&PRSP,&MSSA,&E.faecium((not(E.faecalis)!
o Generally&no&gram&neg.&activity!
Adverse&effects:!
o Pain&and&phlebitis&at&infusion&site!
o Arthralgia&and&myalgia!
Linezolid:!
Synthetic&oxazolidinone&(first&drug&of&this&class)!
Administered&orally&with&100%&bioavailability&(2x/day)&"&good&distrib.!
Metabolized&via&non]enzymatic&oxidation!
o Works&as&a&MAOi&that&causes&the&drug&increases&risk&of&serotonin&
syndrome&when&used&in&patient&taking&SSRI!
Excretion&is&predominantly&via&bile!
Binds&to&50S&subunit&and&there&is&no&cross&resistance!
o Prevents&formation&of&ribosome&complex&that&initiates&protein&
synthesis&"&mutation&of&binding&site&results&in&resistance!
Antibacterial&spectrum:!
o Serious&Gram&pos.&infectiosn&(bacteriostatic)&]&MRSA&!
o M.tuberculosis!
Adverse&effects:&reversible&thrombocytopenia,&myelosuppression&and&
rarely&neuropathy&and&lactic&acidosis!
!

& 60&
Sollas&Notes&2015&

7.3&Pharmacology&of&vasoactive&agents&
& &
Vasoactive(peptides(are(autocoids(with(significant(actions(on(vascular(smooth(
muscle(as(well(as(other(tissues.(They(include(vasoconstrictors,(vasodilators(and(
peptides(with(mixed(effects.(Vasoactive(peptide(probably(all(act(on(cell(surface(
receptors.(Most(act(via(GLprotein(coupled(receptors(and(cause(the(production(of(
wellLknown(second(messengers,(a(few(may(open(ion(channels.(Antagonists(of(these(
peptides(or(the(enzymes(producing(them(have(very(useful(clinical(properties.(
(
Drugs:!
Vasoactive&peptides!
o Vasoconstrictors!
! Angiotensin,II,,endothelins,,neuropeptide,Y!
o Mixed&peptides&"&substance,P!
o Vasodilators!
! Bradykinin,,brain,natriuretic,peptide,(BNP),,atrial,
natriuretic,peptide,(ANP),,calcitonin,genePrelated,
peptide,(CGRP),and,vasoactive,intestinal,peptide,(VIP)!
Antagonists&of&peptides!
o Aliskiren,(renin),,captopril&(ACE),&losartan&(angiotensin),&
conivaptan,(vasopressin),&bosentan,(endothelin),&omapatrilat,
(vasopeptidase),&aprepitant,(substance&P)!
!
Angiotensin!and!its!antagonists:!
Angiotensin&II&is&formed&from&angiotensin&I&by&the&action&of&angiotensin&
converting&enzyme&(ACE)!
o ACE&is&an&octapeptide&that&is&sometimes&called&kininase&II!
! Can&be&blocked&by&ACE&inhibitors!
Captopril,,enalapril,+,more!
Angiotensin&II&is&rapidly&degraded&by&peptidases&(angiotensinases)!
Effects:!
o Angiotensin&II&is&a&potent&arteriolar&vasoconstrictor&and&stimulant&
of&aldosterone&release!
o Directly&increases&peripheral&vascular&resistance!
o Indirectly&causes&renal&sodium&&&water&retention&(aldosterone)!
o Facilitates&release&of&NE&from&nerve&terminals&via&presynaptic&
heteroreceptor&action!
o Mitogenic&and&plays&a&role&in&remodeling&of&the&heart!
All&effects&are&mediated&via&AT1&receptor&(Gq&coupled)!
o AT2&receptor&appears&to&mediate&vasodilation&via&NO&and&is&
probably&most&important&during&fetal&development!
No&longer&used&for&clinical&indications!
Major&importance&is&its&endogenous&effects&in&some&cases&of&HTN&(high]
renin&hypertension)&and&in&heart&failure!
Antagonists&of&ANGII&have&demonstrated&clinical&benefits&in&HTN&and&
heart&failure&(block&the&AT1&receptor)!
o Losartan,,valsartan,+,more!
Aliskiren&is&an&orally&active&renin&inhibitor&that&recudes&ANGI&and&ANGII!

& 61&
Sollas&Notes&2015&

Vasopeptidase!inhibitors:!
Vasopeptidase&enzymes&include&neutral&endopeptidase&24.11&and&ACE!
Omapatrilat!
o Blocks&these&vasopeptidase&enzymes!
o Reduce&cc.&of&ANGII&and&increase&cc.&of&BNP&and&ANP!
o Cause&angioedema&in&significant&number&of&patients&!
! Not&approved&for&clinical&use!
Bradykinin:!
One&of&several&vasodilator&kinins&produced&from&kininogen&by&a&family&of&
enzymes,&the&kallikreins!
Rapidly&degraded&by&various&peptidases&&including&ACE!
Acts&through&B1&and&B2&receptors!
o Causes&the&production&of&IP3&and&DAG,&NO&and&prostaglandins!
One&of&the&most&potent&vasodilator&known!
Involved&in&inflammation&and&causes&edema&and&pain&when&released&or&
injected&into&tissue!
Found&in&saliva&and&may&contribute&to&its&secretion!
No&therapeutic&application!
o But&probably&plays&a&role&in&the&anti]HTN&action&of&ACEi!
Ecallantide,(parenteral&kallikrein&inhibitor)&and&icatibant,(oral&
bradykinin&B2]receptor&antagonist)&are&used&in&angioedema!
!
Natriuretic!peptides:!
ANP,and,BNP&are&synthesized&and&stored&in&the&atria!
o BNP&has&also&been&found&in&brain!
Released&from&the&atria&in&response&to&distension&of&the&chambers!
BNP&seems&to&be&the&most&important!
o Blood&levels&of&BNP&have&been&shown&to&correlate&with&the&severity&
of&heart&failure&and&can&therefore&be&used&as&a&diagnostic&marker!
These&peptides&activate&guanylyl&cyclase&in&many&tissues&via&membrane]
spanning&enzyme&receptor!
Act&as&vasodilators&and&natriuretic&agents!
o Increase&GFR,&decrease&proximal&tubular&reabsorption&and&inhibit&
the&release&of&renin!
o Inhibit&the&action&of&ANGII&and&aldosterone!
o Play&an&important&compensatory&role&in&congestive&heart&failure&by&
limiting&sodium&retention!
Clinical&use:!
o BNP&has&shown&to&have&some&benefit&in&treatment&of&acute&severe&
heart&failure&and&is&currently&used&under&the&name&nesiritide!
! IV&drug&that&has&significant&toxicity!
Endothelins:!
Peptide&vasoconstrictors&formed&in&and&released&by&endothelial&cells&!
Appear&to&function&as&autocrine&and&paracrine&hormones&in&vessels!
Three&identified&endothelins:&ET]1,&ET]2,&ET]3!
Two&receptors:&ETA&&&ETB&both&are&coupled&to&G]proteins!
o ETA&receptor&seems&for&vasoconstriction!
Much&more&potent&than&NE&and&have&relatively&long]lasting&effects!

& 62&
Sollas&Notes&2015&

Other&effects&of&endothelins:!
o Stimulate&the&heart,&increase&natriuretic&peptide&release,&activate&
smooth&muscle&proliferation!
o May&be&involved&in&some&forms&of&HTN&and&other&CV&disorders!
ETA&receptor&antagonist&are&available&for&the&treatment&of&pulmonary&HTN!
o Bosentan,&,ambrisentan!
!
VIP,!substance!P,!CGRP!&!NPY:!
VIP,(vasoactive&intestinal&peptide)!
o Extremely&potent&vasodilator&&&very&important&neurotransmitter!
o Found&in&CNS&and&peripheral&nervous&system&+&GI&tract!
o No&clinical&application&has&been&found!
Neurokinins!(substance!P,!neurokinin!A!and!neurokinin!B)!
o Act&at&NK1&and&NK2&receptors&in&the&CNS&and&periphery!
! Neurokinins&seem&to&be&involved&certain&CNS&conditions&!
Depression,&nausea&&&vomiting!
! Aprepitant&is&a&NK1receptor&antagonist&that&is&used&to&treat&
chemotherapy]induced&nausea&and&vomiting!
o Substance&P&has&mixed&vascular&effects!
! Potent&arteriolar&vasodilator!
! Potent&stimulator&of&veins&+&intestinal&and&airway&sm.muscl!
! May&also&function&as&a&local&hormone&in&the&GI&tract!
! Highest&cc.&is&found&in&the&part&of&the&nervous&system&that&
perceives&pain!
Capsaicin,(the&hot&component&of&chili&peppers)&
releases&substance&P&from&its&stores&in&the&nerve&
endings&and&depletes&the&peptide!
o Used&topically&to&treat&arthritic&joints&and&for&
post]herpetic&neuralgia!
CGRP!(calcitonin&gene]related&peptide)!
o Found&in&high&cc.&in&the&thyroid&and&some&smooth&muscle&tissues!
o Probably&works&as&a&cotransmitter&in&autonomic&nerve&endings&on&
smooth&muscles!
o Most&potent&hypotensive&agent&discovered&to&date!
! Causes&reflex&tachycardia!
o Some&evidence&suggest&that&CGRP&is&involved&in&migraine!
! So&if&there&would&be&oral&antagonist&of&CGRP&it&could&be&
great&in&the&treatment&of&migraine!
o Currently&there&is&no&clinical&application&for&the&peptide!
NPY!(neuropeptide&Y)!
o Potent&vasoconstrictor&that&also&stimulates&the&heart!
o Found&in&CNS&and&periphery!
o Commonly&located&as&a&cotransmitter&in&adrenergic&nerve&endings!
o Effects:!
! CNS&administration&stimulates&feeding,&hypotension&and&
hypothermia!
! Peripheral&administration&causes&positive&chronotropic&&&
inotropic&effects&on&the&heart&and&hypertension!
o Several&receptors&have&been&identified&but&no&clinical&application!

& 63&
Sollas&Notes&2015&

Topic&8&
8.1&Peripherally&acting&skeletal&muscle&relaxants&
&
Skeletal!muscles!relaxants!are!divided!into!2!different!groups:&&
! Neuromuscular&(NM)&blocking&drugs&(peripherally&acting)&
o Act&at&the&skeletal&myoneural&junction&
o Used&to&produce&muscle&paralysis&in&surgery/assisted&ventilation&
! Spasmolytic&drugs&(centrally&acting)&
o Most&act&in&the&CNS&
o Used&to&reduce&abnormally&elevated&tone&caused&by&neurologic&or&
muscle&end&plate&diseases&
In(this(topic(we(are(going(to(talk(about(the(1st(group,(the(neuromuscular(blocking(
drugs.(The(spasmolytic(will(be(discussed(in(topic(28.1(
!
&
Classification!and!prototypes!
Nicotinic&cholinergic&transmission&evokes&skeletal&muscle&contraction&
Blockade&is&clinically&useful&in&producing&muscle&relaxation:&
o Needed&for&surgical&procedure&and&ventilation&control&
NM&blockers&are&quaternary&amines&structurally&related&to&ACh&&
Succinylcholine&is&NM&blocker&
o &Agonist&at&the&nicotinic&end&plate&receptor&(depolarizes)&
&
Nondepolarizing!NM!drugs!(Tubocurarine!!prototype):!
Pharmacokinetics:&
! All&agents&are&given&parenterally&&
! They&are&highly&polar&drugs&and&do&not&cross&BBB&&
! Drugs&that&are&metabolized&(muvacurium)&or&eliminated&in&the&bile&
(vecuronium)&have&shorter&duration&of&action&(10]20min)&than&those&
eliminated&by&the&kidney&(metocurine,,pepecuronium,and,
tubocurarine),&duration&less&than&35&min&
! Atracurium&clearance&involves&rapid&spontaneous&breakdown&to&form&
laudanosine&&
! Increased&level&of&laudanosine,may&cause&seizures&
o Cistracurium,&forms&less&laudanosine&and&is&the&most&common&
muscle&relaxant&in&clinical&use&
Mechanism&of&action&&
! Nondepolarizing&drugs&prevent&the&action&of&ACh&at&the&skeletal&muscle&
end&plate&]&acting&as&surmountable&blockers&
! Compete&with&ACh&at&the&receptor&and&their&effect&can&is&reversed&by&
cholinesterase&inhibitors&
! Some&drugs&act&via&plugging&the&ion&channels&of&the&ACh&receptor&
o Post]tetanic&potentiation&is&preserved&in&the&presence&of&these&
agents,&but&tension&during&the&tetanus&fades&rapidly&
! Larger&muscles&(eg.&diaphragm)&are&more&resistant&to&NM&blockers&
o But&they&recover&more&rapidly&than&smaller&muscles&(e.g&hand)&
! Rocuronium&is&the&drug&with&the&most&rapid&onset&time&(60]120&s)&
&

& 64&
Sollas&Notes&2015&

Depolarizing!NM!blocking!drugs:!
Pharmacokinetics&
! Succinylcholine&(SC)&is&metabolized&by&cholinesterase&in&the&liver&and&
plasma&&short&duration&of&action&if&given&only&once&&
! Blockade&may&be&prolonged&in&patients&with&genetics&variants&of&plasma&
cholinesterase&&making&them&metabolize&SC&more&slowly&
Mechanism&of&action&
! SC&acts&like&a&nicotinic&agonist&and&depolarizes&the&NM&end&plate&&
! Twitching&and&fasciculation&often&accompany&the&initial&depolarization&
o Continuous&depol.&results&in&muscle&relaxation&and&paralysis&
! When&given&by&continuous&infusion,&the&effect&of&SC&changes&from&
continuous&depolarization&(phase1)&to&gradual&repolarization&with&
resistance&to&depolarization&(phase2)&
!
Reversal!of!Blockade!
Increasing&the&concentration&of&normal&transmitter&at&the&receptors&
readily&reverses&the&action&of&nondepolarizing&blockers&&
o Cholinesterase&inhibitors&such&as&neostigmine&
! The&paralysis&produced&by&the&depolarizing&blocker&SC&is&
increased&by&cholinesterase&inhibitors&during&phase&1&
! During&phase&2,&the&block&produced&by&SC&is&usually&
reversible&by&cholinesterase&inhibitors&
Toxicity!
Respiratory&paralysis&
Action&of&full&doses&of&NM&blockers&]&directly&respiratory&paralysis&&
o Mechanical&ventilation&needed&to&prevent&asphyxiation&
Autonomic&effects&and&histamine&release&&
Auto.ggl&are&stimulated&by&SC&&&weakly&blocked&by&tubocurarine&
SC&activates&cardiac&muscarinic&receptors,&where&as&pancuronium&is&
moderate&blocking&agent&and&causes&tachycarida.&&
Tubocurarine,and,mivacurium&usually&cause&histamine&release&&
Specific&effect&of&SC&
Post]op&muscle&pain&is&common,&and&muscle&damage&may&occur&
Hyperkalemia,&especially&in&patients&with&burns&or&spinal&cord&injury,&
peripheral&nerve&dysfunction,&or&muscular&dystrophy&
Increases&in&intragastric&pressure&caused&by&fasciculation&may&promote&
regurgitation&with&possible&aspiration&of&gastric&contents&
Drug&interactions&&
Inhaled&anesthetics,&especially&isoflurane,&strongly&potentiate&and&
prolong&NM&blockade.&A&rare&interaction&of&SC&with&inhaled&anesthetics&
can&result&in&malignant!hyperthermia.&&
o Early&sign&of&this&is&trismus&
Aminoglycoside&&&antiarrhythmic&drugs&may&prolong&the&effect&&
Effects&of&aging&and&diseases&
Older&patients&(>75&years)&and&those&with&Myasthenia&gravis&are&more&
sensitive&to&the&actions&of&the&nondeplarizing&blockers,&and&doses&should&
be&reduced&in&these&patients.&&
Patients&with&severe&burns&or&who&suffer&from&upper&motor&neuron&
disease&are&less&responsive&to&these&agents&
&

& 65&
Sollas&Notes&2015&

8.2&Quinolones&and&fluoroquinolones.&Sulfonamides&&&trimethoprim&
&
Fluoroquinolones:!
Bactericidal!drugs&that&block&bacterial&DNA&synthesis&
o Inhibit&DNA]gyrase&(topoisomerase)&
! Topoisomerase&II&in&case&of&gram]neg.&
! Topoisomerase&IV&in&case&of&gram]pos.&&
Have&postantibiotic&effects&&
Good&oral&bioavailability&and&penetrate&most&tissues&
o Norfloxacin&is&the&worst&for&systemic&infections&since&the&plasma&
cc.&does&not&reach&enough&levels&to&treat&systemic&infections&
Elimination&is&mainly&via&kidneys&via&active&tubular&secretion&
o Can&be&blocked&with&probenecid&
o Dosage&reductions&are&usually&needed&in&renal&dysfunction&
Classified&by&generations:&
o 1st&generation&"&Norfloxacin,&
! Derived&from&nalidixic&acid&
! Active&against&common&pathogens&of&the&urinary&tract&
! Relatively&narrow&spectrum&
o 2 &generation&"&Ciprofloxacin,&,ofloxacin&
nd

! Good&for&gram]neg.&+&gonococcus,&many&gram]pos.,&
mycobacteria&and&agents&of&atypical&pneumonia&
(M.pneumoniae,(Chlamydophila(pnemoniae)&
o 3rd&generation&"&Levoflozacin,,gemifloxacin,&,moxifloxacin&
! Slightly&less&active&than&2nd&generation&against&gram]neg.&&
! Better&for&gram]pos.&cocci&(such&as&S.(pneumonia,&
enterococci&and&MRSA)&
! Called&respiratory&fluoroquinolones&
! Gemifloxacin&and&moxifloxacin&are&good&for&anaerobes&
Resistance&has&emerged&rapidly&in&the&case&of&2nd&generation&drugs&
specially&in&the&case&of&Camphylobacter(jejuni(and&gonococci&+&MRSA&
Clinical&uses:&
o Effective&against&the&infectious&of&the&urogenital&and&GI&tract&that&
are&caused&by&gram]neg.&
o Have&been&used&widely&for&respiratory&tract,&skin&and&soft&tissues&
o Treatment&of&chlamydia&(ofloxacin)&with&a&7&day&doses&
o Meningococcal&carrier&state,&treatment&of&TB&and&prophylaxis&in&
patients&that&have&neutropenia&
Toxicity:&
o GI&distress,&skin&rashes,&headache,&dizziness,&insomnia,&abnormal&
liver&function&tests,&phototoxicity,&tendinitis&and&tendon&rupture&
o Opportunistic&infections&with&C.albicans&and&streptococci&
o Contraindicated&in&kids&and&pregnancy&since&it&damages&growing&
cartilage&and&cause&arthropathy&
o Increase&of&plasma&levels&of&theophylline&&
o Prologation&of&QT]interval&(gemifloxacin,&levofloxacin,&
moxifloxacin)&
&

& 66&
Sollas&Notes&2015&

Sulfonamides:!
Weakly&acidic&compounds&that&have&a&common&chemical&nucleus&
resembling&PABA&(p]aminobenzoic&acid)&
Modest&tissue&penetration,&hepatic&metabolism&and&excretion&of&both&
intact&drug&and&metabolites&via&urine&
o Solubility&may&be&decreased&in&acidic&urine,&resulting&in&
precipitation&of&the&drugs&and&their&metabolites&
! Combo&of&3&separate&sulfonamides&(triple!sulfa)&has&been&
used&to&reduce&this&probably&side&effect&
Short]acting&(e.g.&sulfisoxazole),&intermediate]acting&(e.g.,
sulfamethoxazole)&and&long]acting&(e.g.&sulfadoxine)&
Bind&to&plasma&proteins&at&sites&shared&by&bilirubin&and&other&drugs&
Bacteriostatic!inhibitors&of&folic&acid&synthesis&
o Competitive&inhibitors&of&dihydropteroate&synthase&
! Act&as&substrate&for&the&enzyme&
Resulting&in&synthesis&of&non]functional&folic&acid&
o Result&in&inhibition&of&folic&acid&synthesis&by&the&normal&cells&
! That&causes&the&patient&to&replace&the&loss&by&diet&folic&acid&
Clinical&use:&
o Active&against&gram]pos.&and&gram]neg.,&Chlamydia(and&Nocardia&
o Simple&UT&infections&&oral&(e.g.&triple!sulfa&&&sulfisoxazole)&
o Ocular&infections&&topical&(e.g.&sulfacetamide)&
o Burn&infections&&topical&(e.g.&mafenide,!silver!silfadiazine)&
o Ulcerative&colitis,&RA&&oral&(e.g.&sulfasalazine)&
o Toxoplasmosis&&sulfadiazine!+!pyrmethanmine!+!folinic!acid&
Toxicity:&
o Hypersensitivity&
! Allergic&reactions,&skin&rashes&and&fever&
! Exfoliattive&dermatitis,&polyarthritis&nodosa,&Steven]
Johnsons&syndrome&&all&quite&rare&
o GI,&mild&hepatic&dysfunction&
o Granulocytopenia,&thrombocytopenia&&&aplastic&anemia&(all&rare),&
acute&hemolysis&in&persons&with&G6P&dehydrogenase&deficiency&
o Nephrotoxicity,&crystaluria&and&hematuria&
o Drug&interactions&since&sulfonamides&compete&with&warfarin&and&
methotrexate&for&protein&binding&&
! Increases&the&plasma&cc.&of&these&drugs&
! Displacement&of&bilirubin&from&its&binding&site&
Causing&kernicterus&in&neonate&
Trimethoprim:!
Drug&that&is&similar&to&folic&acid&
Weak&base&that&is&trapped&in&acidic&environments&
o Reaches&high&cc.&in&vaginal&and&prostatic&fluids&
Mainly&excreted&unchanged&by&the&urine&
Intermediate]acting&
Selective&inhibitor&of&bacterial&dihydrofolate&reductase&
o Preventing&the&formation&of&active&tetrahydro&folate&&
! 4]5&more&sensitive&than&normal&human&cells&

& 67&
Sollas&Notes&2015&

Toxicity:&
o Megaloblastic&anemia,&leukopenia&and&granulocytopenia&
! Fixed&with&supplementation&of&folic&acid&
&
Trimethoprim/sulfamethoxazole!(TMP/SMZ):!
When&used&together&antimicrobial&synergy&results&from&the&sequential!
blockade!of&folic&acid&synthesis&
Bactericidal!combo&for&susceptible&organisms&
Effective&orally&in&treatment&of&UTI,&respiratory,&ear&and&sinus&infections&
caused&by&H.influenzae(and(Moraxella(c.&
DOC&in&treatment&of&pneumocystic&pneumonia&
o IV&in&severe&cases&and&in&gram]neg.&sepsis&
DOC&in&nocardosis,&possible&backup&drug&for&cholera,&typhoid&fever&and&
shigellosis,&MRSA&and&Listeria(monocytogenes&
Toxicity&can&be&anything&that&is&toxic&by&sulfas&or&trimethoprims&
o Specially&bad&in&immunocompromised&and&AIDS&patients&
&
&
8.3&Anti?obesity&drugs&
&
Anti]obesity&drugs:&
Drugs&that&alter&the&weight&regulation&of&the&body&by:&
o Altering&appetite&
o Absorption&of&calories&
Main&treatment&is&still&&proper&diet&and&work&out&
In&USA&there&is&only&one&FDA&approved&drug&that&is&used&long&term:&
o Orlistat,(Xenical)&
o It&reduces&intestinal&fat&absorption&by&inhibiting&pancreatic&lipase&
o Side]effects:&Steatorrhea&&&few&cases&of&severe&liver&damage&cases&
In&Europe&there&is&an&additional&drug&called&Rimonabant,&that&works&via&a&
special&blockade&of&the&endocannabinoid&system&
o Reducing&the&munchies&&craving&for&food&
o Not&approved&in&USA&or&Canada&
o Not&used&so&much&
Sibutramine,is&another&drug&that&works&in&the&brain&to&inhibit&
deactivation&of&neurotransmitters&&and&by&that&decreasing&appetite&
o Some&cardiovascular&concerns&lead&to&this&drug&not&to&be&used&
Anti]obesity&drugs&seem&to&have&unfavorable&side]effects&that&can&be&
harmful&(specially&during&long&term&treatment),&hence&they&are&only&used&
if&the&risk&of&the&obesity&is&greater&than&the&risk&of&the&drugs&
&
&
&
&
&
&

& 68&
 Sollas&Notes&2015&

Topic&9&
9.1&Antidepressive&agents&
&
Major(depressive(disorder(is(a(depression(of(mood(without(any(obvious(medical(or(
situational(causes.(Its(usually(due(to(an(inability(to(cope(with(ordinary(events(or(
experience(pleasure.(The(drugs(used(are(varied(in(chemical(structures(that(enhance(
the(CNS(action(of(NE,(Serotonin(or(both.(Antidepressants(usually(take(several(weeks(
to(occur(due(to(changes(in(gene(expression((downregulation(of(receptors).(
(
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&Antidepressants!
MAO!inhibitors! Tricyclic! Heterocyclic! 5/HT/NE! 5/HT! Selective!
(Phenelzine,& antidepressants& antidepressants! reuptake! antagonists& serotonin!
selegine,& (amitriptyline,& (amoxapine,& inhibitors! (nefazodone,& reuptake!
tranycypromine)& clomipramine,& bupropion,& (duloxetine,& trazodone)& inhibitors!
imipramine)& mirtazepine)& venlafaxine)& (fluoxetine,&
fluvoxamine,&
parozetine,&
sertaline&
&
Mechanism!of!antidepressant!action!
Potential&sites&of&action&of&antidepressants&at&CNS&synapses&are:!
o Presynaptic&Noradrenergic&neuron!
o Presynaptic&Serotoninergic&neuron!
o Postsynaptic&Neuron&receptors!
Most&antidepressants&cause&potentiation&of&NE,&5HT&or&both!
Nefazodone,and,trazodone&are&weak&inhibitors&of&NE&and&5HT&!
o Main&action&appears&to&be&antagonism&of&the&5]HT2a&receptor!
Long&time&use&of&TCAs&and&MAOIs&leads&to&downregulation&of&]receptors!
&
Tricyclic!antidepressants!(clomipramine,,imipramine,,amitriptyline),
Non&specific&blockade&of&5HT&and&NE&reuptake&
Used&in:&
o Major&depression,&phobic/panic&anxiety,&obsessive&compulsive&
disorder,&neuropathic&pain,&enuresis&(stage&4&slow&wave&sleep)&
TCA&are&well&absorbed&orally&but&may&undergo&first]pass&metabolism&
Have&high&volumes&of&distribution&and&are&not&readily&dialyzable&
Extensive&hepatic&metabolism&is&required&before&their&metabolism&
Plasma&half]lives&of&8]36hrs&usually&permit&once]daily&dosing&
Both&of&the&drugs&form&active&metabolites&once&taken&
Side&effects:&
o Muscarinic&and&]blockade&
Toxicity:&
o Coma,&convulsions&and&cardiotoxicity&(3Cs)&
Drug&interactions:&
o Hypertensive&crisis&with&MAO&inhibitors&
o Serotonin&symptom&with&SSRIs,&MAO&inhibitors,&meperidine&
o Prevent&antihypertensive&action&of&2&agonists&and&guanethidine&

& 69&
Sollas&Notes&2015&

&
Selective!Serotonin!reuptake!inhibitors!(fluoxetine,,fluvocamine,,
paroxetine,,sertraline,,citalopram!etc)!
!
1st&line&agents&in&treatment&of&depression!
Fluoxetine&is&the&prototype&of&a&group&of&drugs&that&are&selective&
serotonin&reuptake&inhibitors&(SSRIs)&
They&require&hepatic&metabolism&and&have&half]lives&of&18]24h&
Acute&effect&is&a&highly&selective&action&the&serotonin&transporter&(SERT)!
o SSRI&allosterically&inhibit&the&transporter,&binding&at&a&site&other&
than&that&of&the&serotonin!
o Minimals&inhibitory&effects&on&the&NE&tansporter&or&blocking&
action&on&adrenergic&and&cholinergic&receptors!
Uses:!
o Major&depression,&obsessive&compulsive&disorder,&bulimia,&anxiety&
disorders,&premenstrual&dysphoric&disorder!
Side&effects:!
o Anxiety,&agitation,&bruxism&(grinding&of&teeth),&sexual&dysfunction&
(anorgasmia&&SSRIs&can&be&used&in&treatment&of&premature&
ejaculation),&weight&loss&(can&be&used&in&weigh&loss&programs)!
! Since&the&SSRIs&take&few&weeks&to&start&working&we&need&to&
administer&a&benzodiazepine&(alprazolam)&to&minimize&
the&potentials&of&even&worsening&the&symptomst&that&the&
SSRIs&are&supposed&to&be&treating&!
Anxiety&and&agitation&are&the&initial&side&effects&of&
the&SSRIs&(due&to&rapid&increase&in&serotonin)!
Toxicity:!
o Serotonin&syndrome&(increased&risk&with,&MAO&inhibitors,&
meperidine&and&TCAs)!
!
Monoamine!Oxidase!Inhibitors!(phenelzine,,tranylcypromine)!
MAOIs&are&structurally&related&to&amphetamines&and&are&orally&active&
The&older&standard&drugs&inhibit&both&MAOA&and&MAOB&
o MAOA&metabolizes&NE,&5]HT,&tyramine&
o MaOB&metabolizes&dopamine&
Tranylcypromine&is&the&fastest&in&onset&of&effect&but&has&a&shorter&
duration&of&action&(1week)&than&other&MAOIs&(2]3&weeks)&
MAOIs&are&given&daily&even&though&they&have&long&acting&effect&
o Used&in&the&treatment&of&atypical&depression&
Inhibitors&of&hepatic&drug&CYP&enzymes&]&causing&drug&interactions&
o Selegiline,&a&selective&MAOB&inhibitor&was&recently&approved&for&
treatment&of&depression&
Toxicity:&
Hypertensive&reaction&to&indirectly&acting&sympathomimmetics&
Hyperthermia&
CNS&stimulation&leading&to&agitation&and&convulsions&
Hypertensive!crisis&in&patients&eating&tyramine&containing&food&
o Due&to&too&much&NE&

& 70&
Sollas&Notes&2015&

o Tyramine&is&a&indirect&sympathomimetic&drug&(cheese&
effect)&
In&the&absence&of&indirect&sympathomimetic,&MAOIs&lower&blood&pressure&
Overdose&"&shock,&hyperthermia&and&seizures&
MAOIs&+&SSRIs&have&resulted&in&serotonin!syndrome&
&
SNRIs&
Bind&to&transporters&for&both&S&and&NE,&presumably&works&as&agonists&
Venlafaxine&has&less&affinity&for&the&NE&transporter&than&the&other&drugs&&
SNRIs&differ&from&TCA&in&lacking&significant&blocking&effects&on&peripheral&
receptors&including&
o Histamine&H1&receptors,&Muscarinic&receptors&&&]receptors&&
!
Serotonin!5/HT2!receptor!antagonists!!
Major&antidepressant&action&of&nefazodone,and,trazadone&appear&to&
result&from&block&of&the&5]HT2A&receptor&
o A&G]protein&coupled&receptor&located&in&several&CNS&regions&
including&the&neocortex&
o Antagonism&of&this&receptor&is&equated&with&both&the&antianxiety&
and&antidepressant&action&of&these&drugs&
!
Other!Heterocyclic!antidepressants!
Mirtazapine&has&a&specific&action&to&increase&amine&relase&from&nerve&
endings&by&antagonism&of&presynaptic&2&adrenoreceptor&involved&in&
feedback&inhibition&
o Also&an&antagonist&of&serotonin&5]HT2.&&
&
Serotonin!syndrome!!
Life&threatening&
Drug&interaction&causing&this&syndrome&
Predictable&consequence&of&excess&serotonin&on&the&CNS&and/or&PNS&
Severe&muscle&rigidity,&myoclonus,&hyperthermia,&cardiovascular&
instability&and&marked&CNS&stimulatory&effects&
Drugs&which&can&interact&with&serotonin&is&&
o MAOIs,&TCAs,&dextromethorphan&,&St&John`s&wort&and&MDMA&
Managed&by&antisezure&drugs,&muscle&relaxants&and&5HT&antagonists&
&
Toxicity!of!SNRIs,!5/HT2!antagonists!and!Heterocyclic!drugs!
Mirtazapine&(2&antagonist)&"&weight&gain&and&sedation&
Amoxapine&"&dopamine&receptor&blocker&&
o May&cause&akathisia,&parkinsonism,&amenorrhea]galactorrhea&
o Together&with&maprotiline&may&cause&seizures&
Bupropion&"&dopamine&reuptake&blocker&used&in&(smoking&cessation)&
o Anxiety,&agitation,&dizziness,&dry&mouth,&aggravation&of&psychosis&and&at&high&
doses&"&seizures&
Venlafaxine&"&dose&dependent&increase&in&blood&pressure&and&CNS&stimulant&effects&]&
Severe&withdrawal&symptoms&can&occur&even&after&missing&one&dose&of&Venlafaxine&
Nefazodone,and,venlafaxine&are&inhibitors&of&CYP&
&
&

& 71&
Sollas&Notes&2015&

9.2&Antifungal&agents&
&
Fungal(infections(are(difficult(to(treat((specially(in(immunocompromised(or(
neutropenic(patients).(Most(fungi(are(resistant(to(conventional(antimicrobial(
agents,(and(relatively(few(drugs(are(available(for(the(treatment(of(systemic(fungal(
diseases.(Amphotericin,B,and,azoles,(fluconazole,,itraconazole,,ketoconaxole,
and,voriconazole)(are(primary(drugs(in(systemic(infections.(They(are(selectively(
toxic(to(fungi(because(they(interact(with(or(inhibit(the(synthesis(of(ergosterol(
(sterol(that(is(specific(in(fungal(cell(membranes).(
(
Drugs&acting&on&fungi:&
Alterations&of&cell&membrane&permeability&
o Azoles,
o Polyenes,,
o Terbinafine,
Blocking&of&nucleic&acid&synthesis&
o Flucytosine&
Disruption&of&microtubular&function&
o Griseofulvin&
&
Amphotericin!B!
Important&drug&for&the&treatment&of&systemic&fungal&infections!
Polyene&antibiotic&related&to&nystatin!
Poorly&absorbed&from&the&GI&and&is&therefore&usually&administered&IV&!
o As&a&nonlipid&colloidal&suspension,&lipid&complex&or&liposomal&
formulation!
Widely&distributed&to&all&tissues&except&the&CNS!
Elimination&is&mainly&via&slow&hepatic&metabolism&(half]life&approx.&2wk)!
o Small&fraction&is&eliminated&via&urine&and&therefore&dosage&
modification&is&only&needed&in&extreme&renal&dysfunctions!
! Not&dialyzable!
Mechanism&of&action:!
o Fungicidal!due&to&its&effects&on&the&permeability&and&transport&
properties&of&fungal&membranes!
o Binds&to&ergosterol&and&causes&the&formation&of&artificial&pores!
o Resistance&is&very&uncommon!
Clinical&use:!
o One&of&the&most&important&drug&available&for&the&treatment&of&
systemic&mycoses&and&is&usually&given&immediately&!
o Has&the&widest&antifungal&spectrum&and&is&DOC&for!
! Aspergillus,(Blastomyces,(Candida,(Cryptococcus,(
Histoplasma(and(Mucor!
o Usually&given&by&slow&IV&infusion!
! In&fungal&meningitis&its&given&intrathecal&(in&CSF)!
Dangerous&but&sometimes&needed!
o Locally&it&has&been&given&for&mycotic&corneal&ulcers&and&keratitis!
Toxicity:!
o Infusion&related&!

& 72&
Sollas&Notes&2015&

! Fever,&chills,&muscle&spasms,&vomiting,&shock]like&fall&in&BP!
Therefore&infusion&is&usually&done&very&slowly!
o Dose&limiting!
! Decreases&GFR&and&causes&renal&tubular&acidosis&with&Mg&
and&K&wasting,&decreased&production&of&erythropoietin&
resulting&in&anemia!
Saline&infusion&may&reduce&the&damage!
Liposomal&formulations&are&least&toxic!
o Neurotoxicity!
! Intrathecal&administration&may&cause&seizures&and&
neurologic&damage!
Flucytosine!(5/fluorocytosine!(5/FC)):!
5]FC&is&a&pyrimidine&antimetabolite&!
o Related&to&the&anticancer&drug&5]fluorouracil&(5]FU)!
Effective&orally&and&distributed&to&most&body&tissues&+&CNS!
Eliminated&intact&in&urine&and&has&dose]limiting&toxic&effects!
The&drug&is&accumulated&in&fungal&cells&due&to&action&of&permease&and&
deaminase!
o In&the&its&converted&to&5]FU!
! Inhibitor&of&thymidylate&synthase!
o Selective&toxicity&in&normal&cells&is&due&to&this&also!
Commonly&used&in&combinations&with&Am]B&or&azoles!
Clinical&use:!
o Narrow&spectrum&but&is&commonly&used&in&combos!
! Cryptococcus(neoformans,(C.albicans((systemic)!
Toxicity:!
o Reversible&bone&marrow&depression,&aloplecia&and&liver&
dysfunction&+&renal&stuff!
Azoles:!
Imidazole&&ketoconazole!
Triazoles&&fluconazole,,itraconazole,,voriconazole!
Oral&bioavailability&is&variable&(normal&gastric&acidity&is&needed)!
o Fluconazole&and&voriconazole&are&best&orally&absorbed!
Distributed&to&most&tissues&with&low&CNS&involvement!
o Fluconazole&accumulates&more&in&the&CNS&than&others!
Metabolism&is&in&the&liver&except&for&fluconazole&(the&kidneys)!
Mechanism&of&action:!
o Interference&with&fungal&cell&membrane&permeability&by&inhibiting&
the&synthesis&of&ergosterol!
o Resistance&can&occur&&specially&in&prolonged&prophylaxis&in&
immunocompromised&patients!
Clinical&uses:!
o Ketoconazole!
! Narrow&antifungal&spectrum&&not&often&used&anymore!
! More&adverse&effects&than&other&azoles!
! Used&for&chronic&mucocutaneous&candidiasis&and&
dermatophytes!
o Fluconazole!

& 73&
Sollas&Notes&2015&

! DOC&in&esophageal&and&oropharyngeal&candidiasis&and&most&
infectious&caused&by&Coccidoides!
! Single&oral&dose&usually&eradicates&vaginal&candidiasis!
! DOC&and&secondary&prophylaxis&against&cryptococcal&
meningitis&!
! Backup&drug&(with&Am]B)&in&treatment&of&active&disease&due&
to&Cryptococcus(neoformans!
o Itraconazole!
! Wide&spectrum!
! DOC&for&systemic&infections&caused&by&Blastomyces(and(
Sporothrix(+&subcutaneous&chromoblastomycosis!
! Backup&drug&in&Aspergillus,(Coccioides,(Cryptococcus(and(
Histoplasma(infections&!
! Active&against&some&strains&of&C.albicans(that&are&immune&to&
fluconazole&in&esophageal&candidiasis!
! Used&commonly&in&treatment&of&dermatophytoses&!
Specially&onchomycosis!
o Voriconazole!
! Very&wide&spectrum!
! Codrug&of&choice&in&treatment&of&invasive&aspergillosis!
! Alternative&drug&in&candiemia&when&resistant&to&fluconazole!
! Used&in&AIDS&patients&for&treatment&of&candidial&esophagitis&
and&stomatitis!
o Posaconazole!
! Broadest&spectrum&triazole!
! Works&on&most&species&of&Candida(and(Aspergillus!
! Only&one&that&works&for&Rhizopus!
That&is&one&of&the&agents&of&mucormycosis!
! Used&as&prophylaxis&of&during&cancer]chemo&therapy!
! Used&in&severe&aspergillosis!
Toxicity&of&azoles:!
o Vomiting,&diarrhea,&rash,&sometimes&hepatotoxicity!
o Ketoconazole&is&a&potent&inhibitor&of&CYP&isoenzymes&and&may&
increase&plasma&cc.&levels&of&many&drugs!
! Also&interferes&with&synthesis&of&adrenal&and&gonadal&
steroids&and&therefore&may&lead&to&gynacomastia,&menstrual&
irregularities&and&infertility!
o The&other&azoles&are&less&inhibitory&for&the&CYP&enzymes!
o Voriconazole&can&cause&blurred&vision&in&30%&of&cases!
!
Caspofungin,!anidulafungin,!micafungin!:!
An&echinocandins&that&is&used&IV&&widely&distributed&and&eliminated&by&
liver&metabolism&that&all&have&fairly&long&half]lives&
Inhibit&the&synthesis&of&(1]2)glycan&that&is&a&critical&component&of&the&
fungal&cell&wall&
Caspofungin:&
o Used&to&treat&disseminated&and&mucocutaneous&Candida(infections&
in&people&that&dont&respond&to&Am]B&
o Also&used&in&the&treatment&of&mucormycosis&

& 74&
Sollas&Notes&2015&

Anidulafungin&
o Used&in&esophageal&and&invasive&candidiasis&
Micofungin&
o Used&in&mucocutaneous&candidiasis&and&as&a&prophylaxis&of&
Candida(infections&in&case&of&bone&marrow&transplant&patients&
Toxicity:&
o Headache,&GI&distress,&fever,&rash,&flushing&(due&to&histamine&rel.)&
&
Griseofulvin:&
Orally&administered&and&its&absorption&depends&on&the&physical&state&of&
the&drug&itself!
o Ultra]micro]size&formulations&(with&finer&crystals)&are&more&
effectively&absorbed&than&larger&formulations!
o High]fat&food&aid&the&absorption!
Drug&is&distributed&to&the&stratum&corneum&of&the&skin,&where&it&binds&to&
keratin&and&is&therefore&used&as&for&superficial&fungal&infections!
Interferes&with&the&microtubular&function&of&the&dermatophytes&&&inhibits&
synthesis&and&polymerization&of&nucleic&acids!
Fungistatic!mechanism!
Eliminated&via&biliary&excretion!
Not&active&topically!
Toxic&effects&include&&headache,&mental&confusion,&GI&distress,&
photosensitivity&and&liver&function&changes,&decreases&bioavailability&of&
warfarin&and&causes&disulfiram]like&reactions&when&taken&with&alcohol!
o Contraindicated&in&patients&with&porphyrias!
Terbafine:!
Inhibits&squalene&epoxidase&(fungal&enzyme)&resulting&in&toxic&levels&of&
squalene&that&will&interfere&with&ergosterol&synthesis!
Fungiocidal!
Oral&and&topical&forms&(more&effective&for&onchomycosis)!
!
!
!
&
&
&
&
&
&
&
&
&
&
&
&
(
(
(

& 75&
Sollas&Notes&2015&

9.3&Positive&inotropic&drugs&
&
An(inotrope(is(an(agent(that(alters(the(force((energy)(of(muscular(contractions,(
mainly(used(when(talking(about(the(heart(contractility.(Positive(inotropic(agents(
increase(the(strength(of(cardiac(muscular(contractions.(They(are(used(in(the(
treatment(of(decompensated(congestive(heart(failure,(cardiogenic(shock,(septic(
shock,(myocardial(infarction,(and(cardiomyopathy.(One(of(the(most(important(
factors(affecting(inotropic(state(is(the(level(of(Ca2+(in(the(cytoplasm(of(the(cardiac(
muscle(cell.(Positive(inotropes(usually(increase(this(level.(
(
Cardiac&glycosides&]&Digoxin:&
No&longer&considered&first]line&drugs&in&heart&failure&
Digoxin&inhibits&Na+/K+&ATPase&of&the&cell&membrane&&
o Results&in&small&increase&in&IC&Na+&
o This&changes&the&transport&of&Ca2+&out&of&the&cell&via&Na+/Ca2+&
o Increased&IC&Ca2+&increases&the&contractile&force&
Modifies&autonomic&outflow&&influences&electrical&properties&of&the&heart&
Effects:&
o Increased&contractility&results&in&increased&ejection&
o Decreased&end]systolic&and&end]diastolic&size&
o Increased&cardiac&output&
o Decrease&in&the&compensatory&sympathetic&and&renal&responses&
! Decreased&sympathetic&tone&&decreased&HR,&preload,&
afterload&&this&permits&the&heart&to&function&better&
o Early&cardiac&parasympathomimetic&responses&
! Increased&PR]interval&and&flattening&of&T]waves&
! Parasympathetic&effects&on&AV&and&atria&can&be&blocked&
with&atropine&&so&we&dont&slow&the&firing&rate&of&AV&too&
much&(slow&ventricular&rate&compared&to&atria)&
! Shorter&QT,&inversion&of&T&and&ST&depression&&
o Later&arrhythmogenic&actions&
! Toxic&responses&
Toxic&responses:&
o Increased&automaticity&(due&to&increased&IC&Ca2+)&
! Delayed&afterdepolarizations&
Extrasystoles,&tachycardia,&fibrillation&in&any&parts&of&
the&heart&
Premature&ventricular&beats&and&bigeminy&
o Amplified&toxicity&is&obtained&occurs&in&hypokalemia,&
hypomagnesinemia&and&hypercalcemia&
Interactions&with&other&drugs&such&as&quinidine,may&increase&the&serum&
levels&of&digoxin&even&more&and&cause&more&toxicity&and&problems&
o Also&with&amiodarone,,verapamil,etc.&&
Used&in&chronic&heart&failure&(positive&ionotropic&agent)&
o Reduces&symptoms&and&improves&functional&status&
o Does&not&prolong&life&
o More&toxic&than&the&previously&discussed&drugs&
o Long&half]life&that&makes&them&accumulate&in&the&body&
o Dosing&is&very&important&and&proper&monitoring!!!!!&

& 76&
Sollas&Notes&2015&

Used&in&atrial&fibrillation&but&same&here&&need&to&be&monitored&closely&
Symptoms&of&toxicity:&
Arrhythmias,&nausea,&vomiting&and&diarrhea,&confusion&and&hallucinations&
(rare)&and&visual&or&endocrine&abnormalities&may&occur&
Severe/acute&intoxication&(suicide/accidental)&can&result&in&cardiac&arrest&&
Detoxification&is&done&with:&
o Correcting&potassium&or&magnesium&problems&
o Antiarrhythmic&drugs&in&not&so&severe&cases&
o Digoxin&antibodies&(digibind)&are&extremely&effective&and&should&
always&be&used&if&other&therapies&seem&to&be&failing&
Amiodarone:&
Class&III&antiarrhythmic&agent&that&prolongs&phase&3&of&the&cardiac&action&
potential;&the&repolarization&phase&where&there&is&normally&decreased&
calcium&permeability&and&increased&potassium&permeability&
Numerous&other&effects&
o Antiarrhythmic&class&Ia,&II&and&IV&functions&&
o ]blocker&like&and&K+&channel&blocker&like&actions&on&
! &SA&and&AV&nodes&
! Increases&refractory&period&via&Na+&and&K+&channel&effects&
! Slows&intra]cardiac&conduction&of&the&cardiac&AP&via&
sodium]channel&effects&
Clinically&resembles&thyroxine&&
o When&it&binds&to&the&nuclear&thyroid&receptor&might&contribute&to&
some&of&its&pharmacologic&and&toxic&actions&
Dobutamine:&
Positive&inotrope&&
Sympathomimetic&drug&(]agonist)&that&is&used&in&the&treatment&of:&
o Acute&but&potentially&reversible&heart&failure&&
o Congestive&heart&failure&to&increase&CO&
o Septic&or&cardiogenic&shock&
o Direct&stimulation&of&1&receptor&
Not&useful&in&treatment&of&ischemic&heart&disease&since&it&increases&the&HR&
and&thus&increases&the&oxygen&demand&of&the&heart&
Also&used&in&hospital&setting&as&a&pharmacologic&stress&testing&agent&to&
identify&coronary&artery&disease&
Phosphodiesterase&inhibitors:&
Drugs&that&block&one&or&more&of&the&five&subtypes&of&the&enzyme&
phosphodiesterase&(PDE)&
Prevents&the&inactivation&of&the&intracellular&cAMP&and&cGMP&
Inamrione&
o PDE3&inhibitor&that&improves&prognosis&in&patients&with&
congestive&heart&failure&
o Increases&contractions&initiate&in&the&heart&by&high&gain&calcium&
induced&calcium&release&&]&positive&inotrope&effect&of&the&drug&
! Phosphorylation&through&cAMP&dep.&PKA&and&Ca2+]
calmodulin&kinase&pathway&
Other&positive&inotropes&include:&
Epi,&NorEpi,&dopamine,&angiotensin&II,&digoxin,&digitalis&etc.&

& 77&
Sollas&Notes&2015&

Topic&10&
10.1&Opioid&analgesics:&Naturally&occurring&opioids&
&
The(opioids(include(natural(opiates(and(semisynthetic(alkaloids(derived(from(the(
opium(poppy,(pharmacologically(similar(synthetics(surrogates(and(endogenous(
peptides.(On(the(basis(of(their(interaction(with(opioid(receptors,(the(drugs(are(
classified(as(agonists,(mixed(agonistsLantagonists(and(antagonists.(
( Opioid(peptides(released(from(nerve(endings(modulate(transmission(in(the(
brain(and(spinal(cord(and(in(primary(afferents(via(their(interaction(with(specific(
receptors.(Many(of(the(pharmacologic(actions(of(opiates(and(synthetic(opioid(drugs(
are(effected(via(their(interactions(with(endogenous(opioid(peptide(receptors.(
(
Chemical!structure:!
o Phenantrene&derivative&that&is&termed&after&Morpheus&(God&of&dreams)!
o Two&planar&and&two&aliphatic&rings!
o Nitrogen&connectes&substitutive&groups!
o Subdivisions:!
o Phenantrenes!
! Morphine,,codeine,,oxycodone!
o Phenylheptylamines!
! Methadone!
o Phenylpiperidines!
! Diphenoxylate,,loperamide,,fentanyl!
History:!
o Opium&(opos:&juice),&opiate,&opioid!
o Obtained&from&opium&poppy&(Papaver(somniferum)!
o White&substance&"&brown&gum&=&opium!
o Opium&contains&alkaloids&(morphine,&narcotine,&papaverine&etc.)!
Classification:!
o Endogenous&opioids!
o Endorphins,,Enkephalins,,Dynorphins,
o Naturally&occurring!
o Morphine,,Codeine,,Narcotine,
o Semisynthetics!
o Heroine,,Oxycodone,,Hydromorphone,
o Synthetic!
o Fentanyl,,Meperidine,,Methadone!
!
Opioid!receptors:!
GLprotein(coupled(action(that(either(blocks(AC(and(by(that(decreases(cAMP(or(
activate(phospholipase(C(to(block(the(Ca2+(transmission(
o /receptors!(MOR)!!pre&&&postsynaptic&!
o Found&in&cortex,&thalamus,&medulla&oblongata,&dorsal&horn&of&
spinal&cord,&peripheral&tissues,&periaqueductal&gray,&locus&ceruleus!
o Effects:!
! Analgesia,&respiration&depression,&sedation,&GIT&depression!
! Addiction,&modulation&of&neurotransmitter&release!
o /receptors!(KOR)!!presynaptic&!

& 78&
Sollas&Notes&2015&

o Found&in&spinal&cord,&hippocampus&and&limbic&area,&GI]tract&and&
peripheral&tissues!
o Effects:!
! Psychotomimetic&effects&and&GIT&effects,&analgesia,&
anticonvulsant,&diuresis,&miosis,&addiction!
o /receptors!(DOR)!!presynaptic&!
o Found&in&cortex,&brain&stem&and&peripheral&tissues!
o Effects:!
! Analgesia,&antidepressant&effects,&convulsant,&addiction!
! May&modulate&]receptor&mediated&respiratory&depression!
! May&play&a&role&in&the&development&of&tolerance!
o Novel!opioid!receptors!(NOR)!
o Orphanin,opioid,receptor,like,subtype,1,(ORLP1)!
! In&brain&and&spinal&cord!
! Endogenous&receptor&for&nociceptin&(dynorphine&like)!
! Effects:!
Anxiety,&depression,&appetite!
Development&of&tolerance&to&]receptor!
!
Opioid!peptides:!
o Opioid&receptors&are&thought&to&be&activated&by&endogenous&peptides&
under&physiologic&conditions!
o All&are&inhibitory&to&neurons!
o The&peptides:!
o Pendorphin,,enkephalin,and,dynorphins!
o Synthesized&in&the&soma&(nerve&body)&and&are&transported&to&the&
nerve&endings&where&they&accumulate&in&vesicles!
o On&release&they&bind&to&opioid&receptors!
o Can&be&displaced&by&opioid&antagonists!
o Endorphins,have(highest(affinity(for,Preceptors,
o Enkephalins,have(highest(affinity(for(Preceptors,
o Dynorphins,have(highest(affinity,for,Preceptors,
!
Ionic!mechanisms:!
o Opioid&analgesics&inhibit&synaptic&activity&partly&via&direct&activation&of&
opioid&receptors&&&partly&through&release&of&endogenous&opioid&peptides!
o At&the&postsynaptic&level,&activation&of&the&receptors&(via&G]proteins)&can:!
o Open&K+&channels&and&cause&membrane&hyperpolarization!
! Inhibitory&postsynaptic&potentials!
o At&the&presynaptic&level,&activation&(via&G]proteins)&can:!
o Close&voltage&gated&Ca+&channels!
! Inhibits&neurotransmitter&release!
ACh,&NE,&serotonin,&glutamate,&substance&P!
!
Naturally!occurring!opioids:!
o Morphine&&dry&latex&from&the&unripe&seedpods&of&Papaver(somniferum&!
o Codeine,&in&Papaver(somniferum;&2nd&most&abundant&after&morphine!
o Narcotine!
!

