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HD1Pharmacology

LipidLoweringAgents
I) ReviewofCholesterolMetabolism
A) Endogenouspathway
1) LiverusesHMGCoAreductasetosynthesizecholesterolaspartofthemevalonatepathway
B) Exogenouspathway
1) Recyclingofbilesalts
C) Dietaryuptake
1) Dietaryfattyacidsareabsorbedinthegutandpackagedintochylomicrons
2) LipoproteinlipaseproducestriglyceridesfromchylomicronsandVLDL

II) EvaluatingRisk
A) LoweringLDLandraisingHDLlowerrisk
1) ThelowertheLDL,thebetter
B) Therapeuticlifestylechanges(SCOPE)
1) Saturatedfatreductionto<7%totalcalories
2) Cholesterolintakelimitedto200mg/day
3) Obesitytreatment
4) Plantsterols(2g/day)
5) Exercise
III) Statins
A) Mechanism
1) ReversibleinhibitionofHMGCoAreductase,hinderingendogenouscholesterolproductioninthe
liver
2) Byreducingendogenouscholesterolproduction,theliverwithdrawsmoreLDLsfromcirculation,
harvestingtheircholesterolforsyntheticpurposes
B) Pharmacokinetics
1) Oraltabletbeforebedtime,asHMGCoAreductaseismoreactiveatnight
(a) Halflifeof12hours
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2) Hepaticmetabolism(CYP450,CYP3A4)
(a) Otherdrugsthatutilize/interferewiththesamepathwaysmayprecipitatetoxicities
3) Excretioninbile,feces,andurine
C) Sideeffects
1) Myopathy(rhabdomyolysisinexceedinglyrarecases)
2) Liverdisease(elevatedALTandAST)
3) Cognitiveeffects
4) Hyperglycemia
5) Contraindicatedinpregnancy(teratogen)
6) GIcramps,abdominalpain,andconstipation
D) Specificdrugs
1) Lovastatin
2) Pravastatin
3) Simvastatin
4) Fluvastatin
5) Atorvastatin(Lipitor)
6) Rosuvastatin(Crestor)
7) Ingeneral,thenewer,syntheticstatinsaremoreeffective
IV) Fibrates
A) Mechanism
1) PPARagonistthatpromotestranscriptionoflipoproteinlipase(LPL),whichdegrades
chylomicronsandVLDL
2) Thus,freetriglyceridesareloweredandHDLisincreased
B) Pharmacokinetics
1) Oraldosing
2) Excretedinurine
C) Sideeffects
1) GIdisturbance
2) Skinrashes
3) Contraindicatedinhepatic,renal,andgallbladderdisease
D) Specificdrugs
1) Gemfibrozil
2) Fenofibrate
V) BileAcidResins(BARs)
A) Mechanism
1) Chelatebilesaltsinthegut,promotingtheirelimination
2) Becausefewerbilesaltsarebeingrecycled,thelivermustsynthesizenewones,consuming
cholesterolintheprocess
3) Canbeusedinconjunctionwithstatinsforacumulativeeffect
(a) Or,inpatientsadversetostatins,BARscanbeusedwithagreatlyreducedstatinloadtoproduce
anequivalenteffect
B) Sideeffects
1) Asthesearenotsystemicdrugs,thereislittletoxicity
2) Contraindicatedinpatientswithhypertriglyceridemia
C) Specificdrugs
1) Cholestyramine(old,nolongerused)
2) Colestipol(old,nolongerused)
3) Coleselevam(newer,onlyoneused)
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VI) HDLRaisers
A) Mechanism
1) Decreaseslipolysisinadiposetissue
2) Producesafavorableoutcomeinalllipids
B) Sideeffects
1) Numerous,limitinguse
2) Contraindicatedindiabetics,asitmayproducehyperglycemia
C) Specificdrugs
1) Niacin(nicotinicacid,vitaminB3)
VII) NewTherapies
A) Ezetimibe
1) Inhibitscholesterolabsorptioninthegutbyspecificallyblockingintestinalcholesteroltransport
B) CETPinhibitors
1) Inhibitionofcholesterylestertransferprotein(CETP),whichconvertsHDLtoLDL,yieldsamore
favorableHDL:LDLratio
C) PCSK9inhibitors
1) PCSK9reducesthenumberofLDLreceptors,soinhibitingitwouldincreaseLDLRandpromotethe
withdrawalofLDLfromplasma
Drug
Statins
Fibrates
Niacin
BARs