& 79&
Sollas&Notes&2015&

Morphine:!
o Strong&agonist&of&the&opioid&recep.&]&Acts&direct&on&the&CNS&to&relieve&pain&
o Pharmacokinetics:&
o Routes&of&administration&"&oral,&subling.,&buccal,&rectal,&subcut.,&
intranasal,&inhaled&via&nebulizer,&IV,&IM,&intathecal&or&epidural&
! IV!is!the!most!common&method&of&administration&
o Extensive&1st&pass&mechanism&
! If&taken&p.o.&only&40]50%&will&reach&CNS&
Peak&level&after&30&min&
! IM&or&SC&injections&have&similar&bioavailability&as&oral&
Peak&level&after&20&min&
o Metabolized&by&liver&and&around&87%&is&excreated&in&the&urine&
within&72&hours&of&administration&
! M3G&&has&effects&on&GABA&receptors&
Increased&cc.&will&result&in&seizures&&
60%&of&the&morphine&
No&analgesic&effects&and&no&opioid&receptor&binding&
! M6G&&
6]10%&of&the&morphine&
Binds&to&]receptors&and&is&half&as&potent&an&
analgesic&as&morphine&in&the&body&
o Morphine&may&also&be&metabolized&into&small&amounts&of&codeine,&
hydromorphone&and&normorphine&
o Elimination&half]life&is&approx.&120min&(highly&individual&differ.)&
o Does&not&cross&BBB&easily&and&can&accumulate&in&fat&
o Pharmacodynamics:&
o Phenanthrene&opioid&receptor&agonist&(mainly&/receptor)&
o Primary!actions!are!analgesia!and!sedation!
! Euphoria,&physical&dependence&and&respiratory&depression&
! Nausea&and&vomiting&&
Due&to&activation&of&area&postrema&
! Constipation&]&Due&to&decreased&GI&motility&
! Smooth&muscle&contraction&
Biliarocholic&spasms,&increased&sphincter&tones&and&
reduction&in&uterine&tone&(prolonged&labor)&
! Other&effects&include:&
Pruritus&(via&histamine&release),&release&of&ADH&and&
prolactin&and&inhibition&of&LH&release&
o Also&works&on&&and&&receptors:&
! ]effects&are&"&spinal&analgesia,&miosis,&psychotomimetic&
! ]effects&are&"&analgesia&
o Tolerance:&
o Marked&tolerance&can&occur&(except&in&miosis&and&constipation)&
o Mechanism&may&involve&receptor&uncoupling&
o Antagonists&of&NMDA&receptors&(e.g.,ketamine)&+&]receptors&
! Block&opioid&tolerance&
o Cross]tolerance&btw.&drugs&exists&but&is&not&complete&
! Hence&its&possible&to&rotate&btw.&drugs&when&treating&
patients&in&chronic&pain&&(cancer&pain&management)&

& 80&
Sollas&Notes&2015&

o Physical&dependence&(addictive&features):&
o Anticipated&physiologic&response&to&chronic&therapy&with&opioids&
! Especially&the&strong&agonists&
o Revealed&on&abrupt&discontinuation&&abstinence!syndrome&
! Rhinorrhea,&lacrimation,&chills,&gooseflesh,&muscle&aches,&
diarrhea,&yawning&and&hostility&
o More&intense&state&of&precipitated&withdrawal&results&when&an&
opioid&antagonist&(naloxone,,nalmefene,or,naltrexone)&is&
administered&to&a&physically&dependent&individual&&
o Toxicity:&
o Overdose&classically&presents&with&this&triad&of:&
! Pupillary!constriction,!coma!&!respiratory!depression!&
! Diagnosis&of&overdose&is&done&with&the&IV&inj.&of&naloxone&
Antagonist&that&results&in&prompt&signs&of&recovery&
! Treatment&includes&antagonist&and&ventilator&support&
Do!NOT!give!oxygen!to!patients!that!are!in!opioid!overdose!state!
o Since&the&only&mechanism&maintaining&the&very&weakened&
respiration&is&related&to&the&chemoreceptors&in&the&
aortic/carotid&body&and&giving&oxygen&would&increase&the&
oxygen&saturation&of&the&blood&&providing&false&signals&to&these&
chemoreceptor&zones&and&a&even&further&decrease&in&
respiration&and&ultimately&death&due&to&rep.failure!!
&
Codeine:!
o Moderate&agonist&with&uncertain&mechanism&
o Analgesic&actions&are&due&to&its&conversion&to&morphine&while&antitussive&
effects&are&due&to&codeine&itself&
o Much&less&potent&analgesic&than&morphine,&but&it&has&a&higher&oral&
effectiveness&
o It&shows&good&antitussive&activity&at&doses&that&do&not&cause&analgesia&
o The&drug&has&a&lower&potential&for&abuse&then&morphine,&rarely&produces&
dependence&
o It&produces&less&euphoria&and&often&used&in&combination&with&aspirin&or&
acetaminophen&
&
Narcotine!(noscapine):!
o Antitussive&agent&that&doesnt&have&analgesic&effects!
o Seems&to&work&on&]receptors&as&an&agonist!
&
&
&
&
!
!
!
!
!
!
!

& 81&
Sollas&Notes&2015&

10.2&Antiviral&agents&I&&antiretroviral&agents&
&
Antiretroviral(agents(are(the(primary(drugs(in(the(treatment(of(HIV.(The(current(
approach(to(HIV(treatment(is(the(initiation(of(treatment(with(3(or(more(
antiretroviral(drugs,(if(possible,(before(symptoms(appear.(These(initial(
combinations(usually(include:(
Nucleoside(reverse(transcriptase(inhibitors((NRTIs)(
Inhibitors(of(HIV(protease((PI)(
Highly(active(antiretroviral(therapy((HAART)(involving(drug(combinations(can(
slow(or(reverse(the(increases(in(viral(RNA(load(that(normally(accompany(
progression(of(the(disease.(In(many(AIDS(patients,(HAART(slows(or(reverses(the(
decline(in(CD4+(cells(and(decreases(the(incidence(of(opportunistic(infections.(
Drug(management(of(HIV/AIDS(is(constantly(evolving.(
(
Major!antiretroviral!drugs:!
Nucleoside&reverse&transcriptase&inhibitors&(NRTIs)!
Non]nucleoside&reverse&transcriptase&inhibitors&(NNRTIs)!
Protease&inhibitors&(PIs)!
CCR]5&antagonist&(entry&inhibitors)&]&Maraviroc!
Fusion&inhibitor&(entry&inhibitors)&]&Enfuvirtide!
!
Nucleoside!reverse!transcriptase!inhibitors!(NRTIs):!
For&retroviruses&to&be&able&to&multiply&within&the&cell&reverse&
transcriptase&(RNA]dependent&DNA]polymerase)&is&needed&for&the&
conversion&of&viral&RNA&into&dsDNA&that&then&is&used&for&production&of&
viral&progenies&!
NRTIs&are&prodrugs&converted&by&most&host&cell&kinases&to&triphosphates!
o Competitively&inhibit&the&binding&of&natural&nucleotides&to&the&
dNTP]binding&site&of&reverse&transcriptase!
o Act&as&chain&terminators&via&their&insertion&into&the&growing&DNA&
chain!
Since&NRTIs&lack&a&3]hydroxyl&group&on&the&ribose&ring&the&attachment&of&
the&next&nucleotide&becomes&impossible!
Resistance&emerges&rapidly&when&NRTIs&are&used&as&a&single&drug&due&to&
mutations&of&the&pol(gene!
Abacavir!
o Guanosine&analog&with&good&oral&bioavailability!
o HIV&resistance&requires&several&concomitant&mutations!
! Develops&slowly!
o HSR&that&are&occasionally&fatal&are&seen&in&around&5%&of&patients!
Didanosine,(ddl)!
o Oral&bioavailability&is&reduced&with&foods&and&chelating&agents!
o Eliminated&via&kidneys&and&needs&to&be&monitored&for&toxicity!
o Pancreatitis&is&dose]limiting&(higher&chance&in&alcoholics)!
o Peripheral&neuropathy,&diarrhea,&hepatic&dysfunction,&
hyperuricemia&and&CNS&effects!
Emtricitabine!
o Good&oral&bioavailability,&renal&elimination&with&long&half]life!

& 82&
Sollas&Notes&2015&

! Once&a&day&dose!
o Contraindicated&in&pregnancy&and&children&+&liver&dysfunction!
! Due&to&propylene&glycol&in&oral&solution!
Lamivudine,(3TC)!
o 80%&bioavailable&by&oral&route,&eliminated&by&kidneys!
o One&of&the&common&components&of&HAART!
o Also&used&in&HBV&infections!
o Dose]adjustments&in&renal&dysfunction&patients!
o Mild&non]specific&adverse&effects!
Stravudine,(d4T)!
o Good&oral&bioavailability,&penetrates&most&tissues&+&CNS!
o Dose]adjustments&in&renal&d.&cases&&&peripheral&neuropathy!
o Lactic]acidosis&occurs&sometimes!
Tenofovir!
o Used&for&HIV&and&HBV!
o Oral&bioavailability&is&25]40%&and&IC&half]life&is&60hrs!
o Renal&elimination&and&may&impede&elimination&of&acyclovir&and&
ganciclovir!
o Adverse&effects&&GI&distress,&asthenia,&headache,&ARF&and&Falconis&
syndrome&are&rare&side&effects!
Zalcitabine,(ddC)!
o High&oral&bioavailability,&dose]adjustment&in&renal&cases!
o Dose]limiting&peripheral&neuropathy&is&a&major&adverse&effects,&
pancreatitis,&esophageal&ulcerations,&stomatitis&and&arthralgias!
Zidovudine,(ZDV)!
o Orally&active&and&distributed&to&most&tissue&+&CNS!
o Renal&and&hepatic&elimination!
! Dose]limiting&in&renal&dys.&&&cirrhosis!
o Adverse&effects&are&bone&marrow&suppression&leading&to&anemia&
and&neutropenia&(transfusions&may&be&needed)!
o Rifampin&increases&the&clearance&of&the&drug!
!
Non/nucleoside!reverse!transcriptase!inhibitors!(NNRTIs):!
Bind&to&a&site&on&reverse&transcriptase&different&from&that&of&NRTIs!
Does&not&require&phosphorylation&to&become&active&and&dont&compete&
with&nucleoside&triphosphates!
No&cross]resistance&with&NRTIs!
Resistance&from&mutations&in&the&pol(gene&occur&very&rapidly&in&
monotherapy!
Delavirdine!
o Drug&interactions&are&major&problem&of&this&drug&which&is&
metabolized&both&by&CYP3A4&and&CYP2D6!
! Blood&levels&are&decreased&by&antacids,&ddI,&phenytoin,&
rifampin&and&nelfinavir!
! Blood&levels&are&increased&by&azole&antifungals&and&
macrolides!
o The&drug&increases&plasma&cc.&of&several&benzod.,&nifedipine,&PI,&
quinidine&and&warfarin!
o Skin&rashes&in&20%&of&patients&and&contraindicated&in&pregnancy!

& 83&
Sollas&Notes&2015&

Efavirenz!
o Given&orally&once&daily&due&to&its&long&half]life!
o Fatty&foods&increase&the&bioavailability!
o Metabolized&by&CYP&enzymes&and&commonly&causes&d.interactions!
o Toxicity&&CNS&disfunction,&skin&rash,&elevation&of&plasma&cholest.!
o Contraindicated&in&pregnancy!
Etravirine!
o The&newest&NNRTI&approved&for&HIV&treatment&and&may&be&more&
effective&against&strains&of&HIV&that&are&resistant&to&other&NNRTIs!
o Toxicity&&rash,&nausea,&diarrhea,&elevated&cholesterol,&
triacylglycerides&and&transaminase!
o Inducer&of&CYP3A4&and&inhibitor&of&CYP2C9&&drug&interactions!
Nevirapine!
o Good&oral&bioavailability,&penetrates&most&tissues&+&CNS!
o Once&a&day&and&metabolized&by&CYP3A4&!
o Prevents&vertical&transmission&of&HIV&when&given&as&single&doses&
to&mothers&at&onset&of&labor&and&to&the&neonate&!
o HSR&in&15]20%&of&cases&(more&in&females),&Steven]Johnsons&
syndrome&and&a&life]threatening&toxic&epidermal&necrolysis!
o Blood&levels&of&the&drug&are&increased&by&macrolides&and&
cimetidine&and&decreased&by&rifampin!
!
Protease!inhibitors!(PI)!
The&assembly&of&the&HIV&virions&is&dependent&on&an&aspartate&protease&
(HIV]1&protease)&that&is&encoded&by&the&pol(gene!
These&drugs&inhibit&this&protease&and&by&that&inhibit&the&viral&assembly!
Resistance&occurs&due&to&multiple&mutations&of&the&pol(gene!
Very&important&in&the&treatment&of&AIDS!
o In&combo&with&NRTIs&or&NNRTIs&as&a&member&of&HAART!
All&PIs&are&substrates&and&inhibitors&if&CYP3A4&so&they&are&implicated&in&
many&drug&interactions&(both&other&retroviral&and&other&common&drugs)!
Atazanavir!
o Once&a&day,&needs&acidic&environment&for&absorption!
o Penetrates&BBB&and&BTB&&elimination&is&biliary!
o Toxicity&&GI&distress,&peripheral&neuropathy,&skin&rash,&
hyperbilirubinemia,&prolongation&of&QT&interval!
o Potent&inhibitor&of&CYP3A4!
Darunavir,P,Can&cause&sulfonamide&allergy&due&to&its&sulfonamide&moiety!
Fosamprenavir,P,Contraindicated&in&pregnancy&and&kids!
Indinavir,,Good&bioavailability&on&empty&stomach!
Lopinavir/ritonavir,!
Nelfinavir,,Good&bioavailability&with&food&intake,&OK&in&pregnancy!
Ritonavir,P,Good&bioavailability&with&food&intake!
o Very&commonly&a&part&of&HAART!
Saquinavir!
Tipranavir,,newer&and&used&in&resistant&cases!
!
( (

& 84&
Sollas&Notes&2015&

10.3&Drugs&that&promote&upper&GI&motility&
&
Drugs&promoting&upper&GI&motility:&
Prokinetic&drugs&that&stimulates&the&upper&GI&motility&are&helpful&for&
gastro]paresis&ad&post]surgical&gastric&emptying&delay&
Increase&lower&esophageal&sphincter&pressures&
o Good&to&treat&GERD&
Metoclopramide,and,domperidone:&&
o Work&on&the&enteric&nervous&system&&
o D2&dopamine&receptor&antagonists&that&promote&GI&motility&
o &Also&work&on&the&area(postrema&in&the&brainstem&
! Anti]emetic&effect&&
Useful&after&surgical&anesthesia&and&emesis&induced&
by&chemotherapeutic&drugs&
o Chronic&use&of&Metoclopramide&can&cause&symptoms&of&
Parkinsonism,&extrapyramidal&effects&&&hyperprolactinemia&
o Domperidone&does&not&cross&the&BBB&=&no&CNS&toxicity&
Neostigmine&(AchE&inhibitor)&is&useful&for&treating&hospitalized&patients&
with&acute&large&bowel&distention&
Erythromycin&is&a&macrolide&antibiotic&&
o Promotes&motility&&
o Stimulates&motilin&receptors&
o Beneficial&in&gastro]paresis&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&

& 85&
Sollas&Notes&2015&

Topic&11&
11.1&Opioid&analgesic:&Semisynthetic&and&synthetic&derivatives&
&
Semisynthetic!opioids:!
o Created&from&either&the&natural&opiates&or&morphine&esters!
o Oxycodone,,hydromorphone,,heroin,(diamorphine)!
!
Heroin!(diamorphine):!
o Opioid&analgesic&synthesized&by&adding&two&acetyl&groups&to&morphine!
o Diacetyl&derivative&with&a&lipophilic&structure!
! Easily&crosses&BBB!
! Rapidly&acting&and&more&2]4&more&potent&than&morphine!
o Heroin&is&used&medically&under&the&chemical&name&diamorphine!
o Strong&analgesic&in&some&countries&(mainly&UK)!
! In&most&countries&morphine&is&preferred!
o Can&be&given&SC,&IV,&IM&and&intrathecal!
o Used&in&the&treatment&of&acute&pain!
! Physical&trauma,&MI,&post]op&and&in&chronic&pain&(incl.&end]
stage&cancer&and&other&terminal&illnesses)!
o Usage& is& very& strongly& monitored& via& the& government& in& those&
countries&that&permit&the&medicinal&use&of&diamorphine!
o Can&also&be&used&as&a&maintenance&drug&to&treat&certain&groups&of&
addicts&(long]term&chronic&IV&heroin&users)!
! Only&prescribed&following&failure&of&other&treatments!
o When&used&recreationally&the&original&name&heroin,is&usually&used!
o Used&by&addicts&to&reach&intense&euphoria!
o Tolerance&develops&quickly,&hence&increased&doses&are&needed!
o In&the&brain&heroin&is&metabolized&into&6]MAM&and&morphine!
! 6]MAM& is& unique& to& heroin& and& is& thought& to& give& the&
intense&euphoric&effects&that&is&signature&to&heroin!
! 6]MAM&is&also&a&psyco]active&metabolite!
o Effects:!
! Intense&rush,&acute&transcendent&state&of&euphoria!
!
!
!
!
!
&
&
&
&
&
&
&
&
&
&

& 86&
Sollas&Notes&2015&

Pharmacology!of!heroin:!
o Orally&it&undergoes&extensive&first]pass&metabolism&via&deacetylation!
o IV&administration&avoids&first]pass,&rapidly&crosses&BBB&(highly&lipophilic)!
o In&brain&its&deacetylated&to&6]MAM&and&morphine!
! Bind&to&]receptors!
Euphoria,&analgesic&and&anxiolytic&effects!
Repeated&use&of&heroin&will&increase&production&of&]
receptors&(upregulation)!
o Tolerance&and&dependence&develop&quickly&so&cessation&will&result&in:!
o Pain,&anxiety,&muscle&spasms,&insomnia!
! Opioid&withdrawal&syndrome!
! Depending&on&usage&this&has&an&onset&of&24hrs&after&the&last&
dose&of&heroin!
Oxycodone:!
o Semisynthetic&opioid&synthesized&from&the&baine&(opioid&alkaloid&found&in&
the&Persian&poppy&and&opium&poppy)!
o Analgesic&properties&that&is&generally&indicated&for&relief&of&moderate&to&
severe&pain&in&acute&or&chronic&pain&management!
o Improves&quality&of&life&!
o Can&be&very&addictive!
o Controlled]release&oral&tablet&form&is&taken&every&12hrs!
o 2nd&line&alternative&to&oral&morphine&for&cancer&pain!
o Acts&on&/!and!/receptors&in&different&tissues!
o Inhibits&the&release&of&NT&from&the&presynaptic&terminal!
! Via&closing&Ca2+&channels&and&opening&K+&channels!
o Metabolized&by&CYP&enzymes&in&the&liver&so&it&can&be&influenced&by&
enhancers&or&inhibitors!
o Excreted&mainly&by&urine&and&sweat!
!
Hydramorphone:!
o Semi]synthetic&]receptor&agonist!
o Hydrogenated&ketone&of&morphine&that&shares&pharmacological&
properties&typical&of&opioid&analgesics!
o Analgesia,&drowsiness,&mental&clouding,&mood&changes,&euphoria,&
respiratory&depression,&cough&suppression,&decreased&GI&motility,&
nausea,&vomiting,&increased&CSF,&increased&biliary&pressure,&
miosis,&increased&PANS&activity&and&transient&hyperglycemia!
!
Synthetic!opioids!(Fentanyl,,Meperidine,,Methadone):!
o Methadone!
o High&bioavailability&when&taken&orally!
o Long&term&acting&&&Potent&analgesic&effects:!
! ]receptor&agonist!
! Blocks&NMDA&receptors&and&MAO&reuptake&system!
o Lower&euphoria&]&Treatment&of&morphine/diamorphine&addiciton!
o Meperidine!
o No&sedative&effects&but&has&antimuscarinic&action&!
o Works&as&a&strong&agonist&of&]receptors!
o Hallucinogenic&and&convulsing&effects!

& 87&
Sollas&Notes&2015&

o Does&not&effect&the&uterine&smooth&muscles&!
! Can&be&used&as&analgesia&during&labor!
o Adverse&effects:!
! Serotonin&syndrome!
o Fentanyl!
o Potent,&synthetic&opioid&analgesic&with&rapid&onset&and&short&
duration&of&action!
! Strong&agonist&of&]receptors!
o Commonly&used&clinically&for:!
! Cancer&pain&treatment!
! Pre]procedure&pain&reliever&and&anesthetic&when&used&in&
combination&with&benzodiazepine!
o 100x&more&potent&than&morphine&&&20x&more&potent&than&heroin!
o Transdermal!patch!
! Used&in&chronic&pain&management!
! Slowly&releasing&fentanyl&via&the&skin&into&the&bloodstream&
over&48]72hrs&]&Dosage&is&based&on&the&size&of&patch!
! Transdermal&absorption&rate&is&constant&at&a&constant&skin&
temperature,&skin&type,&amount&of&body&fat,&location&!
! Usually&prescribed&with&a&fast]acting&opiate&(morphine&or&
oxycodone)&to&handle&breakthrough&pain&(cancer&pain)!
! Good&for&use&in:& !
People&already&stabilized&on&other&opioids&who&have&
persistent&swallowing&problem&and&cannot&tolerate&
other&parenteral&routes&such&as&SC&administration!
People&with&moderate&to&severe&renal&failure!
People&that&have&too&many&side&effects&to&other&
forms&and&administrations&of&opioids!
o Adverse&effects&are&similar&to&the&other&opioids,&however:!
! Less&histamine&release&=&less&pruritus!
! Less&nausea&but&more&respiratory&depression!
!
Agonist/antagonist!drugs:!
The(analgesic(activity(of(mixed(agonistLantagonists(varies(with(the(individual(drug(but(is(somewhat(
less(than(that(of(strong(full(agonists(like(morphine.(Buprenorphine,,butorphanol,and,nalbuphine,
have(greater(analgesia(than(pentazocine,(which(is(similar(to(codeine(in(analgesic(effects).(
!
Receptors:!
o Butorphanol,,nalbuphine,and,pentazocine,!
o ]agonists&with&weak&]antagonist&activity!
! Nalbuphine,is&possible&resistant&to&naloxone&in&respiratory&depressive&
states!
o Buprenophine&is&a&partial&]agonist&with&weak&]&&&]antagonist&effects!
o Long&duration&of&action&binding&strongly&to&]receptors!
o Resistant&to&naloxone&reversal!
o These&characteristics&can&lead&to&decreased&analgesia&or&precipitate&withdrawal&
symptoms&when&these&drugs&are&used&by&patients&that&normally&take&full&]agonists!
o Naloxone,is&sometimes&included&in&these&drugs&to&discourage&abuse!
!
!
!
!

& 88&
Sollas&Notes&2015&

11.2&Antivirals&II:&ALL&except&for&antiretrovirals&
&
As(obligate(IC(parasites,(the(replication(of(viruses(depends(on(synthetic(processes(of(
the(host(cell.(Antiviral(drugs(can(exert(their(effects(at(several(stages(of(viral(
replication((viral(entry,(nucleic(acid(synthesis,(late(protein(synthesis(and(
processing,(final(stages(of(viral(packaging(and(virion(release).((
(
Antiherpes!drugs:!
Most&of&the&drugs&are&antimetabolites&that&are&bioactivated&via&viral&or&
host&cell&kinases&to&form&compounds&that&inhibit&viral&DNA&polymerases!
!
Acyclovir!(acycloguanosine):!
Guanosine&analog&active&against&herpes&simplex&virus&(HSV]1&and&HSV]2)&
and&varicella]zoster&virus&(VZV)!
Activated&to&form&acyclovir&triphosphate!
o Done&by&thymidine!kinase&"&viral]specific&phosphorylation!
Interferes&with&viral&synthesis&in&2&ways:!
o Competitive&substrate&for&DNA&polymerase&!
o Chain&termination&after&its&incorporation&into&the&viral&DNA!
Resistance&can&involve&changes&in&viral&DNA&polymerase&or&lack&of&
thymidine&kinase&(TK]&strains)!
o Also&cross]resistant&to&famiciclovir,,ganciclovir,&,valacyclovir!
Can&be&administered&orally,&topically&and&IV&(multiple&daily&doses)!
o Short&half]life&and&excreted&via&the&kidneys!
o Oral&administration&is&mainly&for&treatment&of&mucocutaneous&and&
genital&herpes&lesions,&prophylaxis&in&AIDS&and&IC&patients!
o IV&administration&is&used&for&severe&herpes&disease,&including&
encephalitis&and&neonatal&HSV&infections!
Toxic&effects:!
o Orally&&GI&distress&&&headache!
o IV&&Delirium,&tremor,&seizures,&hypotension,&nephrotoxicity!
Newer&drugs&that&are&related&to&acyclovir:!
o Valacyclovir,!
! Prodrug&that&is&converted&into&acyclovir&by&the&liver!
! Reaches&plasma&levels&3]5&times&greater&+&longer&half]life!
o Penciclovir&!
! Activated&by&the&same&mechanism&acyclovir&but&only&works&
on&DNA&polymerase&without&the&chain&termination!
o Famiciclovir!
! Prodrug&that&is&converted&to&penciclovir&by&first]pass&
mechanism&in&the&liver!
o Docosanol!
! Alipathic&alcohol&that&inhibits&fusion&btw&the&HSV&envelope&
and&plasma&membrane&and&by&that&inhibits&viral&entry!
! Used&topically&and&it&shortens&healing&time&of&lesions!
Ganciclovir:!
Guanine&derivative&that&is&triphosphorylated&to&form&a&nucleotide&that&
inhibits&DNA&polymerases&of&CMV&and&HSV&&causes&chain&termination!
First&phosphorylation&step&is&catalyzed&by&virus&specific&enzymes!

& 89&
Sollas&Notes&2015&

Usually&given&IV,&penetrates&well&to&tissues&(including&eye&and&CNS)!
o Oral&bioavailability&is&<10%&!
! Valganciclovir&is&a&prodrug&that&has&good&oral&bioavail.!
o Intraocular&implant&form&of&the&drug&is&used&in&CMV&retinitis!
Clinical&uses:& !
o Prophylaxis&and&treatment&of&CMV&retinitis&and&other&CMV&
infections&in&AIDS&and&IC&patients!
Toxic&effects:!
o Leukopenia,&thrombocytopenia,&mucositis,&hepatic&dys.,&seizures!
o When&used&with&zidovudine&or&other&myelosuppressive&agents!
! Severe&neutropenia!
Cidofovir:!
Activated&exclusively&by&host&cell&kinases&into&active&diphosphate!
o Inhibits&DNA&polymerase&of&HSV,&CMV,&adenovirus&&&HPV!
o Due&to&this&activation&mechanism&the&drug&is&useful&in&treatment&of&
many&acyclovir&and&ganciclovir&resistant&strains!
o Resistance&occurs&due&to&mutations&in&the&DNA&polymerase&gene!
Given&IV&and&undergoes&renal&elminaiton&(adjust&doses&+&good&hydration)!
Effective&in&CMV&retinitis,&mucocutaneous&HSV&and&genital&warts!
Nephrotoxicity&is&the&major&concern!
Foscarnet:!
Phosphonoformate&derivative&that&doesnt&require&phosphorylation!
Inhibits&viral&RNA&polymerase,&DNA&polymerase&and&HIV&reverse&
transcriptase!
Given&IV,&penetrates&well&to&tissues&(also&CNS)&and&eliminated&via&kidneys!
Used&as&an&alternative&for&prophylaxis&and&treatment&of&CMV&retinitis!
o Works&on&ganciclovir]resistant&strains!
Also&used&in&acyclovir]resistant&strains!
Adverse&effects&"&nephrotoxicity,&hypocalcemia,&genitourinary&
ulcerations,&headache,&hallucinations,&seizures!
Other!antiherpes!drugs:!
Vidarabine!
o Adenine&analog&that&works&on&HSV,&VZV&and&CMV!
o Used&topically&for&herpes&keratitis&and&systemic&infections!
o Systemic&use&is&limited&by&the&rapid&metabolic&rate!
! Can&be&toxic&and&cause&GI&irritation,&paresthesias,&tremors,&
convulsions&and&hepatic&dysfunction&+&teratogenicity&!
Idoxuridine,&,trifluridine!
o Pyrimidine&analogs&that&are&used&topically&in&herpes&keratitis!
o Too&toxic&for&systemic&use!
Fomivirsen!
o Antisense&oligonucleotide&that&binds&to&mRNA&of&CMV&and&inhibits&
early&protein&synthesis&&injected&intravitreally&in&CMV&retinitis!
o Can&cause&irits,&vitreitis&and&increased&intraocular&pressure!
!
!
!
!

& 90&
Sollas&Notes&2015&

Anti/influenza!agents:!
Amantadine,and,rimantadine!
o Inhibit&early&step&in&replication&of&Influenza&A&(not&B)!
o Prevent&uncoating&by&binding&to&a&protein&M2&!
! &A&proton&ion&channel&that&is&required&at&the&onset&of&
infection&to&permit&acidification&of&the&virus&core,&that&is&
needed&to&activate&the&viral&RNA&transcriptase!
o Used&as&prophylactic&drugs&agains&influenza&A&and&reduce&the&
duration&of&symptoms&if&given&within&48hrs&after&contact!
! Increased&resistance&to&amantadine&has&been&emerging&in&
the&last&2]3&years!
Some&H3N2&strains&and&H1N1&strains&have&resitance!
o Toxic&effects&include&GI&irritation,&dizziness,&ataxia,&slurred&speech!
o Rimantadine,works&similar&to&amantadine&but&has&a&longer&half]
life&and&requires&no&doses&adjustment&in&renal&failure!
Oseltamirvir,and,zanamivir!
o Inhibitors&of&neuraminidases&produced&by&influenza&A&&&B!
! Neuroaminidases&cleave&sialic&acid&residues&from&viral&
proteins&and&surface&proteins&of&infected&cells!
Function&to&promote&virion&release&and&to&prevent&
clumping&of&newly&released&virions&!
! Inhibitors&therefore&impede&viral&spread!
o Currently&active&agains&H3N2&and&H1N1&strains!
o &Oseltamirvir,is&a&oral&prodrug&that&is&activated&in&the&gut&and&liver!
! May&cause&GI&irritation!
o Zanamivir&is&administered&intranasally!
! May&cause&cough&and&throat&irritation&and&bronchospasms&
in&asthma&patients!
o Both&drugs&decrease&the&symptoms&but&work&best&if&given&withing&
24hrs&of&exposure&to&the&virus!
! When&taken&prophylactically&they&significantly&decrease&
risk&of&getting&infected&by&the&virus!
!
Agents!used!in!viral!hepatitis:!
The(agents(available(for(the(use(in(treatment(of(HBV(are(suppressive(rather(than(
curative.(However,(the(primary(goal(of(drugs(used(in(treatment(of(HCV(is(viral(
eradication.((
(
IFN/:!
A&cytokine&that&acts&through&host&cell&surface&receptor&(#&JAKS)!
o JAKS&phosphorylate&signal&transducers&and&activations&of&
transcription&(STATS)&to&increase&the&formation&of&antiviral&
proteins!
Selective&antiviral&action&is&primarily&due&to&activation&of&a&host&cell&
ribonuclease&that&likes&to&degrade&viral&mRNA&!
IFN]&also&promotes&the&formation&of&NK]cells&and&destroys&infected&cells!
Used&in&chronic&HBV&alone&or&in&combo&with&other&drugs&(ribavirin)!
o IFN]&+&ribavirin&reduces&progression&of&acute&HCV&to&chronic!
o Pegylated&IFN]&+&ribavirin&is&good&in&chronic&HCV!

& 91&
Sollas&Notes&2015&

Other&uses&include&treatment&of&Kaposis&sarcoma,&papillomatosis&and&
topical&treatment&of&genital&warts&!
o Prevention&dissemination&of&herpes&zoster&in&cancer&patients&and&
reduce&CMV&shedding&after&renal&transplants!
Toxicity&"&GI&irritation,&flue]like&syndromes,&neutropenia,&profound&
fatigue,&myalgia,&alopecia,&reversible&hearing&loss,&thyroid&dysfunction,&
mental&confusion&and&severe&depression!
Contraindicated&in&AI&diseases,&pregnancy&and&arrhythmias!
!
Adefovir!dipivoxil:!
Prodrug&of&adefovir&(phosphorylated&by&cellular&kinases)&that&
competitively&inhibits&HBV&DNA&polymerase&that&results&in&chain&
termination!
Good&bioavailability,&eliminated&by&the&kidneys!
The&drug&suppresses&HBV&replication&and&improves&liver&histology&and&
fibrosis!
Toxicity&"&nephrotoxicity&is&dose]limiting,&lactic&acidosis&and&severe&
hepatomegaly&with&steatosis&may&also&occur&
Entecavir:!
Guanosine&nucleoside&that&inhibits&HBV&DNA&polymerase!
Lamivudine:!
Nucleoside&inhibitor&of&HIV&reverse&transcriptase&that&is&active&in&chronic&
HBV&infections!
Has&longer&half]life&in&HBV&infections&than&in&HIV&infections&!
o So&lower&doses&than&in&HIV&treatments!
Monotherapy&rapidly&suppresses&HBV&replication&&&is&relatively&nontoxic!
o Resistant&strains&emerge&at&rate&of&20%&per&year&in&monotherapy!
o If&used&in&coinfections&of&HIV&&&HBV&"&can&cause&pancreatitis!
Ribavirin:!
Inhibits&replication&of&a&wide&range&of&DNA&and&RNA&viruses!
o Influenza&A&&&B,&parainfluenza,&RSV,&paramyxoviruses,&HCV&&&HIV!
Precise&mechanism&is&not&known!
o Inhibition&of&guanosine&triphosphate&formation!
o Prevention&of&capping&of&viral&mRNA!
o Blockage&of&RNA]dependent&RNA&polymerases!
Effective&orally&(worse&with&antacids),&IV&and&in&aerosolic&form!
Eliminated&by&kidneys!
Used&in&combo&with&IFN]&in&treatment&of&chronic&HCV&(monotherapy&NO)!
Early&IV&of&the&drug&decreases&mortality&in&viral&hemorrhagic&fevers!
Toxicity&"&systematically&the&drug&results&in&hemolytic&anemia,&aerosols&
may&cause&conjuctival&and&bronchial&irritation&+&teratogen!!!!
!
Newer!drugs!for!HBV:!
Telbivudine,and,tenofovir,!
o Similar&drugs&as&described&before&but&can&be&used&in&cases&of&
resistance&to&the&others!
!
!

& 92&
Sollas&Notes&2015&

11.3&Drugs&used&in&the&treatment&of&inflammatory&bowel&disease&
&
Drugs&used&in&chronic&inflammatory&bowel&disease&(IBD):&
Aminosalicylates,,5Paminosalicylic,acid,(5PASA),,Mesalamine!,
o Topical&therapy&for&
IBD,
o Precise&mechanism&is&
unknown&(involves&
inhibition&of&the&
synthesis&of&PG&and&
inflammatory&
leukotrienes&and&
cytokines),
Other,drugs,used,in,
treatment,of,Crohns,and,Ulcerative,colitis,
o Antibiotics,
o Glucocorticoids,
o Immunosuppressive(antimetabolites(,
! Azathioprine,,6Pmercaptourine,,methotrexate,
o AntiLtumor(necrosis(factor(drugs,
! Infliximab,
o Humanized(monoclonal(antibody(,
! Natalizumab,,
Blocks&integrins&on&circulating&leukocytes,
Only&used&for&severe&refractory&Crohns&dx,
Has&a&possible&association&with&multifocal&
leukoencephalopathy,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,

& 93&
Sollas&Notes&2015&

Topic&12&
12.1&Opioids&as&abused&drugs.&Treatment&of&morphine&&&heroin&dependence&
The(most(commonly(abused(drugs(in(this(group(are(heroin,,morphine,,codeine,,
oxycodone,,along(with(meperidine,&,fentanyl,(commonly(abused(by(health(
professionals).((
(
Effects:!
Effects&of&IV&heroin&are&described&by&abusers&as&a&rush&of&orgasmic&
feeling&followed&by&euphoria&and&then&sedation!
IV&administration&of&opioids&is&associated&with&rapid&development&of&
tolerance&and&psychological&and&physiological&dependence!
Oral&administration&or&smoking&of&opioids&causes&milder&effects&and&
slower&onset&of&tolerance&and&dependence!
Overdose&of&opioids&leads&to&respiratory&depression&progressing&to&coma&
and&death!
Overdose&is&managed&with&IV&naloxone&or&nalmefene&+&ventilatory&supp.!
Naloxone,,nalmefene,&,naltrexone,!
o Pure&opioid&receptor&antagonists&that&have&few&other&effects&at&
doses&that&produce&marked&antagonism!
o Have&greatest&affinity&for&the&]receptors!
o Used&in&the&management&of&acute&opioid&overdose!
o Naloxone,&,nalmefene(are&given&IV!
! Multiple&doses&might&be&needed&in&case&of&Naloxone!
It&has&a&half]life&of&1]2hrs!
! Half]life&of&nalmefene&is&8]12&hrs!
o Naltrexone&has&a&long&elimination&half]life&and&blocks&actions&of&
strong&]agonists&(e.g.&heroin)&for&up&to&48hrs&after&oral&use!
! Also&reduces&craving&for&ethanol!
Approved&in&alcohol&dependency&therapies!
Methylnaltrexone,&,almivopan!
o Newly&developed&antagonists&!
o Dont&cross&the&BBB&and&hence&only&work&on&peripheral&]R!
! Block&adverse&effects&of&strong&opioids&on&the&GI&tract&(that&
can&be&responsible&for&constipation)!
! Minimal&effects&on&analgesic&actions&and&without&
precipitating&an&abstinence&syndrome&(withdrawal&s.)!
Withdrawal:!
Deprivation&of&opioids&in&physiologically&dependent&individuals&leads&to&an&
abstinence&syndrome!
o Lacrimation,&rhinorrhea,&yawning,&sweating,&weakness,&gooseflesh,&
nausea,&vomiting,&tremor,&muscle&jerks&and&hyperpnea!
o Extremely&uncomfortable&but&very&rarely&leathal!
Treatment&involves&replacement&of&the&illicit&drug&with&a&pharmacological&
equivalent&agent&(e.g.methadone,,buprenorphine)&followed&by&a&slow&dose&
reduction!
Administration&of&opioid&antagonists&in&case&of&non&overdose&can&cause&more&
rapid&and&severe&abstinence&syndrome!

& 94&
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12.2&Antimalarial&agents&
&
Malaria(is(one(of(the(most(common(diseases(worldwide(&(a(leading(cause(of(death.(
Plasmodium(species(that(infect(humans(undergo(a(primary(developmental(stage(in(
the(liver(and(then(paracsitize(RBCs.(P.falciparum(and(P.malariae(have(only(1(cycle(
of(liver(cell(invasion.(The(other(species(have(a(dormant(hepatic(stage(responsible(
for(recurrent(infections(and(relapses.(
(
Antimalarial&agents:&
Chloroquine&
Mefloquine&
Primaquine&
Quinine&
Antifolates&
Other&drugs&
&
Chloroquine:!
4]aminoquinoline&derivative&that&is&rapidly&absorbed&orally,&widely&
distributed&to&tissues&and&extremely&large&volume&of&distribution!
Accumulates&in&the&food&vacuole&of&plasmodia&and&prevents&
polymerization&of&the&Hb&breakdown&product&heme&into&hemozoin!
o Intracellular&accumulation&of&heme&is&toxic&to&the&parasite!
Resistance&can&develop&via&increased&activity&of&membrane&pumps&or&
decreased&intravacuolar&accumulation&of&the&drug&via&a&transporter&
encoded&by&the&pfcrt(gene&(P.falciparum&chloroquine&resistant&transp.)!
DOC&for&attacks&of&nonfalciparum&and&sensitive&falciparum&malaria!
DOC&for&chemoprophylaxis&except&in&regions&that&are&resistant!
Only!blood!schizonticide!
Also&used&in&the&treatment&of&autoimmune&diseases&and&RA!
Toxicity!
o Low&doses&&skin&rashes,&GI&distress&&&headaches!
o High&doses&&severe&skin&lesions,&per.neuropathy,&myocardial&
depression,&retinal&damage,&auditory&impairment&and&toxic&
psychosis&+&porphyria&attacks&in&those&patients!
Quinine:!
Rapidly&absorbed&orally,&metabolized&and&excreted&via&kidneys!
o IV&given&in&severe&cases!
The&drug&makes&a&complex&with&dsDNA&to&prevent&strand&separation!
o Resulting&in&block&of&DNA&replication&and&transcription&of&RNA!
Only!blood!schizonticide!
Used&in&P.falciparum&infections&that&are&resistant&to&chloroquine!
Commonly&used&in&combo&with&doxycycline&or&clindamycin&to&shorten&
therapy&and&limit&toxicity&&also&used&as&prophylaxis!
Quinidine,(dextrorotatory&stereoisomer&of&quinine)&is&used&in&severe&or&
complicated&falciparum&infections&!
Toxicity&&commonly&causes&cinchonism!
o GI&distress,&headache,&vertigo,&blurred&vision&&&tinnitus!
Other&toxic&effects&in&case&of&high&doses&are:!

& 95&
Sollas&Notes&2015&

o Disturbed&cardiac&conduction,&hemolysis&(in&G6PDH&def.)!
o Blackwater&fever&(intravascular&hemolysis)&is&rare&but&fatal&in&
quinine&sensitized&patients!
Contraindicated&in&pregnancy!
!
Mefloquine:!
Synthetic&4]quinoline&derivative&that&is&only&given&orally.&MOA&not&known!
DOC&in&prophylaxis&in&areas&that&are&resistant&to&chloroquine!
Alternative&drug&in&acute&attacks&and&uncomplicated&infections&by&falcip.!
Resistance&has&emerged&in&S]Africa!
Toxicity&&GI&distress,&skin&rash,&headache,&dizziness,&cardiac&conduction&
defects,&psychiatric&disorders,&neurologic&symptoms&and&seizures!
!
Primaquine:!
Synthetic&8]aminoquinoline&given&orally&and&metabolized&extensively!
Tissue!schizonticide!
Limits&malaria&transmission&by&acting&as&a&gametocide!
Used&to&treat:!
o Liver&stages&of&P.vivax(and(P.ovale(!
o Should&be&used&in&combo&with&blood!schizonticide!
o Not&active&alone&for&acute&attacks!
o Used&daily&as&a&prevention!
Usually&well&tolerated&but&contraindicated&in&pregnancy!
!
Antifolate!drugs:!
Pyrimethamine,,proguanil,,sulfadoxine,&,dapsone!
All&absorbed&orally&and&excreted&in&urine!
Either&inhibit&dihydropteroate&synthase&or&dihydrofolate&reductase!
Used&in&combo&to&provide&sequential!blockade!of&2&steps&in&folate&synt.!
Blood!szhizonticides!mainly&for&P.falciparum&!
Toxicity&&skin&rashes,&GI&distress,&hemolysis,&renal&damage,&drug&interact.!
!
Other!antimalarial!drugs:!
Doxycycline!
Amodiaquine!
Atovaquone!
Halofantrine!
Artesunate,,artemether,,dihydroartemisinin!
!
Drugs!for!prevention!of!malaria!in!travelers:!
Chloroquine,(1/week&prophylaxis):&regions&w/o&resistant&P.falciparum(!
Mefloquine,(1/week&propylaxis):&regions&with&resistant&P.falciparum,
Doxycycline/Malarone,(1/day&prophylaxis):&regions&w.&multiresistant&
P.falciparum,
Primaquine&(1/day&for&14&days)&as&terminal&prophylaxis&against&P.vivax(
and(P.(ovale,
&

& 96&
Sollas&Notes&2015&

12.3&Laxatives,&GLP?1&analogs,&DPP?4&inhibitors&and&SGLT?2&inhibitors&in&the&
treatment&of&diabetes&
&
Laxatives:&
Drugs&that&increase&the&probability&of&bowel&movement&by&several&
mechanisms:&
o Irritant&or&stimulating&action&of&the&bowel&wall&
! Aloe,&senna,&cascara,&castor&oil,&bisacodyl&
o Bulk]forming&action&on&the&stool&evoking&reflex&contrac.&of&bowels&
! Psyllium,&methylcellulose,&polycarbophil&
o Softening&action&on&hard/impacted&stools&
! Docusate,&glycerin,&mineral&oil&
o Lubricating&action&that&eases&passage&of&stool&through&rectum&
! Osmotic:&
Magnesium&oxide,&sorbitol,&lactulose,&magnesium&
citrate,&sodium&phosphate,&polyethylene&glycol&
! Chloride&channel&activator&
Lubiprostone&
o Pain&relief&function&
! Methulnaltrexone,&alvimopan&
Exenatide:!
! Glucagon]like&peptide&1&(GLP]1)&analog&that&stimulates&insulin&release,&
slows&gastric&emptying,&inhibits&glucagon&secretion&&&produces&satiety!
! Used&in&combo&with&metformin&or&sulfonylurea&in&treatment&of&DM&type&2!
! Toxicity&&hypoglycemia,&vomiting&(mainly&first&times),&acute&pancreatitis!
Sitagliptin:!
! Oral&inhibitor&of&dipeptidyl&peptidase&4&(DPP]4)&that&is&an&enzyme&that&
normally&degrades&GLP]1!
! Mono&or&combotherapy&with&metformin&!
! &Same&effects&of&exenatide!
SGLT2/inhibitors:!
! Lead&to&a&reduction&in&blood&glucose&levels!
! Potential&use&in&the&treatment&of&DM&type&II!
! Several&drug&candidates&have&been&developed&or&are&currently&undergoing&
clinical&trials!
! Dapagliflozin!
o Inhibits&subtype&2&of&the&sodium]glucose&transport&proteins&!
! These&are&responsible&fore&ate&least&90%&of&glucose&
reabsorption&in&the&kidney!
! Blocking&this&mechanism&causes&blood&glucose&to&be&
eliminated&through&the&urine!
o In&clinical&trials&it&shows&to&lower&HbA1c&by&0.9%&when&added&to&
metformin!
o Application&is&orally&and&the&drug&is&generally&well&tolerated!
o Can&be&used&together&with&insulin,&sulfonylureas&and&biguanides!
!
!

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 Sollas&Notes&2015&

Topic&13&
13.1&Drugs&of&abuse&
&
Drug(of(abuse(is(usually(means(the(use(of(an(illicit(drug(or(the(excessive(or(nonmedical(use(
of(a(licit(drug.(Primary(motivation(for(drug(abuse(is(the(feeling(of(pleasure(derived(from(
CNS(effects.(Physiological(dependence(is(usually(just(called(dependence(while(
psychological(dependence(is(termed(addiction.,
!
CNS!stimulants! Cocaine! Amphetamines!
!
NT(involved( NE,&DA,&5]HT& NE,&DA,&5]HT&
Mechanisms(of(action( Blocks&DA,&NE&and&5HT&reuptake&in&the&CNS;& Blockade&of&reuptake&of&NE&and&DA,&release&
local&anesthetic&action&from&Na+&channel& amines&from&mobile&pool&and&act&as&weak&
blockade.& MAO&inhibitors&
DA&probably&the&reason&for&the&development&
of&addiction&
Effects( Increased&NE:&&
Sympathomimetic&effects&with&#HR&and&contractility&
BP&changes&,&Mydriasis,&Central&excitation,&Hyperactivity&
Increased&DA:&
Psychotic&episodes,&paranoia,&hallucinations&
Possible&dyskinesias,&Endocrine&distrubances&
Increased&5]HT&
Behavioural&changes,&Aggressiveness,&Dyskinesias,&$&appetite&
Toxicity( Excess&NE&
Cardiac&arrhythmias,&generalized&ischemia&with&possible&MI&and&strokes;&acute&
renal/hepatic&failure&
Excess&DA:&
Major&psychosis,&cocaine&delirium&
Excess&DA,&NE&and&5]HT:&
Convulsion,&hyperpyrexia&&&death&
Withdrawal( Craving,&severe&depression,&anhedonia,&anxiety&
Management&is&done&with&antidepressants&
!
!
CNS!depressants! Benzodiazepines! Barbiturates!&!Ethanol!
!
NT(involved( GABA& GABA&
Mechanism(of( Potentiation&of&GABA,&interaction&with& Prolongation&of&GABA,&GABA&mimetic&at&
action( GABAA&receptors&involves&BZ1&and&BZ2& high&doses,&on&GABAA&receptors&
binding&sites&
Effects( Light&to&moderate&CNS&depression& Any&levels&of&CNS&depression&
Toxicity( Sedation,&anterograde&amnesia& Severe&CNS$,&respiratory&depression&
Overdose&is&potentially&reversible&with&IV& and&death.&Overdose&NOT&reversible&
flumazenil, with&flumazenil,&
Withdrawal( Rebound&insomnia&and&anxiety& Agitation,&anxiety,&hyperreflexia,&life]
threatening&seizures&+&delusions&&&
hallucinations&(delirum&tremens)&
Treat&with&IV&lorazepam&
!
!
!
!

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Sollas&Notes&2015&

Opioids! Morphine,!heroin,!fentanyl,!methadone!and!other!opioids!
NT(involved( NE,&DA,&5]HT,&GABA&and&many&others&
Mechanism(of(action( Activate&opioids&,&,&&receptors.&Potent&&receptor&activators&
have&the&most&intense&abuse&and&dependence&liability&(possible&
due&to&increase&in&dopaminergic&transmission&in&the&meso]
limbic&tracts&(nucleus&accumens&&addiction&nucleus)&
Effects( Euphoria,&analgesia,&sedation,&cough&suppression,&constipation&
and&strong&miosis&(except&for&meperidine)&
Toxicity( Respiratory&depression,&coma,&nausea,&vomiting,&midrosis&
Can&be&reversed&with&IV&naloxone&&
Withdrawal( Yawning,&lacrimation,&sweating,&restlessness,&centrally&
originating&pain,&muscle&cramping,&diarrhea&
Not&life]threatening&withdrawals&&but&very&uncomfortable&
Management&with&clonidine,,methadone,
!
Hallucinogens! Marijuana!! Hallucinogens!(LSD,!
mescaline,!psilocybin)!
NT(involved( Many& 5]HT&
Mechanism(of(action( Interaction&of&THC& Interaction&with&several&
(tetrahydrocannabinol)&with&CB1& subtypes&of&5]HT&receptors&
and&CB2&receptors&in&CNS&and&
periphery&(here&the&drug&work&as&
an&immunomodulator)&
Effects( Sedation,&euphoria,&#&HR,&red& Hallucinations,&
conjunctiva/&rabbits&eyes& sympathomimetic,&
(vasodilation),&delusions,& dyskinesias&
hallucinations,&incontrollable&
laughter&
Munchies&(#appetite)&
Toxicity( Flashbacks&(patient&is&not&taking& !
the&drug&but&acts&like&hes&taking&
the&drug)&+&toxicity&associated&
with&smoking&(cancers,&COPD,&CV&
diseases&etc.)&
!
Miscellaneous!drugs!
PCP!!phencyclidine! NMDA]receptor&antagonist,&extremely&toxic.&
(angel!dust)! Horizontal&and&vertical&nystagmus,&paranoia,&rhabdomyolysis&
Tremendous&strength&due&to&activation&of&peripheral&nicotinic&
NMJ&receptors!&Superhuman&strength.&&
Overdose&is&common&with&convulsions&and&death&
Ketamine!(special!K)! Related&to&but&milder&than&PCP&&glutamate&R.&antagonist&
Hallucinations,&vivid&nightmares&
Anticholinergics! Scopolamine&&atropine&like&effects&
Can&cause&3Cs:&cardiotoxicity,&convulsions&and&coma&
MDMA!(ecstasy),! Designer&drugs&(made&by&chemists)&&amphetamine&like&&
MDA,!MDEA! Strong&5]HT&pharmacology&and&act&as&hallucinogens&
Generally&neurotoxic&
Serotonin&syndrome&
Users&that&take&these&drugs&commonly&forget&to&drink&water&
and&therefore&the&most&common&cause&of&death&is&related&to&
severe&dehydration&leading&to&renal&failure&
Inhalants! Solvent&abuse&(gas,&glue&etc.)&&cause&multiple&organ&damage&

& 99&
Sollas&Notes&2015&

!
Some!extra!drugs!that!are!commonly!abused:!
!
Flunitrazepam,(Rohypnol),
o A&rapid&onset&Benzodiazepine&that&is&used&as&a&date&rape&drug&
o Chloral&hydrate&and&y]hydroxybutyrate&(GHB)&
! Usually&added&to&alcohol&$&the&victims&responses&to&resist&
o Y]hydroxybutyrate&is&minor&metabolite&of&GABA&
! Binds&to&GABAB&receptors&in&the&CNS&
o GHB&causes&euphoria,&enhances&sensory&perception&and&amnesia&when&
used&as&a&club&drug&
&
Caffeine!and!Nicotine!(more&on&nicotine&in&topic&27.1)&
Effects&
Tobacco&use&is&associated&with&CV,&respiratory&and&neoplastic&diseases&
Addiction&for&both&of&them&have&been&known&but&recently&demonstration&of&
abstinence&signs&and&symptoms&has&provided&evidence&of&dependence&
Withdrawal&
Caffeine"&lethargy,&irritability&and&headache&
Anxiety&&&mental&discomfort&from&quitting&nicotine&&
Varenicline,
o A&partial&agonist&at&the&ACh]NR&(22)&&
o It&occludes&the&rewarding&effects&of&nicotine&
o Is&used&for&smoking&cessation&
Rimonabant,
o A&agonist&at&cannabinoid&receptors&that&is&approved&for&use&in&obesity&
o Off&label&use&in&smoking&cessation&
Toxicity&
Acute&toxicity&from&both&include&
o Excessive&CNS&stimulation&with&tremor,&insomnia&and&nervousness&
o Cardiac&stimulation&and&arrhythmias&
Nicotine&can&cause&respiratory&paralysis&
o Severe&toxicity&in&children&ingesting&nicotine&gum/patches&
,
Dextroamphetamine,and,metamphetamine,(speed),
Crystal,form,of,metamphetamine&called&ICE&can&be&smoked,
Chr.&high]dose&abuse&leads&to&psychotic&state&with&delusions&&paranoia&,
Symptoms&include&agitation,&restlessness,&tachycardia,&hyperthermia,&
hyperreflexia&and&maybe&seizure,
No&specific&antidote&"Control&body&temperature&and&protection&against&cardiac&
arrhythmia&and&seizures,
Chr.abuse&"&necrotizing&arteritis,&cerebral&hemorrhage&&&renal&failure,
!
Steroids!
Anabolic&steroids&are&controlled&substances&]&Potential&for&abuse!
Effects!
o Increase&in&muscle&mass&and&strength&]]&No&euphoria!
o Excessive&use&can&have&adverse&effects!
! Behavioral&(increased&libido&and&aggression)!
! Cardiovascular&(MI)&&&Musculoskeletal&!
o Acne,&premature&closure&of&the&epiphyses&and&masculinization&in&females!
o Hepatic&dysfunction&&
o Withdrawal&syndrome&"&fatigue&and&depression&of&mood&

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Sollas&Notes&2015&

13.2&Indirectly&acting&parasympathomimetics&
&
Indirectly&acting&agonists:&
2&major&chemical&classes&
o Carbamic&acid&esters&(carbamates)&&e.g.&neostigmine&
o Phosphoric&acid&esters&(organophosphates)&&e.g.&parathion&
3rd&chemical&class&
o Only&one&drug&has&clinical&significance&&edrophonium&(alcohol)&
Mechanisms:&
All&classes&are&inhibitors&that&bind&to&cholinesterase&and&undergo&rapid&
hydrolysis&&this&causes&as&release&of&the&alcohol&portion&of&the&molecule&
to&be&released.&The&acidic&(carbamate&or&phosphate)&part&is&released&more&
slowly,&which&causes&the&inhibition&of&binding&and&hydrolysis&of&
endogenous&ACh.&This&results&in&amplification&of&the&affects&of&ACh&
wherever&the&transmitter&is&released&in&the&body&
&
Examples&of&indirectly&acting&cholinomimetics:&
All&members&act&on&both&N&and&M&receptors&
Edrophonium&&alcohol,&poor&lipid&sol.&(quaternary&structure),&not&orally&
active,&duration&of&action&5]15min&
o Used&to&diagnos&myasthenia&gravis&from&cholinerginc&crisis&
Neostigmine&&carbamate,&poor&lipid&sol.&(quaternary&structure),&orally&
active,&duration&of&action&30min]2hrs&
o Used&to&treat&myasthenia&gravis&and&also&antidote&to&curare&
Phyostigmine&&carbamate,&good&lipid&sol.&(tertiary&structure),&orally&
active,&duration&of&action&30min]2hrs&
o Antidote&in&atropine&overdose&
Pyridostigmine&&carbamate,&poor&lipid&sol.&(quaternary&structure),&
orally&active,&duration&of&action&4]8hrs&
Echothiopate&&organophosphate,&moderate&lipid&sol.,&duration&of&action&
2]7&days&
o Used&in&treatment&of&glaucoma&
Parathion&&organophosphate,&high&lipid&sol.,&duration&of&action&7]30days&
&
Clinical&uses:&
Carbamates&(neostigmine,!physostigmine,!pyridostigmine!and!
ambenonium)&are&used&much&more&than&organophosphates&
These&drugs&are&used&in&the&treatment&of&myasthenia&gravis&
Rivastigmine&(a&carbamate)&is&used&in&the&treatment&of&Alzheimers&dx.&
Organophosphates&are&mainly&used&as&scabicide&(malathion)&and&an&
antihelminthic&agent&(metrifonate)&
Edrophonium!is&used&for&the&rapid&reversal&of&nondepolarizing&NM&
blockade&for&the&diagnosis&of&myasthenia&gravis&and&its&differentiation&
from&cholinergic&crisis&&since&distinguishing&btw.&these&two&condition&is&
difficult&&
&
Toxicity:&
Especially&organophosphates&that&are&used&as&pesticides&have&toxic&behavior.&Most&toxic&
is&parathion&that&can&be&rapidly&lethal&if&antidote&is&not&administered&rapidly&upon&

& 101&
Sollas&Notes&2015&

exposure&(muscarinic&antidote&is&atropine!!no&effects&on&N&receptor&toxicity).&Nicotinic&
toxicity&is&treated&with&regenerating&active&ChE&(pralidoxime)&
DUMBBLESS&symptoms&(diarrhea,&urination,&miosis,&broncoconstriction,&bradicardia,&
excitation&of&sk.muscles&and&CNS,&lacrimation,&salivation&and&sweating)&
&
Effects&of&direct&and&indirect&cholinomimetics&on&major&organ&systems:&
CNS&&
o Complex&stimulatory&effects&
o Nicotine:&elevates&mood,&alerts&and&is&addictive&
o Phyostigmine:&convulsions&and&in&excessive&CC&causes&coma&
Eye&
o Contraction&(miosis)&of&the&sphincter&muscle&of&the&iris&
o Contraction/cyclospasms&of&the&ciliary&muscle&to&accommodate&
near&vision&and&facilitate&outflow&of&aqueous&humor&into&the&canal&
of&Schlemm&&&
Heart&
o SA&node&&negative&chronotropic&effects&(decreased&firing&rate)&
! Note:&Baroreceptor&reflexes&are&activated&due&to&the&lower&
blood&pressure;&this&causes&a&compensatory&sympathetic&
discharge&to&the&heart&that&can&cause&tachycardia&
o Atria&&negative&ionotropic&effects&(decrease&in&contractile&force)&
! This&causes&a&decrease&in&the&refractory&period&
o AV&node&&negative&dromotropic&effects&&
! Decreased&conduction&velocity&which&causes&an&increase&in&
the&refractory&period&
o Ventricles&&small&negative&ionotropic&effects&
Blood&vessels&
o Dilation&via&the&release&of&EDRF&(endothel.derived&relaxing&factor)&
! NO&and&possibly&other&relaxing&substances&&
o Not&a&direct&action&of&cholinomimetics&on&the&blood&vessels&
Bronchi&
o Bronchoconstriction&
GI&tract&
o Increase&in&SM&contraction,&peristalsis&&increased&motility&
o Decreased&in&tone,&relaxation&of&sphincter&muscles&&
! Except&the&gastroesophageal&sphincters&that&contracts&
Urinary&bladder&
o Increased&contraction&of&the&detrusor&muscle&
o Relaxation&of&the&bladder&trigone&&&sphincters&that&causes&voiding&
Skeletal&muscles&
o Activation&of&NM&end&plates&that&results&in&contraction&
Exocrine&glands&
o Increased&secretion&
! Thermoregulatory&sweating,&lacrimation,&salivation,&
bronchial&secretion&and&GI&gland&secretion&
(
&

& 102&
Sollas&Notes&2015&

13.3&Anti?diarrheal&drugs.&Antihelminthic&drugs&
&
Antidiarrheal!agents:!
Most&effective&are&the&opioids&and&their&derivatives&
o Selective&for&their&maximal&antidiarrheal&effect&and&their&minimal&
CNS&involvement&
! Diphenoxylate,&,loperamide&
Meperidine&analogs&w.&very&weak&analgesics&effects&
o Diphenoxylate&
! Formulated&with&anti]muscarinic&alkaloids&(e.g.&atropine)&to&
reduce&the&likelihood&of&abuse&
o Loperamide&&
! &Formulated&alone&
o Kaolin&
! Naturally&occurring&hydrated&magnesium&aluminum&silicate&
! Combined&with&pectin,(an&indigestible&CH&derived&from&
apples)&
! Popular&OTC&drug&that&absorbs&bacterial&toxins&and&fluid&
! Reduced&liquidity&of&the&stools&is&achieved&
&
Antihelminthic!drugs:!
(
Antihelminthic(drugs(have(diverse(chemical(structures,(mechanisms(of(action(and(
properties.(Many(act(against(specific(parasites,(and(few(are(devoid(of(significant(
toxicity(to(host(cells.(In(addition(to(the(direct(toxicity(of(the(drugs,(reactions(to(dead(
and(dying(parasites(may(cause(serious(toxicity(in(patients.(The(drugs(are(divided(
into(three(main(groups:(
Drugs(effective(against(nematodes(
o Albendazole,,Diethylcarbamazine,,Ivermectin(
o Mebendazole,,Pyrantel,pamoate(
Drugs(effective(against(trematodes(
o Bithionol,,Metrifonate,,Oxamniquine,,Praziquantel(
Drugs(effective(against(cestodes(
o Albendazole,,Mebendazole,,Niclosamide,,Praziquantel(
(
Albendazole:!
Works&via&inhibition&of&the&microtubule&assembly&
Larvicidal,in:&ascariasis,&cystercercosis,&hookworm&&&hyatid&disease&&
Ovicidal,in:&ascariasis,&ancyclostomiasis&&&trichuriasis&
Wide&antihelminthic&spectrum&
DOC&in:&Ascariasis,&hookworm,&pinworm&and&whipworm&infections&
Alternative&in:&Threadworm&infections,&filariasis&and&both&visceral&&&
cutaneous&larva&migrans&
Also&used&in&hydatid&disease&and&against&pork&tapeworm&in&larval&stage&
Toxicity:&
o Few&toxic&effects&occur&during&short&therapies&(1]3days)&
o Prolonged&treatment&can&cause&reversible&leukopenia,&alopecia&and&
elevated&liver&enzymes&

& 103&
Sollas&Notes&2015&

o Long&term&animal&toxicity&show&bone&marrow&suppression&and&
fetal&toxicity&
o Not&used&in&pregnancy&and&in&young&children&
Diethylcarbamazine:!
Works&via&immobilization&of&microfilament&by&an&unknown&mechanism!
DOC&in:!
o Filarial&infections&(Wucheria(bancrofti,(Burgia(malayi)!
o Eye&infections((Loa(loa)!
Toxicity:!
o Headache,&malaise,&weakness,&anorexia!
o Reactions&can&occur&by&proteins&released&by&dying&filariae&!
! Fever,&rashes,&ocular&damage,&joint&and&muscle&pain&&&
lymphangitis!
o Reactions&can&also&occur&in&onchocerciasis&&more&severe!
! All&the&above&symptoms&plus&hypotension,&pyrexia,&
respiratory&distress&and&extreme&exhaustion&!
Ivermectin:!
Intensifies&]aminobuteric&acid&(GABA)]mediated&neurotransmission&in&
nematodes&and&cause&immobilization&of&paracites!
o Facilitating&their&removal&by&the&RES!
o Selective&toxicity&results&due&to&the&fact&the&GABA&is&only&located&in&
the&CNS&of&humans!
o The&drug&does&not&cross&the&BBB!
DOC&in:&Onchocerciasis,&cutaneous&larva&migrans,&strongyloidiasis!
Toxicity:!
o Reactions&to&the&dying&worms&in&onchocerciasis&&short&duration!!
! Fever,&headache,&dizziness,&rashes,&itching,&tachycardia,&
hypotension,&joint&pain,&muscle&pain&and&LN&enlargement!
These&reactions&can&usually&be&prevented&with&
antihistamines&and&NSAIDS!
o Not&used&in&pregnancy&and&be&careful&when&taking&other&drugs&that&
enhance&GABA&activity&in&the&body!
Mebendazole:!
Acts&by&selectively&inhibiting&microtubular&synthesis&and&glucose&uptake&
in&nematodes!
DOC&in:&Ascariasis,&pinworm,&whipworm!
Backup&drug&in:&Visceral&larva&migrans!
Less&of&10%&of&the&drug&is&absorbed&systemically&after&oral&administration!
o Metabolized&rapidly&by&liver&enzymes!
o Plasma&levels&may&decreased&by&carbamazepine&or&phenytoin!
o Plasma&levels&may&be&increased&by&cimetidine!
Toxicity:!
o Usually&only&GI&irritation&&&contraindicated&in&pregnancy&!
o High&doses&can&cause&agranulocytopenia&and&alopecia!
Piperazine:!
Paralyzes&ascaris&by&acting&as&an&agonist&at&GABA&receptors!
o Paralyzed&worms&are&expelled&live&by&normal&peristalsis!
Used&as&an&alternative&drug&for&ascariasis!

& 104&
Sollas&Notes&2015&

Toxicity:!
o Mild&GI&irritation!
o Not&used&in&pregnancy&or&in&patients&with&hepatic&or&renal&
dysfunction&or&in&patients&with&seizures!
Pyrantel!Pamoate:!
Stimulates&nicotinic&receptors&present&at&neuromuscular&junctions&of&
nematodes&causing&muscular&contractions&followed&by&a&depolarization]
induced&paralysis!
o Doesnt&work&on&flukes&or&tapeworms!
o Wide&activity&against&nemotodes!
! Kills&adult&worms&in&the&colon&but&not&the&eggs!
DOC&for&hookworms&and&roundworm&infections!
Alternative&drug&for&pinworms!
Poorly&absorbed&when&given&orally!
Toxicity:!
o GI&irritation,&headache&and&weakness!
o Use&with&caution&in&patients&with&hepatic&dysfuncion!
Thiabendazole:!
In&same&family&as&mebendazole&and&works&similarly&on&microtubules!
The&drug&has&anti]inflammatory&and&immunorestorative&actions&on&host!
Toxicity:!
o Much&more&toxic&than&other&drugs!
o GI&irritation,&headache,&dizziness,&drowsiness,&leukopenia,&
hematuria&and&allergic&reactions&+&intrahepatic&cholestasis!
o Reactions&caused&by&dying&parasites:!
! Fever,&chills,&lymphadenopathy&and&skin&rash!
! Irreversible&liver&failure&&&fatal&Stevens]Johnson&syndrome!
! Avoid&in&pregnancy&or&patients&with&hepatic&or&renal&
disease!
Praziquantel:!
Increases&the&membrane&permeability&to&calcium!
o Causing&marked&contraction&and&then&paralysis&of&the&muscles&in&
trematodes&and&cestodes!
o Followed&by&vacuolization&and&parasite&death!
Wide&antihelminthic&spectrum&(both&for&trematodes&and&cestodes)!
DOC&in:!
o Schistosomiasis&(all&species),&clonorchiasis&and&pargonimiasis!
o Infections&caused&by&small&&&large&intestinal&flukes!
o Used&in&combo&with&niclosamide&to&fight&infections&by&cestodes!
Alternative&agent&in&treatment&of&cysticercosis!
Toxicity:!
o Headache,&dizziness,&drowsiness,&malaise,&GI&irritation,&skin&rash&
and&fever!
o Neurologic&effects&can&occur&in&treatment&of&neurocyticercosis!
! Intracranial&hypertension&and&seizures!
o Corticosteroids&can&decrease&the&risk&of&most&serious&side&effects!
o Contraindicated&in&ocular&cysticercosis!
o Shows&increased&risk&of&abortion&in&animal&models!

& 105&
Sollas&Notes&2015&

Bithionol:!
Co]drug&of&choice&in&the&treatment&of&fascioliasis&(sheep&liver&fluke)!
Alternative&agent&in&paragonimiasis!
Mechanism&of&action&is&not&known!
Toxicity:!
o Nausea,&vomiting,&diarrhea,&abdominal&cramps,&dizziness,&skin&rash&
(possibly&due&to&the&dying&worms),&phototoxicity!
o Less&frequently;&pyrexia,&tinnitus,&proteinuria&&&leukoplania!
Metrifonate:!
Organophosphate&prodrug&that&is&converted&in&the&body&to&cholinesterase&
inhibitor&called&dichlovos!
Only&used&for&Schistosoma(haematobium!
Contraindicated&in&pregnancy!
Oxamniquine:!
Only&used&for&Schistosoma(mansoni&!
o Acts&on&male&immature&forms&and&adult&schistosomal&forms!
Causes&paralysis&of&the&worms&via&an&unknown&mechanism!
Toxicity:!
o Dizziness,&headache,&GI&irritation,&pruritus!
o Reactions&against&the&dying&worms:!
! Eosinophilia,&urticarial,&pulmonary&infiltrates!
o Not&used&in&pregnancy&or&in&patients&with&seizures!
Niclosamide:!
Acts&by&uncoupling&oxidative&phosphorylation&or&activating&ATPases!
Alternative&drug&to&praziquantel&for&infections&caused&by&beef,&pork&and&
fish&tapeworms&&NOT&effective&in&cysticercosis&or&hydatid&dx.!
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&

& 106&
Sollas&Notes&2015&

Topic&14&
14.1&Pharmacology&of&alcohols&&
Ethanol!
Pharmacokinetics&
After&ingestion&ethanol&is&rapidly&and&completely&absorbed&
o The&drug&is&then&disturbed&to&most&body&tissues&
o Two&enzyme&system&metabolize&ethanol&to&acetaldehyde&
Alcohol&dehydrogenase&(ADH)&
o Cytosolic&and&NAD+]dependent&enzymes&
o Found&in&liver&and&gut&
o Accounts&for&the&metabolism&of&low&to&moderate&doses&of&ethanol&&
o Has&zero]order&kinetics&
! 7]10&g/h&metabolized&
o GI&metabolism&is&lower&in&women&than&in&men&
o Genetic&variations&in&ADH&affects&the&rate&of&metabolism&
Microsomal&ethanol]oxidizing&system&(MEOS)&
o Blood&ethanol&levels&higher&than&100mg/dl&
! Phase&1&contributes&with&the&metabolism&
! Via&microsomal&mixed&function&oxidase&system&&
o Chr.&ethanol&consumption&induces&CYP&synthesis&&&MEOS&activity&
! Somewhat&responsible&for&ethanol&tolerance&development&
! Primary&isoform&is&CYP2E1&
Converts&acetaminophen&to&hepatotoxic&metabolites&
Acetaldehyde&formed&from&the&oxidation&of&ethanol&
o By&either&ADH&or&MEOS&
o Further&metabolized&to&acetate&by&aldehyde&dehydrogenase&
o Aldehyde&dehydrogenase&found&in&liver&and&many&other&tissues&
! This&enzyme&is&inhibited&by&disulfiram&and&other&drugs&
Metronidazole,,oral,hypoglycemic,,cephalosporins,
! Some&Asians&have&genetic&deficiency&
Get&nausea&and&flushing&reaction&after&ingestion&of&
alcohol&due&to&accumulation&of&Acetaldehyde&
Acute&effects&
CNS&
o Major&acute&effects&are&sedation,&loss&of&inhibition,&impaired&
judgment,&slurred&speech&and&ataxia&
o Ethanol&levels&in&blood&
! 60]80&mg/dl&disturbs&driving&ability&
! 120]160&mg/dl&gross&drunkenness&
! Greater&than&300&mg/dl&may&lead&to:&
Loss&of&consciousness,&anesthesia,&coma&with&fatal&
respiratory&or&cardiovascular&depression&
! Greater&than&500mg/dl&are&usually&lethal&
! People&with&higher&tolerance&can&function&better&than&those&
with&less&tolerance&
o Additive&CNS&depression&occurs&with&ingestion&of&ethanol&together&
with&other&CNS&depressants&

& 107&
Sollas&Notes&2015&

! Sedative]hypnotics,&opioids&agonist,&drugs&that&block&
muscarinic&and&H1&receptors&
! Molecular&mechanism&is&not&understood&
! No&specific&receptors&
! Ethanol&appears&to&modulate&the&function&of&a&number&of&
signaling&proteins&
! Acts&on&GABAA&by&facilitating&the&action&of&GABA&
Inhibits&the&GABA&activation&of&NMDA&receptors&thus&
modifying&activity&of&adenylyl&cyclase,&PLC&and&ion&
channels&
Other&organ&systems&
o Low&blood&concentration&depresses&the&heart&
o Relaxation&of&Smooth&muscle&"&vasodilation,&sometimes&
hypothermia&
Chronic&effects&
Tolerance&and&dependence&
o Tolerance&occurs&mainly&due&to&CNS&adaptation&
o By&an&increased&rate&of&ethanol&metabolism&
o Cross]tolerance&to&sedative&hypnotic&drugs&
! Facilitate&GABA&activity&
o Both&psychological&and&physical&dependence&are&marked&
Liver&
o Liver&is&the&MC&complication&of&chronic&alcohol&abuse&
o Loss&of&liver&function&occurs&with&reversible&fatty&liver&progressing&
to&irreversible&hepatitis,&cirrhosis&and&liver&failure.&
o Hepatic&dysfunction&more&severe&in&women&
GI&system&
o Irritation,&inflammation,&bleeding&and&scarring&of&the&gut&wall&
occur&after&chronic&heavy&use&of&ethanol&
o May&cause&absorption&defects&and&nutrional&deficiencies&
o High&risk&of&pancreatitis&
CNS&
o Peripheral&neuropathy&is&the&MC&neurologic&abnormality&
o Wernicke]Korsakoff&syndrome&
! Thiamine&deficiency&along&with&alcohol&abuse&&
! Ataxia,&confusion&and&paralysis&of&the&extraocular&muscles&
Treatment&with&parenteral&thiamine&is&essential&to&
prevent&a&permanent&memory&disorder&
o Korsakoff`s&psychosis&
Endocrine&system&
o Gynecomastia,&testicular&atrophy&and&salt&retention&can&occur&
! Due&to&altered&steroid&metabolism&in&the&cirrhotic&liver&
Cardiovascular&system&
o Hypertension,&anemia&and&dilated&cardiomyopathy&
o Acute&drinking&for&many&days&can&cause&arrhythmias&
o Modest&quantities&of&ethanol&(10]15&g/day)&raises&serum&levels&of&
high]density&lipoprotein&(HDL)&cholesterol&
! May&protect&against&coronary&heart&disease&
Fetal&alcohol&syndrome&

& 108&
Sollas&Notes&2015&

o In&pregnancy&it&can&cause&teratogenic&effects&&
! Mental&retardation,&growth&deficiencies,&microcephaly&and&
underdevelopment&of&the&midface&region&
Neoplasia&
o Not&primary&carcinogen&
o Chronic&use&associated&with&an&increased&incidence&of&neoplastic&
diseases&in&GI&tract&
! Small&risk&of&breast&cancer&
Immune&system&
o Enhances&inflammation&in&the&liver&and&pancreases&
o Inhibits&immune&function&in&other&tissues&&
Treatment&of&acute&and&chronic&alcoholism&
Excessive&CNS&depression&
o Acute&ethanol&intoxication&is&managed&by&maintenance&of&vital&
signs&and&prevention&of&aspiration&after&vomiting&
o Intravenous&dextrose&
o Thiamine&administration&is&used&to&protect&against&Wernicke]
Korsakoff&syndrome&
o Correction&of&electrolyte&imbalance&may&be&required&
Alcohol&withdrawal&syndrome&
o Discontinuance&of&ethanol&after&chronic&use&can&lead&to&withdrawal&
! Insomnia,&tremor,&anxiety&and&in&severe&cases&life&
threatening&seizures&and&delirium&tremens&(DTs)&
o Peripheral&effects&include&nausea,&vomiting,&diarrhea&&&arrhythm.&
o Managed&by&correcting&of&electrolyte&imbalance,&thiamine&and&
sedative]hypnotic&administration&
o Long&acting&benzodiazepine&is&preferred&
! Contraindicated&in&patients&with&liver&dysfunction&
Treatment&of&alcoholism&
o Naltrexone,"&opioid&receptor&antagonist&
! Decrease&the&effects&of&endogenous&opioid&peptides&in&brain&
o Acamprosate,"&NMDA&glutamate&receptor&antagonist&
o Disulfiram&"&aldehyde&dehydrogenase&inhibitor&&
! If&ethanol&consumed&together&with&disulifiram&
Acetaldehyde&accumulation&
o Nausea,&headache,&flushing&and&hypotension&
Methanol&(wood&alcohol)&
A&constituent&of&windshield&cleaners&and&canned&heat!
Intoxication&causes&visual&dysfunction,&GI&distress,&shortness&of&breath,&loss&of&
consciousness&and&coma!
Methanol&is&metabolized&to&formaldehyde&and&formic&acid!
o Causes&severe&acidosis,&retinal&damage&and&blindness!
o Formaldehyde&formation&is&reduced&by&prompt&IV&administration&of&fomepizole&
or&ethanol&]&inhibits&alcohol&dehydrogenase!
o Ethanol&competitively&inhibits&alcohol&dehydrogenase&oxidation&of&methanol!
Ethylene!Glycol!(EG)!
Industrial&exposure&to&EG&by&inhalation,&skin&adsorption&or&self]administration&
o Leads&to&severe&acidosis&and&renal&damage&from&the&metabolism&of&EG&to&oxalic&
acid&
o Prompt&treatment&with&IV&fomepizole&or&ethanol&&
! May&slow&or&prevent&formation&of&this&toxic&metabolite&

& 109&
Sollas&Notes&2015&

14.2&Serotonin&and&drugs&acting&on&serotonin&receptors&
&
Serotonin!(5/hydroxytryptamine)!
Serotonin&is&produced&from&tryptophan&
Stored&in&vesicles&in&the&enterochromaffin&cells&of&gut&and&neurons&of&the&
CNS&and&ENS&
It&is&metabolized&by&monoamine&oxidase&
o Excess&amount&can&be&detected&by&measuring&its&major&metabolite&
! 5]hydrozyindole&acetic&acid&(5]HIAA)&in&urine&
Serotonin&has&a&physiologic&role&as&a&neurotransmitter&in&both&the&CNS&
and&ENS&
o May&have&a&role&as&a&local&hormone&to&modulate&GI&activity&
Serotonin&is&also&stored&in&platelets&
Large&numbers&of&serotonin&receptors&are&known&(14&till&know)&
o Most&serotonin&agonists&works&on&5]HT1D&receptors&
Serotonin&antagonists&seems&to&act&on&5]HT2&and&5]HT3&receptors&
Receptors&and&effects&
5]HT1&receptors&
o Are&most&important&in&the&brain&
o Gi]protein&coupled&
o Mediate&synaptic&inhibition&via&increased&potassium&conductance&
o Peripheral&5]HT1&receptors&mediate&both&excitatory&and&inhibitory&
effects&in&various&smooth&muscle&tissue&
5]HT2&receptors&
o Important&in&both&peripheral&tissues&and&brain&
o Mediate&synaptic&excitation&in&the&CNS,&smooth&muscle&
contractions&(gut,&bronchi,&uterus,&some&vessels)&or&relaxation&
(other&vessels)&
o Several&mechanisms&are&involved&
! Increased&IP3&
! Decreased&potassium&conductance&
! Decreased&cAMP&&
o Effects&such&vasodilation,&diarrhea&and&bronchoconstriction&(BC)&
may&be&mediated&
! BC&is&a&symptom&of&carcinoid&tumor&&
5]HT3&receptors&
o Found&in&CNS&
! Vomiting&center&and&chemoreceptive&area&
o Peripheral&sensory&and&enteric&nerves&
o Mediate&excitation&via&5]HT&gated&cation&channel&
o Antagonists&acting&at&this&receptor&are&extremely&useful&antiemetic&
drugs&
5]HT4&receptors&
o Found&in&the&GI&tract&
o Play&an&important&role&in&intestinal&motility&
Clinical&use&
Serotonin&has&no&cl.application,&but&other&more&selective&agonists&are&used&
5]HT1D&agonists&&Sumatriptan&is&the&prototype&&

& 110&
Sollas&Notes&2015&

o Naratriptan&and&other&triptans&are&similar&
o First&line&treatment&for&acute&migraine&and&cluster&headache&&
o Orally&active&(sumatriptan&also&available&as&nasal&and&parenteral)&
o Ergot&alkaloids&are&partial&agonists&at&some&5]HT&receptors&
5]HT4&Partial&agonist&&Tegaserod,
o Act&as&agonist&in&the&colon&
o Not&used&anymore,&cardiovascular&toxicity&
Selective&serotonin&reuptake&inhibitors&(SSRI)&
o Antidepressant&drugs&act&to&increase&activity&at&central&
serotonergic&synapses&
! It&inhibits&the&serotonin&reuptake&transporter,&SERT&
o Dexfenfluramine&(not&in&use&anymore)&
! Reuptake&inhibitor&used&only&for&its&appetite&reducing&effect&
! Combined&with&phentermine&in&weight&loss&treatment&
fen]phen&but&its&also&banned&
Hyperpyrexic!Syndromes!!
Serotonin&and&drugs&with&5]HT&agonist&are&associated&with&high&fever,&skeletal&
muscle&effects&and&cardiovascular&abnormalities&
o Can&be&life&threatening&
&
Serotonin!Antagonists!
Classification&and&prototypes&
5]HT2&blockers&"&Ketanserin,,phenoxybenzamine,and,cyproheptadine&
5]HT3&blockers&"&Ondansetron,,granisetron,,dolasetron,and,alosetron&
Ergot&alkaloids&"&Partial&agonists&at&5]HT&and&other&receptors&
o Therefore&they&have&some&antagonist&effects&
Mechanism&and&effects&
Ketanserin,and,cyproheptadine&"&competitive&5]HT2&antagonists&
Phenoxybenzamine&"&is&a&irreversible&blocker&at&5]HT2&receptor&
5]HT2&blockers&are&poorly&selective&agents&
o In&addition&to&serotonin&effects&additional&effect&occur&
! ]blockade&(ketanserin,,phenoxybenzamine)&
! H1]&blockade&(cyproheptadine)&
5]HT3&blockers&
o Have&antiemetic&action&in&the&area&postrema&&
o Also&effect&the&peripheral&sensory&and&enteric&nerves&
o Alosetron&works&on&the&same&receptor&but&it&not&antiemetic&&
Clinical&use&
Ketanserin&is&used&as&antihypertensive&&
5]HT2&blockers&alone&or&together&may&be&used&for&treatment&of&carcinoid&tumor&
Ondansetron&and&its&congeners&
o Used&in&the&control&of&vomiting&associated&with&cancer&chemotherapy&
and&postoperative&vomiting&
Alosetron&"&treatment&of&IBS&associated&with&diarrhea&"&Used&only&for&women&
Toxicity&
Adverse&effects&of&ketanserin&are&those&of&]blockade&and&H1&blockade&
Ondansetron,,granisetron,and,dolasetron&"&Diarrhea&and&headache&
Dolasetron&also&associated&with&QRS&and&QTc&prolongation&in&ECG&
o Contraindicated&in&patients&with&heart&disease&
Alosetron&causes&constipation&in&some&and&have&been&associated&with&fatal&
bowel&complications&

& 111&
Sollas&Notes&2015&

&
14.3&Antituberculotics&
&
The(major(drugs(used(in(the(treatment(of(tuberculosis(are(isoniazid,(INH),,
rifampin,,ethambutol,,pyrazinamide,&&streptomycin.,
Actions(of(these(agents(on(M.tuberculosis(are(bactericidal,or,bacteriostatic,
depending(on(drug(concentration(and(strain(susceptibility.(Appropriate(drug(
treatment(involves(antibiotic(susceptibility(testing(of(microbial(isolates.(
Initiation(of(treatment(usually(involves(3L4(drug(combinations(regimen(depending(
on(known(or(anticipated((rate(of(resistance(to(isoniazid.((
(
(
Isoniazid!(INH):!
Structural&analogue&of&pyridoxine!
Mechanism&of&action&involves&inhibition&of&mycolic&acids!
o That&are&characteristic&components&of&mycobacterial&cell&walls!
Resistance&emerges&rapidly&if&the&drug&is&used&alone!!!!!!
o High&level&of&resistance&is&associated&with&deletion&in&the&katG(gene!
! Coding&for&a&catalase]peroxidase&that&is&involved&in&the&
bioactivation&of&isoniazid!
o Low&level&of&resistance&is&associated&with&deletion&in&the&inhA&gene!
! Coding&for&target&enzyme&(that&is&an&acyl&carrier&protein&
reductase)!
INH&is&bactericidal&for&actively&growing&tubercle&bacilli!
o Less&effective&against&dormant&organisms!
The&drug&is&well&absorbed&orally&and&penetrates&cells&to&act&on&IC&mycob.!
Liver&metabolism&is&by&acetylation&and&is&under&genetic&control!
o Patients&may&be&fast&or&slow&inactivators&of&the&drug!
! Fast&acetylators&(60]90min)&&mainly&Asians!
May&require&higher&doses!
! Slow&acetylators&(3]4hrs)&&mainly&Europeans&and&Africans!
Single!most!important!drug!used!in!treatment!of!TB!
o Also&used&in&the&treatment&of&latent&infection&(prophylaxis)&and&for&
persons&that&come&in&close&contact&with&patients&with&active&TB!
! In&these&cases&the&drug&is&given&alone!
Toxicity:!
o Neurotoxic&effects&are&common!
! Peripheral&neuritis,&restlessness,&muscle&twitches&and&
insomnia&&use(pyridoxine((25L50mg/d)(to(control(this!
o Hepatotoxicity!
! Abnormal&liver&enzymes,&jaundice,&hepatitis!
! Rare&in&children&&more&common&in&adults!
o Inhibition&of&hepatic&metabolism&of&some&drugs!
! Carbamazepine,,phenytoin,,warfarin!
o Hemolysis&in&patients&with&G6PDH&deficiency!
o Lupus]like&syndrome&can&also&occur&&rare!
!
!

& 112&
Sollas&Notes&2015&

Rifampin!
Derivative&of&rifamycin,&inhibits&DNA]dependent&RNA&polymerase!
Bactericidal&against&M.tuberculosis!
Resistance&via&changes&in&drug&sensitivity&of&the&polymerase&often&
emerges&rapidly&if&the&drug&is&used&alone!
Well&absorbed&and&distributed&to&most&tissues&(including&CNS)!
Eliminated&via&enterohepatic&cycling&and&is&partially&metabolized&in&liver!
o Both&free&drug&and&metabolites&are&orange!colored!
! So&orange&colored&feces&can&be&noticed&+&urine!
Normally&the&drug&is&used&in&combination&therapies&against&TB!
o Sometimes&used&as&a&sole&drug&in&latent&TB&in&INH]tolerance&patie.!
Also&used&in&the&treatment&of&leprosy!
o Given&monthly&it&will&delay&the&emergence&of&resistant&to&dapsone!
Can&be&used&along&with&vancomycin,to&treat&MRSA&or&PRSP!
o Also&for&meningococcal&and&staphylococcal&carrier&states!
Toxicity:!
o Light]chain&proteinuria&and&impairs&Ab&responses!
o Skin&rashes,&thrombocytopenia,&nephritis,&liver&dysfunct.&(all&rare)!
o Flu]like&symptoms&and&anemia&when&given&<2&weekly!
o Strong&inducer&of&liver&CYP&enzymes&and&enhances&elimination&of:!
! Anticonvulsants,,contraceptive,steroids,,cyclosporine,,
ketoconazole,,methadone,,terbinafine,and,warfarin,
Rifabutin:!
Equally&effective&as&antimycobacterial&agents&!
Less&likely&to&cause&intense&drug&interactions&than&rifampin!
Preferred&over&rifampin&in&TB&treatment&of&AIDS&patients&!
o Decreased&risk&of&interactions&with&the&HAART&meds!
Rifamixin:!
Derivative&of&rifampin&that&is&not&absorbed&from&the&GI!
Has&been&used&to&treat&travelers&diarrhea&(usually&by&enterotoxic(E.coli)!
!
Ethambutol!(ETB):!
Inhibits&arabinosyl&transferases&(coded&by&embCAB&operon)&that&is&
involved&in&the&synthesis&of&arabinogalactan&(component&of&the&c.wall)!
Resistance&occurs&rapidly&in&the&emb&gene&when&the&drug&is&used&alone!
Well&absorbed&orally&and&distributed&to&most&tissues&(including&CNS)!
o Eliminated&unchanged&in&urine&&dose&restrictions&in&renal&probl.!
Mainly&used&in&the&treatment&of&TB&in&combo&with&other&drugs!
Toxicity:!
o Dose&dependent&visual&disturbances&(decreased&visual&acuity,&red]
green&color&blindness,&optic&neuritis&and&possible&retinal&damage)!
! When&given&in&prolonged&long&term&doses!
! Usually&reversible&changes&that&stop&when&drug&is&stopped!
o Headache,&confusion,&hyperuricemia&and&peripheral&neuritis!
!
!
!
!

& 113&
Sollas&Notes&2015&

Pyraxinamide:!
Mechanism&is&not&known&but&its&bacteriostatic!and&seems&to&need&
metabolic&conversion&via&pyrazinamides&(coded&by&pncA(gene)&that&is&
present&in&M.tuberculosis!
o Resistance&occurs&via&mutation&in&this&gene&&occurs&fast&when&the&
drug&is&used&alone!
o Minimal&cross]resistance&with&other&antimycobacterial&drugs!
Well&absorbed&orally&and&penetrates&most&body&tissues&(+CNS)!
o Partial&metabolites&are&excreted&in&urine&!
Used&as&in&combination&therapy&to&treat&TB!
Toxicity:!
o Approx.&40%&of&patients&develop&nongouty&polyarthralgia!
o Hyperuricemia&is&also&common&but&is&usually&asymptomatic!
o Myalgia,&GI]irritation,&maculopapular&rash,&hepatic&dysfunction,&
porphyria&and&photosensitivity&reactions&are&all&rare!
o Contraindicated&in&pregnancy!
!
Streptomycin:!
Aminoglycoside&that&is&used&more&now&due&to&increased&prevalence&of&
resistant&M.tuberculosis&strains!
Usually&used&in&drug&combinations&to&treat&life]threatening&TB&infections:!
o TB&meningitis,&miliary&dissemination&and&severe&organ&TB!
Read&more&about&aminoglycosides&and&streptomycin&in&topic&5.2!
!
Other!drugs!(alternative!drugs):!
Second&line&drugs&that&are&used&when&the&previously&discussed&first]line&
agents&does&not&work&properly&to&control/treat&the&TB&infection&!
Usually&these&drugs&are&not&more&effective&and&can&have&more&harmful&
adverse&effects&than&the&first]line&drugs!
Amikacin,,ciprofloxacin,,ofloxacin,,ethionamide,,pPAminosalicylic,acid,!
!
Antitubercular!drug!regimens:!
Standard&regimens:!
o For&empiric&treatment&of&pulmonary&TB&(in&<4%&INH&resistance)!
o If&the&infection&is&responding&well&and&the&patient&is&HIV]negative!
o Recommended&initial&3]drug&regimen&is:!
! Isoniazid!(INH),!rifampin!&!pyrazinamide!!
! All&drugs&together&for&2&months!
Then&we&stop&pyrazinamide!
! Isoniazide&+&rifampin&used&for&another&4&months&!
Alternative&regimens:!
o INH&+&rifampin&for&9&months&or&INH&+&ETB&for&18&months!
o Intermittent&(2]3&times/week)&high&dose&4]drug&regimen&also&used!
Resistant&cases:!
o >4%&resistance&to&INH!
! Initial&treatment:!
RIF&+&pyrazinamide&+&ETB&or&streptomycin!
!

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Topic&15&
15.1&Local&anesthetics&&
&
Local(anesthesia(reversibly(inhibits(impulse(generation(and(propagation(in(nerves.(
In(sensory(nerves,(such(an(effect(is(desired(when(painful(procedures(must(be(
preformed,(e.g.(surgical(or(dental(operations.(The(local(anesthetics(constitute(a(
group(of(chemically(similar(agents((esters(and(amides)(that(block(sodium(channels(
of(excitable(membranes(and(by(that(prevents(the(propagation(of(pain(from(the(
peripheral(sensory(nerves(towards(the(CNS(to(be(processed.(Since(the(drugs(can(be(
administered(by(injection(or(topically(the(anesthesia(is(restricted(to(a(local((e.g.(
cornea,(teeth(or(arm).(
(
Local!anesthetics!(LA):!
Esters:!
o Long&acting&"&Tetracaine!
o Short&acting&"&Procaine!
o Surface&action&"&Benzocaine,,cocaine!
Amides:!
o Long&acting&"&Bupivacaine,,ropivacaine!
o Medium&acting&"&Lidocaine!
!
Pharmacokinetics:!
Many&shorter&acting&LA&are&readily&absorbed&into&the&blood&from&the&
injection&site&after&administration!
o Duration&of&local&action&is&therefore&reduced&unless&the&blood&flow&
to&the&area&is&reduced&(this&can&be&done&with&vasoconstrictors)!
! Cocaine&is&an&important&exception&because&it&has&intrinsic&
sympathomimietic&action&due&to&its&inhibition&of&NE&
reuptake&into&nerve&terminals!
Longer&acting&agents&are&less&dependent&on&co]admin.&of&vasoconstrictors!
Surface&activity&(the&ability&to&reach&superficial&nerve&when&applied&to&a&
surface&of&a&mucous&membrane)&can&be&seen&in:!
o Cocaine,,benzocaine,,lidocaine,,tetracaine,!
Metabolism&of&ester&LAs:!
o Is&carried&out&by&plasma&cholinesterases&(pseudocholinesterases)!
! Very&rapid&in&case&of&procaine&(half]life&is&only&1]2&min)!
! Slower&for&cocaine&and&very&slow&for&tetracaine!
Metabolism&of&amide&LAs:!
o Carried&out&in&the&liver&(partly&by&CYP&enzymes)!
! Half]life&of&lidocaine&and&prilocaine&is&approx.&1,5hrs!
! Half]life&of&ropivacaine&and&bupivacaine&is&3,5]4,2hrs&
respectively&!
o Liver&dysfunction&may&increase&the&elimination&half]life&&hence&
increasing&the&possibility&of&toxicity&to&the&drugs!
Acidification&of&the&urine&promotes&ionization&of&LAs&&
o Ionized&forms&are&more&rapidly&excreted&than&non]ionized&forms&
&
&

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Sollas&Notes&2015&

Mechanism!of!action:!
Blockage&of&the&voltage]dependent&sodium&channels,&resulting&in&decreased&
influx&of&sodium&that&prevents&depolarization&of&the&membrane!
o Blocking&the&nerve&action&potential!
LAs&gain&access&to&their&receptors&from&the&cytoplasm&or&the&membrane!
o Lipid]soluble&(non]ionized,&uncharged)&reach&the&receptors&earlier&!
Once&they&are&in&the&axon&the&more&ionized&they&are&"&better&effects!!!!!
THUS!BOTH!IONIZED!AND!NON/IONIZED!FORMS!ARE!IMPORTANT!
o 1st&to&reach&the&receptor&site&(non]ionized)!
o 2nd&to&cause&an&effect&(ionized)!
Affinity&of&receptors&depends&on:!
o State&of&the&sodium&channel&(resting,&open,&inactivated)!
Rapidly&firing&fibers&are&usually&blocked&before&the&slowly&firing&fibers!
High&EC&concentration&of&K+&may&enhance&the&effects&of&LAs!
High&EC&concentration&of&Ca2+&may&decrease&the&effects&of&LAs!
!
Pharmacologic!effects:!
Nerves:!
o Differential&sensitivity&of&various&nerve&fiber&types&depends&on:!
! Fiber&diameter!
! Myelination&!
! Physiological&firing&rate!
! Anatomic&location!
o In&general:!
! Smaller&fibers&are&blocked&easier&than&larger!
! Myelinated&fibers&blocked&easier&than&unmyelinated!
! Peripheral&fibers&blocked&easier&than&core&fibers!
Other&tissues:!
o Most&LAs&can&have&effects&on&the&heart&(see&gr.&Ib&antiarrhythmics)!
o Most&LAs&have&weak&blocking&effects&on&NMJs!
o Mood&elevation&by&cocaine&is&due&to&influences&on&dopamine&recep.!
Clinical!use:!
Commonly&used&in&minor&surgeries&in&combo&w.&vasoconstrictors&(Epi)!
Onset&of&action&may&be&accelerated&by&adding&sodium&bicarbonate!
o Enhances&the&IC&access&of&these&weak&bases!
Used&in&spinal&anesthesia!
Produce&autonomic&blockade&in&ischemic&conditions!
Slow&epidural&infusion&at&low&cc.&is&good&in&postoperative&analgesia!
o Repeated&epidural&injection&may&lead&to&tachyphylaxis!
Oral&and&parenteral&forms&are&sometimes&used&adjunctively&in&neuropathic&pain&
states!
Toxicity:!
CNS&&light&headedness&or&sedation,&restlessness,&nystagmus,&tonic]clonic&convulsions&
(severe&cases&can&result&in&coma&with&CV&and&respir.&Depress.!
CV&effects&&all&are&vasodilators&(except&for&cocaine)!
o Patients&with&preexisting&heart&conditions&may&develop&heart&blocks&and&
arrhythmias&at&high&plasma&concentrations!
o Bupivacaine&is&cardiotoxic&(hypotension&and&arrhythmias)!
o Toxic&mechanism&of&cocaine&is&covered&in&drugs&of&abuse!
Prilocaine&can&cause&methemoglobinemia!
Treatment&of&toxicity&is&to&treat&the&symptoms;&there&are&no&antidotes!
o Convulsions&are&managed&with&IV&diazepam&or&thiopental!
o Hyperventilation&with&oxygen&is&helpful!
!

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15.2&Histamine&and&antihistamine&
&
Histamine:!
Autacoid&that&is&formed&from&the&aminoacid&histidine&!
Stored&in&high&concentrations&in:!
o Vesicles&in&mast&cells!
o Enterochromaffin&cells&in&the&gut!
o Some&neurons&and&few&other&cell&types!
Metabolized&by&MAO&and&diamine&oxidase!
Excess&production&of&histamine&in&the&body&(e.g.&in&systemic&mastocytosis)!
o Detected&by&measurements&of&its&major&metabolite&in&the&urine!
! Imidazole&acetic&acid!
Histamine&is&released&from&the&mast&cells&in&response&to&IgE&mediated&
(immediate)&allergic&reactions&(pathophysiological&property)!
o Seasonal&rhinitis&(hay&fever),&urticarial,&angioneurotic&edema!
Histamine&also&has&a&physiological&role&in&the&control&of&acid&secretion&in&
the&stomach&and&acts&as&a&neurotransmitter!
Histamine&is&associated&with&four&receptors:!
o H1&and&H2&"&involved&in&most&peripheral&actions&(triple&response)!
o H3&and&H4&!
H1&receptor:!
o Gq]protein&coupled&receptor&that&is&important&in&smooth&muscles!
o Typical&response&includes&pain&and&pruritus,&bronchoconstriction&
&&vasodilation&(due&to&consequent&release&of&NO)!
o Capillary&endothelial&cells&contract&and&by&that&open&gaps&
increasing&the&vascular&permeability&&leading&to&local&edema!
o These&reactions&are&due&to&IgE&mediated&responses&to&allergens&
and&can&also&be&seen&in&mastocytosis!
H2&receptor:!
o Gs]coupled&receptor&that&mediates&gastric&acid&secretion&by&the&
parietal&cells&in&the&stomach!
! Also&cardiac&stimulatory&effects!
! Also&works&to&inhibit&further&release&of&histamine&from&mast&
cells&&in&a&negative&feedback&mechanism!
H3&receptor:!
o Gi]coupled&receptor&that&appears&to&be&involved&in&presynaptic&
modulation&of&histaminergic&neurotransmission&in&the&CNS!
o Food&intake&and&body&weight&are&increased&in&knock&out&animals!
H4&receptor:!
o Gi]coupled&receptor!
o Located&on&leukocytes&(mainly&eosinophils)&and&mast&cells!
o Involved&in&chemotactic&response!
!
Histamine!H1!antagonist:!
Wide&variety&of&drugs&that&act&on&the&H1&receptors!
Competitive&antagonists&and&most&effective&if&given&before&histamine&
release&occurs&(so&better&to&use&as&prophylaxis)!
Used&to&treat&allergic&responses&and&also&in&motion&sickness!

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Sollas&Notes&2015&

1st&generation&"&diphenhydramine,!
o Highly&sedating&agents&with&significant&autonomic&receptor]
blocking&effects!
o Half]life&around&4]12hrs!
! Newer&drugs&are&less&sedative!
Chlorpheniramine,and,cyclizine!
2 &generation&"&cetirizine,,fexofenadine,&,loradantine!
nd

o Reduced&sedative&and&autonomic&effects!
o Half]life&around&12]24hrs!
All&of&the&drugs&are&active&orally&and&some&are&used&topically&and&in&eyes!
Most&are&metabolized&extensively&in&the&liver!
Diphenhydramine,,dimenhydrinate,,cyclizine,,meclizine,and,
mpromethazine,are&used&in&motion&sickness!
Diphenhydramine,is&also&used&in&management&of&chemotherapy]induced&
vomiting!
1st&generation&drugs&are&sometimes&used&as&OTC&sleeping&aids!
Toxicity:!
o 1st&generation!
! Sedation,&antimuscarinic&effects&(dry&mouth,&blurred&vision)!
o Promethazine&may&cause&orthostatic&hypotension!
o Drug&interactions&can&result&in&dangerously&high&levels&of&certain&
antihistaminic&drugs!
!
Histamine!H2!antagonists:!
Four&H2&blockers&are&available:!
o Cimetidine&(prototype)!
o Ranitidine!
o Famotidine!
o Nizatidine!
Orally&active&with&half]lives&of&1]3hrs;&relatively&non]toxic&and&can&be&
given&in&high&doses&to&increase&the&duration&of&a&single&dose&up&to&12]24hr!
All&are&available&as&OTC!
Cause&surmountable&pharmacologic&blockade&of&histamine&H2&receptors!
o Relatively&selective&and&dont&work&on&H1&receptors!
All&are&used&in&the&treatment&of&peptic&ulcer&diseases&(acid]peptic&disease)&
to&reduce&the&gastric&acid&secretions!
o Reduce&nocturnal&secretions!
o Accelerate&healing&!
o Reduce&recurrence&of&ulcers!
o Zollinger]Ellison&syndrome&treatment&+&GERD!
! Very&large&doses&are&required!
Thats&why&proton&pump&inhibitors&are&preferred!!!
Toxicity:!
o Cimetidine&is&a&potent&inhibitor&of&CYP&enzymes&&drug&interactions!
! Also&reduces&hepatic&flow!
! Significant&antiandrogenic&effects!
!