LDL

HDL

ComparisonofAntihyperlipidemics
TG
SideEffects
Myalgia,myositis,rhabdomyolysis

Toxicwhenusedwithstatins

Hyperglycemia

Increasedtriglycerides

AntiAnginalDrugs
I) Angina
A) Definition
1) Predictableoccurrenceofsubsternalpainduetotransientmyocardialischemia
B) Threetypesofclinicallyrecognizedangina
1) Stableangina
(a) Occurswithexertion
(b) Predictablepain
(c) Frequentlyduetocoronaryatheromas
(d) 90%ofcasesandfocusofantianginaldrugdevelopment
2) Unstableangina
(a) Platelet/fibrinthrombuswithrupturedplaque
3) Variantangina
(a) Coronaryarteryvasospasm
C) Therapeuticstrategies
1) Decreasemyocardialoxygendemand
(a) 1blockade
(b) Ca2+channelblockade
(c) Nitrovasodilationofsystemicveinsdecreasedpreload
2) Increasemyocardialperfusion
(a) Nitrovasodilationofcoronaryarteries
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3) Importanttonotethatnoneofthesetherapieshavebeenshowntoactuallyreducemortality
II) Blockers
A) Mechanism
1) Antagonismof1receptorsintheheartdecreasedrateandcontractilitydecreasedO2demand
B) Specificdrugs
1) Propranolol(nonselective)
2) Nadolol(nonselective)
3) Metoprolol(1selective)
4) Atenolol(1selective)
C) Pharmacokineticsanddosing
1) Oraldosing(timescaledependsonspecificdrug)
2) Prophylacticuseonly
D) Sideeffects
1) Nonselectivedrugsinduce2blockadevasoconstriction,bronchospasm,Raynaudsphenomenon
2) Heartfailure
3) Bradycardia
4) AVblock
5) Fatigue,depression,andimpotencearerare
III) OrganicNitrates
A) Mechanism
1) Prodrugsthatreleasenitricoxide(NO)inhibitionofguanylylcyclaseincreased[cGMP]
smoothmusclerelaxation
2) Systemicvenousdilationreducedcardiacpreload
3) Coronaryarterydilationincreasedmyocardialperfusion
B) Specificdrugs
1) Glyceryltrinitrate
2) Isosorbidedinitrate
3) Isosorbidemononitrate
C) Pharmacokineticsanddosing
1) Glyceryltrinitrate
(a) 100%firstpassmetabolismfastonset(30sec)andshorthalflife(3min)
(b) Loworalbioavailability(<1%)
(c) Administeredasasublingualtablet
2) Isosorbidedinitrate
(a) Moderateoralbioavailability(~20%)
(b) Administeredasasublingualtablet
3) Isosorbidemononitrate
(a) Nofirstpassmetabolismslowreleasepreparationswithlonghalflife
(b) Highoralbioavailability(100%)
(c) Oral,topical,andtransdermaladministration
(i) Susceptibletorapidtolerancedevelopment
D) Nitratetolerance
1) Tolerancecandeveloprapidlywhensustainedreleaseformulationsareused
2) Tolerancecanbeminimizedbyseveralmethodologies
(a) Limitamountoflonglastingnitrates
(b) Incorporateanitratefreeperiod(~8hours)betweensustainedreleasedosing
(c) Combinationtherapythatreducesnitrateuse
E) Adverseeffects
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1) Doserelatedextensionsofvasodilation
(a) Pulsatingheadache
(b) Posturalhypotension
(c) Dizzinessandsyncope
(d) Reflextachycardia
2) Contraindicatedinpatientswithelevatedintracranialpressure
IV) CalciumChannelBlockers
A) Mechanism
1) Inhibitionofcalciumchannelsintheplasmamembraneofcardiomyocytesdecreasedintracellular
[Ca2+]decreasedcontractilitydecreasedO2demand
2) Inhibitionofcalciumchannelsintheplasmamembraneofvascularsmoothmusclecellsdecreased
intracellular[Ca2+]vasodilationdecreasedcardiacpreloaddecreasedO2demand
B) Specificdrugs
1) Verapamil(cardiacmechanism)
2) Nifedipine(vascularmechanism)
(a) Preferredinpatientswithheartfailure
(b) Usedinsustainedreleaseformulations
3) Diltiazem(cardiacandvascularmechanisms)
C) Pharmacokineticsanddosing
1) Oraladministration
2) Highfirstpasslivermetabolism
D) Sideeffects
1) Contraindicatedinpatientstakingblockers,asadrasticdecreaseincardiaccontractilitymayoccur
2) Headache,nausea,andflushing
V) NewTherapies
A) Ranolazine
1) Indicatedforpatientswhocontinuetobesymptomaticwhiletakingblockers,nitrates,orcalcium
channelblockers
2) Reducescalciumoverloadintheischemiccardiomyocyte
B) Ivabradine
1) Indicatedforpatientswithchronicanginawhocontinuetobesymptomaticwhiletakingblockers,