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Sollas&Notes&2015&

15.3&Drugs&acting&on&the&renin&angiotensin&system&
&
The(renin(angiotensin(aldosterone(system(is(a(hormone(system(that(regulates(BP(
and(water(balance(of(the(body.(When(blood(volume(is(low,(the(juxtaglomerular(
cells(of(the(distal(convoluted(tubules(start(to(secrete(renin(into(the(circulation.(
Plasma(renin(then(carries(out(conversion(of(angiotensinogen((released(by(the(liver)(
to(angiotensin(I.(Then(as(the(angiotensinogen(I(enters(the(pulmonary(circulation(it(
gets(converted(into(angiotensin(II(by(the(angiotensinLconverting(enzyme((ACE).(
Angiotensin(II(is(a(very(potent(vasoactive(peptide(that(causes(vasoconstriction(
resulting(in(an(increase(in(blood(pressure.(Another(function(of(angiotensin(II(is(to(
stimulate(the(secretion(of(the(hormone(aldosterone(from(the(zona(glomerulosa(of(
the(adrenal(cortex.(The(actions(of(aldosterone(is(then(to(increase(reabsorption(of(
sodium(and(water(from(the(renal(tubule,(which(will(further(increase(the(fluid(
volume(of(the(body((resulting(in(a(further(increase(in(blood(pressure.(If(the(RAA(
system(is(abnormally(active(or(in(the(case(of(a(HF(this(compensatory(system(of(the(
kidneys(in(maintaining(normal(CO(can(actually(be(more(harmful(than(beneficial.(
Thats(why(its(important(to(understand(the(importance(of(the(various(drugs(that(
can(be(used(to(control(this(process(and(by(that(lower(BP.((
(
Renin:&
Glycoprotein&that&enzymatically&cleaves&angiotensinogen&to&angiotensin&I&
Released&from&juxtaglomerular&cells&in&response&to&the&following&stimuli:&
o Drop&in&renal&perfusion&pressure&
o Decreased&Na+&or&Cl]&delivered&to&the&distal&convoluted&tubules&
o ]adrenoreceptor&mediated&sympathoactivation&
ACE&(angiotensin&converting&enzyme):&
Non]specific&peptidase&that&cleaves&C]terminal&dipeptides&from&various&
peptides&(dipeptidyl&carboxypeptidase)&
o When&working&as&a&kininase&II&it&contributes&to&inactivation&of&
kinins&such&as&bradykinin&
o Important&in&the&RAA&system&as&a&converter&of&angiotensin&I&into&
angiotensin&II&&which&will&act&as&a&potent&vasoconstrictor&and&
inducer&of&aldosterone&release&from&the&adrenal&cortex&
Present&mainly&on&the&luminal&side&of&the&vascular&endothelium&and&is&
found&in&very&high&concentrations&in&the&pulmonary&circulation&(lungs)&
o Other&locations&of&ACE&&e.g.&kidney&&&heart&
Angiotensin&II:&
Raises&blood&pressure&in&the&following&ways:&
o Causes&vasoconstriction&in&both&arteries&and&veins&
o Stimulates&aldosterone&secretion&from&the&adrenal&cortex&
o Central&increase&in&sympathetic&tone&
o Peripheral&increase&in&the&release/effect&of&NE&
&
In(the(case(of(heart(failure,(hypertension((malignant),(renal(failure(&(diabetes(this(
RAA(system(of(the(kidneys(is(very(important(to(control(so(the(compensatory(
mechanisms(dont(cause(a(further(incase(in(BP,(increase(in(venous(return,(that(will(
increases(CO(and(TPR(that(will(continue(to(increase(the(blood(pressure.(Also(its(
important(to(keep(in(mind(the(sympathoLresponses(of(the(ANS.(Thats(why(we(have(
drug(inhibitors(of(various(steps(of(this(system.(

& 119&
Sollas&Notes&2015&

ACE]inhibitors&(enaplapril,,captopril,,famipril,,fosinopril):&
Drugs&that&are&very&commonly&used&(DOC)&in&HF&as&it&blocks&ACE&from&
converting&angiotensin&I&into&angiotensin&II.&&
o Lower&levels&of&angiotensin&II&will&result&in&vasodilation&as&well&as&
lower&secretion&of&aldosterone.&&
o Also&they&diminish&the&rate&of&bradykinin&inactivaction&and&by&that&
they&cause&even&further,vasodilation&
Action&on&the&heart:&
o Decrease&of&vascular&resistance,&venous&tone&and&BP&
o Decreased&preload&and&afterload&that&results&in&$&CO&
o Decrease&the&usual&angiotensin&II&mediated&increase&in&E&NE&
o Decreased&release&of&aldosterone&that&will&lower&blood&volume&
Indication&for&the&drugs:&
o Heart&failure&(all&stages&of&LHF)&and&hypertension&
! Low&EF&patients&show&great&benefit&from&using&ACE&inhib.&
o Patients&recovering&form&AMI&can&also&benefit&from&ACE&inhibitors&
! Recommended&to&give&them&as&soon&as&possible&post&MI&
o Single]agent&therapy&in&patients&with&mild&dyspnea&on&exertion&
that&dont&show&sings&or&symptoms&of&volume&overload&(edema)&
o Can&be&used&in&combination&with&diuretics,&]blockers,&digoxin&and&
aldosterone&antagonists&
The&older&ACE&inhibitors&have&a&half]lives&of&2]12&hours&and&hence&they&
need&to&be&administered&twice&or&more&a&day&while&some&of&the&newer&
drugs&can&be&administered&once&a&day&
o Incompletely&(but&adequadly)&absorbed&orally&&however&an&they&
need&to&be&taken&on&an&empty&stomach&due&to&this&
o The&drugs&are&usually&prodrugs&(except(captopril)&that&need&to&be&
activated&by&liver&enzymes&to&become&active&&
o Excreted&by&the&kidneys&
Adverse&effects:&
o Postural&hypotension&(orthostatic)&that&is&associated&with&the&
functional&state&of&the&RAA&system&
! In&case&of&activation&by&loss&of&electrolytes,&HF&or&renal&
arterial&stenosis&this&drop&can&be&significantly&high&
o Persistent&dry&cough&&
! Can&be&due&to&the&reduced&inactivation&of&kinins&in&the&
bronchial&mucosa&
o Hyperkalaemia,&angioendema&and&renal&insufficiency&are&rare&
o Not&to&be&used&in&case&of&pregnancy&as&they&are&fetotoxic&&
(
Usually(these(drugs(is(usually(fairly(well(tolerated(and(effective(but(need(careful(
monitoring(due(to(their(possible(hypotensive(effects(
(
Angiotensin]receptor&blockers&(ARBs)&(e.g.&losartan,,valsartan,,candesartan):&
Non]peptide,&orally&active,&extremely&potent&competitive&antagonists&of&
the&angiotensin&type&1&receptor&(AT1)&
Cause&more&complete&blockade&on&the&inhibition&of&aldosterone&release&
Does&not&effect&bradykinin&levels&as&they&dont&act&on&ACE&
Usually&used&as&a&second&choice&drugs&to&ACE&inhibitors&

& 120&
Sollas&Notes&2015&

o E.g.&when&ACE&inhibitors&cannot&be&tolerated&&
Used&in&treatment&of&hypertension&and&HF&when&ACE&inhibitors&cant&be&
used&(e.g.&patients&that&get&severe&cough&or&angioedema)&
Require&once&a&day&dosing&&
o Losartan&differs&from&the&others&by&undergoing&first]pass&hepatic&
metabolism&to&be&converted&into&an&active&metabolite&
o Elimination&of&the&drugs&is&via&kidneys&and&feces&
Adverse&effects&are&similar&to&those&of&ACE&inhibitors&
o No&dry&cough&
o Not&used&in&pregnancy&&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&

& 121&
Sollas&Notes&2015&

Topic&16&
16.1&Hypothalamic&and&pituitary&hormones&
&
The(hormones(produced(by(the(hypothalamus(and(pituitary(gland(are(key(
regulators(of(metabolism,(growth(and(reproduction.(Preparations(of(these(
hormones,(including(products(made(by(recombinant(DNA(technology(and(drugs(
mimicking(or(blocking(their(effects,(are(used(in(the(treatment(of(variety(of(
endocrine(disorders.(
(
Drugs!that!mimic/block!the!effects!of!hypothalamic!&!pituitary!hormones:!
(
Anterior!pituitary:!
Growth&hormone(
o Agonists:&Somatropin,,Mecasermin(
o Antagonists:&Octreotide,,Pegvisomant(
Gonadotrophins(
o Agonists:(
! Mixed&LH&FSH:&Menotropins(
! LH:&Lutopin,,hCG(
! FSH:&Follitropin(
Prolactin(
o Antagonists:&D2,dopamine,agonists,(bromocriptine)(
Posterior!pituitary:!
Oxytocin:!
o Agonists:&Oxytocin!
o Antagonists:&Atosiban!
Vasopressin!
o Agonists:&Desmopressin!
o Antagonists:&Conivaptan!
Hypothalamus:!
Gonadotropin&releasing&hormone&(GnRH)!
o Agonists:&Gonadorelin!
o Antagonists:&GnRH,receptor,agonist,(leuprolide),GnRH,receptor,antagonist,
(ganirelix)!
!
Growth!hormone!related!drugs:!
GH&is&required&for&normal&growth&during&childhood&and&adolescence&&&
acts&as&an&important&regulator&of&lipid&and&CH&metabolism!
o Maintains&lean&body&mass&throughout&life!
o Effects&are&mediated&by&regulating&the&production&in&peripheral&
tissues&of&IGF]1!
Somatropin,(recombinant&form&of&human&GH)&!
o Used&for&GH&deficiency&in&children&and&adults!
o Used&in&treatment&of&children&with&genetic&dx.&with&short&stature!
! Prader]Willi,&Noonan&and&Turner&syndrome!
o Improves&growth&in&children&with&failure&to&thrive!
o In&adults&GH&treatment&has&efficacy&in&AIDS]associated&wasting,&GH&
deficiency,&improving&GI&function&in&patients&that&have&undergone&
GI&resection&with&malabsorption&syndrome!
o GH&is&used&by&athletes&to&improve&their&muscle&mass&performance!
! Banned&by&the&Olympic&Committee&and&others!
o Adverse&effects&in&children&(rare):!

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Sollas&Notes&2015&

! Pseudotumor&cerebri,&slipped&capital&femoral&epiphysis,&
progression&of&scoliosis,&edema&&&hyperglycemia!
o Adverse&effects&in&adults:!
! Peripheral&edema,&myalgia&&&arthralgia!
Mecasermin&(recombinant&human&IGF]1)!
o Administered&parenterally&to&children&with&IGF]1&deficiency!
o Commonly&causes&hypoglycemia&that&can&be&prevented&by&a&meal&
before&the&administration&of&the&drug!
Octreotide,and,lanreotide,(somatostatin&analogs)!
o Inhibit&the&release&of&GH,&glucagon,&insulin&and&gastrin!
o Used&in&the&treatment&of&acromegaly,&carcinoids,&gastrinoma,&
glucagonoma&and&other&endocrine&tumors!
o Administered&subcutaneously&(2]4&times&daily)&or&intramuscular&
(once&every&4&weeks)&for&long&term!
o Adverse&effects:!
! GI&disturbances,&gallstones,&cardiac&conduction&problems!
Bromocriptine,(dopamine&D2&receptor&agonist)!
o More&effective&at&inhibiting&prolactin&release&than&GH!
o High&doses&have&some&efficacy&in&the&treatment&of&small&GH]
secreting&tumors!
Pegvisomant,(GH&receptor&antagonist)!
o Used&in&the&treatment&of&acromegaly!
o Works&via&its&cross]linkage&of&GH&receptors&that&will&inhibit&the&
conformational&change&required&for&receptor&activation!
!
Gonadotropin!related!drugs:!
In&women!
o FSH&directs&follicle&development!
o FSH&+&LH&collaborate&in&regulating&ovarian&steroidogenesis!
o Gonadotropins&and&their&analogs&are&used&to&induce&ovulation&in&
women&with&anovulation&that&is&not&responsive&to&other&therapies!
o All&ovulation&induction&protocols&that&used&gonadotropins&have&3&
basic&steps:!
! 1st&&endogenous&gonadotropin&production&is&inhibited&by&
administration&of&GnRH&agonists&or&antagonists!
! 2nd&&follicle&development&is&driven&by&daily&injections&of&
FSH&preparations&(menotropins,,FSH,or,FSH,analog)!
! 3rd&&oocyte&maturation&is&induced&with&LH&or&hCG&injection!
In&males!
o FSH&is&primary&regulator&of&spermatogenesis!
o LH&is&main&stimulator&for&testicular&androgen&production!
o Gonadotropins&and&their&analogs&are&used&to&stimulate&
spermatogenesis&in&infertile&men!
Menotropins,are&mixtures&of&FSH&and&LH&that&are&purified&from&the&urine&
of&postmenopausal&women&(that&have&has&high&levels&of&FSH&and&LH)!
FSH,+,analogs!
o Urofollitropin,&purified&from&urine&of&postmenopausal&women!
o Follitropin,,and,&&recombinant&forms&of&human&FSH!
LH,+,analogs!

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Sollas&Notes&2015&

o hCG&&purified&from&urine&or&recombinant&(structure&like&LH)!
o Lutropin&&recombinant&form!
Gonadotropin/releasing!hormone!and!analogs!
Decapeptide&that&stimulates&Gn]release&when&its&secreted&in&pulsatile&
pattern&by&the&hypothalamus!
Leuprolide,,goserelin,,histrelin,,nafarelin,,triptorelin,(GnRH&agonists)!
o Inhibit&gonadotropin&release&by&downregulation&of&GnRH&
receptors&in&the&pituitary&cells&&decreasing&secretion&of&
gonadotropins!
o Used&in&the&1st&step&of&the&ovulation&induction&protocol,&
endometriosis,&uterine&leiomyoma,&men&with&advanced&prostate&
cancer,&in&early&pubertal&transgender&adolescents&and&children&
with&central&precocious&puberty!
o Adverse&effects&of&long&term&treatment:& !
! Symptoms&of&menopause,&osteoporosis&and&bone&loss,&
gynecomastia,&reduced&libido&and&decreased&hematocrit!
Ganirelix,,cetrorelix,,degarelix,(GnRH&antagonists)!
o Used&during&ovulation&induction&to&suppress&endogenous&
gonadotropin&production,&advanced&prostate&cancer&(degarelix)!
Prolactin!antagonists!(Dopamine!D2!receptor!agonist):!
Dopamine&is&the&physiologic&inhibitor&of&prolactin&release!
Prolactin&secreting&adenomas&usually&retain&their&dopamine&sensitivity!
Bromoctriptine,(cabergoline,,pergolide),are&effective&in&reducing&serum&
prolactin&cc.&in&hyperprolactinemia!
o Restoring&fertility!
!
Posterior!pituitary!hormones:!
! Oxytocin,!
o Nonapeptide&synthesized&in&cells&of&paraventricular&nuclei&of&
hypothalamus&and&transported&via&axons&down&to&the&post.pituit.!
o Effective&stimulant&of&uterine&contraction&!
! Used&IV&to&induce&or&reinforce&labor!
! Atosiban!
o Antagonist&of&oxytocin&receptor!
o Used&in&some&countries&as&a&tocolytic&agent&in&preterm&labor!
! Vasopressin,(ADH)!
o Acts&through&V2&receptors&in&increase&the&insertion&of&water&
channels&in&the&apical&membranes&of&collecting&duct&cells&&
producing&an&antidiuretic&effect!
o Extra]renal&V2&receptors&regulate&release&of&coag.factor&VIII&and&
von&Willebrand&factor!
o Desmopressin,a&selective&agonist&of&V2&receptors&can&be&
administered&orally,&nasally&or&parenterally&in&patients&with&
pituitary&diabetes&insipidus,&mild&hemophilia&A&and&von&
Willenbrands&dx.!
o Vasopressin&also&contracts&vascular&smooth&muscle&by&activation&
of&V1&receptors&]&Used&to&control&bleeding&from&esophageal&varices&
or&colon&diverticula&!

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Sollas&Notes&2015&

16.2.&Ergot&alkaloids&and&pharmacotreatment&of&migraine&
&
Ergot(alkaloids(are(complex(molecules(that(are(produced(by(a(fungus(found(in(wet(
of(spoiled(grain.(They(are(responsible(for(epidemics(of(St.(Anthonys(fire(
(ergotism).(At(least(20(naturally(occurring(members(of(the(family(but(only(few(are(
used(as(therapeutic(agents.(Most(are(partial(agonists(at(Ladrenoreceptors(and(
5HT(receptors.(Some(are(potent(agonists(at(dopamine(receptors.(
(
Classification!and!effects:!
The&ergot&alkaloids&can&be&divided&into&3&major&subgroups&on&bases&on&the&
organ&or&tissue&where&they&have&their&primary&effects:!
Vessels:!
o Produce&marked&and&prolonged&]receptor&mediated&vasoconst.!
o Ergotamine,is&the&prototype!
o Overdose&can&cause&ischemia&and&gangrene&of&limbs&or&bowel!
! Antidote&is&nitroprusside!
o Can&be&used&in&epinephrine&reversal!
! Since&it&works&to&block&]agonist&effects&of&sympathomim.!
Uterus:!
o Produce&powerful&constriction&in&the&smooth&muscles&of&the&uterus!
o Ergonovine,is&the&prototype!
o Can&cause&abortion&or&miscarriage!
o Effective&in&the&treatment&of&postpartum&bleedings!
! Via&powerful&long]lasting&contractions&decreasing&bleeding!
! MUST&NOT&BE&GIVEN&BEFORE&DELIVERY&OF&PLACENTA!
Brain:!
o Lysergic,acid,diethylamide,(LSD)&can&cause&hallucinations&
! Semisynthetic&prototypical&hallucinogenic&ergot&derivative&
! Potent&5]HT&blocker&in&peripheral&tissues&
! Actions&in&the&CNS&is&thought&to&be&due&to&agonist&actions&at&
dopamine&receptors&
o In&the&pituitary&some&of&the&ergots&can&be&used&to&inhibit&prolactin&
secretions&due&to&their&agonistic&effects&on&dopamine&receptors&
o Bromocriptine,&,pergolide&are&potent&semisynthetic&ergot&
derivatives&that&act&on&D2&receptors&in&the&pituitary&and&basal&ggl.&
! Both&drugs&have&been&used&in&the&treatments&of&
prolactinemia&and&Parkinsons&
!
Treatment!of!migrane:!
Ergotamine,is&a&DOC&in&treatment&of&acute&migraine&attacks!
o Used&in&combination&with&caffeine!
Methysergide,,dihydroergonovine,&,ergonovine&!
o Used&in&prophylaxis&of&migraine&attacks!
!
Toxic!effects:!
Prolonged&vasoconstriction,&ischemia&&&gangrene,&unusual&CT&hyperplasia&!
Hydronephrosis,&cardiac&valvular&and&conduction&system&problems!
GI&irritation!
Abortions&and&miscarriage&&]&migraine&treatment&stopped&in&pregnancy!

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Sollas&Notes&2015&

16.3&Antianginal&drugs&
&
Angina(pectoris(refers(to(a(strangling(or(pressureLlike(pain(caused(by(cardiac(ischemia.(
The(pain(is(usually(substernally,(but(sometimes(precieved(in(the(neck,(shoulder(and(arm(
(and(even(the(epigastrium).(Occurs(later(in(women(than(men.(The(drugs(used(in(angina(are(
mainly(to(reduce(the(oxygen(demand(of(the(heart(and(increase(the(oxygen(delivery(to(the(
myocardium.(
Different&types&of&angina:&
Atherosclerotic&angina&(classic&angina/angina&of&effort)&&90%&of&cases&
o Associated&with&atherosclerotic&plaques&that&partially&occlude&one&of&
more&of&the&coronary&arteries&
o With&increased&workload&of&the&heart,&this&occlusion&results&in&
inadequate&oxygen&delivery&that&causes&accumulation&of&acid&metabolites&
and&ischemic&changes&that&stimulate&the&myocardial&pain&endings&
o Rest&usually&leads&to&complete&relief&of&the&pain&within&15min&
Vasospastic&angina&(rest&angina/variant&angina/Prinzmentals&angina):&
o Less&than&10%&of&cases&
o Reversible&spasms&of&the&coronaries&&usually&around&a&plaque&
o There&spasms&may&occur&at&any&times&&even&at&night&
o Could&develop&into&unstable&angina&
Unstable&angina&(acute&coronary&syndrome):&
o Increased&frequency&and&severity&of&attacks&that&result&from&a&combo&of&
atherosclerotic&plaques,&platelet&aggregation&and&vasospasm&
o Immediate&precursor&of&myocardial&infarction&&emergency!&
Factors&that&determine&the&cardiac&oxygen&demand&requirement:&
Myocardial&fiber&tension&(high&tension&&high&oxygen&demand)&due&to:&
Preload&(diastolic&filling&pressure):&
o Function&of&blood&volume&and&venous&tone&
o Venous&tone&is&mainly&controlled&by&sympathetic&outflow&
Afterload&
o Determined&by&arterial&BP&and&large&artery&stiffness&
Heart&rate&
o Fast&heart&rate&=&myocardial&fibers&remain&in&systolic&tension&and&hence&
they&will&require&more&oxygen&to&maintain&the&tension&
o Diastole&time&is&cut&short&&less&oxygenation&of&the&coronaries&
Double&product&
o HR&and&systemic&arterial&blood&pressure&
o Main&contributories&to&increased&oxygen&demand&
o Sensitive&to&SANS&
Force&of&contraction&
o Systolic&factor&that&is&controlled&by&SANS&
o Ejection&time&prolongation&will&increase&oxygen&demand&
Therapeutic&agents:&
&
Main!goal!is!to!increase!oxygen!delivery!and!reduce!oxygen!demand!
Traditional&pharmacological&treatment&includes:&&
Nitrates,,calcium,channel,blockers,and,betaPblockers,
(
Newer(treatments(attempt(to(increase(efficiency(of(oxygen(utilization(by(shifting(
the(energy(substrate(preference(of(the(heart(from(FA(to(glucose(
( Partial,fatty,acid,oxidation,inhibitors,(pFOX,inhibitors),
&

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Sollas&Notes&2015&

Myocardial&revascularization&corrects&obstruction&(bypass&or&angioplasty)&
Nitrates:&
!
Nitroglycerine!is&the&most&important&of&the&therapeutic&nitrates&
Range(of(duration((10L20(minutes((
Sublingual(administration(for(relief(of(acute(attacks(
Range(of(duration((8L10(hours(
Transdermal(for(prophylaxis(
Nitroglycerin&(glyceryl&trinitrate)&is&rapidly&denitrated&in&the&liver&and&smooth&m.&
Retaining&a&significant&vasodilating&effects&
High&enzyme&activity&in&the&liver&makes&the&first&pass&effect&90%&(oral)&
o Sublingual&bypasses&this&system&and&therefore&its&very&effective&
Other&nitrates:&
Isosorbide&dinitrate&&other&commonly&used&nitrate&
o Sublingual&and&oral&
o Rapidly&denitrated&in&liver&and&smooth&muscle&&
Isosorbide&mononitrate&&also&active&orally&
Amyl&nitrate&&volatile&and&rapidly&acting&vasodilator&&inhaled&
o Rarely&prescribed&
Mechanism&of&action:&
Nitrates&release&nitric&oxide&(NO)&within&the&smooth&muscle&
o Probably&due&to&mitochondrial&enzyme&aldehyde&DH]2&(ALD2)&
NO&stimulates&guanylyl&cyclase&(GC)&and&causes&the&release&of&cGMP&resulting&in&smooth&
muscle&relaxation&by&dephosphorylating&the&myosin&light]chain&phosphate&
o Identical&mechanism&in&nitroprusside&
Actions:&
Cardiovascular:&
o Smooth&muscle&relaxation&leading&to&significant&venodilation&
resulting&in&reduced&cardiac&size&and&cardiac&output&through&
reduced&preload&
! Venodilation&also&leads&to&reduced&diastolic&heart&size&and&
tension&on&the&myocardial&fibers&
o Relaxation&in&the&arterial&smooth&muscle&increases&flow&through&
partially&occluded&coronary&arteries&
o Reduced&afterload&&due&to&relaxation&of&the&resistant&arteries&
results&in&increased&ejection&and&further&decrease&in&cardiac&size&
o Compensatory&mechanism&that&occurs&sometimes&when&the&
nitrates&have&a&hypotensive&effects&results&in&reflex&tachycardia&
and&increased&force&of&contraction&&baroreceptor&mechanism&
Other&organs:&
o Nitrates&relax&smooth&muscles&of&the&bronchi,&GI]tract,&GU]tract&&
! Clinically&insignificant&since&the&effects&are&small&
o Intravenous&nitroglycerine&are&sometimes&used&unstable&angina&to&
reduce&the&aggregation&of&the&platelets&
Toxicity:&
Responses&evoked&by&vasodilation&
o Reflex&tachycardia&(baroreceptor),&orthostatic&hypotension&(venodilator)&and&
throbbing&headache&from&meningeal&arterial&artery&vasodilation&(increased&
intracranial&pressure)&
Erectile&dysfunction&(when&combo&with&sildenafil&and&similar&drugs)&
Methemoglobinemia&&high&serum&cc.&
o Makes&them&potential&drugs&to&use&as&antidotes&in&cyanide&poisonings&

& 127&
Sollas&Notes&2015&

&
Calcium]channel&blockers:&
Several&types&are&used&in&angina&,
Nifedipine,,dihydropyridine,,diltiazem,,verapamil,
Mechanism:&
Blockage&of&the&voltage]gated&L]type&calcium&channels&
o Most&important&channels&in&cardiac&and&smooth&muscle&
o Reduce&intracellular&calcium&concentration&and&m.&contractility&
Actions:&
Relax&blood&vessels&(lesser&extent&&uterus,&bronchi&and&gut)&
Rate&and&contractilitly&of&the&heart&
o Reduced&by&diltiazem&and&verapamil&
o Also&used&to&treat&AV]nodal&arrhythmias&
Nifedipine&and&dihydropyridines&evoke&greater&vasodilation&
o Possible&resulting&in&reflex&tachycardia&
All&reduce&blood&pressure&&&the&double&products&in&angina&
Effective&prophylactic&agents&in&effort&and&vasospastic&angina&
Very&important&agents&in&combo&with&nitrates&when&treating&
severe/unstable&angina&&
Other&uses:&
o Hypertension,&supraventricular&tachycardia,&migrane,&preterm&
labor,&stroke&and&Reynauds&phenomenon&
Toxicity:&
Constipation,&pretibial&edema,&nausea,&flushing,&dizziness&
Heart&failure,&AV]blockade,&sinus&node&depression&
o Mainly&in&verapamil&
&
Beta]blockers&in&angina:&
Beneficial&antiangial&effects&&
o Decreased&heart&rate,&cardiac&force,&blood&pressure&
Beneficial&detrimental&effects&
o Increased&heart&size,&longer&ejection&period&
Reduce&&cardiac&work,&double&product&and&oxygen&demand&
Only&used&prophylactically&for&angina&
o No&value&in&acute&attacks&
o Effective&in&preventing&exercise]induced&angina&
o Ineffective&agains&vasospastic&form&
o Useful&in&preventing&the&compensatory&effects&of&the&nitrates&
(tachycardia&and&increased&cardiac&force)&
Newer&drugs&for&angina:&
&
Ranolazine,,reduces(the(lateLprolonged(sodium(current(in(the(myocardial(cells(
Reduction(in(cardiac(force((
Might(alter(cardiac(metabolism(and(switch(the(preference(for(FA(out(for(
glucose(
Moderately(effective(in(prophylaxis(of(angina(
Ivabradine,,experimental(drug(that(inhibits(funny(current(in(SALnode(
Decreased(HR(and(cardiac(work(

& 128&
Sollas&Notes&2015&

Topic&17&
17.1&Thyroid&and&antithyroid&drugs&
&
The(thyroid(secretes(2(types(of(hormones;(iodineLcontaining(amino(acids((thyroxine(
and(triiodothyronine)(and(a(peptide((calcitonin).(Thyroxine(and(triiodothyronine(
have(broad(effects(on(growth,(development,(and(metabolism.(Calcitonin(is(
important(in(calcium(metabolism.(Now(we(will(go(in(more(details(into(the(drugs(
that(are(used(in(the(treatment(of(hypoL(and(hyperthyroidism.(
(
Drugs&used&in&hypothyroidism:&
! Levothyroxine,(T4),&,Liothyronine,(T3)&
Drugs&used&in&hyperthyroidism:&
! Propythiouracil,(thioamide),,Lugol,solution,(iodide),,Propanolol,,131I&
&
Thyroid!hormones:!
! Thyroid&hormones&accelerate&metabolism&in&the&body!
! Their&release&is&regulated&by&thyroid&stimulating&hormone&(TSH)&&a&
pituitary&glycoprotein&that&is&controlled&by&the&release&of&thyroid&
releasing&hormone&(tripeptide)&coming&from&the&hypothalamus!
o Secretion&of&TSH&decreases&as&blood&levels&of&thyroid&hormones&
rises&&by&a&mean&of&negative&feedback&that&adjusts&the&hormone&
production&to&serve&the&demand&of&the&body!
! The&thyroid&releases&predominantly&T4&(thyroxine)&&less&active&form!
o T4&is&converted&into&T3&in&target&tissues,&liver&and&kidney!
! T3&(triiodothyronine)&&more&active&form!
! T3&has&10]fold&higher&affinity&than&T4!
o Effects&develop&more&rapidly&and&with&shorter&duration&than&T4!
!
However!T4!(levothyroxine)!is!preferred!choice!of!therapy!
Gives&more&constant&blood&levels!
Slower&degradation!
Absorption&from&gut&is&best&on&an&empty&stomach!
o &hour&before&breakfast!
! Toxicity&of&thyroid&hormones:!
o Thyrotoxicosis&and&stimulation&of&the&heart&in&elderly!
! Doses&are&titrated&up&to&limit&these&effects!
!
Antithyroid!drugs:!
!
Thioamides!(Methimazole!&,propylthiouracil,(PTU)):!
! Small&sulfur]containing&thiamides&that&inhibit&thyroid&hormone&synthesis&
by&blocking:!
o Peroxidase]catalyzed&reactions!
o Iodination&of&tyrosine&residues&of&thyroglobulin!
o Coupling&of&DIT&and&MIT!
! Inhibit&peripheral&conversion&of&T4&to&T3!
! Onset&of&action&is&slow&(3]4&weeks&for&full&effect)!
o This&is&since&they&dont&inhibit&the&release&of&preformed&hormones!

& 129&
Sollas&Notes&2015&

! Given&orally&and&are&effective&in&young&patients&with&small&glands&and&
mild&diseases!
! Methimazole,is&generally&preferred&(administered&1&per/day)!
! PTU,is&preferred&in&pregnancy&since&its&less&likely&to&cross&the&placenta&
and&enter&breast&milk!
! Toxicity:!
o Skin&rash&(common),&vasculitis,&agranulocytosis,&
hypoprothrombinemia&and&liver&dysfunctions&(all&rare)!
o Effects&are&usually&reversible!
!
Iodide!salts!and!iodine!
! Inhibit&iodination&of&tyrosine&and&thyroid&hormone&release&!
! Decrease&size&and&vascularity&of&a&hyperplastic&thyroid&gland!
! Onset&of&action&is&rapid&(2]7&days)!
o Since&they&inhibit&the&release&and&synthesis!
! Effects&are&transient&!
o The&thyroid&gland&escapes&from&the&iodide&block&after&several&
weeks&of&treatment!
! Used&in&management&of&thyroid&storm&and&prepare&patients&for&surgical&
resection&of&an&hyperactive&thyroid!
! Lugols,solution!!(iodine&and&potassium&iodide)&is&the&usual&form!
! Adverse&effects:!
o Rash,&drug&fever,&metallic&taste,&bleeding&disorders&&&anaphylaxis!
!
Radioactive!iodine!(131!I)!
! Taken&up&and&concentrated&in&the&thyroid&gland!
! Large&enough&dose&severely&damages&the&thyroid&&and&only&the&thyroid!
! Can&produce&permanent&cure&of&thyrotoxicosis&without&surgery!
! Contraindicated&in&pregnancy&and&nursing&women&!
!
Anion!inhibitors!
! Thiocyanate,(SCNP),and,perchlorate,(ClO4P),block&uptake&of&iodide&by&
the&thyroid&through&competitive&inhibition&if&the&iodide&transporter!
! Can&cause&aplastic&anemia&and&are&rarely&used!
!
Other!drugs!
! ]blockers&are&important&in&the&treatment&of&thyrotoxicosis!
o Control&tachycardia&and&other&cardiac&problems!
o Propanolol,also&inhibits&the&peripheral&conversion&of&T4&to&T3!
! Amiodarone&is&iodine]containing&antiarrhythmic!
o Can&cause&hypothyroidism&via&its&ability&to&block&peripherial&
conversion&of&T4&to&T3!
o Can&cause&hyperthyroidism&either&through&iodine]induced&
mechanism&in&persons&with&underlying&thyroid&disease&
(multinodular&goiter)&or&through&an&inflammatory&mechanism&
releasing&thyroid&hormones&into&the&circulation!
! Hypothyroidism&is&treated&with&thyroid&hormones!
! Hyperthyroid&due&to&dx&is&treated&with&thioamides!
! Hyperthyroid&due&to&inflammation&is&treated&with&steroids!

& 130&
Sollas&Notes&2015&

17.2&Pharmacological&treatment&of&inflammation&
Inflammation(is(a(complex(response(to(cell(injury(that(primarily(occurs(in(
vascularized(CT(and(often(involves(the(immune(response.(The(mediators(of(
inflammation(function(to(eliminate(the(cause(of(cell(injury(and(clear(away(cell(
debris,(to(prepare(for(tissue(repair.(But(inflammation(also(comes(with(some(cons;(
the(most(noticeable(is(pain(on(location(and(the(possibility(of(the(acute(
inflammation(to(develop(into(a(chronic(inflammatory(state(that(is(dominated(by(
tissue(damage(and(chronic(pain((e.g.(RA).((
( NSAIDs(and(acetaminophen(are(often(effective(in(controlling(inflammatory(
pain.(Other(treatment(strategies(applied(to(the(reduction(of(inflammation(are(
targeted(at(immune(processes.(These(include(glucocorticoids(and(diseaseL
modifying(antiLrheumatic(drugs((DMARDs).(
(
Inflammation:!
Subcategorized&into:(
o Acute(
o Subacute&(
o Chronic(
Cardinal&signs:(
o Dolor&(pain)(
o Calor&(heat)(
o Rubor&(redness)(
o Tumor&(swelling)(
o Functio&laesa&(loss&of&function)(

(
Treatment!strategy!for!inflammation:!
NSAIDs!
o Symptomatic&relief&for&pain&and&inflammation!
o Long&term&treatment&periods!
o Have&no&influence&on&disease&progression&!
o Rapidly&effective!
DMARDs!
o Modify&the&disease&and&block&disease&progression!
o Slow&acting!

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Sollas&Notes&2015&

Classification!of!anti/inflammatory!drugs:!
According&to&selectivity:!
o Selective&COX]1&inhibitors!
! Asprin,,tolmetin!
o COX]1&inhibitors&(low&selectivity)!
! Ibuprofene,,indomethacin,,piroxicam!
o COX]1,&COX]2&inhibitors!
! Diclofenac!
o Selective&COX]2&inhibitors!
! Meloxicam,,celecoxib,,etodolac,,rofecoxib!
According&to&mechanism&of&action!
o Irreversible&!
! Aspirin!
o Reversible!
! Indomethacin,,ibuprofen!
!
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&

& 132&
Sollas&Notes&2015&

17.3&Antiarrhythmic&drugs&
&
Antiarrhythmic&drugs:&
Group&of&drugs&that&are&used&to&suppress&abnormal&cardiac&rhythms:& &
o Atrial&fibrillation&and&flutter&
o Atrioventricular&nodal&reentry&(SVT)&
o Premature&ventricular&beats&(PVBs)&
o Ventricular&tachycardia&and&ventricular&fibrillation&(VFib)&
Important&aspect&of&the&antiarrhythmic&drugs&is&a&good&understanding&of&
the&cardiac&action&potential,&in&nodal&cells&as&well&as&normal&cardiac&
myocytes&and&the&His]bundle&branches.&Ion&channels&to&keep&in&mind:&
o Fast&acting&Na+&channels&&phase&0&
o Slow&acting&Ca2+&channels&&phase&2&&&phase&0&in&nodal&AP&
o Slow&Delayed&rectifier&K+&channelsphase&2]3&&&3&in&nodal&AP&
o Fast&Delayed&rectifier&K+&channels&&phase&3&&&phase&3&in&nodal&AP&
o Inward&rectifier&K+&channels&&phase&3]4&
o Transient&Ca2+&channels&&phase&3&of&nodal&AP&

&
Classification&of&antiarrhythmic&agents&can&be&very&tricky.&This&is&due&to&the&
multiple&actions&of&the&various&drugs,&where&a&specific&antiarrhythmic&drug&can&
act&on&one&or&more&of&the&ion&channels&in&the&action&potentials&simultaneously.&
Even&though&this&can&make&classification&difficult&the&antiarrhythmic&drugs&have&
been&classified&in&to&4&main&groups&(and&one&group&for&drugs&that&cant&be&
categorized)&on&the&basis&of&Vaughan]Williams&classification:&
Class&I:&Na+&channel&blockers&
Class&II:&]adrenoceptor&blockers&
Class&III:&K+&channel&blockers&&
Class&IV:&Ca2+&channel&blockers&
Class&V:&Drugs&that&work&by&other&or&unknown&mechanisms&
&
With(regards(to(management(of(atrial(fibrillation,(class(I(and(III(are(used(as(
rhythm(controllers(while(class(II(and(IV(are(used(as(medical(cardioversion(agents(
to(control(the(heart(rate(
Class&I:&

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Sollas&Notes&2015&

Further&subcategorized&on&the&basis&of&their&effects&on&AP&duration&
o Class&Ia:&
! Block&the&fast&Na+&channels&(INa)&in&activated&state&
! Slows&down&the&action&potential&&
! Act&on&the&QRS&complex&
! #&AP&duration&(APD)&&&effective&refractory&period&(ERP)&
! Blocks&K+&channels&that&results&in&prolonged&repol.&
! Example:&
Quinidine,!procainamide,&disopyramide&
! Used&for:&
Ventricular&arrhythmias,&preventing&paroxysomal&
recurrent&atrial&fibrillation&that&is&triggered&by&vagal&
overactivity&
Procainamide&is&used&in&Wolf]Parkinson]White&&
o Class&Ib:&
! Block&the&fast&Na+&channels&(INa)&in&inactivated&state&
Good(in(the(case(of(hypoxic(myocardial(tissue,(where(
its(important(to(keep(the(AP(in(its(refractory(period.(
This(prolongs(the(repolarization(and(the(time(it(takes(
to(get(back(to(resting(state.(By(this(we(ensure(that(we(
have(more(time(in(diastole(to(reLperfuse(the(hypoxic(
tissue(
! $&APD&(due&to&inhibition&of&the&slow&Na+&window&current)(
Normally(this(would(be(proLarrhythmic,(but(in(the(
hypoxic/ischemic(heart(this(slows(the(conduction((
allowing(the(myocytes(to(recover((
! Example:(
Lidocaine,&mexiletine,&tocainide,&phenytoin(
! Used&for:(
Post&MI&treatment(
During&open&heart&surgery(
Ventricular&tachycardia(
o Class&Ic:(
! Non]selective&&so&they&block&ALL&Na+&channels&(
Especially&the&His]Purkinje&system(
! Used&as&last&resort&drugs&&when&the&others&dont&work&
properly&(
! Example:(
Flecainide,&encainide,&propafenone(
! Used&in:(
Paroxysmal&atrial&fibrillation(
Recurrent&tachyarrhythmias&of&abnormal&conduction&
system(
! Contraindicated:(
In&post&MI&patients(
Can&cause&Torsade&de&pointes&due&to&prolonged&AP(
(
&

& 134&
Sollas&Notes&2015&

Class&II&(Beta]adrenoceptor&blockers):&
$&SA]&and&AV&nodal&activity&(by&blocking&the&pacemaker&current)&
$&slope&of&phase&4&
Act&by&blocking&the&effects&of&
catecholamines&at&the&1]receptors&
o Decreasing&sympathetic&
activity&on&the&heart&
o Making&the&parasympathetic&
system&the&predominant&
system&
Used&in:&
o Prophylaxis&post]MI&
! The&negative&
inotropic&effect&to&decrease&the&O2&demand&
o Supraventricular&tachyarrhytmias&
o Decrease&conduction&through&the&AV]node&
Selective:&
o Acebutolol,&esmolol,&metaprolol,&nebivolol&
Non]selective:&
o Propanolol,&carvedilol,&sotalol&&
Class&III&(K+]channel&blockers):&
$&IK&by&slowing&phase&3&
#&APD&and&ERP&
#&QT&interval&
Prolongs&repolarization&markedly&
Used&when&other&anti]arrhythmic&fail&
Used&in:&
o A]fib,&atrial&flutter&
o Ventricular&tachycardias&
! Sotalol,,amiodarone&
Toxicity:&
o Sotalol&&torsades&de&pointes,&excessive&]blockade&
o Ibutilide&torsades&de&pointes&
o Amiodarone&&pulmonary&fibrosis,&hepatotoxicity,&
hypo/hyperthyroidism,&corneal&deposits,&skin&deposits&(blue/gray)&
resulting&in&photodermatitis,&neurologic&effects,&constipation,&CV&
effects&such&as&bradycardia,&AV]block&and&CHF&
! Class&I,&II,&III,&IV&drug&
Class&IV&(Ca2+]channel&blockers):&
$conduction&velocity,&#ERP,&#PR&interval&
$phase&0&and&4&
$SA&&&AV]nodal&activity&
Used&in:&prevention&of&nodal&arrhythmia,&rate&control&in&A]fib&
Toxicity:&Constipation,&flushing,&edema,&CV&effects&(CHF,&AV]block,&sinus&
node&depression&&
Verapamil,&,diltiazem&
&
&

& 135&
Sollas&Notes&2015&

Topic&18&
18.1&Adrenocorticosteroids&and&adrenocortical&antagonists&
&
The(corticosteroids(are(steroid(hormones(produced(by(the(zona(fasiculata(of(the(
adrenal(cortex.(They(consist(of(2(major(physiologic(and(pharmacologic(groups:(
! Glucocorticoids((Prednisone)(
o That(have(important(effects(on(intermediary(metabolism,(
catabolism,(immune(responses(and(inflammation(
! Mineralocorticoids((Fludrocortisone)(
o That(regulate(sodium(and(potassium(reabsorption(in(the(collecting(
tubules(of(the(kidneys(
Antagonists(of(these(steroid(hormones(either:(
! Inhibit(the(receptors(
o Glucocorticoid(receptor(antagonist((Mifeprostone)(
o Mineralocorticoid(receptor(antagonist((Spironolactone)(
! Inhibits(the(synthesis((Ketoconazole)(
&
Glucocorticoids:!
! Enter&the&cell&to&bind&to&cytosolic&receptors&that&transport&the&steroids&
(steroid]receptor&complexes)&into&the&nucleus&where&they&bind&to&GREs&
(glucocorticoid&response&elements)&and&mineralocorticoid]specific&
enzymes&to&alter&gene&expressions!
! Metabolic!effects:! !
o Stimulation&of&gluconeogenesis&causing!
! Increase&in&blood&glucose&levels!
! Muscle&protein&catabolization!
! Stimulation&of&insulin&secretion!
o Stimulation&of&lipolysis&and&lipogenesis!
! Net&increase&of&fat&deposition&in&certain&areas!
Face,&shoulders&and&back!!!
o Causing&moon&face,&buffalo]hump&appearance!
! Catabolic!effects:!
o Muscle&protein&catabolism&!
o Lymphoid&and&CT,&fat&and&skin&undergo&wasting&in&high&cc.!
o Bone&catabolism&can&lead&to&osteoporosis!
! In&kids&the&growth&is&inhibited!
! Immunosuppressive!effects:!
o Inhibition&of&cell]mediated&immunity&(mainly&lymphocytes)!
! Actively&lymphotoxic&&that&makes&them&good&in&treatment&
of&hematologic&cancers!
o Delay&rejection&reactions&in&patients&with&organ&transplants!
! Anti/inflammatory!effects:!
o Induce&synthesis&of&the&inhibitor&of&phospholipase&A2&!
! Decreasing&the&mRNA&production&for&expression&of&COX]2!
! Decreasing&IL]2&and&IL]3&+&platelet&activating&factor&(PAF)!
All&being&inflammatory&cytokines!
o Dramatic&effects&on&distribution&and&function&of&leukocytes!
! Increase&neutrophils!

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Sollas&Notes&2015&

! Decrease&lymphocytes,&eosinophils,&basophils&and&
monocytes!
o Migration&of&leukocytes&is&also&inhibited!
! Other!effects:!
o Cortisol&is&needed&for&normal&renal&excretion&of&water&loads!
o CNS&effects&that&can&cause&behavioral&changes&in&large&doses!
o Stimulation&of&gastric&acid&secretion&with&decreased&resistance&to&
ulcer&formation!
! Important!glucocorticoids:!
o Cortisol,(hydrocortisone),&the&major&natural&glucocorticoid!
! Physiological&regulation&is&done&by&ACTH&and&varies&during&
the&day&(following&the&circadian&rhythm)!
Peaks&in&the&morning&and&stops&around&midnight!
! 95%&bound&to&corticosteroid&binding&protein&(CBP)&in&
plasma&&but&only&the&free&form&is&active!
! Given&orally,&well&absorbed&from&the&gut,&cleared&by&the&
liver&and&has&short&duration&of&action!
! Poorly&absorbed&through&the&intact&skin&&but&easily&
absorbed&in&case&of&inflamed&skin&and&mucous&membranes!
! Small&but&important&salt]retention&effects!
Important&cause&of&HTN&in&patients&with&Cushings&
syndrome&(ACTH]secreting&tumor)&or&cortisol]
secreting&adrenal&tumor!
o Prednisone,,prednisolone,,dexamethasone,,triamcinolone!
! Synthetic&glucocorticoids&similar&to&cortisol!
! Longer&half]life,&duration&of&action,&reduced&salt]retention&
effects&and&better&penetration&of&lipid&barriers&!
Making&them&better&for&topical&use!
o Beclomethasone,and,budesonide!
! Specially&developed&for&use&in&asthma&!
! Readily&penetrate&airway&mucosa&!
! Very&short&half]lives&after&they&enter&the&blood!
Reducing&systemic&effects&and&toxicity!
!
! Clinical!uses!of!glucocorticoids:!
o Adrenal&disorders!
! Essential&to&preserve&life&in&patients&with&Addisons&
(chronic&adrenal&cortical&insufficiency)!
! Essential&in&acute&adrenal&insufficiency&associated&with&life]
threatening&shock,&infection&or&trauma!
! Some&types&of&congenital&adrenal&hyperplasia!
To&suppress&the&ACTH&secretion&to&reduce&synthesis&
of&the&abnormal&steroids!
o Non&adrenal&disorders!
! Immunological&and&inflammatory&disorders!
Asthma,&organ&transplant&rejection,&collagen&dx.&
Rheumatic&disorders!

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Sollas&Notes&2015&

! Treatment&of&hematopoietic&cancers,&neurologic&disorders,&
chemo]therapy&induced&vomiting,&hypercalcemia&and&
mountain&sickness!
! Toxicity:!
o Growth&inhibition,&diabetes,&muscle&wasting,&osteoporosis,&salt&
retention,&psychosis!
o Important&is&to&taper&down&the&doses&very&slowly&to&prevent&
adrenal&insufficiency&that&can&occur&due&to&the&long&inhibition&!
!
Mineralocorticoids!
! Aldosterone,(major(natural(mineralocorticoid!
o Regulated&by&ACTH&and&RA]system!
o Very&important&in&the&regulation&of&the&blood&volume&and&BP!
o Short&half]life&and&little&glucocorticoid&activity!
! Deoxycorticosterone,(L(naturally(occurring(precursor(of(aldosterone!
! Fludrocortisone((has(significant(glucocorticoid(activity!
o Long&duration&of&action&!
o Favored&in&replacement&therapy&after&adrenalectomy&!
!
Cortico/!and!mineralocorticosteroid!antagonists!
! Receptor&antagonists:!
o Spironolactone,and,eplerenone!
! Antagonists&of&aldosterone&&used&as&diuretics!
o Mifepristone,(RUP486)!
! Competitive&inhibitor&of&glucocorticoid&as&well&as&
progesterone&receptors!
! Has&been&used&in&Cushings&syndrome!
! Used&as&a&medical&abortion&pill!
! Synthesis&inhibitors:!
o Ketoxonazole,,aminoglutethimide,,metyrapone!
o Ketoxonazole&(an&antifungal&drug)&inhibits&cytP450&enzymes&that&
are&necessary&for&the&synthesis&of&all&steroids!
! Used&in&adrenal&carcinoma,&hirsutism,&breast&&&prostate&c.&!
o Aminoglutethimide&!
! Blocks&conversion&of&cholesterol&to&pregnenolone!
! Inhibits&synthesis&of&all&hormonally&active&steroids!
! Used&in&treatment&of&steroid]producing&adrenocortical&canc.!
o Metyrapone&inhibits&normal&synthesis&of&cortisol&but&not&cortisol&
precursors!
! Used&as&diagnostic&test&of&adrenal&function!
!
!
!
!
!
!
!
!
!

& 138&
Sollas&Notes&2015&

18.2&Non&steroidal&anti?inflammatory&drugs&(NSAIDs)&
&
NSAIDs(are(a(class(of(drugs(that(provide(analgesic,(antipyretic(and(antiL
inflammatory(effects.(The(most(prominent(members(of(this(group(are(the(aspirin,(
ibuprofen(and(naproxen.(All(of(these(drugs(are(available(as(OTC(drugs(in(most(
countries.(Acetaminophen(is(generally(not(considered(as(an(NSAID(because(it(has(
only(a(very(limited(antiLinflammatory(activity.(It(treats(pain(mainly(by(blocking(
COXL2(in(the(CNS,(and(has(very(little(antiLinflammatory(effects(in(the(body.(
NSAIDs(inhibit(the(activity(of(both(COXL1(and(COXL2,(and(thereby,(the(synthesis(of(
prostaglandins(and(thromboxanes.(The(adverse(effects(of(the(COXL1(inhibitors(can(
be(dangerous,(especially(in(the(case(of(prolonged(usage.(These(effects(include(GIL
bleedings(and(ulcer(formations,(and(therefore(these(drugs((mainly(aspirin)(need(to(
be(used(with(great(precaution.((
(
Pharmacokinetic!features:!
Weak&organic&acids&"&pKa&&3.0&!
o This&results&in&their&rapid&absorption&from&the&gut!
Metabolized&in&the&liver&via&the&CYP&enzymes&and&excreted&by&kidneys!
o Mainly&CYP3A&and&CYP2C!
Accumulate&in&high&cc.&in&synovial&fluid&following&repeated&exposures!
Highly&protein&bound&(98%)!
!
Pharmacodynamic!features:!
Inhibition&of&immune&responses&(anti]inflammatory)!
o Inhibition&of&chemotaxis!
o Decreased&sensitivity&to&histamine&in&vessel&wall!
! And&by&that&decreasing&vascular&permeability!
o Down&regulate&the&IL]1&producion!
o Decrease&the&production&of&free&radicals&and&superoxide!
Antipyretic&effects:!
o Decrease&of&cAMP&in&hypothalamic&thermoregulation&centers!
! Located&in&the&anterior&and&posterior&hypothalamic&nuclei!
Analgesic&effects:!
o Peripheral&inhibition&of&nociception!
Antithrombotic&effects:!
o Decrease&the&production&of&thromboxane&A2&&(TXA2)!
o Decrease&platelet&aggregation!
!
General!adverse!effects!of!NSAIDs:!
CNS:!
o Headache,&tinnitus,&dizziness!
Cardiovascular:!
o Fluid&retention,&HTN,&edema!
Gastrointestinal&tract:!
o Inhibition&of&prostaglandins&in&the&gastric&mucosa&causes&loss&of&
the&protective&functional&mucosa&!
! Ulcers,&bleedings,&nausea,&vomiting,&pancreatitis!
Hematological&(bone&marrow&suppression)!

& 139&
Sollas&Notes&2015&

o Thrombocytopenia,&neutropenia,&aplastic&anemia!
Hepatic&(metamizol,,aspirin)!
o Hepatitis!
o Reyes&syndrome&(rare)!
! Occurs&when&children&with&viral&infections&are&given&aspirin!
! Rapid&liver&degeneration&and&encephalopathy!
Pulmonary&(due&to&increase&in&leukotrienes)!
o Aspirin&asthma!
! Abnormally&low&levels&of&PGE2&(protective&for&lungs)!
! Overexpression&of&cysteinyl&leukotriene&receptor&1&and&
leukotriene&C4&synthase!
! Attachment&of&platelets&to&certain&leukocytes&in&the&blood&
that&contributes&to&the&overproduction&of&leukotrienes!
Renal:!
o Decreased&renal&blood&flow!
o Renal&insufficiency,&renal&failure,&hyperkalemia&!
Aspirin!(acetylsalicyclic!acid):!
Prototype&of&the&salicylates&and&other&NSAIDs&!
Isolated&from&willow&(bark)!
Irreversible&inhibitor&of&COX]1!
o Resulting&in&longer&duration&of&its&antiplatelet&effects!
o COX]1&is&primarily&expressed&in&non]inflammatory&cells!
Weak&acid&that&is&rapidly&absorbed&from&stomach&and&small&int.!
Elimination:!
o At&low&doses&the&salicylic&acid&is&eliminated&via&first&order&kinetics!
! Half]life&is&3]5hrs&!
o At&high&doses&its&eliminated&via&zero&order&kinetics!
! Half]life&is&15hrs&or&more!
Excretion&is&via&the&kidneys!
Antipyretic,&analgesic,&anti]inflammatory&effects!
Antithrombotic&effects&due&to&decrease&platelet&aggregation!
o Hence&its&commonly&used&in&low&doses&as&an&anticoagulant!
! <300&mg/day!
! Used&in&TIA&(stroke)&or&AMI!
! Secondary&prevention&of&AMI&and&stroke!
Clinical&uses:!
o 0,5]2,5&g/day&&antipyretic&and&analgesic&effects!
o 2,5]4&g/day&&anti]inflammatory&effects!
o 5&g/day&&uricosuric&!
! Increase&excretion&of&uric&acid&resulting&in&decreased&cc.&of&
uric&acid&in&the&plasma&!
! For&the&treatment&of&gout!
Adverse&effects:!
o Gastric!upset!
! Upper&GI&bleedings,&gastric&ulcers!
o Renal&effects&(acute&failure&or&interstitial&nephritis)!
o Aspirin&asthma,&Reyes&syndrome,&hepatotoxicity!
o Respiratory&alkalosis,&hyperventilation,&metabolic&acidosis,&
dehydration,&hyperthermia,&collapse,&coma,&death!

& 140&
Sollas&Notes&2015&

Non/selective!COX!inhibitors:!
Diclofenac!
o Phenylacetic&acid&derivative&that&inhibits&both&COX]1&and&COX]2!
o Potent&analgesic&effects!
o Selective&for&muscle&&&joint&inflammation!
o Causes&ulcerations&of&the&GI!
! Good&to&keep&in&mind&to&co]apply&omeprazole,&famotidine&
or&misoprostole&to&decrease&the&possibility&of&ulcers!
o Doses:&150(mg/day!
o Used&as&"&Topical&gel&(1]3%),&IM&injections,&ophthalmic&prepar.!
Ibuprofen!
o Phenylpropionic&acid&derivative!
o Analgesic&effects&and&anti]inflammatory&effects&!
! >2400mg&=&4000mg&aspirin!
o Indicated&for&closure&of&patent&ductus&arteriosus&(PDA)!
! In&premature&infants&(500]1,500&gr),&who&are&no&more&than&
32&weeks&gestational&age&when&the&usual&medical&
management&(e.g.&fluid&retention,&diuretics,&respiratory&
support)&is&ineffective!
Administered&orally,&IM&injections&or&as&topical&crmes!
Used&in&treatment&of:&!
o Headaches,&dental&pain,&premenstrual&pain&etc.!
Adverse&effects:!
o Nausea,&dyspepsia,&GI]effects,&raised&liver&enzymes,&diarrhea,&
constipation,&nosebleed,&headache,&dizziness,&rash,&fluid&retention,&
HTN&all&known&side&effects!
o Rare&side&effects&include:!
! Heart&failure,&hyperkalemia,&renal&impairment,&confusion,&
broncospasms,&increased&incidence&and&severity&of&asthma!
!
Indometacin:!
Indol&derivative&and&one&of&the&oldest&NSAIDs!
Non]selective&inhibitor&of&COX!
o Inhibits&phospholipase&A&and&C!
o Decreases&migration&of&neutrophils&to&site&of&inflammation!
o Decreases&proliferation&of&T]&and&B]cells!
Used&similarly&as&ibuprofen&in&the&closure&treatment&of&PDA!
Adverse&effects:!
o GIT]effects&!
o Pancreatitis!
o Dizziness,&confusion,&hallucinations!
o Thrombocytopenia,&aplastic&anemia&!
o Renal&papillary&necrosis!
Ketoprofen:!
Propionic&acid&derivative&that&inhibits&COX&and&LPO!
100]300&mg/day!
Adverse&effects&are&similar&as&with&ibuprofen!
Ketorolac:!
Analgesic&but&NO&anti]inflammatory&effects!

& 141&
Sollas&Notes&2015&

IV&or&IM&administration!
Co]applied&with&morphine&for&postoperative&analgesia!
Naproxen:!
Naphtylpropionic&acid&derivative!
Used&in&rheumatic&disorders,&treatment&of&migraine,&osteoarthritis,&kidney&
stones,&gout,&ankylosing&spondylitis,&premenstrual&pain,&tendinitis&+&more!
!
Acetaminophen!(paracetamol):!
Analgesic,&antipyretic&effects&&NO&anti]inflammatory&effects!!!!
Weak&COX]1&and&COX]2&inhibitor&in&peripheral&tissues!
o This&accounts&for&its&non]anti]inflammatory&effects!
o Some&evidence&of&COX]3&inhibition&in&the&brain!
Well&absorbed&orally,&metabolized&by&the&liver!
o Half]life&is&2]3hrs&in&persons&with&normal&hepatic&function!
Aspirin&alternative&when&aspirin&cannot&be&tolerated&!
o Aspirin&asthma,&hemophilia&or&gastric&ulcers!
o In&children&with&viral&infection&(since&they&CANNOT&get&aspirin)!
Works&similarly&as&a&intermediate&dose&of&aspirin!
Clinical&uses:!
o Hyperpyrexia&&in&children!
o Headache,&myalgia&and&postpartum&pain!
Adverse&effects:!
o >4g/day&&HEPATOTOXICITY!!!!
! N]acetyl]benzokinone&is&formed&that&is&a&toxic&metabolite!
Mechanism&of&toxicity&involves&oxidation&of&this&
cytotoxic&intermediate&that&is&produced&by&phase&I&
reaction;&specially&when&phase&II&conjugation&
reactions&(acetate&and&glucuronide)&are&lacking!
Prompt&administration&of&acetyl/cysteine!(SH]
donor)&can&be&life]saving&following&an&overdose!
Regular&alcohol&use&(3&drinks&a&day)&predisposes&
the&liver&for&this&dangerous&reaction!
!
!
!
!
!
!
!
!
!
!
!
!
!
!

& 142&
Sollas&Notes&2015&

18.3&Pharmacotherapy&of&congestive&heart&failure&
&
Heart(failure(results(when(CO(is(inadequate(for(the(needs(of(the(body.(Major(
manifestations(are(dyspnea(and(fatigue.(A(defect(in(cardiac(contractility(is(
complicated(by(multiple(compensatory(processes(that(further(weaken(the(failing(
heart.((
(
The&drugs&used&in&heart&failure&fall&into&3&major&groups:&
Positive&ionotropic&drugs&
o Cardiac&glycosides&,digoxin&
o Beta&agonists&&dobutamine&
o PDE&inhibitors&&inamrinone&
Vasodilators&
o PDE&inhibitors&&inamrinone&
o Nitroprusside,,nitrates,,hydralazine,
o Loop&diuretics,&ACE&inhibitors,&Nesiritide&
Miscellaneous&drugs&for&chronic&failure&
o Loop&diuretics,&ACE&inhibitors,&Nesiritide&
o Beta&blockers,&Spironolactone&
Causes&of&heart&failure&are&still&not&completely&understood&but&they&are&related&to&
Loss&of&functional&myocardium&(post&MI)&
Chronic&hypertension,&valvular&diseases,&coronary&artery&diseases&and&
cardiomyopathic&diseases&
Systolic&failure:&
1/3&&reduction&of&cardiac&contractile&force&and&ejection&fraction&
Diastolic&failure:&
1/3&&stiffening&or&other&ventricular&changes&preventing&filling&
Ejection&fraction&might&be&normal&
Combination&of&systolic&and&diastolic&failures:&
1/3&of&cases&
&
Therapeutic&strategies:&
Removal&of&salt&and&water&with&diuretics&
Reduction&of&afterload&and&salt&and&water&retention&by&ACE]inhibitors&
Reduction&of&excessive&sympathetic&stimulation&by&beta]blockers&
Reduction&of&preload&or&afterload&with&vasodilators&
Direct&augmentation&of&depressed&cardiac&contractility&with&positive&
ionotropic&drugs&such&as&digoxin&(this&is&in&systolic&failure)&
Current&clinical&evidence&suggest&that&acute&heart&failure&should&be&treated&with:&
Loop&diuretic&
Beta]agonists&or&phosphodiesterase&inhibitor&(when&severe&failure)&
Vasodilators&used&as&needed&to&optimize&filling&pressures&and&BP&
Nesiritide&(recombinant&form&of&natriuretic&peptide)&has&a&vasodilating&
and&diuretic&properties&and&has&been&widely&used&in&acute&failure&
Chronic&failure:&
Best&treated&with&diuretics&(loop&+&spironolactone)&
ACE&inhibitors&&
Beta]blockers&(if&they&can&be&tolerated)&

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Digitalis&is&helpful&if&the&systolic&failure&is&prominent&
Diuretics:&
First&line&therapy&in&both&systolic&and&diastolic&failure&
Used&before&digitalis&and&other&drugs&are&considered&
Furosemide&is&useful&for&immediate&reduction&of&the&pulmonary&
congestion&and&severe&edema&
o Used&in&acute&failure&and&moderate/severe&chronic&failure&
Hydrochlorothiazide&used&in&mild&chronic&failure&
Spironolactone,and,eplerenone,(aldosterone&antagonist&diuretics)&have&
good&long&term&benefits&and&can&reduce&mortality&in&chronic&failure&
Angiotensin&antagonists:&
First&line&drugs&for&chronic&heart&failure&
Shown&to&reduce&morbidity&and&mortality&of&chronic&HF&
Reduce&aldosterone&secretion,&salt&and&water&retention&and&vascular&
resistance&
Angiotensin&receptor&blockers&(ARBs&&e.g.&losartan)&have&similar&
benefits&as&ACE&inhibitors&(e.g.&captopril)&but&their&experience&is&not&as&
extensive&
Beta1]adrenoreceptor&agonists:&
Dobutamine,and,dopamine,are&useful&in&acute&failure&where&systolic&
function&is&markedly&depressed&
Not&appropriate&for&chronic&failure&because&of&tolerance,&lack&of&oral&
efficacy,&and&significant&arrhythmogenic&features&
Beta]blockers:&
Not&used&in&acute&failure&
Carvedilol,,labetalol,,metoprolol,have&been&shown&to&reduce&
progression&of&chronic&heart&failure&
Nebivolol,(a&newer&type&of&blocker)&is&with&additional&vasodilator&effects&
Phosphodiesterase&inhibitors:&
Not&so&frequently&used&and&NOT&used&in&chronic&failure&&
o Seem&to&increase&morbidity&and&mortality&&
Inamrinone,and,milrinone&
These&drugs&increase&cAMP&and&cause&an&increase&in&IC&Ca2+&
Cause&vasodilation&
Vasodilators:&
Often&used&for&acute&severe&failure&with&congestion&
Nitroprusside,or,nitroglycerin&
Reduce&cardiac&size&and&improve&the&efficiency&of&the&heart&
o Adjust&preload&and&afterload&
Nesiritide,also&causes&vasodilation&(given&IV&in&acute&failure)&
o Monitoring&of&renal&functions&is&needed&
Hydralazine,and,isosorbide,dinitrate,are&a&good&combo&to&use&in&
chronic&heart&failure&
Nonpharmacologic&therapy:&
Surgical&procedures&to&remove&nonfunctional&regions&of&damaged&
myocardium&(mixed&results)&
Pacemaker&resynchronization&the&LV&and&RV&have&been&beneficial&in&
patients&with&long&QRS&(conduction&abnormalities)&

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Coronary&revascularization&has&also&been&proven&to&help&
&
Cardiac&glycosides&]&Digoxin:&
No&longer&considered&first]line&drugs&in&heart&failure&
Digoxin&inhibits&Na+/K+&ATPase&of&the&cell&membrane&&
o Results&in&small&increase&in&IC&Na+&
o This&changes&the&transport&of&Ca2+&out&of&the&cell&via&Na+/Ca2+&
o Increased&IC&Ca2+&increases&the&contractile&force&
Modifies&autonomic&outflow&&influences&electrical&properties&of&the&heart&
Effects:&
o Increased&contractility&results&in&increased&ejection&
o Decreased&end]systolic&and&end]diastolic&size&
o Increased&cardiac&output&
o Decrease&in&the&compensatory&sympathetic&and&renal&responses&
! Decreased&sympathetic&tone&&decreased&HR,&preload,&afterload&&
this&permits&the&heart&to&function&better&
o Early&cardiac&parasympathomimetic&responses&
! Increased&PR]interval&and&flattening&of&T]waves&
! Parasympathetic&effects&on&AV&and&atria&can&be&blocked&with&
atropine&&so&we&dont&slow&the&firing&rate&of&AV&too&much&(slow&
ventricular&rate&compared&to&atria)&
! Shorter&QT,&inversion&of&T&and&ST&depression&&
o Later&arrhythmogenic&actions&
! Toxic&responses&
Toxic&responses:&
o Increased&automaticity&(due&to&increased&IC&Ca2+)&
! Delayed&afterdepolarizations&
Extrasystoles,&tachycardia,&fibrillation&in&any&parts&of&the&
heart&
Premature&ventricular&beats&and&bigeminy&
o Amplified&toxicity&is&obtained&occurs&in&hypokalemia,&hypomagnesinemia&
and&hypercalcemia&
Interactions&with&other&drugs&such&as&quinidine,may&increase&the&serum&levels&
of&digoxin&even&more&and&cause&more&toxicity&and&problems&
o Also&with&amiodarone,,verapamil,etc.&&
Used&in&chronic&heart&failure&(positive&ionotropic&agent)&
o Reduces&symptoms&and&improves&functional&status&
o Does&not&prolong&life&
o More&toxic&than&the&previously&discussed&drugs&
o Long&half]life&that&makes&them&accumulate&in&the&body&
o Dosing&is&very&important&and&proper&monitoring!!!!!&
Used&in&atrial&fibrillation&but&same&here&&needs&to&be&monitored&closely&
Symptoms&of&toxicity:&
Arrhythmias,&nausea,&vomiting&and&diarrhea,&confusion&and&hallucinations&(rare)&
and&visual&or&endocrine&abnormalities&may&occur&
Severe/acute&intoxication&(suicide/accidental)&can&result&in&cardiac&arrest&&
Detoxification&is&done&with:&
o Correcting&potassium&or&magnesium&problems&
o Antiarrhythmic&drugs&in&not&so&severe&cases&
o Digoxin&antibodies&(digibind)&are&extremely&effective&and&should&always&
be&used&if&other&therapies&seem&to&be&failing&

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Topic&19&
19.1&The&endocrine&pancreas.&Insulin&preparations&and&the&treatment&of&insulin&resistance&
&
In(the(endocrine(pancreas,(the(Islets(of(Langerhans(contain(at(least(4(types(of(
endocrine(cells:(
! (cells((producing(glucagon(
! (cells((producing,insulin,&,amylin(
! (cells((producing(somatostatin(
! ((PP)((producing(pancreatic,polypeptide(
The(most(common(pancreatic(disease(requiring(pharmacologic(therapy(is(diabetes(
mellitus((DM)((a(deficiency(of(insulin(production(or(effects.(Different(formulations(
of(insulin(and(noninsulin(diabetic(agents(exist.(Glucagon(affects(the(liver,(
cardiovascular(system(and(GI(tract(is(used(in(the(treatment(of(severe(hypoglycemia(
(
Drugs!for!diabetes!mellitus:!
! Insulin&preparations!
o Rapid&short]acting&"&lispro,,regular!
o Intermediate]acting&"&NPH,,lente!
o Slow]acting&"&glargine!
! Non]insulin&antidiabetic&drugs!
o Insulin&secretagogues&"&glipizide!
o Biguanides&"&metformin!
o ]glucosidase&inhibitors&"&acarbose!
o Thiazolidinediones&"&pioglitazone!
o Amylin&analogs&"&pramlintide!
o Incredin&modulators!
! GLP]1&analog&"&exenatide!
! DPP]4&inhibitor&"&sitagliptin!
Insulin:!
! Synthesized&from&proinsulin&that&is&cleaved&&&cross]linked&to&result&in:!
o 2]chain&51&peptide&insulin&molecule!
o 31]amino&acid&residual&C]peptide&!
! Effects&of&insulin:!
o Important&effects&on&almost&all&tissues&in&the&body!
o Liver:!
! Increased&glycogenesis&via&insertion&of&GLUT2!
! Increased&synthesis&of&pyruvate&kinase,&
phosphofructokinase&and&glucokinase!
! Decreased&protein&metabolism!
o Skeletal&muscle:!
! Stimulation&of&glycogenesis&and&protein&synthesis!
Via&GLUT4!
o Adipose&tissue:!
! Increased&triglyceride&storage&by&activation&of&plasma&
lipoprotein&lipase&!
! Reduced&intracellular&lipolysis!
Via&GLUT4&!
Insulin!preparations:!
! Human&insulin&is&manufactured&by&bacterial&recombinant&DNA&technology!

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! Goal&of&insulin&therapy&is&to&control&both&basal&and&postprandial&glucose&
levels&while&minimizing&the&risk&of&hypoglycemia!
! Rapid!acting!(insulin,lispro,,insulin,aspart,,insulin,glulisine)!
o Rapid&onset&and&early&peaks&of&activity!
o Permit&control&of&postprandial&glucose&levels!
o Small&alterations&in&their&primary&amino&acid&sequences!
! Permits&their&fast&entry&into&the&circulation!
o Injected&before&meal!
o Preferred&insulin&for&subcutaneous&infusion&devices!
o Also&used&in&emergency&treatment&of&diabetic&ketoacidosis!
! Short!acting!(regular,insulin)!
o Used&intravenously&in&emergencies&or&subcutaneously&normally!
o Sometimes&mixed&with&intermediate&or&long]acting&preparations!
o Requires&administration&approx.&1&hour&before&meal!
! Intermediate!acting!(NPH,insulin)!
o NPH&&neutral&protamine&Hagedorn&insulin!
o Combination&of&regular&insulin&and&protamine!
o Delayed&onset&and&peak&of&action!
o Often&used&with&short&and&rapid&acting&insulin&preparatios!
! Long!acting!(insulin,glargine,&,insulin,detemir)!
o Modified&forms&of&human&insulin&that&provides&a&peakless&basal&
insulin&level&&lasting&>20hrs!
! Prevents&the&production&of&hypoglycemia!
!
Insulin!delivery!systems:!
! Standard&therapy&is&subcutaneously&with&conventional&disposable&needles&
and&syringes!
! Portable&pen]sized&injections&with&or&without&replaceable&cartridges!
! Continuous&subcutaneous&insulin&infusion&device&avoid&the&need&for&
multiple&daily&injections&and&provide&flexibility!
! Programmable&pumps&deliver&a&constant&24hr&basal&rate!
!
Hazards!of!insulin!use:!
! Most&common&complication&is&hypoglycemia&resulting&from&high&doses!
o Prevented&by&prompt&administration&of&glucose!
! Candy,&IV&glucose,&IM&glucagon!
! Formation&of&antibodies&to&insulin&or&noninsulin&proteins&resulting&in&
resistance&or&allergic&reactions!
o Highly&purified&human&insulin&reduces&this&problem!
!
Treatment!of!insulin!resistance:!
! Primary&treatment&for&insulin&resistance&is&exercise&and&weight&loss!
! Carbohydrate&low&diet!
! Metformin,and,thiazolidinediones&improve&insulin&resistance!
! Amylomaize,resistant&starch&from&high]amylose&corn&reduces&insulin&
resistance&in&healthy&individuals&and&type&2&DM!
! Omega,3,is&a&good&prophylaxis&supplement&!

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19.2&Drugs&used&in&the&treatment&of&gout&
&
Gout(is(associated(with(increased(serum(concentrations(of(uric(acid.(Acute(attacks(
involve(joint(inflammation(initiated(by(precipitation(of(uric(acid(crystals.(
Treatment(strategies(include:(
Reducing(inflammation(during(attacks(
o Colchicine,,NSAIDs,or,glucocorticoids(
Accelerating(renal(excretion(of(uric(acid(uricouric(drugs(
o Probenecid,or,sulfinpyrazone(
Reducing(the(conversion(of(purines(to(uric(acid(by(xanthine(oxidase(
o Allopurinol,or,febuxostat(
(
Anti/inflammatory!drugs!used!in!treatment!of!gout:!
NSAIDs&(indomethacine)!
o Effective&in&inhibiting&the&inflammation&of&acute&gouty&arthritis!
o Act&through&the&reduction&of&PG&formation&and&the&inhibition&of&
crystal&phagocytosis&my&macrophages!
o Preferred&to&use&in&treatment&of&acute&gouty&arthritis&attacks!
! Along&with&glucocorticoids!
o Orally&absorbed!
o Can&cause&renal&damage&and&bone&marrow&depression!
Glucocorticoids!
o Preferred&to&use&in&treatment&of&acute&gouty&arthritis&!
! Along&with&NSAIDs!
o Orally&or&parenteral&given!
o Can&cause&behavioral&changes&and&impaired&glucose&control!
Colchicine!
o Selective&inhibitor&if&microtubule&assembly!
o Reduces&leukocyte&migration&and&phagocytosis!
o Reduces&the&production&of&leukotriene&B4&and&decreases&free&
radical&formation!
o General&mitotic&poison&because&of&its&interference&with&the&
microtubule&assembly!
o Oral&or&parenteral&preparations!
o Lower&doses&are&used&to&prevent&attacks&in&patients&with&history&of&
multiple&gouty&attacks!
o Also&used&in&the&management&of&familial&Mediterranean&fever!
! Disease&that&is&characterized&by&fever,&hepatitis,&peritonitis,&
pleuritis,&arthritis,&and&occasionally&amyloidosis!
! Unknown&origin!
o Causes&significant&GI&disturbance,&severe&damage&to&liver&and&
kidneys!
! Doses&must&be&carefully&monitored&and&limited!
Overdosing&is&often&fatal!
Uricosuric!agents!(probenecid,,sulfinpyrazone):!
Mechanism:!
o Normally&over&90%&of&the&uric&acid&filtered&by&the&kidneys&is&
reabsorbed&in&the&proximal&tubules!

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o The&uricouric&agents&are&weak&acids&that&compete&with&uric&acid&
transport&mechanism&in&the&proximal&tubules&!
! Increase&uric&acid&excretion!
o At&low&doses&they&may&also&compete&with&uric&acid&for&secretion&by&
the&tubule&and&therefore&they&might&elevate&uric&serum&cc.&!
! This&can&especially&occur&when&these&drugs&are&used&along&
with&aspirin&(also&a&weak&acid)!
Effects:!
o The&drugs&inhibit&the&secretion&of&a&large&number&of&other&weak&
acids&(e.g.&penicillin,&methotrexate)!
o Inhibit&reabsorption&of&uric&acid&from&the&tubules!
! Resulting&in&increase&excretion!
Used&orally&to&treat&chronic!gout!and&have&no&effects&in&acute&epidodes!
Toxicity:!
o Can&precipitate&an&attack&of&acute&gout&during&the&early&phase&of&
their&action!
! Avoided&by&administrating&colchicine&or&indomethacin&at&
the&same&time&as&a&combo]therapy!
o Allergy!
! Since&the&drugs&are&sulfonamides!
!
Xanthine!oxidase!inhibitors:!
Reduce&the&production&of&uric&acid&by&xanthine&oxidase!
o Xanthine&oxidase&(XO)&is&an&enzyme&that&converts&hypoxanthine&to&
xanthine&and&xanthine&to&uric&acid!
Allopurinol&is&converted&to&oxypurinol&(alloxanthine)&by&XO!
o Alloxanthine&is&an&irreversible&suicide&inhibitor&of&XO!
o Used&in&the&treatment&of&chronic&gout!
o Also&used&as&an&adjunct&in&cancer&chemotherapy!
! To&slow&formation&of&uric&acid&from&purines&released&by&the&
death&of&large&numbers&of&neoplastic&cells!
! Preventive&for&gout&in&these&cases!
Febuxostat!
o Newer&drug&that&is&a&nonpurine&inhibitor&of&XO!
o More&selective&than&allopurinol&and&alloxanthine!
These&drugs&are&given&orally&in&the&management&of&chronic&gout!
Used&in&combination&with&NSAIDs&or&colchicine&to&avoid&an&acute&attack&!
o Similarly&to&the&uricosuric&agents!
Toxicity:& !
o Allopurinol&causes&GI&distress,&rash&and&rarely&peripheral&neuritis,&
vasculitis&or&bone&marrow&disfunction&(aplastic&anemia)!
! Inhibits&metabolism&of&mercaptopurine&and&azathioprine!
Drugs&that&depend&on&XO&for&elimination!
o Febuxostat&can&cause&liver&function&abnormalities,&headache&and&
gastrointestinal&upset!
&
!

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Sollas&Notes&2015&

19.3&Beta&sympatholytics&
&
Beta]blockers&are&drugs&that&target&the&beta]adrenoreceptor.&These&receptors&are&
found&on:&
Myocardial&cells&
Arterial&and&bronchial&smooth&muscle&cells&
Kidneys&and&more&tissues&that&are&under&the&influence&of&the&SANS&
They&interfere&with&the&binding&of&NE,&E&and&other&stress&hormones&to&their&
receptors&and&by&that&they&weaken&the&effects&of&the&SANS&
Propanolol&was&the&first&beta]blocker&to&be&introduced&(1965)&
&
Types:&
Basic&structure:&&
o Side&chain&(shared&by&most)&
o Aromatic&nucleus&
! Determines&whether&the&compound&possesses&intrinsic&
sympathomimetic&activity&(partial&agonist)&or&acts&as&a&partial&
antagonist&
o Levorotatory&enantiomer&form&has&100x&fold&higher&affinity&than&the&
dextrorotatory&form&&makes&them&very&selective&for&beta]receptors&
Cardioselectivity&
o Some&have&higher&affinity&for&cardiac&1]receptors&(e.g.&metoprolol,&acebutolol&
and&bisoprolol)&
&
Therapeutic&effects:&
Block&cardiac&beta]receptors:&
o Protection&of&the&heart&from&oxygen&wasting&effects&of&the&SANS&
ionotropism:&
! Prophylactic&in&treatment&of&angina&to&prevent&myocardial&
stress&that&possibly&could&trigger&ischemia&
o Lower&cardiac&rate&(sinus&tachycardia)&and&elevated&blood&
pressure&due&to&high&cardiac&output&
o Topical&treatment&to&the&eye&in&the&management&of&glaucoma&as&
they&lower&the&production&of&aqueous&humor&without&affecting&the&
drainage&
Indicators&for&the&use&of&beta]blockers:&
Angina&pectoris&
Atrial&fibrillation&and&other&cardiac&arrhythmias&&
o Esmolol,&sotalol,&landilol&
Congestive&heart&failure&
o Carvedilol,&sustained]release&metoprolol,&nebivolol&
Essential&tremor&(benign&tremor&&mainly&of&the&hands)&
o Propranolol&&
Glaucoma&
o Betaxolol,&carteolol,&levobunolol&
Hypertension&
Myocardial&infarction&
o Atenolol,&metoprolol,&propanolol&
Mitral&valve&prolapse&
Pheochromocytoma&(in&combo&with&a]blockers)&

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Sollas&Notes&2015&

o Propanolol&
Symptomatic&control&in&anxiety&and&hyperthyroidism&
Also&have&been&used&for:&
Acute&aortic&dissection&
Hypertrophic&obstructive&cardiomyopathy&
Marfan&syndrome&
Prevention&of&variceal&bleedings&in&portal&hypertension&
Adverse&effects:&
Nausea,&diarrhea,&bronchospasm,&dyspnea,&cold&extremeties,&Raynauds&
syndrome,&bradycardia,&hypotension,&heart&failure,&heart&block&fatigue,&
dizziness,&alopecia,&abnormal&vision,&hallucinations,&insomnia,&sexual&
dysfunction,&erectile&dysfunction&alteration&of&glucose&&&lipid&metabolism&
Mixture&of&alpha1/beta]antagonist&therapy&commonly&causes&orthostatic&
hypotension&
Carvedilol&is&commonly&associated&with&edema&
Lipophilic&beta]blockers&(propranolol&and&metoprolol)&cross&BBB,&hence&
they&are&more&likely&to&cause&sleep&distrubances&
Beta2]blockers&more&commonly&cause&bronchospasms,&peripheral&
vasoconstriction&and&alteration&of&glucose&and&lipid&metabolism&
Beta1]blockers&inhibit&renin&release&and&thus&they&decrease&release&of&
aldosterone&&resulting&in&hyponatremia&and&hyperkalemia&
Hypoglycemia&due&to&beta2]blockers&(since&glycogenolysis&and&glucagon&
release&is&inhibited)&&this&is&especially&bad&for&DM&patients&
o Use&Beta1]receptors&instead&
Not&used&in&treatment&of&cocaine,&amphetamine&overdose&&cause&
increased&HTN&and&hence&less&blood&flow&to&the&coronaries&&
o Use&vasodilators,&alpha]blockers&and&diuretics&
Contraindications:&
Patients&with&asthma&and&drug&stimulating&overdose&(cocaine,&amph.)&
Common&drugs:&
Nonselective&agents:&
o Carvedilol&(has&additional&alpha]blocking&activity)&
o Propranolol&
o Sotalol&
o Nadolol&
1]selective&agents:&
o Atenolol&
o Acebutolol&(intrinsic&sympathomimetic&activity&&partial&agonist)&
o Bisoprolol,&Esmolol&
o Metoprolol,&Nebivolol&(increases&NO&release&for&vasodilation)&
2]selective&agents:&
o Butaxamine&
Agents&with&intrinsic&sympathomimentic&actions:&
Acebutolol,&mepindolol,&pindolol&
Hydrophilic&agents&
Atenolol,&sotalol&
Membrane&stabilizing&&
Acebutolol,&propranolol&

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Sollas&Notes&2015&

Topic&20&
20.1&Oral&antidiabetic&agents&
&
Four(wellLestablished(groups(of(antidiabetic(drugs(are(used(most(commonly(to(
treat(type(2(diabetes.(These(include:(
! Insulin,secretagogues,
! Biguanide,metformin,
! Thiazolidinediones,
! Pglucosidase,inhibitors,
Three(novel(agents(target(endogenous(regulators(of(glucose(homeostasis(
! Pramlintide(
! Exenatide(
! Sitagliptin(
(
Insulin!secretagogues:!
! Stimulate&the&release&of&endogenous&insulin&by&promoting&closure&of&
potassium&channels&in&the&pancreatic&&cell&membrane!
o Channel&closure&depolarizes&the&cell&&triggering&the&insulin&release!
! These&drugs&dont&work&in&patients&with&non&functioning&&cells!
! Most&of&these&agents&are&categorized&as&sulfonylureases!
o 1st&generation&&tolbutamide,,chlorpropamide!
o 2nd&generation&&glyburide,,glipizide,,glimepiride!
! More&potent&and&more&common&than&1st&generation!
! Repaglinide,&,nateglinide!
o Have&rapid&onset&and&short&duration;&making&them&useful&for&
administration&just&before&a&meal&to&control&postprandial&levels!
! Toxicity:!
o Hypoglycemia&(but&much&less&commonly&than&with&normal&insulin)!
o Weight&gain&and&rashes!
!
Biguanide!metformin:!
! Reduces&postprandial&and&fasting&glucose&levels&by:!
o Inhibition&of&hepatic&and&renal&gluconeogenesis!
o Stimulation&of&glucose&uptake&into&tissues!
o Stimulation&of&glycolysis&in&peripheral&tissues!
! Slowing&glucose&absorption&from&the&GI!
o Reduction&of&plasma&glucagon&levels!
! In&insulin&resistance&patients&it&reduces&endogenous&insulin&production&
through&enhanced&insulin&sensitivity!
! First&drug&of&choice&in&overweight&patients&with&DM&type&2!
! Restores&fertility&in&anovulatory&women&with&polycystic&ovary&disease&!
! Toxicity:!
o Does!not!cause!hypoglycemia!
o GI&distress&(nausea,&diarrhea),&lactic&acidosis&!
!
!
!
!

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Thiazolidinediones!(rosiglitazone,&,pioglitazone):!
! Increases&target&tissue&sensitivity&to&insulin&by&activation&of&peroxisome&
proliferator]activated&receptor]gamma&nuclear&receptor&(PPAR]&R)!
o Nuclear&receptor&that&regulates&transcription&of&genes&encoding&
proteins&involved&in&CH&and&lipid&metabolism!
! Increase&glucose&uptake&into&muscles&and&adipose&tissue!
! Inhibit&hepatic&gluconeogenesis!
! Effects&on&lipid&metabolism&and&distribution&of&body&fat!
! Reduce&both&fasting&and&postprandial&glucose&levels!
! Used&as&monotherapy&or&combo&with&insulin&or&other&oral&antidiab.&drugs!
! Also&used&in&insulin&resistance&therapy&!
! Toxicity:!
o Hypoglycemia&is&rare&when&used&as&a&monotherapy!
o Fluid&retention,&mild&anemia,&edema,&increased&risk&of&heart&failure!
o Recent&data&link&rosiglitazone&to&increased&risk&of&MI!
o Increased&risk&of&bone&fractures&in&women!
o Effects&on&3A4&isoenzyme&that&reduces&the&serum&cc.&of&oral&
contraceptives,&cyclosporins&and&more!
!
/glucosidase!inhibitors!(acarbose,,miglitol):!
! Carbohydrate&analogs&that&act&in&the&intestine&to&inhibit&]glucosidase!
o Enzyme&that&is&needed&to&convert&complex&starches,&
oligosaccharides&and&disaccharides&into&monosaccharide!
! Slows&down&absorption&of&glucose&from&the&gut&and&decreases&
postprandial&hyperglycemia!
! Dont&act&on&fasting&glucose&levels&and&are&taken&just&before&a&meal!
! Toxicity:!
o Flatulence,&diarrhea,&abdominal&pain&due&to&increased&
fermentation&of&unabsorbed&CH&in&the&gut&by&bacteria!
o Hypoglycemia&(treated&with&oral&glucose!!!&As&it&is&a&monosacc.)!
!
Pramlintide:!
! Injectable&synthetic&analog&of&amylin!
o Amylin&contributes&to&glycemic&control&by&suppression&of&glucagon&
release,&slows&gastric&emptying&and&works&in&the&CNS&to&reduce&
appetite!
! Rapidly&absorbed,&short&duration,&used&in&combo&with&insulin!
! Adverse&effects&are&hypoglycemia&and&GI&disturbances!
!
Exenatide:!
! Glucagon]like&peptide&1&(GLP]1)&analog&that&stimulates&insulin&release,&
slows&gastric&emptying,&inhibits&glucagon&secretion&&&produces&satiety!
! Used&in&combo&with&metformin&or&sulfonylurea&in&treatment&of&DM&type&2!
! Toxicity&&hypoglycemia,&vomiting&(mainly&first&times),&acute&pancreatitis!
Sitagliptin:!
! Oral&inhibitor&of&dipeptidyl&peptidase&4&(DPP]4)&that&is&an&enzyme&that&
normally&degrades&GLP]1!
! Mono&or&combotherapy&with&metformin&!
! &Same&effects&of&exenatide!

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20.2&Alpha&sympatholytics&
&
Non]selective&]blockers&affect&both&1&and&2&receptors&simultaneously.&They&
can&be&further&subcategorized&into&irreversible,&longer&acting&(e.g.&
phenoxybenzamine)&and&reversible,&shorter&acting&(e.g.&phentolamine)&groups.&
&
Effects:&
Block&]mediated&responses&of&SANS&&&exogenous&sympathomimetics&
Most&important&effects&are&those&on&the&cardiovascular&system&
o Reduction&in&vascular&sympathetic&tone&&vaso/venodilation!&
! Decreased&arterial&and&venous&pressures&
o Cause&a&baroreceptor&reflex]mediated&tachycardia&due&to&the&
marked&decrease&in&MAP&
! Due&to&the&blockade&of&2&receptors&on&adrenergic&nerve&
terminals&in&the&heart,&which&normally&would&reduce&the&
net&release&of&NE&
Epinephrine&reversal&
o Predictable&effect&in&patients&receiving&&blockers&&
o Reversal&of&the&BP&effect&of&large&doses&of&E&from&a&pressor&
response&(mediated&by&&receptors)&to&a&depressor&response&
(mediated&by&2&receptors)&&
! Not&seen&with&NE&or&phenylephrine&because&they&lack&
adequate&2&effects&
Clinical&uses:&
Non]selective&]blockers&have&limited&clinical&applications&
Mainly&used&in&the&presurgical&treatment&of&pheochromocytoma&&
o Patients&that&have&severe&and&life]threatening&hypertension&and&
reduced&blood&volume&that&is&needed&to&be&corrected&before&going&
through&the&stress&of&a&surgery&
! Phenoxybenzamine&is&the&DOC&presurgically&while&
phentolamine&is&sometimes&used&during&the&surgery&itself&
Phenoxybenzamine&is&occasionally&used&in&treatment&of&carcinoid&tumors&
o Due&to&its&serotonin&receptor]blocking&effects&
Phenoxybenzamine&is&also&used&in&the&treatment&of&mastocytosis&
o H1&antihistaminic&effect&
Phentolamine&is&sometimes&used&to&prevent&tissue&damage&(ischemia&and&
necrosis)&in&the&case&of&local&infiltration&of&potent&]aginists&such&as&NE&
o Also&used&in&case&of&rebound&hypertension&that&is&caused&by&
sudden&cessation&of&clonidine&therapy&
Amphetamine,&cocaine&or&phenylpropanolamine&overdoseing&that&causes&
severe&hypertension&its&possible&to&use&]blockers&to&correct&the&HTN&
Reynauds&phenomenon&sometimes&responds&to&]blockers&
Erectile&dysfunction&can&be&treated&with&a&direct&injection&of&
phentolamine&or&yohimbine&that&results&in&penile&erection&&
Toxicity:&
Mainly&severe&reflex&tachycardia&&
Nausea&and&vomiting&
&

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Sollas&Notes&2015&

Selective!alpha/blockers:!
]blockers&are&divided&into&primary&subgroups&on&basis&of&their&receptor&
selectivity&into&1&selective,&2]selective&or&non]selective.&Also&its&possible&to&
classify&them&on&the&basis&of&their&reversibility&as&well&as&duration&of&action.&
&
Selective&1&receptor&blockers&include:&
Prazosin,
o Symptoms&of&BPH&
o Hypertension&
o Used&in&treatment&of&post&traumatic&stress&disorder&
Tamsulosin,
o Symptoms&of&BPH&
Doxazosin,
o Symptoms&of&BPH&
o Hypertension&
Terazosin,
o Symptoms&of&BPH&
o Hypertension&
All&of&these&can&cause&1st&dose&orthostatic&hypotension,&dizziness&and&
headache&
&
Selective&2&receptor&blockers&include:&
Mirtazapine,
Yohimbine,
Both&used&in&the&treatment&of&depression&
Toxicity&can&result&in&sedation,&#serum&cholesterol&and&#appetite&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&

& 155&
Sollas&Notes&2015&

&
20.3&Disease&modifying&antirheumatic&drugs&(DMARDs)&
&
DMARDs(are(heterogenous(group(of(agents(that(have(antiLinflammatory(actions(in(
several(connective(tissue(diseases.(They(are(called(disease(modifying(because(some(
evidence(shows(slowing(or(even(reversal(of(joint(damage((effects(that(are(not(seen(
with(NSAIDs).(These(drugs(are(also(called(slowLacting(antirheumatic(drugs,(
because(it(may(take(6(weeks(to(6(months(for(their(benefits(to(become(apparent.(
(
Mechanism!of!action!&!effects:!
Mechanism&of&action&of&most&DMARDs&in&the&treatment&of&RA&are&poorly&
understood,&however&the&following&drugs&are&most&commonly&used:!
o Cytotoxic&drugs&(e.g.&methotrexate)&probably&act&by&reducing&the&
number&of&immune&cells&available&to&maintain&the&inflammatory&
response!
! Many&of&these&drugs&are&also&used&in&cancer&chemo&treatm.!
o Other&drugs&appear&to&interfere&with&the&activity&of:!
! &T]lymphocytes!
Sulfasalazine,,hydroxychloroquine,,cyclosporine,,
leflunomise,,mycophenolate,mofetil,,abatacept!
! B]lymphocytes&"&Rituximab!
! Macrophages&"&Gold,compounds!
o In&the&recent&years&immunoglobulin&based&biologic&agents&that&
inhibit&the&action&of&tumor&necrosis&factor]&(TNF])&have&been&
used&in&RA&treatment!
! Infliximab,,adalimumab,,etanercept!
o Recombinant&human&interleukin]1&receptor&antagonist&is&also&used!
! Anakira!
!
Pharmacokinetics!and!clinical!use:!
Oral&administration:& !
o Sulfasalazine,,hydroxychloroquine,,methotrexate,,cyclosporine,,
penicillamine,,leflunomide,,auranofin,(gold&compound),
Injection:,
o TNFP,interfering,drugs,
Parenteral&use:,
o Gold,compounds,(gold,sodium,thiomalate,&,aurothioglucose),
DMARDs&(especially&methotrexate)&are&initiated&relatively&early&in&
treatment&of&patients&with&moderate&to&severe&RA&in&attempt&to&reduce&or&
reverse&disease&progression&,
Some&of&the&DMARDs&are&also&used&in&treatment&of&SLE,&Sjgrens,&juvenile&
rheumatoid&arthritis&and&ankylosing&spondylitis&along&with&other&
immunologic&disorders,
Toxicity:!
All&DMARDs&can&cause&sever&or&fatal&toxicities!
o Therefore&careful&monitoring&is&mandatory!
o List&of&toxicity&of&various&drugs&is&on&next&page!
!

& 156&
 Sollas&Notes&2015&

!
Drug! Other!clinical!uses! Toxicity!when!used!for!RA!
Abatacept& & Infection,&worsening&of&COPD,&HSR&reactions&
Anakinra& & Injection]site&reaction,&infection,&
neutropenia&
Anti&IL]6&drugs& & Upper&respiratory&tract&infections,&headache,&
(tocilizumab)& HTN&&&elevated&liver&enzymes&
Anti&TNF&drugs& Inflammatory&bowel& Infection,&lymphoma,&hepatotoxicity,&
(infliximab,&etanercept,& disease,&other& hematological&effects,&HSR&reactions,&
adalimumab,&golimumab,& rheumatic&disorders& cardiovascular&toxicity&
certolizumab)&
Cyclosporine& Tissue&transplantation&& Nephrotoxicity,&HTN,&liver&toxicity&
Gold&compounds& & Many&&incl.&diarrhea,&dermatitis,&
hematologic&abnormalities&
Hydroxychloroquinone,& Antimalarial& Rash,&GI&disturbances,&myopathy,&
chloroquine& neuropathy,&ocular&toxicity&
Leflunomide& & Teratogen,&hepatotoxicity,&GI&upset,&skin&
Methotrexate& Anticancer& Nausea,&mucosal&ulcers,&hematotoxicity,&
hepatotoxicity,&teratogenicity&
Penicillamine& Chelating&agent& Many&incl.&proteinuria,&dermatitis,&GI&upset,&
hematologic&abnormalities&
Rituximab& Non]Hodgkins& Infusion&reaction,&rash,&infection,&cardiac&
lymphoma& toxicity&
Sulfasalazine& Inflammatory&bowel& Rash,&GI&upset,&dizziness,&headache,&
disease& leukopenia&
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!

& 157&
Sollas&Notes&2015&

Topic&21&
21.1&Gonadal&hormones&and&inhibitors&
This&topic&is&a&bitch&]&Im&sorry&for&that.&&
&
The(gonadal(hormones(include(the(steroids(of(the(ovary((estrogens(and(progestins)(and(
testis((mainly(testosterone).(Because(of(their(importance(as(contraceptives,(many(synthetic(
estrogens(and(progestins(have(been(produced.(

(
Estrogens:!
Major&ovarian&estrogen&in&women&is&estradiol!
o Low&oral&bioavailability!
o Available&in&micronized&form&!
! Orally&active&,transdermal&patch,&vaginal&cream&or&IM&injection!
o Long]acting&esters&of&estradiol&(e.g.&estradiol,cypionate)!
! Converted&in&the&body&to&estradiol!
! Administered&as&IM&injection!
o Mixtures&of&conjugated&estrogens&from&biologic&sources&(e.g.&premarin)!
! Used&orally&for&hormone&replacement&therapy&(HRT)!
o Synthetic&estrogens&w.&high&bioavailability&(e.g.&ethinyl,estradiol)!
! Used&as&hormonal&contraceptives!
Effects:!
o Estrogen&is&essential&for&normal&female&reproductive&development!
o Estrogen&has&many&metabolic&effects:!
! Modifies&serum&protein&levels&!
! Reduces&bone&resorption&!
! Enhances&coagulability&of&blood!
! Increases&plasma&triglyceride&levels!
! Reduce&LDL&cholesterol&and&increase&HDL&cholesterol!
o Continuous&administration&of&estrogen,&especially&in&combo&with&a&
progestin,&inhibits&the&secretion&of&gonadotropins&from&the&ant.pituitary!
Clinical&uses:!
o Used&in&treatment&of&hypogonadism&in&young&females!
o HRT&in&women&with&estrogen&deficiency&resulting&from&premature&
ovarian&failure,&menopause&or&surgical&removal&of&the&ovaries!
! Can&increase&hot&flushes&and&atropic&changes&in&the&UG&tract!
o Effective&in&preventing&bone&loss&and&osteoporosis!

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Sollas&Notes&2015&

o Components&of&hormonal&contraceptives!
Toxicity:!
o Premature&closure&of&the&epiphysis&of&long&bones!
o When&used&as&HRT&it&can&increase&risk&of&endometrial&cancer!
! This&effect&is&prevented&by&coadministration&of&progestin!
o In&postmenopausal&women&is&associated&with&small&increase&in&the&risk&
of&breast&cancer&&&cardiovascular&events&(MI&or&stroke)!
o Dose]dependent&toxicity&includes&nausea,&breast&tenderness,&increased&
risk&for&migraine,&thromboembolic&effects&(DVT),&gallbladder&diseases,&
hypertriglyceremia&and&HTN!
o Diethylstilbestrol,(DES),!
! Nonsteroidal&estrogenic&compound!
! Associated&with&infertility,&ectopic&pregnancy&and&vaginal!
adenocarcinoma!in&the&daughters&of&women&who&were&treated&
with&the&drug&during&pregnancy&in&a&misguided&attempt&to&
prevent&recurrent&spontaneous&abortion!
Progestins:!
Progesterone&is&a&major&progestin&in&humans!
Micronized&form&is&used&orally&for&HRT&and&progesterone]containing&vaginal&
creams&are&also&available!
Synthetic&progestins&(medroxyprogesterone)&have&improved&oral&bioav.!
Older&drugs&(LPnorgestrel,&,norethindrone)&are&more&androgenic&than&newer&
progestins&(norgestimate,,desogestrel)!
Effects:!
o Progesterones&induce&secretory&changes&in&the&endometrium!
! Required&to&maintain&pregnancy!
o Other&progestins&stabilize&the&endometrium&but&dont&support&pregnancy!
o Stimulate&deposition&of&fat&and&affect&carbohydrate&metabolism!
o High&doses&suppress&GnRH&secretion&and&often&cause&anovulation&!
Clinical&uses:!
o Contraceptives&(alone&or&in&combo&with&an&estrogen)!
o HRT&+&estrogen&is&used&prevent&estrogen]induced&endometrial&cancer!
o Progesterone&is&used&in&assisted&reproductive&technology&methods&to&
promote&and&maintain&pregnancy!
Toxicity:!
o Low&toxicity&]&May&increase&blood&pressure&and&decrease&HDL!
o High&doses&in&long&term&treatments&might&lead&to&osteoporosis!
! Side&effect&from&the&ovarian&suppression!
Hormonal!contraceptives:!
Contain&either&a&combo&of&estrogen&and&a&progestin&or&progestin&alone!
Available&as:!
o Oral&pills,&long]acting&injections,&transdermal&patches,&vaginal&rings&or&
intrauterine&devises&(IUDs)!
Three&types&of&oral&contraceptives&are&available&in&USA:!
o Combination&estrogen]progestin&tablets&that&are&taken&continuously&
throughout&the&menstrual&cycle!
! Monophasic&preparations!
o Combination&preparations&in&which&the&progestin&or&estrogen&dosage,&or&
both,&changes&during&the&month!
! Biphasic&or&triphasic&preparations!
! More&closely&mimics&the&normal&hormonal&changes!
o Progestin&mono&therapy!
Postcoital&contraceptives&(emergency&contraception/morning&after&pill)!

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Sollas&Notes&2015&

o Prevent&pregnancy&if&administered&72hrs&after&unprotected&sex!
o Mechanism&is&not&well&understood!
! Before&LH&surge&they&inhibit&ovulation!
! After&LH&surge&they&effect&cervical&mucosa,&tubal&function&and&
endometrial&linings!
Mechanism&of&action&of&OCPs:& !
o Inhibition&of&ovulation&(primary&action)!
! Mainly&the&effect&of&estrogens!
o Effects&on&the&cervical&mucous&glands,&uterine&tubes&and&endometrium&
(secondary&actions)!
! This&decreases&the&possibility&of&fertilization&and&implantation&
into&the&uterine&wall!
! This&is&the&main&effect&of&progestin!
Other&clinical&uses:!
o Primary&hypogonadism&to&prevent&estrogen&deficiency!
o Combo&pills:&acne,&hirsutism,&dysmenorrhea,&endometriosis!
o Combo&pills&reduce&risk&of&ovarian&cysts,&ovarian&and&endometrial&
cancers,&benign&breast&disease&and&pelvic&inflammatory&disease,&lowers&
incidence&of&ectopic&pregnancies,&iron&deficiency&anemia&and&RA!
Toxicity&incidence&has&lowered&dramatically&since&the&introduction&of&low]dose&
combined&oral&contraceptives!
Toxicity:!
o Thromboembolism&(Less&risk&than&in&normal&pregnancy)!
! Due&to&the&effects&of&estrogen&on&the&blood&coagulation!
! Well&documented&increase&in:!
Myocardial&infarction,&stroke,&DVT,&PE!
o Specially&in&older&women&and&smokers!
o Genetic&problem&of&clotting&factors!
o Breast&cancer!
! Life]time&risk&is&not&increased&maybe&earlier&onset&!
o Other&toxicities:!
! Breast&tenderness,&headache,&skin&pigmentation,&depression!
! Weight&gain,&acne,&hirsutism&(mainly&due&to&progestins)!
!
Antiestrogens!and!antiprogestins:!
Selective&estrogen&receptor&modulators&(SERMs)!
o Mixed&estrogen&agonists&that&have&estrogen&agonist&effects&in&some&
tissues&and&act&as&partial&antagonists&of&estrogen&in&other&tissues!
Tamoxifen,&,toremifene!
o Effective&in&treatment&of&hormone]responsive&breast&cancer!
o Antagonist&effects:!
! Prevent&receptor&activation&by&endogenous&estrogens!
Used&as&a&prophylaxis&in&women&with&high&risk!
! Causes&hot&flushes!
o Agonist&effects:!
! Works&on&endometrial&receptors&to&promote&hyperplasia&that&
increases&the&risk&of&endometrial&cancer!
! Increases&risk&of&DVT!
! Agonistic&effects&on&bone&in&postmenopausal&women!
So&it&prevents&(slows&down)&osteoporosis!
Raloxifene!
o Approved&for&prevention&and&treatment&of&osteoporosis&in&
postmenopausal&women!

& 160&
Sollas&Notes&2015&

! Partial&agonistic&effects&on&bone!
o Works&like&tamoxifen&on&breast&tissue&to&decrease&risk&of&b.cancer!
o No&estrogenic&effects&on&endometrium&!
! Hence&it&does&not&increase&risk&of&endometrial&cancer!
o Adverse&effects&include&hot&flushes&and&DVT&like&in&tamoxifen!
Clomiphene!
o Nonsteroidal&compound&with&tissue]selective&actions!
o Used&to&induce&ovulation&in&anovulatory&women&that&are&trying&to&get&
pregnant!
o Selectively&block&estrogen&receptors&in&the&pituitary!
! Reduces&negative&feedback&and&increases&FSH&&&LH&output!
This&increase&stimulates&ovulation!
Pure!estrogen!receptor!antagonists:!
Fulvestrant,!
o Pure&estrogen&receptor&antagonist&(in&all&tissues)!
o Used&in&treatment&of&women&with&breast&cancer&that&has&developed&
resistance&to&tamoxifen!
Synthesis!inhibitors:!
Aromatase&inhibitors&(anastrozole,,letrozole)!
o Nonsteroidal&competitive&inhibitors&of&aromatase&(enzyme&needed&for&
the&last&step&in&estrogen&synthesis)!
o Exemestane!
! Irreversible&aromatase&inhibitor&&used&in&breast&cancer!
Danazole!
o Inhibits&several&cytP450&involved&in&gonadal&steroid&synthesis!
o Weak&partial&agonist&of&progestin,&androgen&&&glucocorticoid&R.&!
o Sometimes&used&in&the&treatment&of&endometriosis&and&fibrocystic&
disease&of&the&breast!
!
Gonadotropin/releasing!hormone!and!analogs!(see&topic&16.1)&
!
Antiprogestins:!
Mifepristone,(RU486)!
o Orally&active&steroid&antagonist&of&progesterone&and&glucocorticoids!
o Major&use&is&in&abortion&in&early&pregnancy&(up&to&49&days)!
o Used&in&combo&with&prostaglandin&E&analog&(misoprostol)!
! 95%&result&in&abortions!
! Severe&side&effects&can&be&serious&infection,&sepsis&and&even&
death&due&to&unusual&infection&(Clostridium(sordelli)!
Androgens:!
Testosterone&and&related&androgens&are&produced&in&the&testis,&adrenals&and&in&
small&extent&the&ovary!
o Synthesized&from&progesterone&and&DHEA!
o Partially&plasma&bound&to&sex&hormone&binding&globulin&(SHBG)!
o Converted&in&several&organs&(e.g.&prostate)&to&dihydrotestosterone!
! By&5&reductase&enzyme!
! Active&hormone&in&those&tissues!
o May&be&given&in&injections&in&the&form&of&long]acting&esters&or&in&
transdermal&patches&(since&oral&administration&is&not&so&effective)!
Many&androgens&have&been&synthesized&in&an&effort&to&increase&the&anabolic&
effect&&anabolic&steroids!
Mechanism&of&action:!
o Androgens&enter&cells&and&bind&to&cytosolic&receptors!

& 161&
Sollas&Notes&2015&

o The&hormone]receptor&complex&enters&the&nucleus&and&modulates&
expressions&of&target&enzymes!
Effects:&!
o Testosterone&is&needed&for&normal&male&development&and&is&responsible&
for&major&secondary&male&sexual&characteristics&during&puberty!
! Can&cause&male&pattern&baldness!
o Anabolic&action&that&involves&increase&muscle&size&and&strength!
o Increases&RBC&production!
o Reduces&excretion&of&urea&nitrogen!
o Helps&to&maintain&normal&bone&density!
Clinical&use:!
o Replacement&therapy&in&hypogonadism!
o Stimulation&of&RBC&production&in&certain&anemias!
o Promotes&weight&gain&in&patients&with&wasting&syndrome&(e.g.&in&AIDS&
patients)!
o Anabolic&effects&have&been&exploited&by&athletes&to&increase&muscle&mass,&
strength&and&athletic&performance&&]&tested&for!!!
Toxicity:!
o In&females:&Virilization!
! Hirsutism,&enlarged&clitoris,&deepened&voice,&menstrual&
irregularities&!
o In&males:!
! Feminization&due&to&feedback&inhibition&of&the&pituitary&and&
conversion&of&the&exogenous&androgens&to&estrogens!
Gynecomastia,&testicular&shrinkage,&infertility!
o In&both&sexes:!
! Anabolic&steroids&can&cause&cholestatic&jaundice,&elevation&of&
liver&enzymes&and&possibly&hepatocellular&carcinoma!
Antiandrogens:!
Important&in&the&therapy&of&both&BPH&and&prostate&cancer,&precocious&puberty,&
hair&loss&and&hirsutism&!
Receptor!inhibitors:!
o Flutamide,!
! Non&competitive&antagonists&of&androgen&receptors!
! Decrease&the&action&of&endogenous&androgens&in&prostate&cancer!
o Spironolactone!
! Primarily&used&as&K+&sparing&diuretic!
! Also&inhibits&androgen&receptors&!
! Used&in&the&treatment&of&hirsutism&in&women!
5/reductase!inhibitors:!
o Finasteride!
! Used&to&treat&BPH!
! Lower&dose&can&prevent&hair&loss&in&men!
&
&
&
&
&
&

& 162&
Sollas&Notes&2015&

21.2&Pharmacodynamic&drug&interactions&
&
Pharmacodynamic&interactions&are&categorized&as&followed:&
&
Interactions&based&on&opposing&actions&or&effects&
Antagonism&is&the&simplest&type&of&drug&interaction&
o Antagonism&of&the&bronchodilating&effects&of&2]agonist&used&in&
asthma&occurs&if&a&]blocker&is&given&for&another&condition&
o Actions&of&catecholamines&on&HR&(]agonists)&is&antagonized&by&
inhibitors&of&AChE&that&acts&through&ACh&via&muscarinic&receptors&
o Antagonism&by&mixed&agonist]antagonist&drugs&(e.g.&pentazocine)&
or&partial&agonist&(e.g.&pindolol)&is&not&easily&predicted&but&should&
be&expected&when&used&with&pure&agonists&
NSAIDs&may&decrease&the&antihypertensive&actions&of&ACE]inhibitors&by&
reducing&renal&elimination&of&sodium&
&
Interactions&based&on&additive&effects&
Described&by&the&algebraic&summing&of&the&effects&of&two&drugs&
o The&2&drugs&may&not&act&on&the&same&receptor&
! TCA&combo&with&diphenhydramine&or&promethazine&
predictively&causes&excessive&atropine&like&effects,&since&all&
these&drugs&are&muscarinic&receptor&blockers&
o Most&common&and&most&important&drug&interactions&is&the&
additive&depression&of&CNS&function&caused&by&administration&of&
sedatives,&hypnotics,&opioids&and&ethanol&
o Additive&effects&of&anticoagulants&can&lead&to&bleedings&
! In&case&of&warfarin&treatment&with&aspirin&addition,&
thrombolytics&and&thyroid&hormones&(enhancing&clotting&
factor&catabolism)&
Supra]additive&(synergistic)&interactions&are&said&to&occur&when&the&result&
of&interaction&is&greater&than&the&sum&of&the&drugs&used&alone&
o Example&is&sulfonamides&and&dihydrofolic&acid&reductase&inhibitor&
Potentiation&occurs&when&a&drugs&effect&is&increased&by&another&agent&that&
has&no&such&effects&
o Example&is&the&combo&of&]lactamase&inhibitors&with&clavulanic&a.&
&
Interactions&of&herbal&medications&with&other&drugs&
Some&herbal&interactions&enhance&the&actions&of&anticoagulants&
o Dong&quai&(warfarin)&&increased&anticoagulation&&bleeding&
o Garlic&&&ginkgo&(anticoag.+antiplatelets)&&increased&bleeding&risk&
St.&Johns&wort&increases&metabolism&of&drugs&and&decreases&the&efficacy&
o Oral&contraceptives,&digoxin,&HIV&protease&inhibitors,&warfarin&
o Also&increases&effects&of&antidepressants&
Liquorice&root&extract&increases&salt&retention&and&hypertension&
Ginseng&increases&the&effects&of&antidepressants&and&causes&mania&

& 163&
Sollas&Notes&2015&

&
21.3&Drugs&used&in&acid?peptic&disease&
&
Ulceration(and(erosion(of(the(lining(of(the(upper(portion(of(the(GILtract(are(
common(problems(that(manifest(as(GERD,(gastric(and(duodenal(peptic(ulcers(and(
stressLrelated(mucosal(injury.(Drugs(used(in(acidLpeptic(dx(reduce(intragastric(
acidity(by(manipulation(systems(controlling(hydrogen(acid(secretion,(promote(
mucosal(defense(or,(in(the(case(of(peptic(ulcers,(eradicate(H.pylori((detectable(in(
over(80%(of(patients(with(gastroLduodenal(ulcers)(
(
Antacids:&
Weak&bases&that&neutralize&stomach&acid&by&reacting&with&protons&in&the&
lumen&of&the&gut&and&may&also&stimulate&functions&of&gastric&mucosa&
Used&regularly&in&high&doses&they&reduce&the&recurrence&rate&of&peptic&
ulcers&
Magnesium,hydroxide,(strong(laxative(action&
Aluminum,hydroxide,(strong(constipation(action&
o These&drugs&can&be&found&also&in&a&combination&
o Both&are&weak&bases&&not&significantly&absorbed&from&the&gut&
Calcium,carbonate,and,sodium,bicarbonate&
o Weak&bases&&significantly&absorbed&from&the&gut&&
! So&they&have&more&systemic&effects&
o Less&popular&antacids&
&
H2]receptor&antagonists:&
Cimetidine,,ranitidine,,famotidine,&,nizatidine&
Inhibit&stomach&acid&production&
Used&in&treatment&of:&&
o GERD,&peptic&ulcer&dx,&non]ulcer&dyspepsia,&prevention&of&stress]
related&gastritis&in&seriously&ill&patients&
Still&used&widely&but&are&starting&to&be&replaced&by&more&effective&and&
equally&safe&proton]pump&inhibitors&
&
Proton]pump&inhibitors:&
Omeprazole,,esoeprazole,,lansoprazole,,rabeprazole&
Lipophilic&weak&bases&that&diffuse&into&the&parietal&cell&canaliculi&where&
they&become&protonated&and&concentrated&more&than&1000]fold&
o Turn&into&compounds&that&irreversibly&inactivate&the&parietal&cell&
H+/K+&ATPase&(the(transporter(that(is(primarily(responsible(for(
producing(stomach(acid)&
The&oral&formulations&are&enteric&coated&to&prevent&acid&inactivation&in&
stomach&&and&after&they&are&absorbed&they&are&rapidly&metabolized&in&the&
liver&to&become&active&
Half]life&is&~&1]2hrs,&duration&of&action&~24hrs&and&usually&need&~3]4&
days&to&achieve&their&full&effectiveness&
Used&in&treatment&of&(more&effective&than&H2&receptor&antagonists):&

& 164&
Sollas&Notes&2015&

o GERD,&peptic&ulcer&dx,&non]ulcer&dyspepsia,&prevention&of&stress]
related&gastritis&in&seriously&ill&patients&
o Zollinger]Ellison&syndrome&
Adverse&effects:&
o Diarrhea,&abdominal&pain,&headache,&hypergatrinemia&(in&chr.use)&
o Might&decrease&oral&bioavailability&of&vitamin&B12&and&certain&drugs&
that&require&acidity&for&the&GI&absorption&(e.g.&digoxin,&
ketoconazole)&
o Slight&increase&in&risk&of&acquiring&respiratory&&&enteric&infections&
&
Sucralfate:&
Aluminum,sucrose,sulfate,
Small,&poorly&soluble&molecule&that&polymerizes&in&the&acidic&stomach,
o The&polymerize&binds&to&injured&tissue&to&form&a&protective&coating&
over&ulcer&beds,
! Accelerates&healing&of&peptic&ulcers&and&reduces&rate&of&
recurrence,
Must&be&taken&4&times&daily,
Very&safe&drug&that&is&not&absorbed&in&the&GI&and&hence&has&very&low&
systemic&effects,
,
Misoprostol:&
Analog&of&PGE1&&
Increases&mucosal&protection&and&inhibits&acid&secretion&
Effective&in&decreasing&risk&of&ulcers&in&chronic&NSAID&usage&patients&
Needs&multiple&daily&doses&and&can&cause&diarrhea&and&GI&irritation&
&
Colloidal&bismuth:&
Multiple&actions&
o Formation&of&a&coat&on&ulcers&
o Stimulation&of&mucosal&protective&mechanisms&
o Direct&antimicrobial&effects&
o Sequestration&of&enterotoxins&
o Reduces&stool&frequency&and&liquidity&in&infectious&diarrhea&
! Bismuth,subsalicylate&
Causes&black&stools&
&
Antibiotics:&
Antibiotics&are&used&to&treat&and&eliminate&chronic&infection&that&is&caused&
by&Helicobacter(pylori&&
Clarithromycin,and,amoxicillin,(metronidazole)&
&
&
&
&
&
&
&
&

& 165&
Sollas&Notes&2015&

Topic&22&&
&
22.1&Alkylating&agents&and&antimetabolites&in&the&treatment&of&neoplastic&dx.&
&
Alkylating!agents:!
Cell]cycle&nonspecific&antineoplastic&drugs&(CCNS)&&
Form&reactive&molecular&species&that&alkylate&nucleophilic&groups&on&DNA&&
o Mainly&the&N]7&position&of&guanine&
Alkylation&leads&to:&
o Cross]linking&of&bases&
o Abnormal&base]pairing&
o DNA&strand&breakage&
Tumor&cell&resistance&to&the&drugs&occurs&through&increased&DNA&repair,&
decreased&drug&permeability&and&production&of&trapping&agents&such&as&
thiols&
&
Groups:&
Nitrogen&mustards&"&Chlorambucil,,cyclophosphamide,,mechlorethamine&
Nitrosoureas&"&Carmustine,,lomustine&
Alkyl&sulfonates&"Busulfan&
Other&drugs&acting&as&alkylating&agents&"&Cisplatin,,dacarbazine,,procarbazine,
,
Cyclophosphamide:!
Pharmacokinetics:&
o Hepatic&cytochrome&P450]mediated&biotransformation&is&needed&
for&antineoplastic&activity&&
o One&of&the&breakdown&products&is&acrolein&
Clinical&use:&
o Leukemia,&non]Hodgkins&lymphoma,&breast&&&ovarian&cancers&+&
neuroblastoma&
Toxicity:&
o GI&distress,&myelosuppression&&&aloplecia&(hair&loss)&are&expected&
o Hemorrhagic&cystitis&due&to&the&acrolein&may&be&decreased&by&
intensive&hydration&and&use&of&mercaptoethanesulfonate,(mesna)&
o Cardiac&dysfunction,&pulmonary&toxicity&and&SIAHD&&
Mechlorethamine:!
Pharmacokinetics:&
o Spontaneous&conversion&into&reactive&cytotoxic&product&
Clinical&use:&
o Hodgkins&and&non]Hodgkins&lymphomas&
Toxicity:&
o GI&distress,&myelosuppression,&aloplecia&and&sterility&are&common&
o Causes&marked&blisters&
!
Platinum!analogs!(cisplatin,!carboplatin,!oxaliplatin)!
Pharmacokinetics:&
o Cisplatin&is&used&IV&and&is&distributed&to&most&tissues&and&cleared&
in&unchanged&form&by&the&kidney&

& 166&
Sollas&Notes&2015&

Clinical&use:&
o Cisplatin&&&carboplatin:&Testicular,&bladder,&lung&&&ovarian&cancers&
o Oxaliplatin:&Used&in&advanced&colon&cancer&
Toxicity:&
o Cisplatin:&
! GI&distress,&mild&hematotoxicity&
! Neurotoxic&&peripheral&neuritis&and&CN&VIII&damage&
! Renal&damage&that&can&be&reduced&by&use&of&mannitol&with&
forced&hydration&of&the&patient&
o Carboplatin:&
! Less&nephrotoxic&than&cisplatin&
! Less&likely&to&cause&tinnitus&and&hearing&loss&
! Greater&myelosuppressant&actions&
o Oxaliplatin:&
! Dose]limiting&neurotoxicity&
Procarbazine:!
Reactive&agent&that&forms&H2O2&that&generates&free&radicals&causing&DNA&
strand&scission&
Pharmacokinetics:&
o Orally&active&and&penetrates&most&tissues&(incl.&CSF)&
o Eliminated&via&hepatic&metabolism&
Clinical&use:&
o Hodgkins&and&non]Hodgkins&lymphomas&+&brain&tumors&
Toxicity:&
o GI]distress,&myelosuppressant,&CNS&dysfunction,&peripheral&
neuropathy&and&skin&reaction&
o Inhibition&of&many&enzymes&including&MAO&and&those&involved&in&
hepatic&drug&metabolism&
o The&drug&is&leukemogenic&
Other!alkylating!agents:!
Busulfan&is&used&in&chronic&myelogenous&leukemia&
o Causes&adrenal&insufficiency,&pulmonary&fibrosis&&&skin&pigment.&
Carmustine&and&lomustine&are&highly&lipid&soluble&
o Used&as&adjuncts&in&management&of&brain&tumors&
Dacarbazine&is&used&in&Hodgkins&&
o Causes&aloplecia,&skin&rashes,&GI]distress,&myelosuppresion,&
phototoxicity&and&flu]like&syndrome&
&
Antimetabolites:!
Structurally&similar&to&endogenous&compounds&and&are:&
o Antagonists&of&folic&acid&(methotrexate)&
o Antagonists&of&purines&(mercarptourine,,thioguanine)&
o Antagonists&of&pyrimidines&(fluorouracil,,cytarabine,,
gemcitabine)&
Cell]cycle&specific&drugs&(CCS)&acting&primarily&in&the&S]phase&
Cytotoxic&and&immunosuppressant&action&
&
&
&

& 167&
Sollas&Notes&2015&

Methotrexate:!
Inhibitor&of&dihydrofolate&reductase&&leading&to&decreased&synthesis&of&
thymidylate,&purine&nucleotides&and&amino&acids&
o Thus&interfering&with&nucleic&acid&and&protein&metabolism&
Formation&of&polyglutamate&derivatives&is&important&for&cytotoxic&action&
Tumor&cell&resistance&mechanisms&include&decreased&drug&accumulation,&
changes&in&drug&sensitivity&or&activity&of&dihydrofolate&reductase&along&
with&decresed&formation&of&polyglutamates&
Pharmacokinetics:&
o Oral&and&IV&affords&good&tissue&distribution&(except&CNS)&
o Not&metabolized&and&the&clearance&is&renal&
! Good&hydration&is&essential&to&prevent&crystallization&in&
renal&tubules&
Clinical&use:&
o Effective&in&choriocarcinoma,&acute&leukemias,&non]Hodgkins&and&
primary&CNS&lymphomas,&number&of&solid&tumors&(breast,&head&&&
neck,&bladder&
o Also&used&in&treatment&of&Rheumatoid&arthritis,&psoriasis&and&
ectopic&pregnancy&
Toxicity:&
o Bone&marrow&suppression,&skin&and&mucosal&irritation&
o Effect&on&normal&cells&is&reduced&by&administration&of&leucovorin,
(folinic&acid)&&treatment&called&leucovorin&rescue&
o Long&term&use&can&lead&to&hepatotoxicity&&&pulmonary&fibrosis&
!
Mercaptopurine!(6/MP)!and!Thioguanine!(6/TG):!
Purine&antimetabolites&and&both&are&activated&by&hypoxanthine]guanine&
phosphoribosyltransferases&(HGPRT]ases)&
o Producing&toxic&nucleotides&that&inhibit&several&enzymes&involved&
in&purine&mechanism&
! Resistant&tumor&cells&have&decreased&activity&of&HGPRTase&
Pharmacokinetics:&
o Low&bioavailability&due&to&first]pass&by&hepatic&enzymes&
o Drug]interactions&(allopurinol&&&febuxostat)&will&inhibit&6]MP&
metabolism&by&xanthine&oxidase&
Clinical&use:&
o Acute&leukemias&and&chronic&myelocytic&leukemia&
Toxicity:&
o Bone&marrow&suppression&that&is&dose]limiting&
o Hepato]dysfunction&(cholestasis,&jaundice,&necrosis)&may&occur&
Fluorouracil!(5/FU):!
Converted&in&cells&into&5]FdUMP,&which&inhibits&thymidylate&synthase&
o Leads&to&thymineless&death&of&cells&
FdUMP&is&also&incorporated&into&DNA&which&will&inhibit&synthesis&
Pharmacokinetics:&
o IV&&widely&distributed&&including&CSF&
o Elimination&mainly&by&metabolism&
Clinical&use:&

& 168&
Sollas&Notes&2015&

o Bladder,&breast,&colon,&anal,&head&neck,&liver&and&ovarian&cancer&
o Used&topically&for&keratosis&and&superficial&basal&cell&carcinoma&
Toxicity:&
o GI&distress,&myelosuppression&&&alopecia&are&common&
Cytarabine!(ARA/C):!
Pyrimidine&antimetabolite&that&is&activated&by&kinases&to&AraCTP,&an&
inhibitor&of&DNA&polymerases!
Most&specific&for&the&S]phase&of&the&cell&cycle!
Resistance&can&occur&as&a&result&of&decreased&uptake&or&decreased&
conversion&into&AraCTP!
Gemcitabine:!
Deoxycytidine&analog&that&is&converted&into&the&active&diphosphate&
nucleotide&form&&this&inhibits&ribonucleotide&reductase&!
o Diminishes&the&deoxyribonucleoside&triphosphates&pool&that&is&
required&for&DNA&synthesis!
Gemcitabine&triphosphate&can&be&incorporated&into&DNA&&causing&chain&
termination&!
Elimination&is&done&mainly&by&metabolism!
Clinical&use:!
o Pancreatic&cancer,&non]small&cell&lung&cancer,&bladder&cancer,&non]
Hodgkins!
Toxicity:!
o Myelosuppression,&neutropenia,&pulmonary&toxicity!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!

& 169&
Sollas&Notes&2015&

22.2&Pharmacokinetic&drug&interactions&
&
Drug(interactions(occur(when(one(drug(modifies(the(actions(of(another(drug.(These(
interactions(can(result(from(pharmacokinetic(alterations,(pharmacodynamics(
changes,(or(a(combination(of(both.(Although(hundreds(of(drug(interactions(have(
been(documented,(relatively(few(are(of(enough(clinical(significance(to(constitute(a(
contraindication(to(simultaneous(use(or(to(require(a(change(in(dosage.(In(patients(
taking(many(drugs,(the(likelihood(of(significant(drug(interactions(is(increased.(
Elderly(patients(have(a(high(incidence(of(drug(interactions(because(the(often(have(
ageLrelated(changes(in(drug(clearance(and(commonly(take(multiple(medications.(
(
Pharmacokinetic!interactions:!
Interactions&based&on&absorption!
o Absorption&from&the&GI&tract&may&be&influenced&by:!
! Agents&that&bind&drugs!
Resins,&antacids,&Ca2+]containing&foods!
o Antacids!decrease&GI&absorption&of&digoxin,&
ketoconazole,&quinolones&and&tetracyclines!
o Grapefruit&juice&can&inhibit&P]glycoproteins&
which&will&increase&net&absorption&of&drugs!
! Agents&that&increase&or&decrease&GI&motility!
Metoclopramide&or&antimuscarinics&respectively!
! Agents&altering&P]glycoprotein&and&organic&anion&
transporters&in&the&intestine!
o Absorption&from&subcutaneous&sites&can&be&slowed&predictably&by&
vasoconstrictors&given&simultaneously&(e.g.&local&anesthetics&&&epi)&
&&by&cardiac&depressants&that&decrease&tissue&perfusion&(e.g.&]
blockers)!
Interactions&based&on&distribution&&&binding!
o Distribution&of&a&drug&can&be&altered&by&other&drugs&that&compete&
for&binding&sites&on&plasma&proteins!
! Sulfonamides&can&displace&methotrexate,&phenytoin,&
sulfonylureas&and&warfarin&from&binding&sites&on&albumin!
o Changes&in&distribution&can&also&occur&in&one&agents&alters&the&size&
of&the&physical&compartment&in&which&another&drug&distributes!
! Diuretics&reduce&total&body&water,&can&increase&plasma&
levels&of&aminoglycosides&and&lithium!
Possibly&enhancing&drug&toxicities!
Interactions&based&on&metabolic&clearance!
o Well&documented&and&are&very&clinical&significant&interactions!
o Very&associated&with&the&P450&isozymes&in&the&liver!
o Induction&of&drug]metabolizing&enzymes&can&occur&chronic&
administration&of:!
! Barbiturates,&carbamazepine,&ethanol,&phenytoin&or&
rifampin!
o Decrease&of&drug]metablizing&enzymes&can&occur&with:!
! Cimetidine,&disulfiram,&erythromycin,&grapefruit&juice&
(furanocoumarins),&ketoconazole,&quinidine,&ritonavir,&
sulfonamides&and&many&others!

& 170&
Sollas&Notes&2015&

! CYP3A4&is&the&dominant&form&in&the&liver&and&is&particularly&
sensitive&to&these&inhibitory&agents!
o Drugs&that&reduce&hepatic&blood&flow&(e.g.&propranolol)&may&
reduce&clearance!
! Specially&morphine&and&verapamil!
o Drugs&that&release&stores&of&endogenous&substances&that&have&been&
trapped&by&other&drugs&in&an&endogenous&pool!
! Can&have&catastrophic&effects&upon&massive&release!
Patients&on&MAO]inhibitors,&amphetamine,&
phenylpropanolamine&can&experience&extreme&
hypertensive&crisis&in&response&to&ordinary&dosis&of&
cold&remedies,&decongestants&and&appetite&
suppressants!
Interactions&based&on&renal&function!
o Excretion&of&drugs&can&be&changed&by&drugs&that&reduce&renal&
blood&flow&(e.g.&]blockers)&or&inhibit&specific&renal&transport&
mechanisms&(e.g.&aspirin&on&uric&acid&secretion&in&PCT)!
o Drugs&altering&urinary&pH&can&alter&ionization&states&of:!
! Weak&acids&or&weak&bases!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!

& 171&
Sollas&Notes&2015&

22.3&Botanical&(Herbal)&medications&
&
Herbal(medicines(are(an(increasingly(common(form(of(alternative(therapy((
Botanic(therapy(=(phytomedicines(=(phytotherapy(
&
These(indicate(the(use(of(herbs(their(natural(and(unprocessed(form(
Conventional(medicine(also(uses(drugs(of(plants(origin(but(these(are(given(in(
processed(unnatural(form.(Herbal(medicines(should(be(controlled(to(make(sure(they(
don't(contain(contaminants.(This(is(difficult(since(herbs(contain(complex(mixtures(
and(because(the(constituents(responsible(for(the(claimed(effects(are(often(unknown.(
In(addition,(there(are(often(discrepancies(between(label(information(and(actual(
content.(
&
Echinacea:&(leave&and&roots&of&Echinacea&species)&
In&vitro&studies&have&shown&that&echinacea&has&cytokine&activation&and&
antiIinflammatory&properties&
Leaves&of&Ecinacea&purpura&may&be&useful&in&the&early&treatment&of&colds&
Toxicity&and&drug&interactions:&unpleasant&taste&and&GI&effects,&sometimes&
dizziness&or&headache&
Ephedra!(Ma!Huang):&(plant&of&genus&ephedra)& &
Contains&ephedrine&and&pseudoephedrine,&which&are&indirectly&acting&
sympathomimetics&that&release&NE&from&sympathetic&nerve&endings&
They&are&used&as&nasal&decongestants,&and&ephedrine&is&a&pressor&agent&
Ephedra&herbal&products&are&used&to&treat&respiratory&dysfunctions,&such&
as&asthma&and&bronchitis&
Toxicity&and&drug&interactions:&
o Dizziness,&insomnia,&anorexia,&flushing,&palpitations,&tachycardia&
and&urinary&retention&
o At&high&levels&it&can&cause&hypertension,&arrhythmias&and&toxic&
psychosis&
Contraindications&include&anxiety,&bulimia,&arrhythmias,&diabetes,&heart&
failure,&hypertension,&hyperthyroidism,&glaucoma&and&pregnancy&
&
Garlic:!
Garlic&(Allium&sativum)&contains&organic&thiosulphates&that&can&form&
allicin&(the&characteristic&odor)&via&enzymes&activated&by&disruption&of&the&
garlic&bulb.&Allicin&inhibits&hydroxymethylglutary&coenzyme&A&(HMG]CoA)&
reductase&and&ACE,&blocks&platelet&aggregation,&increases&nitric&oxide,&is&
fibrinolytic,&and&antibacterial&activity,&and&reduces&carcinogen&activation&
Toxicity&and&drug&interactions:&nausea,&hypotension&and&allergic&reactions&
may&occur.&Caution&in&patients&receiving&anticoagulant&or&antiplatelet&
drugs.&
&
Ginkgo:&(leaves&of&Ginkgo&Biloba)&
Contains&flavone&glycosides&and&terpenoids&
In&vitro&studies&show&that&ginkgo&has&antioxidant&and&radical&scavenging&
effects&and&increase&NO&formation.&May&have&a&mild&benefit&in&dementia&
and&cognitive&impairment,&animal&studies&show&reduced&blood&viscosity&

& 172&
Sollas&Notes&2015&

Toxicity&and&drug&interactions:&
o GI&effects,&anxiety,&insomnia&and&headache&
o May&have&antiplatelet&action&
o Gingko&may&be&epileptogenic&and&should&be&avoided&in&patients&
with&seizure&disorders.&
&
Ginseng:&(genus&of&Penax)&
Contains&multiple&triterpenoid&saponin&glycosides&
May&improve&mental&and&physical&performance,&but&clinical&evidence&for&
this&is&limited&
Ginseng&may&have&some&cold&prevention&effect&and&it&may&lower&
postprandial&glucose&
Toxicity&and&drug&interactions:&estrogenic&effects&include&mastalgia&
(breast&pain)&and&vaginal&bleeding&
&Careful&in&patients&receiving&anticoagulant,&antihypertensive,&
hypoglycemic&or&psychiatric&medications.&
&
Milk!Thistle:&(seeds&of&silbum&marianum)& &
Nature:&from&the&fruit&and&seeds&of&Silbum&marianum&
Pharmacology:&in&vitro&studies&show&that&it&reduces&lipid&peroxidation,&
scavenges&free&radicals,&enhances&superoxide&dismutase,&inhibits&
leukotriene&formation,&and&increase&hepatic&RNA&polymerase&activity.&
Toxicity:&loose&stools&
&
St.!Johns!wart!(dried&flowers&of&Hyperium&perforatum)&&
Contains&active&hyperurin&and&hyperforin&
Pharmacology:&decrease&activity&of&serotoning&reuptake&mechanism.&
Hypericin&when&photoactivated,&may&have&&antiviral&and& anticancer&effects&
Toxcity&and&drug&interactions:& &
o Mild&GI&effects,&photosensation& &
o Avoid&in&patients&using&selective&serotonin&reuptake&inhibitors&
monoamine&oxidase&inhibitors&and&in&those&with&a&history&of& &
bipolar&and&psychotic&disorder&
o Decrease&effect&of&birth&control&pill,&cyclosporin,&digoxin,&HIV& &
protease&inhibitors&and&warfarin&if&regularly&taking&them&
&
!
!
!
!
!
!
!
!
!
!
!
!
!

& 173&
Sollas&Notes&2015&

Topic&23&
23.1&Drugs&that&effect&bone&mineral&homeostasis&
&
Calcium(and(phosphorus,(the(2(major(elements(of(bone,(are(crucial(not(only(for(the(
mechanical(strength(of(the(skeleton(but(also(for(the(normal(function(of(many(other(
cells(in(the(body.(Accordingly,(a(complex(regulatory(mechanism(has(evolved(to(
tightly(regulate(calcium(and(phosphate(homeostasis.(Parathyroid(hormone((PTH)(
and(vitamin(D(are(primary(regulators,(whereas(calcitonin,(glucocorticoids,(and(
estrogens(play(secondary(roles.(These(hormones(or(drugs(that(mimic(or(suppress(
their(actions(are(used(in(the(treatment(of(bone(mineral(disorders((e.g.(osteoporosis,(
rickets,(osteomalacia,(Pagets(disease),(as(are(several(nonhormonal(agents.(
(
Regulators!of!bone!mineral!homeostasis:!
! Hormonal!
o Parathyroid&hormone!
o Vitamin&D!
o Calcitonin!
o Estrogen!
o Glucocorticoids!
! Nonhormonal!
o Bisphosphonates!
o Fluoride!
o Calcimimetics!
!
Parathyroid!hormone:!
! Peptide&that&acts&on&G]protein&receptors&to&increase&intracellular&cAMP&in&
bone&and&renal&tubular&cells!
o PTH&in&kidney!
! Inhibits&calcium&excretion!
! Promotes&phosphate&excretion!
! Stimulates&the&production&of&active&vitamin&D&metabolites!
o PTH&in&bone!
! Promotes&bone&turnover&by&increasing&the&activity&of:!
Osteoblasts&and&osteoclasts!
! Osteoclast&activation&is&indirectly&resulting&from&PTH&
stimulation&of&osteoblast&formation&of&RANK&ligand&!
RANKL&is&a&member&of&the&TNF&cytokine&family&that&
stimulates&the&activity&of&mature&osteoclasts&and&the&
differentiation&of&osteoclast&precursors!
! At&continuous&high&plasma&cc.&levels&of&PTH&(e.g.&hyperparathyroidism)&
the&net&effect&will&be&increased&bone&resorption,&hypercalcemia&and&
hyperphosphatemia!
! Low&intermittent&doses&of&PTH&produce&a&net&increase&in&bone&formation!
o Teriparatide,(recombinant&truncated&form&of&PTH)!
! Used&in&parenteral&treatment&of&osteoporosis!
! The&synthesis&and&secretion&of&PTH&is&primarily&regulated&by&serum&
concentration&of&free&ionized&calcium!
o A&drop&will&result&in&increased&PTH&release&!

& 174&
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Vitamin!D:!
! Fat]soluble&vitamin&!
o Synthesized&in&the&skin&from&7]dehydrocholesterol&under&the&
influence&of&UV]light!
o Absorbed&from&diet&in&its&natural&form&(vitamin&D3,&
cholecalciferol)&or&the&plant&form&(vitamin&D2,&ergocalciferol)&!
! Active&metabolites&are&formed&in:!
o Liver:&25]hydroxyvitamin&D&or&calciferol!
o Kidney:&1,25]dihydroxyvitamin&D&or&calcitriol!
! Renal&synthesis&is&stimulated&by&PTH&and&fibroblast&growth&
factor&23&(FGF23)!
! Renal&synthesis&is&inhibited&by&phosphate&and&vitamin&D!
! Action&of&vitamin&D&is&mediated&by&activation&of&nuclear&receptors&that&
regulate&gene&expression!
! Active&vitamin&D&effects:!
o Net&increase&in&serum&cc.&of&calcium&and&phosphates!
! Due&to&increased&intestinal&absorption&and&bone&resorption&
along&with&decreased&renal&excretions!
! Inhibit&PTH&secretion&directly&and&indirectly&by&increasing&
the&serum&calcium&concentration!
o Required&for&normal&mineralization&of&bone!
! Deficiency:&Rickets&in&children&and&osteomalacia,in&adults!
! 2&forms&are&available&as&oral&supplements&(added&to&dairy&products):!
o Cholicalciferol,and,ergocalciferol!
! In&patients&with&impaired&vitamin&D&activation&(ch.liver&or&kidney&dx)&an&
active&form&of&the&vitamin&(calcitriol)&is&needed!
! Clinical&uses:!
o Treatment&of&deficiency&in&cases&of:!
! Nutritional&deficiency,&intestinal&osteodystrophy,&chronic&
kidney&or&liver&diseases,&hypoparathyroidism,&and&
nephrotic&syndrome!
o Used&in&combination&with&calcium& !
! Treat&and&prevent&osteoporosis&in&elderly!
o Topical&formulations&are&used&in&psoriasis!
o Treatment&of&secondary&hyperparathyroidism!
! Calcitriol&reduces&PTH&levels,&corrects&hypocalcemia&and&
improves&bone&disease!
! But&adverse&effects&can&be&hypercalcemia&and&
hypercalciuria&through&direct&effects&on&in&intestinal,&bone&
and&renal&handling&of&calcium&and&phosphates!
! Some&drugs&have&been&designed&with&different&properties&and&effects:!
o Doxercalciferol,,paricalcitol,&,calcipotriene!
! Analogues&of&calcitriol!
! Selectively&inhibit&PTH&formation&!
! Less&risks&of&developing&hypercalcemia&&&hypercalciuria!
! Doxercalciferol,!
Used&in&treatment&of&secondary&hyperparathyroid!
! Adverse&effects&of&overdose&of&vitamin&D:&Hypercalcemia,&hypercalciuria&
and&hyperphosphatemia!

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Sollas&Notes&2015&

Calcitonin:!
! Peptide&hormone&secreted&by&the&thyroid&gland!
! Decreases&serum&calcium&and&phosphate&by&inhibition&of&bone&resorption&
and&inhibition&of&renal&excretion&!
! Salmon&calcitonin&is&preferred&over&human&due&to&its&longer&half]life!
! Administration&is&via&nasal&sprays&or&injections!
! Used&when&acute&reduction&of&serum&calcium&is&needed&!
o Pagets&disease&of&the&bone&and&hypercalcemia!
o Treatment&of&osteoporosis!
! Increases&bone&mass&and&reduces&spinal&fractures!
Estrogens:!
! Estrogens&and&selective&estrogen&receptor&modulators&(SERMs)&can&
prevent&or&delay&bone&loss&in&postmenopausal&women!
! Act&involves&the&inhibition&of&PTH]stimulated&bone&resorption!
! More&to&read&in&topic&21.1!
Glucocorticoids:!
! Inhibit&bone&mineral&maintenance!
! Prolonged&use&can&therefore&result&in&osteoporosis!
! Useful&in&the&intermediate]term&treatment&of&hypercalcemia&!
!
Bisphosphonates!(alendronate,,etidronate,,ibandronate,,pamidronate,,
risedronate,,tiludronate,and,zoledronic,acid):!
! Short&chain&organic&polyphosphate&compounds!
! Effects:!
o Reduce&bone&resorption&and&formation!
! By&an&action&on&the&basic&hydroxyapatite&crystal&structure!
o Effects&on&vitamin&D&production!
o Effects&on&calcium&absorption&from&GIT!
o Direct&effects&on&osteoclasts!
! Inhibition&of&farnesyl&pyrophosphate&synthase!
Enzyme&that&is&important&in&osteoclast&survival!
o Increases&bone&density&and&reduce&fractures!
! Clinical&uses:!
o Management&of&hypercalcemia&associated&with&some&malignancies!
o Treatment&of&Pagets&disease!
o Treatment&of&all&forms&of&osteoporosis!
! Daily&oral&doses&(alendronate,,risedronate,ibandronate)!
! Weekly&oral&doses&(alendronate,,risedronate)!
! Monthly&oral&doses&(ibandronate)!
! Quarterly&injections&(ibandronate)!
! Yearly&injections&(zoledronate)!
! Toxicity:!
o Low&doses&of&oral&drugs&"&gastric&and&esophageal&irritation!
o Higher&doses&"&renal&impairment&and&osteonecrosis&of&jaw!
!
Rank!ligand!inhibitors!(RANKL):!
! Denosumab,!
o Human&monoclonal&antibody&that&binds&to&and&prevents&the&action&
of&RANKL!

& 176&
Sollas&Notes&2015&

o Inhibits&osteoclast&formation&and&activity!
o Used&for&the&treatment&of&postmenopausal&osteoporosis!
o Administered&subcutaneously&every&6mths!
o Drug&is&generally&well&tolerated&but&can&potentially&result&in&
increased&risk&of&infection&due&to&RANKs&role&in&immune&sys.!
Calcimimetics:!
! Cinacelcet!
o Lowers&PTH&by&activating&the&calcium]sensing&receptor&in&the&
parathyroid&gland!
o Used&for&oral&treatment&of&secondary&hyperparathyroidism&in&
chronic&renal&disease&and&treatment&of&hypercalcemia&in&patients&
with&parathyroid&carcinoma!
o Toxicity&"&hypocalcemia&and&adynamic&bone&disease!
Fluoride:!
! Appropriate&cc.&of&fluoride&in&drinking&water&or&in&toothpastes&have&well&
documented&ability&to&reduce&dental&caries!
! Chronic&exposure&in&high&cc.&may&increase&new&bone&synthesis!
! Acute&poisoning&show&GI&and&neurological&symptoms!
Other!drugs:!
! Strontium,ranelate!
o Organic&ion&bond&to&2&atoms&of&strontium!
o Promotes&osteoclast&apoptosis&and&increases&cc.&of&bone&formation&
markers!
o Used&in&treatment&of&osteoporosis!
! Gallium,nitrate!
o Effective&to&manage&hypercalcemia&associated&with&some&
malignancies&and&possibly&Pagets&disease!
o Acts&by&inhibition&of&bone&resorption!
o Can&be&nephrotoxic&&so&ask&patients&to&drink&a&lot&of&water!
! Plicamycin,(mithramycin)!
o Antibiotics&that&have&been&used&to&reduce&serum&calcium&and&bone&
resorption&in&Pagets&and&hypercalcemia!
o Serious&side&effects&restrict&the&treatment&to&only&short&term!
! Thrombocytopenia,&hemorrhage,&hepatic&and&renal&damage!
! Diuretics,(thiazides,and,furosemide)!
o Can&affect&serum&and&urinary&calcium&levels&!
! Sevelamer!
o Phosphate&binding&gel&that&is&used&in&combo&with&calcium&
supplements&and&dietary&phosphate&restrictions&to&treat&
hyperphosphatemia!
! Hyperphosphatemia&commonly&occurs&in&renal&failure,&
hypoparathyroidism&and&in&vitamin&D&intoxications!
!
!
!
!
&
&
&

& 177&
Sollas&Notes&2015&

23.2&Selective&COX?2&inhibitors&
&
Selecoxib,!rofecoxib,!valdecoxib:!
! NSAIDs&that&directly&target&COX]2!
! Have&less&effect&on&the&prostaglandins&involved&in&homeostatic&function!
o Particularly&those&in&the&GI&tract&!
o Reduces&the&risk&of&developing&peptide&ulcers!
o Cause&significant&increase&in&heart&attacks&and&stokes!
! Due&to&increased&risk&of&arterial&thrombi&formation!
Due&to&their&increased&inhibitory&effects&on&
endothelial&prostacyclin&(PGI2&)&than&on&platelet&
TXA2&formation!
PGI2&promotes&vasodilation&and&inhibits&platelet&
aggregation&while&TXA2&has&the&opposite&effects!
! Some&of&these&drugs&have&been&taken&off&market&or&have&
special&warning&labels&for&this&thrombotic&risk!
!
23.3&Calcium&antagonists&
(
Calcium(channel(blockers(are(group(4(antiarrhythmic(drugs.((They(inhibit(the(
influx(of(Ca2+(through(the(slow(channels((LLtype(CaLchannels)(that(are(located(in(
the(myocardium,(His(bundle,(Purkinje(fibers(as(well(as(vascular(smooth(muscles.(
Therapeutically(the(Ca2+(channel(blockers(can(be(divided(into(3(subgroups:(
&
1. Dihydropyridine&derivatives:&
E.g.&Amlodipine,,felodipine,,nifedipine&
Uncharged&hydrophobic&substances&
Have&high&affinity&for&the&smooth&muscle&&causes&vasodilation&of&
the&resistance&vessels,&reduced&BP&and&reduced&afterload&
Regarded&as&vasoselective&Ca2+&antagonists&
Their&effect&is&very&beneficial&in&lowering&afterload&and&by&that&
they&reduce&the&workload&of&the&heart&and&that&results&in&better&
diastolic&blood&perfusion&to&the&myocardium&&
o Also&reduces&vasospasms&of&coronary&art.&&&cerebral&art.&
(Prophylactic&in&case&of&post]subarachnoidal&strokes)&
Used&in:&
o Angina&pectoris&and&hypertension&
Adverse&effects:&
o Reflex&tachycardia&due&to&hypotension,&headaches,&GI&
disturbances,&gingival&hyperplasia&and&pretibial&edema&
&
2. Non]dihydropyridine&derivatives:&
E.g.&verapamil,&diltiazem&
Block&both&L]type&Ca2+&channels&as&well&as&T]type&Ca2+&channels&
Verapamil&contains&a&positively&charged&nitrogen&atom&at&
physiological&pH&levels&&cationic(amphiphilic(molecule&
Has&affinity&for&cardiac&myocytes&as&well&as&vascular&smooth&m.&
Verapamil&has&negative&chrono],&dromo]&and&ionotrophic&effects&

& 178&
Sollas&Notes&2015&

Used&in:&&
o Supraventricular&tachyarrhythmias&
! Antiarrhythmic&effects&(SA]nodal&inhibition)&
o Atrial&flutter&and&fibrillation&&
! Reduced&ventricular&firing&rate&(AV]nodal&inhibition)&
o Hypertension&and&angina&pectoris&
Adverse&effects:&
o GI&disturbances,&AV]blocks&and&myocardial&insufficiency&
can&occur,&in&case&of&hypotension&verapamil&effects&the&
formation&of&reflex&tachycardia&from&the&cardiac&centers&so&
heart&rate&rarely&changes&and&even&bradycardia&can&develop&
&
3. T]selective&blockers:&
Mibefradil&shows&a&relative&selectivity&for&T]type&Ca2+&&
Does&not&have&negative&ionotropic&effects&
Its&beneficial&use&is&contraindicated&by&the&many&drug&interactions&
associated&with&the&drug&as&well&as&its&inhibition&of&cyt&P450&
o CYP&1A2,&2D6&and&3A4&
Doses&are&titrated&against&response&to&aim&for&the&best&BP&possible!&
&
Calcium&channel&blockade&in&epilepsy&treatment:&
Ethosuximide,inhibits&low]threshold&(T]type)&Ca2+&currents,&mainly&in&the&
thalamic&neurons&that&act&as&pacemakers&to&generate&rhythmic&cortical&
discharge!
Valproic,acid,,gabapentin,and,pregabalin&have&similar&actions&as&
ethosuzimide!

&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
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&
&
&
&

& 179&
Sollas&Notes&2015&

&
Topic&24&
24.1&Plant&alkaloids,&antibiotics,&hormonal&&&miscellaneous&anticancer&agents&
&
Plant!alkaloids:!
CCS&drugs!
Vinica&alkaloids&"&vinblastine,,vincristine,,vinrelbine!
Podophyllotoxins&"&etoposide,,teniposide!
Camptothecins&"&topotecan,,irinotecan!
Taxanes&"&paclitaxel,,docetaxel!
!
Vinica!alkaloids!(vinblastine,!vincristine,!vinrelbine):!
Block&formation&of&mitotic&spindle&by&preventing&assembly&of&tubulin&dimers&in&
the&microtubules&&act&in&M]phase!
Resistance&can&occur&from&increased&efflux&of&drug&from&tumor&cells&via&
membrane&drug&transporter!
Pharmacokinetics:!
o Given&parenterally&and&penetrate&most&tissues&ex.&CSF!
o Cleared&mainly&via&biliary&excretion!
Clinical&use:!
o Vincristine&&acute&leukemia,&lymphomas,&Wilms,&neuroblastoma!
o Vinblastine&&lymphomas,&neuroblastoma,&testicular&and&Kaposis!
o Vinrelbine&&non]small&cell&lung&cancer&and&breast&cancer!
Toxicity:!
o Vinblast&&&vinorelbine&]&GI&distress,&alopecia,&BM&suppression!
o Vincristine&&neurotoxic,&areflexia,&perip.&neuritis,&paralytic&ileus!
Podophyllotoxins!(etoposide,!teniposide):!
Induce&DNA&breakage&via&inhibition&of&topoisomerase&II!
o Most&active&in&late&S]&&&early&G2]phase!
Oral&administration&with&distribution&to&most&tissues!
Elimination&via&kidneys&!
Clinical&use:!
o Used&in&combo&therapy&for&lymphoma,&lung,&germ&cell&and&gastric!
Toxicity:&BM&suppression,&alopecia,&GI]irritation!
Camptothecins!(topotecan,!irinotecan):!
Inhibit&topoisomerase&I&to&cause&DNA&damage!
Irinotecan&is&a&prodrug&that&is&converted&into&active&in&the&liver!
o Eliminated&via&bile&and&feces!
Topotecan&is&eliminated&renally!
Clincal&use:&!
o Topotecan&]&2nd&line&therapy&for&advanced&ovarian&and&small&cell&lung&
cancer!
o Irinotecan&&metastatic&colorectal&cancer!
Toxicity&&myelosuppression&and&diarrhea&!
Taxanes!(paclitaxel!and!docetaxel):!
Interfere&with&the&mitotic&spindle&differently&from&the&vinca&alkaloids!
o Prevent&microtubule&disassembly&into&tubulin&monomers!
Given&IV&and&are&used&in&number&of&solid&tumors&such&as&breast,&ovarian,&lung,&
gastroesophageal,&prostate,&bladder,&head&neck!
Paclitacel&causes&neutropenia,&thrombocytopenia&and&peripheral&neurpathy!
!

& 180&
Sollas&Notes&2015&

Antitumor!antibiotics:!
!
Antracyclines:!
CCNS&drugs!
Intercalate&between&base&pairs,&inhibit&topoisomerase&II&and&generate&free&
radicals&&by&this&they&block&RNA&and&DNA&synthesis&&&cause&DNA&scission!
Drugs:!
o Doxorubicin,,daunorubicin,,epirubicin,,mitoxantrone!
Pharmacokinetics:!
o Doxorubicin&and&daunorubicin&must&be&given&IV&since&they&are&
metabolized&in&the&liver&and&their&products&excreted&in&bile&&&urine!
Clinical&use:!
o Doxorubicin&&Hodgkins&and&non]Hodgkins,&myelomas,&sarcomas,&
breast,&lung,&ovarian&and&thyroid&cancers!
o Daunorubicin&&acute&myelogenous&leukemia!
o Epirubicin&&breast&and&gastroesophageal!
o Mitoxantrone&&acute&myeloid&leukemias,&non]Hodgkins,&breast!
Toxicity:!
o Bone&marrow&suppression,&GI]distress&and&severe&alopecia!
o Most&severe&effect&is&cardiotoxicity!
! Arrhythmias&and&slowly&developing&cardiomyopathy&and&
congestive&heart&failure!
Dexrazoxane&can&protect&against&this!
Bleomycin:!
CCS&drug&&active&in&G2&]&phase!
Mixture&of&glycopeptides&generating&free&radicals,&that&bind&to&DNA,&
causing&strand&breakage&and&inhibition&of&DNA&synthesis!
Must&be&given&parenterally&and&is&inactivated&by&tissue&aminopeptidase!
o Some&renal&clearance&of&intact&drug&is&also&seen!
Clinical&use:!
o Hodgkins&&&testicular&cancer,&lymphomas&and&squamous&cell&carc.!
Toxicity:!
o Pulmonary&dysfunction&(slowly&developing&and&dose&limiting)!
o Hypersensitivity&reactions&and&alopecia,&blisters&&&hyperkeratosis!
Mitomycin:!
CCNS&drug&that&is&metabolized&by&liver&enzymes&for&form&an&alkylating&
agent&that&cross]links&DNA&&given&IV&and&is&cleared&via&the&liver!
Acts&against&hypoxic&tumors&and&in&combo&in&cancers&such&as&
adenocarcinoma,&cervical,&stomach,&pancreas&and&lung.!
Toxic&effects&&severe&myelosuppression,&cardio],hepato],pulmonary&and&
nephrotoxicity!
!
Hormonal:!
Glucocorticoids&(predisone)!
o Widely&used&in&leukemias&and&lymphomas!
Gonadal&hormone&antagonists&(tamoxifen,,toremifene,,flutamide)!

& 181&
Sollas&Notes&2015&

o Tamoxifen&is&a&selective&estrogen&receptor&modulator&that&blocks&
the&binding&of&estrogen&to&receptors&located&on&estrogensensitive&
cancer&cells&in&breast&tissue!
! Used&in&receptor&positive&breast&carcinoma!
! Protective&role&in&women&at&risk!
! Increases&risk&of&endometrial&hyperplasia&and&neoplasia!
Due&to&opposite&effects&on&the&endometrial&cells&in&
the&uterus&&causing&stimulation!
! Can&also&cause&nausea,&vomiting,&hot&flashes,&vaginal&
bleedings&and&venous&thrombosis!
o Toremifene&is&newer&than&tamoxifen&and&is&used&in&advanced&
breast&cancer&!
o Flutamide&is&an&androgen&receptor&antagonist&used&in&prostatic&
carcinoma!
! Adverse&effects&are&gynecomastia,&hot&flushes&and&hepatic&
dysfunction!
Gonadotropin]releasing&hormone&analogs&(leuprolide,,goserelin,,
nafarelin)!
o Are&effective&in&prostatic&carcinoma&by&inhibition&of&LH&and&FSH&
secretion&from&the&pituitary!
Aromatase&inhibitors&(anastrozole)!
o Inhibition&of&aromatase&will&block&conversion&of&androstenedione&
to&estrone&&these&are&used&in&advanced&breast&cancer!
Miscellaneous!anticancer!drugs:!
Tyrosine&kinase&(TK)&inhibitors&(imatinib)!
o Inhibits&tyrosine&kinase&activity&of&bcrLabl!oncogene&that&is&
commonly&expressed&in&CML!
o Also&effective&in&treatment&of&GI&stromal&tumors&(cLkit(TK)!
o Toxicity&may&include&diarrhea,&myalgia,&edema&and&congestive&HF!
Growth&factor&receptor&inhibitor&(trastuzumab,,cetuximab,,
panitumumab,,gefitinib,,bevacizumab)!
o Trastuxumab&&monoclonal&AB&recognizes&HER]2/neu&receptor!
! Inhibits&the&binding&of&EGF&to&this&receptor!
! Adverse&effects&are&nausea,&vomiting,&congestive&HF!
Rituximab!
o Monoclonal&AB&that&binds&to&surface&proteins&of&non]Hodgkins&
lymphoma&cells&and&induces&complement]mediated&lysis,&direct&
cytotoxicity&and&induces&apoptosis!
o Currently&used&in&combo&therapies&with&older&cancer&drugs!
Interferons!
o Glycoproteins&with&antineoplastic,&immunosuppressive&and&
antiviral&actions!
! Alpha]interferons&are&effective&agains&hairy]cell&leukemia,&
early&CML&and&T]cell&lymphomas!
Asparaginase!
o Used&in&T]cell&auxotropic&cancers&that&requires&asparagine&for&
growth&&given&IV&and&may&cause&severe&HSR,&acute&pancreatitis!
Proteasome&inhibitors!
o Bortezomib,,reversible&inhibitor&of&chymotrypsin&used&in&multiple&myeloma!

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24.2&Emetics&and&anti?emetics&
&
Drugs&with&antiemetic&actions:&
A(variety(of(drugs(are(valuable(in(the(prevention(and(treatment(of(vomiting((
especially(cancer(chemotherapyLinduced(vomiting(
H1(histamineLblocking(drugs(
o Diphenhydramine,&,several(phenothiazines(
AntiLmuscarinic(drugs(
o Scopolamine(
Corticosteroids(
o Dexamethasone(
Cannabinoid(receptor(agonist(
o Dronabinol,&,nabilone(
5LHT3(antagonist(
o Ondansetron,,granisetron,,dolasetron,&,palonosetron(
o Particularly&useful&in&preventing&nausea&and&vomiting&after&general&
anesthesia&and&in&patients&receiving&cancer&chemotherapy(
Neurokinin(1((NK1)(receptor(antagonist(
o Aprepitant(
o Receptor&in&the&area&postrema&of&the&CNS&that&is&activated&by&
substance&P&and&other&tachykinins(
o Used&in&combo&with&other&antiemetics&for&prevention&of&nausea&
and&vomiting&due&to&chemotherapeutic&agents(
o Causes&fatigue,&dizziness&and&diarrhea&(
Emetics:&
Used(when(a(substance(needs(to(be(expelled(from(the(body(immediately(before(the(
body(absorbs(the(injurious(substance(
Ipecac,syup:(acts(locally(by(irritating(the(gastric(mucosa,(and(centrally(by(
triggering(the(area(postrema.(Bulimics(abuse(the(drug.(
Salt,water,and,mustard,water,
Cooper,sulfate((too(toxic,(not(longer(used(
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&

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24.3&Cholinomimetic&drugs&
&
Cholinomimetics(are(drugs(that(have(acetylcholine(effects.(They(can(act(directly(on(
the(ACh(receptor(or(indirectly(via(inhibition(of(cholinesterase.(Direct(acting(
cholinomimetic(drugs(can(be(further(subcategorized(after(which(type(of(cholinergic(
receptor(they(work(on;(nicotinic(or(muscarinic(receptors.(Indirectly(acting(drugs(
can(be(short(acting((edrophonium),(intermediate(to(long(acting((carbamates)(or(
very(long(acting((organophosphates)(
&
Directly&acting&cholinomimetics:&
Group&of&choline&esters&
o Acetylcholine,&methacholine,&carbachol&and&bethanechol&
Naturally&occurring&alkaloids&&
o Muscarine,&pilocarpine,&nicotine&and&lobeline&
Classification:&
Muscarinic&agonists&are&parasympathomimetic;&mimic&the&action&of&a&
parasympathetic&nerve&stimulation&
o 5&types&of&muscarinic&receptors&&
o All&muscarinic&agonists&available&for&clinical&use&are&nonselective&
on&these&5&receptors&
Nicotinic&agonists&are&not&specified&on&which&they&act&on&ganglions&or&NMJ&
o Therefore&their&agonist&selectivity&is&limited&
o We&have&relatively&selective&antagonists&for&the&two&different&
nicotinic&receptors&(NM&or&NN)&
Molecular&mechanisms&for&each&subtype&of&both&muscarinic&and&nicotinic&
receptors&have&been&previously&described&in&topic&1&
Examples&of&directly&acting&cholinomimetics:&
Acetylcholine&&works&on&both&M&and&N&receptors&
o Rapidly&hydrolyzed&by&cholinesterase&(ChE)&
o Duration&of&action&is&5]30&sec&&
o Poor&lipid&solubility&
o No&clinical&use&&only&endogenous&
Bethanechol&&works&only&on&M&receptors&
o Resistant&to&ChE&and&is&active&orally&
o Duration&of&action&is&30min]2hours&
o Poor&lipid&solubility&
o Used&in&treatment&of&paralytic&ileus&and&urinary&retention&
Carbachol&&works&on&M&and&N&receptors&
o Otherwise&the&same&effects&as&bethanechol&
Pilocarpine&&works&on&M&receptors&
o Not&an&ester&and&therefore&has&good&lipid&solubility&
o Duration&of&action&is&30min]2hours&
o Used&topically&as&eye&drops&to&treat&glaucoma,&xerostomia&(dry&mouth)&for&the&
treatment&of&Sjgrens&syndrome&
o Also&used&in&the&diagnosis&of&cystic&fibrosis&
! Screening&sweat&test&&used&to&increase&sweat&production&
Nicotine&&works&on&N&receptors&
o Like&pilocarpine&and&has&high&lipid&solubility&
o Duration&of&action&is&1]6&hours&
Varenicline&&works&on&N&receptors&
o Partial&agonist&of&the&N&receptors&and&has&high&lipid&solubility&
o Duration&of&action&is&12]24&hours&
&

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Toxicity:&
Muscarinic&&CNS&stimulation,&miosis,&spasm&in&accommodation,&
bronchoconstriction,&increased&SM&activity&in&GI&and&genitourinary&tract,&
increased&secretory&mechanisms&and&too&much&vasodilation.&Transient&
bradycardia&occurs&with&a&compensatory&reflex&tachycardia.&Diarrhea&and&
vomiting&can&also&occur&followed&by&hepatic&and&renal&necrosis&(specially&
in&the&case&of&mushroom&poisoning)&&this&can&be&lethal!!&
Nicotinic&&ganglionic&stimulation&and&block,&NM&end&plate&depol.that&
leads&to&fasciculations&and&paralysis.&&CNS&toxicity&can&result&in&
convulsions&and&stimulation&followed&by&depression.&Nicotine&is&very&
addictive,&even&in&very&small&doses.&&
&
Indirectly&acting&agonists:&
2&major&chemical&classes&
o Carbamic&acid&esters&(carbamates)&&e.g.&neostigmine&
o Phosphoric&acid&esters&(organophosphates)&&e.g.&parathion&
3rd&chemical&class&
o Only&one&drug&has&clinical&significance&&edrophonium&(alcohol)&
Mechanisms:&
All&classes&are&inhibitors&that&bind&to&cholinesterase&and&undergo&rapid&
hydrolysis&&this&causes&as&release&of&the&alcohol&portion&of&the&molecule&
to&be&released.&The&acidic&(carbamate&or&phosphate)&part&is&released&more&
slowly,&which&causes&the&inhibition&of&binding&and&hydrolysis&of&
endogenous&ACh.&This&results&in&amplification&of&the&affects&of&ACh&
wherever&the&transmitter&is&released&in&the&body&
Examples&of&indirectly&acting&cholinomimetics:&
All&members&act&on&both&N&and&M&receptors&
Edrophonium&&alcohol,&poor&lipid&sol.&(quaternary&structure),&not&orally&active,&
duration&of&action&5]15min&
Neostigmine&&carbamate,&poor&lipid&sol.&(quaternary&structure),&orally&active,&duration&
of&action&30min]2hrs&
Phyostigmine&&carbamate,&good&lipid&sol.&(tertiary&structure),&orally&active,&duration&of&
action&30min]2hrs&
Pyridostigmine&&carbamate,&poor&lipid&sol.&(quaternary&structure),&orally&active,&
duration&of&action&4]8hrs&
Echothiopate&&organophosphate,&moderate&lipid&sol.,&duration&of&action&2]7&days&
Parathion&&organophosphate,&high&lipid&sol.,&duration&of&action&7]30days&
Clinical&uses:&
Carbamates&(neostigmine,!physostigmine,!pyridostigmine!and!
ambenonium)&are&used&much&more&than&organophosphates&
These&drugs&are&used&in&the&treatment&of&myasthenia&gravis&
Rivastigmine&(a&carbamate)&is&used&in&the&treatment&of&Alzheimers&dx.&
Organophosphates&are&mainly&used&as&scabicide&(malathion)&and&an&
antihelminthic&agent&(metrifonate)&
Edrophonium!is&used&for&the&rapid&reversal&of&nondepolarizing&NM&
blockade&for&the&diagnosis&of&myasthenia&gravis&and&its&differentiation&
from&cholinergic&crisis&&since&distinguishing&btw.&these&two&condition&is&
difficult&&
&
&

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Toxicity:&
Especially&organophosphates&that&are&used&as&pesticides&have&toxic&behavior.&Most&toxic&
is&parathion&that&can&be&rapidly&lethal&if&antidote&is&not&administered&rapidly&upon&
exposure&(muscarinic&antidote&is&atropine!!no&effects&on&N&receptor&toxicity).&Nicotinic&
toxicity&is&treated&with&regenerating&active&ChE&(pralidoxime)&
DUMBBLESS&symptoms&(diarrhea,&urination,&miosis,&broncoconstriction,&bradicardia,&
excitation&of&sk.muscles&and&CNS,&lacrimation,&salivation&and&sweating)&
&
Effects&of&direct&and&indirect&cholinomimetics&on&major&organ&systems:&
CNS&&
o Complex&stimulatory&effects&
o Nicotine:&elevates&mood,&alerts&and&is&addictive&
o Phyostigmine:&convulsions&and&in&excessive&CC&causes&coma&
Eye&
o Contraction&(miosis)&of&the&sphincter&muscle&of&the&iris&
o Contraction/cyclospasms&of&the&ciliary&muscle&to&accommodate&
near&vision&and&facilitate&outflow&of&aqueous&humor&into&the&canal&
of&Schlemm&&&
Heart&
o SA&node&&negative&chronotropic&effects&(decreased&firing&rate)&
! Note:&Baroreceptor&reflexes&are&activated&due&to&the&lower&
blood&pressure;&this&causes&a&compensatory&sympathetic&
discharge&to&the&heart&that&can&cause&tachycardia&
o Atria&&negative&ionotropic&effects&(decrease&in&contractile&force)&
! This&causes&a&decrease&in&the&refractory&period&
o AV&node&&negative&dromotropic&effects&&
! Decreased&conduction&velocity&which&causes&an&increase&in&
the&refractory&period&
o Ventricles&&small&negative&ionotropic&effects&
Blood&vessels&
o Dilation&via&the&release&of&EDRF&(endothel.derived&relaxing&factor)&
! NO&and&possibly&other&relaxing&substances&&
o Not&a&direct&action&of&cholinomimetics&on&the&blood&vessels&
Bronchi&
o Bronchoconstriction&
GI&tract&
o Increase&in&SM&contraction,&peristalsis&&increased&motility&
o Decreased&in&tone,&relaxation&of&sphincter&muscles&&
! Except&the&gastroesophageal&sphincters&that&contracts&
Urinary&bladder&
o Increased&contraction&of&the&detrusor&muscle&
o Relaxation&of&the&bladder&trigone&&&sphincters&that&causes&voiding&
Skeletal&muscles&
o Activation&of&NM&end&plates&that&results&in&contraction&
Exocrine&glands&
o Increased&secretion&
! Thermoregulatory&sweating,&lacrimation,&salivation,&
bronchial&secretion&and&GI&gland&secretion&

& 186&
Sollas&Notes&2015&

Topic&25&&
25.1&Immunopharmacology&
&
Although(the(immune(system(is(essential(for(protection(against(pathogens,(in(
certain(situations(its(powerful(destructive(mechanism(does(more(harm(than(good.(
Harmful(effects(of(the(immune(system(include:(Hypersensitivity(reactions,(
autoimmune(disorders(and(rejection(reactions(to(transplanted(tissues.((
Drugs(suppressing(the(immune(system(play(important(roles(in(the(treatment(of(
these(conditions.(Monoclonal(antibodies(targeting(proteins(with(key(immunological(
functions(are(constantly(being(developed(as(immunosuppressive(agents.(In(
addition,(in(some(situations(there(are(drugs(that(potentiate(the(immune(response(
to(provide(benefit.(This(chapter(describes(the(drugs(modulating(the(immune(
function.(
(
(
Drugs&that&modulate&immune&function&can&be&divided&into:&
Immunosuppressants&
o Corticosteroids&(prednisone)&
o Immunophilin&ligands&(cyclosporine,,tacrolimus,,sirolimus)&
o Mycophenolate&mofetil&
o Cytotoxic&drugs&(azathioprine)&
o Immunoglobulin&based&agents&(etanercept)&
Immune&potentiators&
o Aldesleukin&
o Interferons&
&
A&little&immune]intro!&
The&immune&system&is&composed&of&the&innate&and&the&adaptive&immunity.&&
The&innate&initiates&defense&against&pathogens&and&antigenic&insults:&
o Composed&of&the:&
! NK]cells,&complement&components,&phagocytic&cells&
The&adaptive&is&kick&started&if&the&innate&response&is&inadequate:&
o Composed&of&the:&
! Cell&mediated&immunity&(T]lymphocytes&CD4+,CD8+)&
! Humoral&immunity&(B]lymphocytes)&
o Important&factors&of&the&adaptive&system&are&the&following:&
! Antigen&presenting&cells&(APCs)&
Processing&antigents&into&small&peptides&that&will&be&
recognized&by&T]cell&receptors&on&CD4+&TH&cells&
! Major&histocompability&complex&(MHC)&class&I&and&II&&
Recognized&by&TH&cells&when&they&are&bound&to&
antigen&fragments&
MHC&I&are&expressed&by&all&cells&
MHC&II&are&expressed&by&APCs&
Cell&mediated&immunity& &
o Activated&TH&cells&secrete&IL]2&(cytokine&that&initiates&proliferation&
and&activation&into&TH1&and&TH2&subsets)&
o TH1&are&involved&in&cell]mediated&imm.&&&delayed&HSR&

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! Produce&IFN],&IL]2&and&TNF]&
! All&are&cytokines&that&activate&macrophages,&CD8+&cytotoxic&
T&lymphocytes&(CTLs)&and&NK]cells&
! Recognize&MHC&I&molecules&on&virus&infected&or&tumor&cells&
! CTLs&initiate&target&cell&death&via&lytic&enzymes&and&NO&by&
the&stimulation&of&apoptosis&
! CTLs&also&play&a&role&in&AI&diseases&by&reacting&to&normal&
tissue&such&as:&
o Synovium&in&Rheumatoid&arthritis&
o Myelin&in&multiple&sclerosis&
Humoral&immunity:&
o Mediated&by&the&B]lymphocytes&that&are&capable&of&differentiating&
into&antibody]forming&cells&and&trigger&humoral&response&when&
they&bind&antigen&via&their&surface&immunoglobulins&
! Antigens&are&internalized,&bound&to&MHC&II&and&presentet&
on&the&B]cell&surface&
Recognized&by&T]cell&receptors&on&TH2&cells&that&start&
to&release&interleukins&(IL]4,5,6,10,13)&
These&IL&induce&B]cell&proliferation&and&
differentiation&in&to&memory&B]cells&and&antibody]
secreating&plasma&cells&
Antibodies&produced&by&plasma&cells&bind&to&
antigens&on&the&surface&of&the&pathogens&and&trigger&
precipitation&of&viruses&and&destruction&of&bacteria&
by&phagocytic&cells&or&lysis&via&the&complement&syst.&
&
Abnormal&immune&responses:&
Hypersensitivity&
o Immediate&is&usually&antibody&mediated&
! Hemolytic&disease&of&the&newborn&&&anaphylaxis&
o Delayed&is&cell]mediated&
! Associated&with&extensive&tissue&damage&
Autoimmunity&
o Arises&from&lymphocytes&that&react&to&self&antigens&
! RA&and&SLE&+&many&more&
Immunodeficiency&states&
o Can&be&genetically&acquired&&DiGeorge&syndrome,&SCID&
o Extrinsic&factor&acquired&&HIV&
!
Immunosuppressive!agents:!
!
Corticosteroids&(better&described&in&topic&18.1)&
Act&at&multiple&cellular&sites&to&produce&broad&effects&on&inflammatory&
and&immune&processes&by&decreasing&prostaglandin,&leukotriene,&cytokine&
and&other&signaling&molecule&(e.g.&platelet&act.&factor)&production&along&
with&inhibiting&proliferation&of&T&cells&&
Impair&cell]mediated&immunity&to&a&great&extent&
o Dampens&humoral&immunity&by&lowering&IgG&
Clinical&use:&

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o Used&alone&or&in&combination&with&other&agents&in&a&wide&variety&
of&diseases&with&an&underlying&undesirable&immunologic&reactions&
! Also&used&in&pre]transplantation&treatment&and&in&
treatment&of&hematological&cancers&
Toxic&effects:&
o Adrenal&suppression,&growth&inhibition,&muscle&wasting,&
osteoporosis,&salt&retention,&glucose&intolerance&and&behavioral&
changes&
&
Immunophilin&inhibitors:&
Interfere&with&T]cell&function&by&binding&to&immunophilins&(small&
proteins&playing&a&critical&role&in&T]cell&responses)&
Cyclosporine&binds&to&cyclophilin&Tacrolimus,binds&to&FK]binding&
protein&(FKBP)&
o Both&inhibit&calcineurin&(cytoplasmic&phosphatase)&that&results&in&
decreased&production&of&IL]2,&IL]3&and&IFN]&
Sirolimus&and&its&analogs&(everolimus,&,temsirolimus)&bind&to&FKBP&12&
that&inhibits&kinase&activity&of&mammalian&target&of&rapamycin&(mTOR)&
o Inhibiting&T]cell&proliferation&response&to&IL]2&
Clinical&use:&
o Major&factor&in&the&success&of&solid&organ&transplantation&to&
prevent&and&treat&graft&vs.&host&(GVH)&disease&in&recipients&of&
allogeneic&stem&cell&transplantation&
o Autoimmune&diseases&such&as&RA,&uveitis,&psoriasis,&asthma,&DM&I&
o Sirolimus]eluting&stents&are&used&to&prevent&restenosis&after&
coronary&angioplasty&
o Everolimus&and&temsirolimus&are&used&in&various&cancers&
Toxicity:&
o Cyclosporine&and&tacrolimus&]&Renal&dysfunction,&HTN,&
neurotoxicity,&hyperglycemia,&hyperlipidemia,&gall&stones&
o Sirolimus&+&analogs&&hypertriglyceremia,&hepatotoxicity,&diarrhea,&
myelosuppression&
Mycophenolate&mofetil:&
Inhibits&inosin&monophosphate&dehydrogenase&and&by&that&suppresses&
both&B]&and&T]cell&activation&
o More&susceptible&due&to&lack&of&alternative&salvage&pathway&in&GTP&
synthesis&in&lymphocytes&
Used&as&a&sole&agent&in&kidney,&liver&&&heart&transplant&
Drug&can&cause&GI&disturbances&and&myelosuppression&(neutropenia)&
Thalidomide:&
Sedative&drug&that&is&known&for&its&teratogenic&effects&
Suppresses&TNF]&production,&increases&IL]10,&reduces&neutrophil&
phagocytosis,&alters&adhesion&molecule&expression&and&enhances&cell]
mediated&immunity&
Clinical&use:&
o Some&forms&of&leprosy&reactions,&SLE&and&as&an&anticancer&drug&
o Effective&in&treating&aphthous&ulcers&&&wasting&syndrome&in&AIDS&
Lenalidomide&is&a&derivative&of&thalidomide&that&has&been&approved&for&
multiple&myeloma&

& 189&
Sollas&Notes&2015&

&
Antibody/based!immunosuppressive!agents:!
&
Antilymphocyte&globulin&and&antithymocyte&globulin:&
Antisera&that&is&produced&in&horses&or&sheep&by&immunization&against&
human&thymus&cells&
Antibodies&in&these&preparations&bind&to&T]cells&involved&in&antigen&
recognition&and&initiate&their&destruction&by&serum&complement&
o Selective&block&of&cellular&immunity&
Clinical&use:&
o Used&before&allogeneic&stem&cell&transplantation&to&prevent&GVH&
o Also&used&in&combo&for&solid&transplantation&&
Toxicity:& &
o Can&cause&HSR&(since&humoral&immunity&is&still&OK)&
o Pain&and&erythema&at&injection&sites&&
&
Immune&globulin&intravenous&(IGIV):&
Usually&IgG&prepared&from&pools&of&thousands&of&healthy&donors&
Thought&to&have&normalizing&effect&on&an&individuals&immune&networks&
Used&in&Ig]deficiencies,&AI&disorders,&HIV&and&stem&cell&transplantation&&
Renal&toxic&(can&lead&to&ARF)&
&
Rh0(D)&Immune&globulin:&
Rh0GAM&is&a&human&IgG&preparation&that&contains&antibodies&against&red&
cell&Rh0(D)&antigens&
Administration&of&this&antibody&to&Rh0(D)]negative&mothers&at&time&of&
antigen&exposure&(e.g.&birth&of&an&Rh0(D)]positive&child)&blocks&the&
primary&immune&response&to&the&foreign&cells&
Used&in&prevention&of&Rh&hemolytic&disease&of&the&newborn&
&
Monoclonal&antibodies&(MAbs):&
Have&high&specificity&because&they&can&be&developed&for&interaction&with&a&
single&molecule&
Humanization&of&murine&monoclonal&antibodies&and&wholly&human&
monoclonal&Ab&(genetic&engineering&of&transgenic&mice&that&make&human&
antibodies)&
o Reduced&probability&of&formation&of&neutralizing&Ab&and&immune&
reactions&
Three&types&of&MAbs&are&used&as&immunosuppressive&agents:&
o MuromonabPCD3,
! Binds&to&CD3&antigen&on&thymocytes&and&mature&T]cells,
! Blocks&the&killing&action&of&CTLs&and&interferes&with&other&
T]cell&function,
! Used&to&manage&renal,&cardiac,&liver&transplant&rejection,
! Serious&anaphylaxis&can&occur&(mainly&in&first&few&doses),
! Neuropsychiatric&and&HSR&also&can&occur,
o Infliximab,

& 190&
Sollas&Notes&2015&

!Humanized&MAb&that&targets&TFN]&and&by&that&decreases&
formationof&IL&and&adhesion&molecules&involved&in&
leukocyte&activation,
! Used&in:,
Crohns&disease&to&reduce&remissions,
RA&as&a&combination&with&methotrexate&,
Effective&in&ulcerative&colitis,&ankylosing&spondylitis&
and&psoriatic&arthritis,
! Infusion&reactions&and&an&increased&rate&of&infection,
! Adalimumab,is&a&completely&human&IgG&MAb&that&binds&to&
TNF]&and&is&used&in&RA,
! Etanercept,is&an&immunoglobulin]based&agent&that&also&
binds&with&high&affinity&to&TNF]&,
Used&in&arthritis,&psoriasis&and&ankylosing&
spondylitis&,
! All&of&the&anti]TNF]&increases&the&risk&of&serious&infections&
and&lymphoma,
o Daclixumab,
! Highly&specific&MAb&that&binds&to&]subunit&of&the&IL]2&
receptor&and&prevents&its&activation&by&IL]2,
! Used&in&combo&to&prevent&renal&transplant&rejection,
! Basiliximab&is&a&chimeric&human]mouse&IgG&with&similar&
functions&as&daclixumab,
,
Immunomodulating!agents:!
Agents&that&can&possibly&used&in&treatment&of&immune&deficiency&diseases,&
chronic&infectious&diseases&and&cancers!
Aldesleukin:&
Is&an&recombinant&IL]2&that&is&indicated&for&adjuvant&treatment&of&renal&
cell&carcinoma&and&malignant&melanoma&
Investigational&drug&for&its&possible&efficacy&in&restoring&immune&function&
in&AIDS&and&other&immune&deficiency&disorders&
Interferons:&
Interferon]]2a&inhibits&cell&proliferation&&
o Used&in&hairy&cell&leukemia,&CML,&malignant&melanoma,&Kaposis&
sarcoma,&HBV&&&HCV&
Interferon]]1b&has&beneficial&effects&in&relapsing&MS&
Interferon]]1b&seems&to&increase&synthesis&of&TNF&
o Used&in&chronic&granulomatous&disease&treatment&&
&
&
&
&
&
&
&
&

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Sollas&Notes&2015&

25.2&ADH&antagonists&
&
Antidiuretics&and&their&inhibitors:&
Antidiuretics&are&drugs&that&are&used&to&reduce&diuresis&in&the&body:&
o Treatment&of&pituitary&diabetes&insipidus&
! Not&used&in&nephrogenic&DI&
The&drugs&are&peptides&that&are&given&parenterally&
o Antagonistic&drugs&of&ADH&are:&
! Conivaptan,and,tolvaptan&
! Lithium,also,has,this,effect,but,is,not,used,for,this,purpose&
ADH&facilitates&H2O&reabsorption&from&the&collecting&ducts&by&activation&of&V2&
(vasopressin&type&II)&receptor&that&stimulates&AC&via&Gs&
o Increased&cAMP&will&cause&insertion&of&extra&aquaporin&AQP2&water&
channels&into&the&luminal&membrane&in&the&c.tubule&
! Conivaptan,inhibits&both&V1&and&V2&receptors&
! Tolvaptan,is&selective&for&V2&receptors&
Agonists:&
o ADH,and,desmopressin&
! Reduce&urine&volume&
! Treatment&of&pituitary&diabetes&insipidus&
Lack&of&vasopressin&production&&
Causes&extreme&loss&of&blood&volume&
ADH&and&desmopressin&have&no&effect&on&the&nephrogenic&
type&of&DI&
! Nephrogenic&DI&
Here&thiazides,&loop&diuretics,&salt&restriction,&water&
restriction&therapies&are&used&to&influence&the&
reabsorption&of&urine&from&the&proximal&tubules&
o Strong&stimulators&of&the&proximal&tubular&
reabsorption&
From&Wikipedia&&to&explain&nephrogenic&DI&treatment&a&little&better!!!&
&
Desmopressin(will(be(ineffective(in(nephrogenic(DI(and(is(treated(by(reversing(the(
underlying(cause((if(possible)(and(replacing(the(free(water(deficit.(
The(diuretic(hydrochlorothiazide((a(thiazide(diuretic)(or(indomethacin(can(be(used(to(
create(mild(hypovolemia,(which(encourages(salt(and(water(uptake(in(proximal(tubule(and(
thus(improve(nephrogenic(diabetes(insipidus.(Amiloride(has(additional(benefit(of(blocking(
Li(uptake.(Thiazide(diuretics(are(sometimes(combined(with(amiloride(to(
prevent(hypokalemia.(It,seems,paradoxical,to,treat,an,extreme,diuresis,with,a,
diuretic,(and(the(exact(mechanism(of(action(is(unknown(but(the(thiazide(diuretics(will(
decrease(distal(convoluted(tubule(reabsorption(of(sodium(and(water,(thereby(causing(
diuresis.(This(decreases(plasma(volume,(thus(lowering(GFR(and(enhancing(the(absorption(
of(sodium(and(water(in(the(proximal(nephron.(Less(fluid(reaches(the(distal(nephron,(so(
overall(fluid(conservation(is(obtained(
Antagonists&(conivaptan,&,tolvaptan):&
o Oppose&actions&of&ADH&and&other&naturally&occurring&peptides&acting&on&
the&V2&receptor&
o These&peptides&can&be&overly&produced&in&certain&types&of&tumors&(e.g.&
small&cell&carcinoma&of&the&lung)&and&can&cause&significant&water&
retention&and&dangerous&hyponatremia&
! Called&syndrome&of&inappropriate&ADH&secretion&(SIADH)&
Treated&with&antidiuretic&antagonists&
o Lithium&is&also&used&but&it&has&greater&toxicity&

& 192&
Sollas&Notes&2015&

25.3&Antihypertensive&drugs&&
&
Antihypertensive(therapy(seeks(to(prevent(the(complications(of(high(blood(pressure(
(mainly(stroke(and(MI).(Evidence(suggests(that(reduction(of(BP(by(5(mmHG(can(
decrease(risk(of(complication(tremendously((34%(!(risk(of(strokes(and(21%!(of(
ischemic(heart(disease)(and(therefore(it(is(very(important(to(treat(and(monitor(
these(patients(well.((
(
In&this&topic&you&need&to&combine&the&drugs&you&have&already&seen&and&read&about&before&in&
previous&topics.&I&will&write&a&general&treatment&plan&for&the&treatment&of&hypertension&but&
individual&drugs&and&their&detailed&mechanism&will&not&be&discussed&here,&for&that&I&will&refer&
back&to&topics&where&that&knowledge&is&to&be&found.&Have&fun&%&&
&
General!treatment!strategy!of!HTN:!
Diagnosis&should&be&made&by&3]6&independent&measurements!
Important&to&determine&the&cause!
o Primary&(essential)&hypertension&(95%&of&cases)!
o Secondary&hypertension&(5%)!
! Cause&of&underlying&pathology&must&be&found&and&treated!
This&topics&is&focused&on&the&prevention&and&treatment&of&primary&HTN!
(
Life!style!modifications:!
Modifications&in&patients&life]style&are&very&important&!
o Specially&in&premalignant&and&early&HTN&cases!
What&to&advise?!
o Stop&smoking!
o Reduce&dietary&fat&contents&(trans&and&saturated&fatty&acids)!
o Minimize&salt&dietary&intake&(<100mmol/day)!
o Reduce&alcohol&to&<21&units&(men)&and&<14&units&(women)!
o Regular&physical&exercise&if&not&contraindicated!
o Achieve&and&maintain&a&healthy&BMI&(20]25)!
o Consume&at&least&5&portions&of&fruits&or&greens&per&day!
!
Antihypertensive!drugs:!
ACE/ARB&inhibitors&(topic&15.3)!
Beta&blockers&(topic&19.3)!
Calcium&channel&blockers&(topic&23.3)!
Diuretics&(Thiazides&and&others)&(topic&26.2)!
The&mnemonic&ABCD&is&good&to&keep&in&mind&to&remember&the&categories&&
Peripheral&1&receptor&antagonists&(topic&20.2)&
Central&sympatholytics&(2&agonists)&
Direct&renin&inhibitors&(topic&15.3)&
Vasodilators&(topic&16.3)&
(
Treatment:!
Which&type&of&medication&to&use&initially&for&HTN&varies&greatly&and&is&
very&dependent&on&patients&age,&comorbidities&and&end]organ&damage&(to&
name&a&few)!
o Therefore&the&treatment&is&very&variable&in&individual&patients!

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Sollas&Notes&2015&

Combination!therapy&is&usually&preferred&over&single&drug&therapy!
o This&both&results&in&lower&amount&of&doses&of&individual&drug&
categories&and&has&a&synergistic&effects&on&lowering&HTN!
o There&are&endless&possibilities&of&combination&therapies!
! Depend&greatly&on:!
Patients&age,&comorbidities,&ethnicity,&genes,&life]
styles,&status&of&organs&and&tolerance&to&drugs!
!
According&to&the&2nd&edition&of&Oxford&handbook&of&Cardiology&the&ABCD&
treatment&plan&is&as&follows:!
o A&(ACEi&or&ARBi)&or&B&(]blocker)!
! Effective&1st&line&agents&in&treatment&of&young!
! Typically&renin]hypertension&that&responds&well&to&these&
classes!
o C&(Ca2+channel&blockers)&or&D&(diuretics&&thiazides/loops)!
! Effective&1st&line&treatment&in&elderly&and&African]American&
individuals!
! Typically&have&lower&levels&of&renin&and&therefore&dont&
respond&as&good&as&the&young&one&to&A&or&B!
!
Other!drugs!than!can!also!be!used!in!treatment!of!HTN:!
!
Vasodilators:!
Act&directly&on&smooth&muscle&of&arteries&to&relax&their&walls!
o Only&used&in&hypertensive&emergencies&or&when&other&drugs&have&
failed&&and&evens&so&are&rarely&given&alone!
Sodium,nitroprusside,and,hydralazine!
o No&longer&indicated&as&1st&line&therapy&for&HTN&due&to&side&effects&
and&safety&concerns&&but&are&sometimes&used&in&emergencies!
o Hydralazine&is&still&DOC&in&gestational&hypertension!
!
Benzodiazepines:!
Off]label&purpose&!
Agonists&of&GABAA&"&slowing&down&neurotransmission&"&vasodilation!
Inhibit&the&reuptake&of&adenosine!
o So&adenosine&can&serve&as&a&coronary&vasodilator!
Aldosterone!receptor!antagonists:!
Spironolactone,and,eplerenone&!
o Mainly&used&in&treatment&of&heart&failure&!
Central!alpha/2!receptor!agonists:!
Clonidine,,methyldopa,,guanabenz!
Lower&BP&by&stimulation&of&alpha]receptors&in&the&brain&which&vasodilate&
the&peripheral&arteries!
Used&when&all&other&anti]hypertensive&medications&have&failed!
Usually&administered&in&combination&with&a&diuretic&!
!
!
!
!

& 194&
Sollas&Notes&2015&

Topic&26&
26.1&Introduction&to&toxicology.&Management&of&the&poisoned&patient&
&
Toxicology(is(a(branch(of(biology,(chemistry(and(pharmacology(that(is(concerned(
with(the(study(of(the(adverse(effects(of(chemicals(on(the(body.(It(also(studies(the(
harmful(effects(of(chemical,(biological(and(physical(agents(in(biological(systems(
that(establish(the(extent(of(damage(in(living(organisms.(Relationship(between(dose(
and(effect(is(very(important(in(toxicology.(Factors(that(influence(toxicity(include(the(
dosage((acute(or(chronic),(route(of(exposure,(age,(sex(and(environment.(The(goal(of(
toxicity(assessment(is(to(identify(adverse(effects(of(a(substance.(
(
Introduction!to!toxicology:!
!
Poison:!
Non]living&material&which,&after&having&entered&the&body,&will&result&in&
damage&by&its:!
o Chemical,&physico]chemical&or&physical&properties!
Everything&is&poison&&nothing&is&completely&harmless.&Only&the&dose&can&
separate&the&poison&from&the&drug!
o Dosis(sola(facit(venenum!
Branches!of!toxicology:!
Descriptive&toxicology!
o Animal&experiments&&very&essential&in&developments&of&drugs!
! Valuation&of&a&toxic&or&non]toxic&elements!
o Search&for&alternative&methods&in&drug&treatments!
o Expensive,&time]consuming&and&difficult&!
Occupational&toxicology!
Environmental&toxicology!
Ecotoxicology!
Forensic&toxicology!
Clinical&toxicology!
!
Factors!influencing!the!effects!of!poisons:!
Species:&!
o For&example&rabbits&and&humans&have&very&different&reactions&and&
effects&to&the&same&drug!
! Atropine&lethal&dose:!
Human&"&2mg/kg!
Rabbit&"&1500mg/kg!
Age:!
o Infants&are&more&sensitive&to&most&drugs&(morphine,,ethanol,etc.)!
o Elderly&have&slower&drug&eliminations&and&diseases&affecting&drug&
metabolism&and&excretions&leading&to&possible&build&up&of&toxins&&!
Dose&(dose]response&curves):!
o Graded!
o Quantal&"&sensitivity&of&the&population,&log]normal&distribution!
! ED50&and&LD50!

& 195&
Sollas&Notes&2015&

Concentration&!
Exposure&time!
Combinations&(additive,&potentiating&or&antagonistic)!
!
Toxicokinetics:!Factors(influencing(the(effects(of(poisons(
Absorption&"&depends&on&solubility!
Distribution&"&depends&on&time&and&tissue&specificity!
o Volume&of&distribution&(Vd)!
Elimination!
o Biotransformation&(inducers&or&inhibitors)!
o Excretion&(kidney,&liver,&bile,&skin,&lungs)&!
! Can&be&modified&"&change&in&urine&pH,&increase&diuresis&etc!
o Clearance&(zero&or&first&order&kinetics)!
Doses:!
o Large&doses&can&saturate&elimination&mechanisms,&plasma&protein&
binding&sites&(increasing&free&fractions&of&drugs)!
o Decrease&first&pass&effects&(increasing&bioavailability)!
o Can&damage&eliminating&organs&&&circulation!
o Result&in&decreased&clearance,&increased&half]life&and&#&toxicity!
&
Management!of!the!poisoned!patient:!
Management&of&a&poisoned&patient&consists&of:&
o Maintenance&of&vital&functions&(ABCD)&
o Identification&of&the&toxic&substance&
o Decontamination&procedures&
o Enhancement&of&elimination&
o Administration&of&specific&antidote&
&
Maintenance&of&vital&functions:&
Most&important&aspect&of&the&treatment&and&is&remembered&by&ABCD&
o A&&Airway&must&be&open&and&protected&
o B&&Breathing&must&be&ensured&with&effective&ventilation&
o C&&Circulation&should&be&evaluated&and&supported&
! Assessment&of&heart&functions&and&blood&pressure&
o D&&Dextrose&(50%&IV&solution)&should&be&given&&
! To&prevent&brain&damage&due&to&hypoglycemia&
o D&&Decontamination&to&remove&the&toxin&ASAP&
Identification&of&the&poison:&
Many&toxins&cause&characteristic&syndromes&that&can&be&helpful&to&identify&
o See&tables&at&the&end&of&this&topic&and&some&agents&talked&about&
earlier&in&this&topic&&
When&the&agent&cannot&be&identified&easily&the&doctor&much&search&via:&
o Intense&physical&examination&and&history&taking&
o Laboratory&methods&can&be&helpful&
o Examination&of&blood&and&urine&&
o ECG&or&radiological&findings&
Osmolar&gap&

& 196&
Sollas&Notes&2015&

o Difference&btw.&measured&serum&osmolarity&(measured&by&the&
freezing&point&depression&method)&and&the&osmolarity&predicted&
by&measured&serum&cc.&of&sodium&glucose&and&BUN&
! This&should&normally&be&zero&
o Significant&gap&is&produced&by&high&serum&cc.&of&intoxicants&of&low&
molecular&weight&such&as&ethanol,&methanol&&&ethylene&glycol&
Anion&gap!&
o !"#$"!!"#! = ! (!"! + ! ! ! ) ! ! (!"#! ! + ! !" ! )&
o Normally&12]16&mEq/L&
o Significant&increase&can&be&due&to:&
! Diabetic&ketoacidosis,&renal&failure,&drug]induced&metabolic&
acidosis&caused&by&drugs&such&as:& &
Cyanide,&ethanol,&ethylene&glycol,&ibuprofen,&
isoniazid,&iron,&methanol,&phenelzine,&salicylates,&
valproic&acid&and&verapamil&
Serum&potassium&
o Potassium&levels&have&high&impact&on&myocardial&cells&
o Hyperkalemia&can&be&caused&by:&
! ]blockers,&digitalis&(overdose),&fluoride,&lithium&&&K]
sparing&diuretics&
o Hypokalemia&can&be&caused&by:&Barium,&]agonists,&
methylxanthines,&most&diuretics&and&toluene&
Decontamination:&
The&removal&of&any&unabsorbed&poison&from&the&skin&or&GI&tract&
o Clothing&should&be&removed&and&patient&should&be&washed&
! Medical&professionals&should&protect&themselves&&
o For&most&cases&of&ingested&toxins&activated&charcoal&is&used&
! Given&orally&or&by&a&stomach&tube&
! Very&effective&in&adsorbing&any&remaining&toxin&in&gut&
! Good&for:&
Amitriptyline,&barbituates,&carbamazepine,&digitalis,&
phencyclidine,&propoxyphene,&theophylline,&TCAs&
and&valproic&acid&
! Doesnt&work&or&works&poorly&on:&
Iron,&lithium,&potassium&(NOT)&
Alcohol,&cyanide&(POOR)&
o Gastric&lavage&(less&commonly&used)&
o Induced&vomiting&with&ipecac&syrup&(old&method)&
o Whole&bowel&irritation&with&polyethylene]glycol&electrolytes&
o Decrease&absorption&and&speed&removal&via&agents&such&as&sorbitol&
&
Enhancement&of&elimination:&
Possible&for&some&toxins&
Manipulate&urine&pH&to&accelerate&renal&excretion&of&weak&acids&and&bases&&
o Alkaline&diuresis&is&effective&in&toxicity&caused&by&fluoride,&
isoniazid,&fluoroquinolones,&phenobarbital&and&salicylates&
o Acidic&diuresis&is&effective&in&toxicity&caused&by&amphetamines,&
nicotine,&phencyclidine&

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 Sollas&Notes&2015&

! Be&careful&to&prevent&acidosis&and&renal&failure&in&
rhabdomyolysis&
Hemodialysis&allows&removal&of&many&toxic&compounds&and&is&used&for:&
o Ethylene&glycol,&lithium,&metformin,&procainamide,&salicylates,&
valproic&acid&and&to&correct&fluid&and&electrolyte&imbalances&
Antidotes:&
Exist&for&several&important&poisons&
Sometimes&needs&to&be&given&repeatedly&since&their&duration&of&action&is&
commonly&much&shorter&than&that&of&the&intoxicants&
&
Important&antidotes:&
!
Antidote! Poison(s)!
&
Acetylcysteine& Acetaminophen&(best&w.in.&8]10&hrs)&
Atropine& Cholinesterase&inhibitors&
Bicarbonate,&sodium& Quinidine,&TCAs&
Calcium& Fluoride,&Calcium&channel&blockers&
Deferoxamine& Iron&salts&
Digoxin&antibodies& Digoxin&and&related&glycosides&
Esmolol& Caffeine,&theophylline,&sympathomimetics&
Ethanol& Methanol,&ethylene&glycol&
Flumazenil& Benzodiazepines,&zolpidem&
Fomepizole& Methanol,&ethylene&glycol&
Glucagon& ]blockers&
Glucose& Hypoglycemic&drugs&
Hydroxocobalamin& Cyanide&
Naloxone& Opioids&
Oxygen& Carbon&monoxide&
Physostigmine& Muscarinic&receptor&blockers&
Pralidoxime& Organophosphate&cholinesterase&inhibitors&
&
&
&
&

&
&
&
&

&
&
&
(

& 198&
Sollas&Notes&2015&

26.2&Diuretics&
&
Diuretics(elicit(increased(production(of(urine.(In(the(strict(sense,(the(term(is(applied(
to(drugs(with(a(direct(renal(action.(The(predominant(action(of(such(agents(is(to(
augment(urine(excretion(by(inhibiting(the(reabsorption(of(NaCl(and(water.(The(
effects(of(the(agents(are(predictable(from(knowledge(of(the(function(of(the(segment(
of(the(nephron(in(which(they(act.(
Indications(for(administration(of(diuretics:(
Edema(
o Mobilization(of(edema(fluid(from(interstitial(space(to(the(
intravascular(space(then(to(be(excreted(by(the(kidneys(
Hypertension(
o Important(in(the(treatment(of(HTN(since(they(lower(blood(pressure(
by(decreasing(peripheral(resistance(and(lower(blood(volume(
o Some(diuretics(work(independently(of(their(diuretic(effects(to(
influence(lowering(of(hyptertension((thiazides(and(loops)(
Congestive(heart(failure(
o Lower(peripheral(resistance(and(improve(EF(of(the(heart(by(reducing(
the(afterload(L(increasing(CO(and(exercise(tolerance(
Renal(failure(prophylaxis(
o In(anuria(that(can(occur(due(to(shock((secondary(to(hemorrhage)(
o Used(to(maintain(urinary(flow(
Make(urine(more(alkaline(
o Efficient(in(the(treatment(of(aspirin(overdose(or(poisoning(
&
Mode&of&action&and&classification&is&demonstrated&on&the&following&picture:&

& 199&
Sollas&Notes&2015&

Potassium/sparing!diuretics:!
Agents&that&act&in&the&distal&part&of&the&distal&tubule&&&the&proximal&part&of&
the&collecting&ducts&where&Na+&is&reabsorbed&in&exchange&for&K+&or&H+&
Diuretic&effects&are&relatively&mild&
No&increase&in&K+&secretion&
o Rather&there&is&a&risk&of&hyperkalemia&
Suitable&for&oral&administration&
Triamterene,and,amiloride:&
o Undergo&glomerular&filtration&and&secretion&in&the&proximal&tubule&
o Act&on&the&luminal&membrane&&
! Inhibit&entry&of&Na+&
! Hence&inhibit&the&exchange&for&K+&and&H+&&
That&will&not&be&lost&from&the&body&via&urine&
o Mostly&used&in&combo&with&thiazides&
! &Their&opposing&effects&on&K+&excretion&cancel&each&other&
! Their&effects&on&secretion&of&NaCl&complement&each&other&
Spironolactone,&,eplerenone,(aldosterone,antagonists):&
o Steroid&derivatives&that&are&pharmacologic&antagonists&of&
aldosterone&in&the&collecting&tubules&
! Aldosterone&normally&promotes&reabsorption&of&Na+&
(followed&by&water&and&Cl])&in&exchange&for&K+&
o Full&diuretic&effects&of&aldosterone&antagonists&is&achieved&few&
days&after&full&treatment&potentials&
o Commonly&used&conditions&of&increased&aldosterone&secretion,&
such&as&in&liver&cirrhosis&with&ascites&and&in&heart&failure&
o Adverse&effects:&
! The&drug&spironolactone&interferes&with&gonadal&hormones&
Development&of&gynecomastia&can&occur&&
o Eplerenone&bypasses&this&effect&
! Hyperkalemia&
Should&never&be&given&with&potassium&supplements&
! Extra&caution&when&these&drugs&are&used&with&ACE&
inhibitors&and&ARBs&
&
Carbonic!anhydrase!inhibitors!(acetazolamide):!
Sulfonamide&derivatives&that&block&CA&in&the&brush&border&and&cytoplasm&
of&the&proximal&tubule&(PTC)&of&the&kidneys&
o And&also&in&cells&of&the&choroid&plexus&that&secretes&CSF&and&the&
ciliary&epithelium&cells&secreting&the&aqueous&humor&of&the&eye&
! CSF&acidosis&that&results&in&hyperventilation&that&can&
protect&against&high&altitude&sickness&
! Decreases&intraocular&pressure&and&is&hence&good&for&the&
treatment&of&glaucoma&
Causes&bicarbonate&diuresis&(by&excreating&NaHCO3)&&
o Resulting&in&depletion&of&bicarbonate&and&metabolic&acidosis&
o K+&wasting&
! As&excess&sodium&is&reabsorbed&and&potassium&secreted&
Self]limiting&diuresis&
o Due&to&bicarbonate&depletion&

& 200&
Sollas&Notes&2015&

o Effects&on&the&intraocular&pressure&and&the&CSF&acidosis&are&not&
self]limiting&like&in&the&case&of&the&PTC&of&the&kidneys&
Uses:&
o Parenterally&used&in&treatment&of&severe&acute&glaucoma&
! Dorzolamide,&,brinzolamide&
o Orally:&Acute&mountain&sickness&prevention&&
o Orally:&Diuretic&but&ONLY&if&edema&is&accompanied&with&significant&
metabolic&alkalosis&
Adverse&effects:&
o Drowsiness&and&paresthesia&are&common&after&oral&treatment&
o Renal&stones&due&to&alkalization&of&the&urine&
! Calcium&salts&
o Hypokalemia&
o Hyperammonemia&in&patients&with&hepatic&diseases&
! Hepatic&encephalitis&
&
Thiazide!
Thiazides(are(a(class(of(diuretics(that(is(often(used(to(treat(hypertension(and(edema(
(caused(by(heart,(liver(or(kidney(failures).(They(have(proven(to(be(very(effective(in(lowering(
the(mortality(rate(of(hypertensive(related(problems,(such(as;(stoke,(myocardial(infarction(
and(heart(failure(plus(they(are(cheap(and(can(be(administered(on(a(daily(basis.(They(are(
active(by(the(oral(route(and(have(a(duration(of(action(of(6L14(hours((longer(than(most(loop(
diuretics)(
&
Structure:&
The&prototypical&agents&are&all&sulfonamide&derivatives&that&have&a&
thiazide&ring&in&their&structure:&
o Hydrochlorothiazide,!Bendroflumethiazide,!Xipamide!etc.!
Thiazide]like&drugs&are&also&sulfonamide&derivatives&but&they&lack&the&
characteristic&thiazide&ring&in&their&structure&&NB!(This(does(NOT(
influence(their(effects:(
o Indapamide,!Clopamide,!Chlorthalidone!etc.&
! In&addition&being&diuretics&"&direct&vasodilating&effects&
All&thiazide&and&thiazide]like&drugs&are&actively&secreted&into&the&proximal&
tubule&but&their&action&is&in&the&distal&convoluted&tubules&(DCT)&
&
Mechanism&of&action:&
Inhibition&of&the&NaCl&transport&in&the&early&segments&of&the&distal&
convoluted&tubules&(DCT)&
o Producing&moderate&but&sustained&Na+&and&Cl]&diuresis&
o Inhibition&of&the&Thiazide&sensitive&Na+Cl]&symporter&
This&results&in&reduced&intracellular&sodium&levels&within&the&luminal&cells&
of&the&DCT&which&further&promotes&sodium]calcium&exchange&at&their&
basolateral&membrane&via&the&Na+Ca2+&antiporter&,&causing:&
o Increased&reabsorption&of&calcium&from&the&urine&and&a&decrease&in&
urine&calcium&levels&&this&is&an&opposite&effect&of&loop&diuretics&
o Increase&in&calcium&in&the&interstitium&and&lower&intracellular&Ca2+&
that&further&induces&reabsorption&from&the&lumen&

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Sollas&Notes&2015&

Thiazides&might&reduce&the&excretion&of&water,&causing&dilutional&
hyponatremia&&this&is&since&they&act&on&the&DCT&
&
Actions&in&various&organs:&
Renal&effects:&
o Inhibition&of&Na+&reabsorption&in&DCT&"&decreased&Na+&retention&
! Less&pronounced&diuretic&effects&than&loop&diuretics&
o Increased&Ca2+&reabsorption&from&the&lumen&
Extrarenal&effects:&
o Decreased&preload&of&the&heart&"&decreased&afterload&
o Long&term&effects&(2]3&weeks)&"&Pulm.vascul.resistance&decreases&
&
Indications&for&use&of&thiazides&&&thiazide]like&drugs:&
Arterial&hypertension&&Major&application&for&the&use&of&these&drugs&
Milder&forms&of&chronic&heart&failure&
Recurrent&kidney&stones&that&arise&from&idiopathic&hypercalciuria&
Nephrotic&syndrome&
Nephrogenic&diabetes&insipidus&(when&kidneys&are&unresponsive&to&ADH)&
Corticosteroid&&&estrogen&therapy&patients&
Might&be&useful&in&osteoporosis&
Adverse&effects&for&the&use&of&thiazides&and&thiazide]like&drugs:&
Hypokalemia&&&metabolic&alkalosis&
o Since&the&cortical&collecting&tubules&compensate&for&the&increased&
Na2+&load&by&wasting&K+&&&&H+&via&excretion&
Impaired&glucose&tolerance&
o Due&to&hypokalemic&inhibition&of&insulin&secretion&(?)&
Dyslipidemia&
o Increases&total&cholesterol,&LDL&and&potentially&TAGs&
Hyperuricemia&
o Blocking&effects&(prevented/corrected&with&allopurinol)&
Hypercalcemia,&hyponatremia&&&hypovolemia&
Allergic&reactions&to&the&sulfonamide&structure&
o Skin&rashes&and&rarely&hemolytic&anemia&
&
Its(recommended(to(use(Thiazides(in(low(doses.(While(this(does(not(seem(to(affect(
the(therapeutic(response(of(the(drug(it(also(lowers(the(risk(of(complications.(
Recommended(dose(to(be(used(in(hypertension(is(6,25/12,5((25mg/day.(
&
Dose&response&curve&of&thiazides&in&relation&to&loop&diuretics:&
&
On&this&D]R&graph&it&is&clearly&shown&that&loop&diuretics&have&a&much&
higher&diuretic&effects&than&the&thiazides.&Even&though&this&is&true&for&
diuresis,&the&antihypertensive&properties&of&thiazide&make&sure&that&its&
still&one&of&the&primary&drugs&in&the&treatment&of&hypertension.&

& 202&
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&
&
&
&
&
&
&
&
(
(
(
&
&
&
&
&
Osmotic&diuretics:&
Mannitol&&the&prototypical&osmotic&diuretic&&given&intravenously!!&
o 10]20%&solution&
o Freely&filtered&in&the&glomerulus&&&poorly&reabsorbed&in&tubules&
! This&results&in&that&it&remains&in&the&lumen&and&holds&
water&there&by&osmotic&effects&
Mainly&in&proximal&convoluted&tubule&(PCT)&
Also&in&descending&loop&of&Henle&and&collecting&tub.&
These&are&all&locations&where&the&nephron&is&
penetrable&for&water&
! Minor&Na+&excretion&
o Used&mainly&in&situations&where&its&important&to&loose&water&
volume&without&loosing&Na+&
! Prevention&of&anuria&in&ARF&due&to&load&of&pigments&
Hemolysis&or&rhabadomyolysis&
! Infections&&&hemorrhage&
! Used&to&decrease&pathologically&elevated&intracranial&or&
intraocular&pressures&(since&they&increase&plasma&
osmolarity&that&results&in&extraction&of&water&from&these&
compartments&and&increase&in&amount&of&urine)&
Adverse&effects:&
o Pronounced&water&extraction&from&IC&compartments&and&
expansion&of&intravascular&and&interstitial&fluid&volume&
! This&can&result&in:&
Acute&pulmonary&edema&
Heart&failure&
Headaches,&nausea&and&vomiting&&COMMON&
Dehydration&and&hypernatremia&&Overdose!!&
&
Loop&diuretics&(furosemide,,bumetanide,&,torsemide):&
Sulfonamide&derivatives&(except&ethacrynic,acid&that&is&phenoxyacetate)&
Inhibit&cotransport&of&Na+/K+/Cl]&&
Relatively&short&acting&&

& 203&
Sollas&Notes&2015&

o Diuresis&~&4hrs&after&intake&of&dose&
Produces&massive&NaCl&diuresis&if&GFR&is&normal&
o Causing&a&significant&reduction&in&blood&volume&
o Rapid&removal&of&edema&fluid&if&tissue&perfusion&is&good&
o K]wasting&resulting&in&hypokalemia&
o Excretion&of&protons&resulting&in&metabolic&alkalosis&
Reduce&pulmonary&vascular&pressures&via&unknown&mechanism&
Reduced&action&occurs&when&the&loops&are&used&with&NSAIDs&since&the&
inhibition&of&prostaglandins&will&result&in&improved&glomerular&filtration&
o Decreased&efficacy&of&the&loops&
Uses:&
o Treatment&of&edematous&states&
! Heart&failure,&ascites,&acute&pulmonary&edema&
o Treatment&of&hypertension&
! When&thiazides&dont&work&properly&
o Treatment&of&severe&hypercalcemia&
! Supplemented&by&Na+&and&K+&to&accommodate&for&loss&
Adverse&effects:&
o Hypokalemic&metabolic&acidosis&
o Hypovolemia&and&cardiovascular&problems&
o Ototoxic&
o Sulfonamide&allergies&
! Then&use&ethacrynic,acid&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&

& 204&
Sollas&Notes&2015&

26.3&Cholinolytics&and&cholinesterase&reactivators&
&
Substances(that(act(antagonistically(at(the(muscarinic(cholinergic(receptors(are(called(
parasympatholytics((prototype(being(the(natural(occurring(alkaloid(atropine).(
Therapeutic(use(of(these(agents(is(complicated(by(their(low(organ(selectivity,(but(the(
possibility(for(a(targeted(action(include:(
Local(application(
Administration(of(drugs(that(possess(a(receptor(subtype(selectivity(
Selection(of(drugs(with(either(good(or(poor(membrane(permeability((
&
Parasympatholytics!are!used!in!the!following!cases:!
Inhibition&of&exocrine&glands&
Bronchial&secretion&&
o Atropine&blocks/prevents&possible&hypersecretion&of&the&bronchial&
mucous&glands&in&the&case&of&anesthesia&and&intubation&
o When&the&patient&cannot&cough&up&on&his&own&
Gastric&secretion&
o Pirenzepine&is&a&drug&that&has&been&used&in&the&treatment&of&gastric&&&
duodenal&ulcers&&inhibits&the&M1&mainly&and&also&M3&that&both&are&
involved&in&secretions&of&HCl&from&the&parietal&cells&
Relaxation&of&smooth&muscles&
Bronchodilation&
o Ipratropium&is&used&in&dx&that&have&increased&airway&resistance&such&as&
in&chronic&obstructive&bronchitis&&&bronchial&asthma&
! Quaternary&compound&that&is&used&as&a&inhalation&drug&and&due&
to&that&it&has&only&local&effects&and&low&systemic&absorption&
Spasmolysis&
o N]butylscopolamine&is&used&for&biliary&and&renocolic&spasms&
! Quaternary&nitrogen&that&doesnt&pass&the&BBB&&
! Spasmolytic&action&is&especially&marked&because&of&its&additional&
ganglionic&blocking&and&direct&muscle&relaxant&actions&
Decreased&pupillary&sphincter&tone&
o Homatropine&or&&tropicamide&
o Drugs&that&results&in&pupillary&dilation&(mydrasis)&&
o Can&be&used&as&a&diagnostic&drugs&to&take&a&closer&look&at&the&optic&fundus&
&so&these&drugs&are&used&only&for&a&short&time&
o Pure&atropine&would&have&a&longer&half]life&(few&days)&which&is&very&
harmful&in&the&long&run&for&the&function&of&the&eye&
Cardioacceleration&
Ipratropium&is&used&in&bradycardia&and&AV]blocks&to&raise&HR&and&to&facilitate&
cardiac&impulse&conduction&
o Quaternary&compound&that&doesnt&penetrate&BBB&so&effects&on&the&brain&
are&not&a&complication&of&the&drug&
o High&oral&doses&are&required&due&to&poor&intestinal&absorption&rate&of&the&
drug&&
&
Atropine!itself!is!used!to!prevent!cardiac!arrest!
&
CNS&dampening&effects&
Scopolamine&
o Prophylaxis&in&case&of&motion&sickness&(kinetosis)&
o Penetrates&BBB&faster&than&atropine&

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Sollas&Notes&2015&

o Also&used&in&the&case&of&achieving&sedation&in&case&of&psychotic&
excitement&cases&&also&used&as&a&anesthetic&in&some&cases&
Parkinson&treatment&
o Parasympatholytics&are&used&in&treatment&of&Parkinson&to&restore&the&
dopamine]cholinergic&balance&in&the&corpus&striatum&
! Benzatropine&penetrates&BBB&easily&
! Less&effects&on&the&peripheral&tissues&than&atropine&
Contraindications!for!the!use!of!parasympatholytics:!
Glaucoma&
o Normally&the&drainage&of&the&aqueous&humor&is&blocked&when&the&
pupillary&sphincter&muscles&are&relaxing&&hence&its&dangerous&for&these&
patients&to&be&administered&atropine&due&to&its&relaxing&effects&on&the&
sphincter&
o This&increased&aqueous&humor&within&the&intraocular&space&will&
eventually&increase&the&intraocular&pressure&which&has&a&very&harmful&
effects&specially&in&the&case&of&glaucoma&
Prostatic&hypertrophy&with&impaired&micturition&
o Loss&of&parasympathetic&control&of&the&detrusor&muscle&of&the&bladder&
causes&difficulties&while&voiding&
Atropine!poisoning:!
Charachterized&by:&
o Tachycardia&"&Due&to&its&cardiac&effects&
o Dry&mouth&"&Due&to&inhibition&of&salivary&secretions&&
o Hyperthermia&"&Due&to&the&inhibition&of&sweat&gland&secretions&
o Constipation&"&Due&to&decreased&GI&motility&
o Motor&restlessness,&manic&behaviors,&psychic&disturbances,&
disorientations&and&hallucinations&
! Elderly&people&are&more&sensitive&to&these&central&effects&
These&effects&can&be&reversed&in&most&cases&with&out&any&damage&by&the&use&of&
the&direct&parasympathomimetic&physostigmine&
Overdoes&of&any&muscarinic&antagonist&will&result&in&the&3&Cs:&
Cardiotoxicity&
Convulsions&
Coma&
&
Cholinesterase!regenerators:!
! Pralidoxime!
o Prototype&cholinesterase&regenerator!
o Chemical&antagonist&that&contains&an&oxime&group!
! That&has&extremely&high&activity&for&the&phosphorus&atom&in&
organophosphate&insecticides!
! They&bind&to&the&receptor&for&the&phosphorus&with&greater&
affinity&than&the&phosphorus&and&by&that&is&able&to&displace&it&
from&the&binding&site&&reversing&the&binding!
This&is&possible&if&the&poisoning&occurred&not&too&long&
time&ago&(before&the&cell&starts&to&age)!
o Used&to&combat&poisoning&by&organophosphates&or&acetylcholinesterased&
inhibitors&(nerve&gases)&in&conjugation&with&atropine&and&diazepam!
! Reverses&the&paralysis&of&the&respiratory&muscles&but&due&to&its&
poor&BBB&penetration,&it&has&little&effects&of&centrally]mediated&
respiratory&depression!
Thats&why&atropine&is&co]administered!
o Excellent&BBB&penetration!

& 206&
Sollas&Notes&2015&

Topic&27&
27.1&Pharmacology&of&nicotine&
&
Nicotine(is(a(potent(parasympathomimetic(alkaloid(member(of(the(nightshade(
family(of(plants.(Its(made(in(the(roots(of(and(accumulates(in(the(leaves(of(the(
nightshade,(and(constitutes(around(0,6L3,0%(of(the(dry(weight(of(tobacco.(Its(
mainly(used(in(the(treatment(of(smoking(cessation(but(its(also(used(as(an(
insecticide.((
(
Nicotinic!mechanism:!
! Nicotinic&acetylcholine&Ach&receptor&is&located&on&a&channel&protein&that&is&
selective&for&sodium&and&potassium!
! When&the&receptor&is&activated,&the&channel&opens&and&depolarization&of&
the&cell&occurs&as&a&direct&result&of&the&influx&of&sodium,&causing&an&
excitatory&postsynaptic&potential&(EPSP)!
o If&large&enough&the&EPSP&evokes&a&propagated&AP&in&the&
surrounding&membrane!
! The&nicotinic&receptors&on&sympathetic&and&parasympathetic&ganglion&
cells&(NN)&differ&slightly&from&those&on&neuromuscular&end&plates&(NM)!
!
Pharmacokinetics:!
! As&it&enters&the&body,&its&distributed&quickly&through&the&blood,&crosses&
the&BBB&and&enters&the&brain&around&10]20&seconds&after&inhalation!
! Elimination&half]life&is&around&2hrs!
! Metabolized&in&the&liver&by&cytochrome&P45o&enzymes&(mainly&CYP2A6&
and&CYP2B6)!
o Major&metabolite&is&cotinine!
! Used&as&a&biomarker&for&the&exposure&of&tobacco&smoke!
! Can&be&used&to&estimate&level&of&usage&and&is&therefore&good&
to&estimate&nicotine&dependence&prior&to&nicotine&
supplementation&treatments!
o Glucuronidation&and&oxidative&metabolism&of&nicotine&and&cotinine&
are&both&inhibited&by&menthol&(additive&of&menthol&cigarettes)!
! Increases&the&half]life&of&nicotine&in&the&body!
!
Effects!in!the!central!nervous!system:!
! Nicotine&binds&to&nicotinic&acetylcholine&receptors&and&by&that&increases&
the&levels&of&several&neurotransmitters!
! Ganglionic&stimulation&of&parasympathetic&system&results&in&!
o Increased&production&of&gastric&juices!
o Enhanced&bowel&motility&(laxative&effects)!
o Decreased&heart&rate!
! That&is&actually&overwritten&by&the&sympathetic&effects!
! Ganglionic&stimulation&of&sympathetic&system&results&in&!
o Increased&heart&rate!
o Vasoconstriction&that&increases&peripheral&resistance!
o Increased&release&of&&epinephrine&from&the&adrenal&medulla!

& 207&
Sollas&Notes&2015&

! Nicotine&is&thought&to&increase&levels&of&dopamine&in&the&reward&circuits&
of&the&brain!
o Major&contributor&of&euphoria&and&relaxation!
o Causes&the&addiction&effects!
o This&nicotinic]induced&dopamine&release&occurs&via&the&
cholinergic]dopamine&reward&link&which&is&mediated&by&the&
neuropeptide&ghrelin&in&the&ventral&tegmentum!
! Nicotine&has&higher&affinity&for&AChR&in&the&CNS&than&in&the&skeletal&m.!
o Therefore&at&toxic&doses&it&can&induce&contractions&and&respiratory&
paralysis!
! Tobacco&smoke&also&contains&MAO&inhibitors&(Harman,and,norharman)!
o These&inhibitors&significantly&decrease&MAO&activity&in&smokers!
! Decreased&breakdown&of&dopamine,&NE&and&serotonin!
! This!is!probably!the!most!possible!reason!for!its!very!
addictive!properties!
!
Effects!in!the!adrenal!medulla!
! By&binding&to&NN&type&receptors&in&the&adrenal&medulla,&nicotine&increases&
release&of&epinephrine&(stimulating&hormone&and&neurotransmitter)!
o Binding&causes&cell&depolarization&and&Ca2+&influx&via&VG&channels!
! This&increase&of&Epi&increases&heart&rate,&blood&pressure&and&respiration&
as&well&as&increases&blood&glucose&levels&(glycogenolysis)&along&with&
increased&lipolysis!
o Sensation&of&hunger&is&therefore&suppressed!
Effects!on!baroreceptors:!
! Partial&depolarization&of&baroreceptors&enables&activation&of&the&reflex&to&
occur&at&a&relatively&smaller&rise&in&blood&pressure!
o Leads&to&decreased&sympathetic&vasoconstrictor&activity!
Effects!on!the!neurohypophysis:!
! Release&of&vasopressin&results&in&lowered&urinary&output!
Effects!on!the!carotid!body:!
! Sensitivity&to&arterial&pCO2&increases!
o Increased&afferent&input&changes&respiratory&rate&and&depth!
Other!effects:!
! Sensitivity&of&pressure,&pain&and&temperature&receptors&is&increased!
! Sensitization&of&chemoreceptors&in&area&postrema&leads&to&excitation&of&
the&medullary&emetic&center&(nausea,&vomiting)!
! At&low&concentrations&nicotine&is&able&to&change&the&excitability&of&motor&
endplate&at&the&NMJ!
o Can&be&seen&in&heavy&smokers&in&the&form&of&muscle&cramps&(calf&
muscle&cramps)&and&soreness!
!
Consequences!of!chronic!uses!of!nicotine:!
! Enhanced&risk&of&vascular&diseases&(e.g.&coronary&stenosis,&myocardial&
infarction,&central&and&peripheral&ischemic&disorders&such&as&stroke&and&
intermittent&claudication)!
! Endothelial&impairment&that&can&possibly&lead&to&atherosclerosis!
! Increases&plasma&glucose&levels&and&free&fatty&acids,&promotes&platelet&
aggregability,&lowers&fibrinolytic&activity&of&blood&&&enhances&coagulation!

& 208&
Sollas&Notes&2015&

! Nicotine&also&stimulates&angiogenesis&&&promotes&tumor&growth!
! It&has&significant&performance&enhancing&effects,&particularly&in&motor&
skills,&attention&and&memory!
! Reduction&in&the&risk&of&developing&ulcerative&colitis!
! Nicotine&itself&has&potential&to&prevent&and&treat&Alzheimers&!
o While&tobacco&itself&seems&to&increase&the&risk&of&Alzheimers!
! Chr.&low&doses&lead&to&desensitization&of&nicotine&receptors&(tolerance)!
o Results&in&antidepressant&effects!
o Nicotine&patches&can&be&used&to&treat&major&depression&in&non]
smokers!
! Nicotine&crosses&the&placental&barrier&and&likely&causes:!
o Hypoxia,&malnourishment&of&the&fetus,&direct&vasoconstrictive&
effects&on&the&placental&umbilical&vessels!
o Abnormal&brain&development&with&impaired&orientation&and&
autonomic&regulation&and&abnormalities&of&muscle&tone!
Clinical!uses:!
! Nicotine&can&be&found&in&many&over&the&counter&remedies:!
o Gum&(2&&&4&mg&for&few&weeks&every&1]2&hrs&then&reduce)!
o Patches&(11]14&mg&for&4]6&weeks&and&then&half&dose&for&2&weeks)!
o Lozange&(2]4&mg&for&few&weeks&similar&to&gum)!
! Nicotine&can&also&be&prescribed&as:!
o Nasal&spray&and&inhalers&!
! Drugs&used&for&smoking&cessation&that&dont&have&nicotine!
o Bupropion!
! Antidepressant&drug&that&increases&levels&of&dopamine&&&NE!
! Used&as&an&antidepressant&and&aid&in&smoking&cessation!
! Commonly&the&administration&is&started&1&week&before&
smoking&cessation&and&is&often&used&with&a&patch&initially!
! Contraindicated&in&seizures&or&in&case&of&serious&head&
trauma&(skull&fractures)!
! Adverse&effects:!
Sleep&disturbances&and&dry&mouth!
o Varenicleine!
! Partial&agonist&of&the&ACh]N(22)&subtype&nicotinic&recep.!
! Decreases&withdrawal&symptoms&reduces&the&feeling&of&
euphoria&that&occurs&during&smoking&!
! Typically&started&one&week&before&smoking&cessation!
! Adverse&effects:!
Nausea,&headache,&insomnia&&&vivid&dreams!
Rarely&it&has&been&shown&to&cause&serious&
psychiatric&symptoms&such&as&depression,&agitation&
and&suicidal&thoughts!
o Nortriptyline!
! Tricyclic&antidepressant&that&has&shown&to&help&in&smoking&
cessation!
! Acts&by&increasing&the&levels&of&the&brain&NE!
! Usually&used&as&a&last&resort!
! Side&effects&can&be&dry&mouth!
!

& 209&
Sollas&Notes&2015&

27.2&Biopharmaceuticals,&biological&therapy&(monoclonal&antibodies,&
interleukins&etc.)&
&
Biopharmaceuticals((biologics)(are(medicinal(products(manufactured(in(or(
extracted(from(biological(sources(or(semisynthesized(from(them.(Examples(include(
vaccines,(blood(or(blood(components,(allergenics,(somatic(cells,(gene(therapies,(
tissues(&(recombinant(therapeutic(proteins.(They(are(isolated(from(a(variety(of(
natural(sources((human,(animal(or(microorganisms.(
(
Biologics!that!are!extracted!from!bodies!of!animals!and!other!humans:!
Some&of&the&oldest&forms&of&biologics!
o Whole&blood&and&other&blood&components!
o Organs&and&tissue&transplants!
o Stem&cell&therapy!
o Antibodies&for&passive&immunization&(e.g.&to&treat&virus&infection)!
o Some&biologics&that&were&previously&extracted&from&animals&but&
are&now&produced&by&recombinant&DNA!
! Insulin&!
Biologics!produced!by!recombinant!DNA:!
Class&of&therapeutics&that&are&produced&by&means&of&biological&processes&
involving&recombinant&DNA&technology!
These&are&usually&one&of&three&types:!
o Substances&that&are&(nearly)&identical&to&the&bodys&own&key&
signaling&proteins!
! Erythropoietin!
! Growth&hormone!
! Biosynthetic&human&insulin&and&its&analogs!
o Monoclonal&antibodies&!
! Similar&to&the&antibodies&that&the&immune&system&uses&to&
fight&off&bacteria&and&viruses!
! Customly&designed!
Hybridoma&technology&or&other&methods!
! Made&specifically&to&counteract&or&block&any&given&
substance&in&the&body,&target&any&specific&cell&type!
o Receptor&constructs&(fusion&proteins)&based&on&a&naturally]
occurring&receptor&linked&to&the&immunoglobulin&frame!
! The&receptor&provides&the&construct&with&detailed&
specificity!
Pros!of!biologics:!
Profound&impact&on&many&medical&fields,&primarily&rheumatology&&&
oncology&but&also&cardio],&dermato],&gastroentero],&neurology&+&more&!
Cons!of!biologics:!
Very&expensive&treatments!
Typical&monoclonal&antibody&treatment&for&relatively&common&disease&
costs&around&&7,000]14,000&per&year!
Certain&risk&for&getting&other&diseases&specially&in&elderly!
Major!categories!of!biopharmaceuticals!include:!
Blood&factors&(FVII&and&FIX)!

& 210&
Sollas&Notes&2015&

Thrombolytic&agents&(tissue&plasminogen&activator)!
Hormones&(insulin,&glucagon,&growth&hormone,&gonadotrophins)!
Hematopoietic&growth&factors&(erythropoietin,&colony&stimulating&factors)!
Interferons&(,,)!
Interleukin]based&products&(IL]2)!
Monoclonal&antibodies&(multiple&different&types)!
Others&(tumor&necrosis&factor,&therapeutic&enzymes)!
!
Few!examples!of!biologics!made!with!recombinant!DNA!technology:!

&
Vaccines:!
Vaccines&are&biological&preparations&that&provide&active&acquired&
immunity&to&a&particular&disease!
Types&of&vaccines:!
o Inactivated!
! Previously&virulent&microorganism&that&has&been&destroyed&
with&chemicals,&heat,&radioactivity&or&antibiotics!
! Influenza,&cholera,&bulbonic&plaque,&polio,&HAV,&rabies!
o Live&attenuated!
! Cultivated&under&conditions&that&disable&their&virulent&
properties!
! Yellow&fever,&MMR&(measles,&mumps,&rubella)&BCG&(TB)!
o Toxoid!
! Made&from&inactivated&toxic&compounds!
! Tetanus,&dipheria&!
o Subunit&(Surface&proteins&+&more)!
! HBV&and&HPV!
o Conjugate&(Polysaccaride&capsular&vaccine)!
! Hemophilus&influenze&type&b!
o Experimental!

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Sollas&Notes&2015&

! Dendritic&cell&vaccines&to&use&in&treatment&of&brain&tumors!
! DNA&vaccines!
!
Vaccination!schedule!in!Europe!and!Hungary:!
BCG&(TB)&and&HBV&vaccine&are&given&at&birth!
DTaP&(dipheria,&tetanus,&pertussis)!
o 2,&3,&4mths&+&booster&at&18mths,&6yrs&and&11&yrs!
IPV&(polio&vaccine)!
o 2,&,3,&4mths&+&booster&at&18moths&&&6yrs!
Hib&(hemophilus&influenze&type&b)!
o 2,&3,&4mths&+&booster&at&18mths!
Pneumococcal&vaccine!
o 2,&4,&12mths!
MMR&(measles,&mumps,&rubella)!
o 15mths&&&11yrs!
HPV&vaccine&(girls&only&to&prevent&cervical&cancer)!
o 12,&13yrs!
!
Monoclonal!antibodies!(MAbs):!
Have&high&specificity&because&they&can&be&developed&for&interaction&with&a&
single&molecule&
Humanization&of&murine&monoclonal&antibodies&and&wholly&human&
monoclonal&Ab&(genetic&engineering&of&transgenic&mice&that&make&human&
antibodies)&
o Reduced&probability&of&formation&of&neutralizing&Ab&and&immune&
reactions&
Three&types&of&MAbs&are&used&as&immunosuppressive&agents:&
o MuromonabPCD3,
! Binds&to&CD3&antigen&on&thymocytes&and&mature&T]cells,
! Blocks&the&killing&action&of&CTLs&and&interferes&with&other&
T]cell&function,
! Used&to&manage&renal,&cardiac,&liver&transplant&rejection,
! Serious&anaphylaxis&can&occur&(mainly&in&first&few&doses),
! Neuropsychiatric&and&HSR&also&can&occur,
o Infliximab,
! Humanized&MAb&that&targets&TFN]&and&by&that&decreases&
formationof&IL&and&adhesion&molecules&involved&in&
leukocyte&activation,
! Used&in:,
Crohns&disease&to&reduce&remissions,
RA&as&a&combination&with&methotrexate&,
Effective&in&ulcerative&colitis,&ankylosing&spondylitis&
and&psoriatic&arthritis,
! Infusion&reactions&and&an&increased&rate&of&infection,
! Adalimumab,is&a&completely&human&IgG&MAb&that&binds&to&
TNF]&and&is&used&in&RA,
! Etanercept,is&an&immunoglobulin]based&agent&that&also&
binds&with&high&affinity&to&TNF]&,

& 212&
Sollas&Notes&2015&

Used&in&arthritis,&psoriasis&and&ankylosing&
spondylitis&,
! All&of&the&anti]TNF]&increases&the&risk&of&serious&infections&
and&lymphoma,
o Daclixumab,
! Highly&specific&MAb&that&binds&to&]subunit&of&the&IL]2&
receptor&and&prevents&its&activation&by&IL]2,
! Used&in&combo&to&prevent&renal&transplant&rejection,
! Basiliximab&is&a&chimeric&human]mouse&IgG&with&similar&
functions&as&daclixumab,
,
Immunomodulating!agents:!
Agents&that&can&possibly&used&in&treatment&of&immune&deficiency&diseases,&
chronic&infectious&diseases&and&cancers!
Aldesleukin:&
Is&an&recombinant&IL]2&that&is&indicated&for&adjuvant&treatment&of&renal&
cell&carcinoma&and&malignant&melanoma&
Investigational&drug&for&its&possible&efficacy&in&restoring&immune&function&
in&AIDS&and&other&immune&deficiency&disorders&
Interferons:&
Interferon]]2a&inhibits&cell&proliferation&&
o Used&in&hairy&cell&leukemia,&CML,&malignant&melanoma,&Kaposis&
sarcoma,&HBV&&&HCV&
Interferon]]1b&has&beneficial&effects&in&relapsing&MS&
Interferon]]1b&seems&to&increase&synthesis&of&TNF&
o Used&in&chronic&granulomatous&disease&treatment&&
&
!
!
!

!
&
&
&
&
&
&
&
&
&
&
&
&
&
(

& 213&
Sollas&Notes&2015&

27.3&NO&donors&and&inhibitors&
&
Nitric(oxide(is(an(autacoid((biological(factor(acting(like(a(local(hormone,(that(has(a(
brief(duration(and(acts(near(the(site(of(its(synthesis)(produced(from(arginine(in(the(
body.(Exogenous(NO(can(be(in(the(form(of(NO(donors((nitrates,(nitroprussides)(or(
NO(gas.(Endogenous(NO(donors(are(for(example(acetylcholine(and(histamine.(
Endogenous(NO(can(be(inhibited(by(hemoglobin.(
&
Functions&of&NO:&
Important&paracrine&vasodilator&(autocoid)&in&
o All&vascular&beds&(powerful)&
o Relaxant&in&most&other&smooth&muscles&(potent)&
May&play&a&role&in&cell&death&and&in&neurotransmission&
Physiological&role&in&erectile&tissue&function&
o Influx&of&blood&to&cause&erection&
Pathophysiological&contributor&to&hypotension&in&septic&shock&
Cell&adhesion&reduction&
o Decreased&platelet&aggregation&
o Decreased&neutrophil&adhesion&to&vascular&endothelium&
Facilitation&of&inflammation&directly&and&indirectly&via&stimulation&of&
prostaglandin&synthesis&by&COX]2&
&
Endogenous&NO:&
Synthesized&by&a&family&of&enzymes&collectively&called&nitric&oxide&
synthase&(NOS)&&NOS&is&activated&by&Ca2+&influx&or&by&cytokines&
o Arginine&is&converted&by&NOS&to&citrulline&and&NO&
Three&forms&of&NOS&are&known:&
o Isoform&1&(bNOS,&cNOS&or&nNOS)&
! Constitutive&form&found&in&epithelial&en&neuronal&cells&
o Isoform&2&(iNOS&or&mNOS)&
! Inducible&form&found&in&macrophages&and&smooth&m.&cells&
o Isoform&3&(eNOS)&
! Constitutive&form&found&in&endothelial&cells&
NOS&can&be&inhibited&by&arginine&analogs&(L]NMMA)&
In&some&circumstances&(e.g.&ischemia)&NO&can&be&formed&from&nitrate&ion&
NO&is&not&stored&in&cells&&&since&its&a&gas&at&37C&it&diffuses&very&rapidly&
from&site&of&synthesis&to&surrounding&tissues&
Drugs&that&induce&endogenous&NO&release&include:&
o Muscarinic&agonists,&histamines&and&certain&vasodilators&(e.g.&
bradykinin,&hydralazine)&
Inhibition&of&NO&can&be&done&by&hemoglobin&and&heme&
&
Exogenous&NO&donors:&
NO&is&released&from&several&important&drugs&such&as:&
o Nitroprusside&
! Spontaneous&release&in&blood&in&the&presence&of&oxygen&
o Nitrates&&&nitrites&

& 214&
Sollas&Notes&2015&

! Intracellular&release&that&requires&presence&of&ALD2&(a&
mitochondrial&enzyme&and&a&thiol&(e.g.&cysteine)&
Glutathione&&
Tolerance&may&develop&to&nitrates&&&nitrites&if&endogenous&thiol&
compounds&are&depleted&
&
Nitrates:!
!
Nitroglycerine&is&the&most&important&of&the&therapeutic&nitrates&
Range(of(duration((10L20(minutes((
Sublingual(administration(for(relief(of(acute(attacks(
Range(of(duration((8L10(hours(
Transdermal(for(prophylaxis(
Nitroglycerin&(glyceryl&trinitrate)&is&rapidly&denitrated&in&the&liver&and&smooth&m.&
Retaining&a&significant&vasodilating&effects&
High&enzyme&activity&in&the&liver&makes&the&first&pass&effect&90%&(oral)&
o Sublingual&bypasses&this&system&and&therefore&its&very&effective&
Other&nitrates:&
Isosorbide&dinitrate&&other&commonly&used&nitrate&
o Sublingual&and&oral&
o Rapidly&denitrated&in&liver&and&smooth&muscle&&
Isosorbide&mononitrate&&also&active&orally&
Amyl&nitrate&&volatile&and&rapidly&acting&vasodilator&&inhaled&
o Rarely&prescribed&
Mechanism&of&action:&
Nitrates&release&nitric&oxide&(NO)&within&the&smooth&muscle&
o Probably&due&to&mitochondrial&enzyme&aldehyde&DH]2&(ALD2)&
NO&stimulates&guanylyl&cyclase&(GC)&and&causes&the&release&of&cGMP&
resulting&in&smooth&muscle&relaxation&by&dephosphorylating&the&myosin&
light]chain&phosphate&
o Identical&mechanism&in&nitroprusside&
Actions:&
Cardiovascular:&
o Smooth&muscle&relaxation&leading&to&significant&venodilation&
resulting&in&reduced&cardiac&size&and&cardiac&output&through&
reduced&preload&
! Venodilation&also&leads&to&reduced&diastolic&heart&size&and&
tension&on&the&myocardial&fibers&
o Relaxation&in&the&arterial&smooth&muscle&increases&flow&through&
partially&occluded&coronary&arteries&
o Reduced&afterload&&due&to&relaxation&of&the&resistant&arteries&
results&in&increased&ejection&and&further&decrease&in&cardiac&size&
o Compensatory&mechanism&that&occurs&sometimes&when&the&
nitrates&have&a&hypotensive&effects&results&in&reflex&tachycardia&
and&increased&force&of&contraction&&baroreceptor&mechanism&
Other&organs:&
o Nitrates&relax&smooth&muscles&of&the&bronchi,&GI]tract,&GU]tract&&
! Clinically&insignificant&since&the&effects&are&small&

& 215&
Sollas&Notes&2015&

o Intravenous&nitroglycerine&are&sometimes&used&unstable&angina&to&
reduce&the&aggregation&of&the&platelets&
Toxicity:&
Responses&evoked&by&vasodilation&
o Reflex&tachycardia&(baroreceptor),&orthostatic&hypotension&
(venodilator)&and&throbbing&headache&from&meningeal&arterial&
artery&vasodilation&(increased&intracranial&pressure)&
Erectile&dysfunction&(when&combo&with&sildenafil&and&similar&drugs)&
Methemoglobinemia&&high&serum&cc.&
o Makes&them&potential&drugs&to&use&as&antidotes&in&cyanide&
poisonings&
&
Clinical&investigations&of&NO&usage:&
Treatment&of&preeclampsia,&pulmonary&hypertension,&and&acute&
respiratory&distress&syndrome&is&currently&under&investigation&
Early&results&from&pulmonary&disease&studies&are&promising&
o INOmax&(NO&gas)&has&been&approved&for&use&in&neonates&with&
hypoxic&&respiratory&failure&and&in&adults&with&pulmonary&HTN&
Preclinical&studies&suggest&that&chronic&use&of&NO&donor&drugs&or&dietary&
supplementation&with&arginine&may&assist&in&slowing&down&
atherosclerosis&(specially&in&grafted&organs)&
o However&acute&rejection&to&grafts&may&be&partially&due&to&
upregulation&of&NOS&enzymes&
! Hence&inhibition&of&NOS&might&be&a&good&feature&to&prolong&
graft&survival&time&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&
&

& 216&
Sollas&Notes&2015&

Topic&28&
&
28.1&Centrally&acting&muscle&relaxant&
This&topic&does&correlate&with&topic&8.1&
In&this&topic&the&focus&will&be&on&the&spasmolytic&drugs,&which&reduce&abnormally&
elevated&tone&caused&by&neurologic&or&muscle&endplate.&
&

spasmolytics&

Acute&use&
chronic&use& (cyclobenzap
rine)&

CNS&action&
(baclofen,& Muscle&action&
diazepam,& (dantrolene)&
tizandine)&&
Spasmolytics!drugs!!
Certain&chronic&diseases&of&the&CNS&are&associated&with&abnormally&high&
reflex&activity&in&the&neuronal&pathways&that&control&skeletal&muscle!
o e.g&Cerebral&palsy,&multiple&sclerosis&and&stroke!
o it&will&result&in&painful&spasm!
Bladder&control&and&anal&sphincter&control&are&also&affected&in&most&cases&
and&may&require&autonomic&drugs&for&management.!
Acute&injury&or&inflammation&of&muscle&leads&to&spasm&and&pain!
Goal&of&spasmolytic&therapy&in&both&chronic&and&acute&condition&is&
reduction&of&excessive&skeletal&muscle&tone&without&reduction&of&strength.!
Reduced&spasm&result&in&reduction&pain&and&improved&mobility!
Drugs!of!chronic!spasm!
Classification&
Spasmolytic&drugs&do&not&resemble&ACh&in&structure&or&effect&
They&act&in&the&CNS&and&skeletal&muscle&cell.&
Chronic&condition&treatment&drugs&include&
o Diazepam,&a&benzodiazepine&
o Baclofen,&GABA&agonist&
o Tizanidine,&a&congener&of&clonidine&(congener&=&same&genus)&
o Dantrolene,&acting&on&SR&of&skeletal&muscle&
! These&agenst&are&administered&by&oral&route&
Botulinum&toxin&(BT)&injected&into&skeletal&muscles&can&reduce&pain&
caused&by&spasms.&
o BT&also&used&for&ophthalmic&purposes&and&in&Cerebral&palsy&
Gabapentin&and&pregabalin&"&antiseizure&drugs&
o Effective&spasmolytic&in&patients&with&Multiple&sclerosis&
Mechanism&of&action&
The&spasmolytic&drugs&act&by&several&mechanisms&&

& 217&
Sollas&Notes&2015&

Baclofen,&diazepam&and&tizanidine&act&in&the&spinal&cord&
Baclofen&acts&as&a&GABAB&agonist&at&both&presynaptic&and&postsynaptic&
receptors,&causing&membrane&hyperpolarization.&
o Presynaptically&&
! it&reduces&calcium&influx&
! Decreases&synaptic&receptors&
! Facilitates&the&inhibitory&action&of&GABA&
Diazepam&facilitates&GABA]mediated&inhibition&via&its&interaction&with&
GABAA&receptors&
Tizanidine.&an&imidazoline&related&to&clonidine&with&significant&2&agonist&
activity&
o It&reinforces&presynaptic&inhibition&in&the&spinal&cord&
All&3&drugs&reduce&the&tonic&output&of&the&primary&spinal&motoneurons.&
Dantrolene&acts&in&the&skeletal&muscle&
o Its&main&action&is&to&reduce&the&release&of&activator&calcium&from&
SR&via&interaction&with&the&ryanodine&receptor&(RYR1)&channel.&
o Cardiac&and&smooth&muscle&are&minimally&depressed.&
o It&is&used&in&the&treatment&of&Malignant&hyperthermia&(MH)&
! A&disorder&characterized&with&massive&calcium&release&from&
the&SR&of&skeletal&muscle.&&&
! MH&can&be&triggered&by&general&anesthesia&protocols&that&
include&succinyl&choline&or&tubocurarine.&
! Dantrolene&is&given&IV&to&block&calcium&release&
Toxicity&
Sedation&produced&by&diazepam&is&significant&but&still&milder&than&other&
sedative]hypnotic&drugs.&
Baclofen&produces&less&sedation&than&diazepam&but&tolerance&occurs&with&
chronic&use&
o Withdrawal&should&be&accomplished&slowly&
Tizanidine&may&cause&ansthenia,&drowsiness,&dry&mouth&and&hypotension.&
Dantrolene&causes&significant&muscle&weakness&but&less&sedation&than&the&
other&two&drugs&
Drugs!for!ACUTE!muscle!spasm!
Many&drugs&are&promoted&for&the&treatment&of&acute&spasm&resulting&from&
muscle&injury&
o Cyclobenzaprine,&metaxalone,&methocarbamol,&orphenadrine&
Most&of&these&drugs&are&sedatives&or&act&in&the&brain&stem.&
Cyclobenzaprine&
o Act&in&the&brain&stem,&possibly&by&interfering&with&polysynaptic&
reflexes&that&maintain&skeletal&muscle&tone.&
o Drug&is&active&by&oral&route&&
! Has&sedative&and&antimuscarinic&actions&
o Cyclobenzaprine&may&cause&confusion&and&visual&hallucinations&&
None&of&these&drugs&are&effective&in&muscle&spasms&resulting&from&
cerebral&palsy&or&spinal&cord&injury.&
Patients&with&renal&failure&often&have&decreased&levels&of&plasma&
cholinesterase&thus&prolonging&the&duration&of&action&of&mivacurium&or&
succinylcholine.&&

& 218&
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28.2&Drugs&acting&on&uterus&and&smooth&muscles&
&
Smooth(muscles(are(found(within(the(walls(of(blood(vessels((tunica(media(layer),(
urinary(bladder,(uterus,(male(and(female(reproductive(tracts,(GI(tract,(respiratory(
tract,(erector(pili(of(the(skin,(ciliary(muscle(and(iris(of(the(eye.(Due(to(this(wide(
distribution(within(the(body(many(disorders(and(diseases(are(related(to(
dysfunctions/hyperfunctions(within(these(muscles.(Therefore(its(important(to(keep(
in(mind(that(the(pharmacological(treatments(of(smooth(muscles(can(vary(a(lot(and(
focused(on(different(receptors(and(elements(of(the(smooth(muscle(cell.(
(
Pharmacological!targets!on!smooth!muscle!cells:!
! mAch&(M1&and&M3&receptors)!
! adrenoreceptors&(&&&)!
! L]type&Ca2+&channels!
! Prostaglandin&receptors!
! 5]HT&receptors!
! K+&channels&!
! Histamine&receptors!
! Angiotensin&receptors!
! NO&diffusion!
! Atrial&natriuretic&peptide&receptors!
! Phosphodiesterase&inhibitors!
!
Contraction&is&the&result&of&decreased&cAMP&and&increased&Ca2+&&&
Relaxation!is&the&result&of&increased&cAMP&and&increased&cGMP&
&
Drugs!acting!on!uterine!smooth!muscle:!
! Physiologic&and&neuroendrocrine&regulation&of&the&uterine&tone,
o Pacemaker&cells&are&found&in&myometrium&in&the&fundus&,
! Regular,&rhythmic,&coordinated,&spontaneous&contractions&
occur&in&the&direction&from&the&fundus&and&towards&the&
cervix,
! Uterine&adrenergic&system&,
o Hormones&that&are&associated&with&menstrual&cycle&and&pregnancy,
! Estrogen&&&progesterone,
! Oxytocin&&&prostaglandins,
o Hormones&that&are&related&to&labor,
! Fetal&cortisol&increase&,
! Increase&in&estrogen&and&progesterone&from&placenta,
Estrogen! Progesterone!
Membrane&depolarization&(in&myometrium)& Membrane&stabilizing&effects&(in&the&
myometrium&
Increased&expression&of&oxytocin&receptors& Decreased&expression&of&oxytocin&receptors&
Increased&sensitivity&of&]receptors& Increased&sensitivity&and&expression&of&]
receptors&
Increased&endogenous&PG&synthesis&in&decidua& Decreased&endogenous&PG&synthesis&
Increased&gap&junctions& &
!
Prostaglandin!synthesis!(PGF2,!PGE2!and!PGI2):!
! Endogenous&synthesis&in&the&endometrium&and&myometrium!

& 219&
Sollas&Notes&2015&

! Made&in&the&second&phase&of&the&menstrual&cycle&(luteal&phase)&&estrogen!
! Influences:!
o Increased&motility,&frequency&and&amplitude!
o Facilitates&cervical&dilation!
! Synthesis&can&be&stimulated&by:!
o Ca2+,&platelet&activating&factor,&]agonists,&estrogen,&TGF],&cortisol,&
Epidermal&growth&factor&(EGF),&IL]1&(&),&lipopolysaccharides,&
TNF,&ACTH,&corticotropin&releasing&hormone&(CRH)!
! Synthesis&can&be&inhibited&by:!
o Lipocortin,&progesterone,&INF],&chorial&phospholipase&A2&
inhibitor&(lipocortin&VII)!
!
Drugs!acting!on!the!uterus!
!
Uterotonics:!
! Clinical&uses:!
o Labor&induction&(delivery,&abortions)!
o Labor&stimulation&or&enhancement&(in&inertia&uteri)!
o 3rd&stage&of&labor&induction&(birth&of&the&placenta)!
o Prevention&and&therapy&of&postpartum&hemorrhage&(tonic&contact.)!
! All&these&drugs&are&given&IV&&&monitored&via&cardiotocography&(CTG)!
! Contraindicated&in:!
o Rupture&of&the&uterus,&placenta&praevia&or&placental&abruption!
! Oxytocin:!
o Synthesized&and&stored&in&the&hypothalamus!
! Supraoptic&and&paraventricular&nuclei!
o Sent&via&axons&down&into&the&neurohypophysis&where&its&secreted&
upon&stimuli!
o Half]life:&5min!
o Effects:!
! Oxytocin&receptors&(binding&increases&intracellular&Ca2+)!
! Increases&uterine&contractions!
! Increases&myoepithelial&contractions&in&the&breast!
Release&of&the&milk&from&the&breast!
! Clinical&use:!
2]3&IU&(1IU&=&0,5mg)!
o 1st&and&2nd&stage&of&labor!
5]10&IU!
o 3rd&stage&&&prevention&of&p.p.&hemorrhage!
High&doses&causes&tonic&uterine&contractions!
! Adverse&effects:!
Hypotension,&tachycardia,&rupture&of&uterus,&
electrolytes&disturbances!
! Ergot,alkaloids!
o Produce&powerful&constriction&in&the&smooth&muscles&of&the&uterus!
o Ergonovine,is&the&prototype&&methylergometrine,(also&used)!
o Can&cause&abortion&or&miscarriage!
o Effective&in&the&treatment&of&postpartum&bleedings!
! Via&powerful&long]lasting&contractions&decreasing&bleeding!

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! MUST&NOT&BE&GIVEN&BEFORE&DELIVERY&OF&PLACENTA!
o Effects:!
! Hallucinogene&(via&5]HT2&receptor&agonist)!
! Extrapyramidal&effects&(D2&receptor&agonist)!
! Migrane&therapy&(5]HTreceptor)!
! Increased&heart&rate&(]receptor&and&D]receptor)!
! Effects&on&uterus:!
Low&doses:&rhythmic,&regular,&phasic&contractions!
High&doses:&tonic,&constant&contractions!
o Dangerous!!!
o Adverse&effects:!
! Tachycardia,&angina&pectoris,&necrosis&in&extremities!
! Prostaglandins!
o Influences:!
! Increased&motility,&frequency&and&amplitude!
! Facilitates&cervical&dilation!
o Clinical&uses:!
! Local&gel&(prepidil,,PGE2&or&prostinE2,(dinoprostone))!
! Injection&(prostinE2,(dinoprostone))!
! Injection&(sulproston,(nalodor)!
Used&in&postpartum&hemorrhage!
o Adverse&effects:!
! Headache,&GI&disturbances,&bronchospasm,&chest&pain!
o Contraindications:!
! Asthma,&epilepsy!
Tocolytics:!
! Inhibit&uterine&motility&(tone)!
! Clinical&uses:!
o Delaying&premature&birth&(25%&decrease)!
o Used&in&emergency!
! Acute&fetal&distress!
! Placenta&previa!
! Rupture&of&the&uterus!
! Main&purpose&of&the&uses&is&to&delay&delivery&until&the&fetal&lungs&have&
matured&enough&to&be&born&(this&lowers&risk&of&fetal&distress)!
o Can&be&used&for&48]72hrs&!
o Co]administration&of&steroids&to&the&mother&to&try&to&speed&up&
maturation&of&the&fetal&lungs&and&prevent&IRDS!
! Contraindicated&in:!
o Hemorrhage,&maternal&DM&and&arrhythmia&!
o Fetal&distress&(such&as&infections,&abortion&and&dead&fetus)!
! Psympathomimetics,(fenoterol,,salbutamol)!
o Asthma&bronchiale&(selective&2&agonists)!
o Adverse&effects:!
! Tachycardia,&hypotension,&hyperglycemia!
! Atosiban!
o Oxytocine&receptor&antagonists!
! MgSO4!
o Bivalent&cation&that&increases&]sensitivity!

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o Clinical&use:!
! Tocolytic&in&premature&contractions!
! Ventricular&tachycardia&(torsade&de&pointes)!
o Adverse&effect:!
! AV]block,&bradycardia,&dizziness!
! NSAIDs!
o Significant&tocolytic&effects!
o Aspirin&can&increase&postpartum&hemorrhage&due&to&its&
anticoagulation&effects&&needs&to&be&monitored&!
o Can&only&be&used&before&28th&gestational&week!
o Can&cause&premature&closure&of&ductus&arteriosus!
! Ca2+,channel,blockers!
o Block&L]type&Ca2+&channels!
o Not&recommended&in&pregnancy!
! Can&cause&fetal&distress&and&pulmonary&edema!
! Methylzanthines,(aminophylline)!
o cAMP&PDE]inhibition!
o Works&temporarily&!
! Ethanol!
o Decreases&hypophysial&oxytocin&release!
o Direct&relaxing&effects!
!
Drugs!acting!on!smooth!muscle:!
!
Spastics!! Spasmolytics!!
Cholinomimetics& Cholinolytics:&
! Pilocarpine,&muscarine,& ! Atropine,&homatropin,&
neostigmine,&organophosphates& ipratropium]bromid&
&
Ergot]alkaloids,&5]HT&receptor&agonist& Sympathomimetics&&
! Ergometrin&& ! Selective&]receptor&agonists&
! Fenoterol,&salbutamol&
Oxytocin& Smooth&muscle&relaxants&
! Papaverin,&drotaverin&
Prostaglandins& !
!
Spasmolytics:!
! Papaverine,(found&in&the&opium&poppy)!
o Opium&alkaloid&antispasmodic&drug!
o Used&primarily&in&the&treatment&of&visceral&spasm,&vasospasm&
(especially&those&involving&the&heart&and&the&brain)&&&occationally&
in&the&treatment&of&erectile&dysfunction!
o Blocks&voltage&gated&Ca2+&channels&and&inhibits&PDE2,3&and&4!
o Increases&plasma&protein&binding!
o Uses:!
! GI&tract,&biliary&tract,&urogenital&tract,&respiratory&tract!
! Negative&chronotropic&effects,&vasodilator&($&HR)!
! Vasodilates&in&pulmonary&arteries&and&cerebral&arteries!
Good&for&migraine&and&emboli&treatments!

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! Analgesic&and&sedative&effects&in&high&doses!
o Adverse&effects:!
! Bradycardia,&AV]blocks,&V]fib,&extrasystole!
! Drotaverine!
o Isoquinolone&derivative!
o Greater&potency&than&papaverine,&increased&bioavailability!
o Application:&orally,&IV&and&IM!
o Co]application:&ibuprofen/diclofenac&+&drotaverine!
! Caroverine,,mebeverine!
o Voltage&gated&Ca2+&inhibitors!
o 10x&more&potent&than&papaverine!
o Well&absorbed&orally!
o Used&for&spasms&in&the&GI&and&biliary&tracts!
! Trimebutine!
o Peripheral&agonist&of&,&,&&receptors!
o Used&in&the&therapy&of&inflammatory&bowel&disease&!
! Pinaverine,(pinaverine,bromide)!
o Smooth&muscle&relaxant!
o Blocks&voltage&gated&Ca2+&channels!
o Cholinolytic&effects!
o Clinical&uses:!
! GI&and&biliary&tract!
! Urogenital&tract!
! PMS&and&dysmenorrhea!
! ACh,blocking,drugs!
o Broad&side&effect&profile&!
! Used&in&the&treatment&of&atropine&intoxication&!
o Co]application&(+NSAIDs)&&synergism:!
! Troparinum&combination&(hometropine,+,papaverine)!
! Meristin&(papaverine,+,phenobarbital)!
! Steralgin&(methylhomatropine,+,drotaverine)!
! Reasec&(atropine,+,diphenoxylate)!
!
!
!
!
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28.3&Expectorans&and&antitussives&
&
Mucokinetics&are&a&class&of&drugs,&which&aid&in&the&clearance&of&mucus&from&
airways,&lungs,&bronchi&and&trachea.&These&drugs&can&further&be&subcategorized&
by&their&mechanism&of&action:&
Mucolytics&
Expectorants&
Hypoviscosity&agents&
Surfactants/abhesives&
Expectorants&and&mucolytic&agents&are&different&types&of&medications&
Have&in&common&that&they&intent&to&promote&drainage&of&mucus&
Expectorant:&
Drugs&that&signal&the&body&to&increased&the&hydration&of&secretions&
o Reduces&viscosity/thickness&of&the&mucus&
Results&in&more&&yet&clearer&secretions&
o Easier&to&cough&up&
Lubricates&the&irritated&respiratory&tract&
Common&expectorants:&
o Guaifenesin&
o Potassium&iodide&
Mucolytic&agent:&
Drug&that&dissolves&thick&mucus&by&dissolving&various&chemical&bonds&
within&the&secretions&
o Lower&viscosity&by&alterations&of&the&mucin]containing&component&
Common&mucolytics:&
o Acetylcisteine&
Antitussives:&
o Agents&that&help&in&suppressing&of&the&cough&reflex&by&unknown&
mechanisms&
o They&are&considered&as&members&of&opioids,&acting&as&agonists&
o Prototypical&drugs&include&codeine&and&dextromethorphan.&
Codeine:,
o Analgesic&actions&are&due&to&its&conversion&to&morphine&while&antitussive&
effects&are&due&to&codeine&itself&
o Much&less&potent&analgesic&than&morphine,&but&it&has&a&higher&oral&
effectiveness.&
o It&shows&good&antitussive&activity&at&doses&that&do&not&cause&analgesia.&
o The&drug&has&a&lower&portential&for&abuse&then&morphine,&rarely&produces&
dependence&
o It&produces&less&euphoria&and&often&used&in&combination&with&aspirin&or&
acetaminophen&
Dextroamphetamine:,
o Belonging&to&amphetamines&family,&inhibiting&transporters&of&CNS&amines&
including&dopamine,&norepinephrine,&and&serotonin.&
o Causing&a&feeling&of&euphoria&and&self]confidence&that&contributes&to&the&rapid&
development&psychological&dependence.&
o Symptoms&of&overdose&include&agitation,&restlessness,&tachycardia,&
hyperthermia,&hyperreflexia&and&possibly&seizures.&
o Antidepressant&drugs&may&be&indicated&for&reducing&withdrawal&side]effects&

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