nitrates,orcalciumchannelblockers
2) Blockscardiaccurrentdecreasedheartrate
VI) TherapeuticPreventionofMI
A) Drugs
1) Primaryprevention
(a) Aspirin
(b) Statins
2) Secondaryprevention(postMI)
(a) ACEinhibitors
(b) blockers
B) Surgeryisineffectiveatreducinganginasymptoms
PharmacologicalTreatmentofObstructiveLungDiseases
I) AsthmaTreatmentGoals
A) Pharmacotherapyhastwoaims
1) Symptomaticrelief(relievingbronchoconstriction)
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(a) 2agonists
(b) Leukotrienereceptor(CysLTR1)antagonists
(c) Muscarinicantagonists
(d) Xanthines
2) Diseasemodification(alleviatingunderlyinginflammationandlungdamage)
(a) Corticosteroids
(b) Cromones
(c) AntiIgEtherapy
II) 2Agonists
A) Mechanism
1) Agonismof2receptorsintherespiratorytractbronchodilation
B) Deliveredviainhalation,providingthemostrapidonsetofaction
1) Shortactingdrugsaretypicallyusedforquickreliefinemergentsituations
2) Longactingdrugsaretypicallyusedaspartofacombinationtherapyformanagingmoderate/severe
persistentasthma
C) Sideeffects
1) Paradoxicalbronchospasm
2) Tachycardia
3) Hypokalemia
D) Specificdrugs
1) Albuterol(shortlasting)
2) Terbutaline(shortlasting)
3) Salmeterol(longlasting)
III) AntiLeukotrieneAgents
A) Mechanism
1) Leukotrienesareeicosanoidmediatorsofinflammationthattriggercontractionofbronchiolar
smoothmusclecells
2) CysLTR1antagonistsblocktheleukotrienereceptor,preventingbronchoconstriction
3) LeukotrienesynthesisinhibitorsblockthesynthesisofLTs,preventingbronchoconstriction
B) Deliveredorally
1) Notusefulforimmediaterelief
2) Canbeusedinconjunctionwith2agonistsforanadditiveeffect(ordosereductionofthelatter)
3) Typicallyusedforearlymanagementofmildasthma
C) Sideeffects
1) Hepatotoxicity
D) Specificdrugs
1) Zafirlukast(CysLTR1antagonist)
2) Montelukast(CysLTR1antagonist)
3) Zileuton(inhibits5lipoxygenase)
IV) MuscarinicAntagonists
A) Mechanism
1) Antagonismofmuscarinicreceptorsinbronchialsmoothmusclebronchodilation
2) Antagonismofmuscarinicreceptorsinparasympatheticgangliabronchodilation
B) Deliveredviainhalation
1) Usedassecondlinedrugswhenothermethodsfailtocontrolasthma
C) Sideeffects
1) Drymouth
2) Glaucoma
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3) Urinaryretention
D) Specificdrugs
1) Ipratroprium
2) Tiotropium
V) Xanthines
A) Mechanism
1) Mayactasphosphodiesteraseinhibitorsbronchodilation
2) Mayactasadenosineblockersbronchodilation
B) Deliveredorally
1) Usedassecondlinedrugswhenothermethodsfailtocontrolasthma
C) Sideeffects
1) Arrhythmia
2) Nauseaandvomiting
D) Specificdrugs
1) Theophylline
VI) Glucocorticoids
A) Mechanism
1) Transcriptionaldownregulationofproinflammatorymediators(PLA2,TH2,cytokines,PGI2,PGE2)
B) Dosingandindications
1) Inhaledcorticosteroids(ICS)areusedasthefirstlinetherapyforalllevelsofpersistentasthma
2) Systemic(oral)corticosteroidsareusedfortreatmentofsevereandemergencyasthma
3) Combinationtherapywithlongacting2agonistsmayhelpcontrolseverepersistentasthma
C) Sideeffects
1) Hepatotoxicity,especiallywheninhaledimproperly
D) Specificdrugs
1) Fluticasone(highpotency)
2) Budesonide(highpotency)
3) Beclomethasone(lowpotency)
4) Flunisolide(lowpotency)
5) Prednisone(oral)
VII) Cromones
A) Mechanism
1) Poorlyunderstood
B) Dosingandindications
1) Inhalationdrugonlyusefulprophylactically
2) Especiallyeffectiveinchildren
C) Veryfewsideeffects
D) Specificdrugs
1) Cromolyn
2) Nedocromil
VIII) AntiIgEAntibodyTherapy
A) Mechanism
1) HumanizedIgGmonoclonalantibodiesbindIgEandhindermastcelldegranulation
B) Intravenoustherapyonlyusedinthemostseverepersistentasthma
1) Hinderinglyexpensive
C) Specificdrugs
1) Omalizumab
IX) Phosphodiesterase4Inhibitors
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A) Mechanism
1) InhibitionofPDE4maytreatthechronicinflammationunderlyingCOPD
B) Oraladministration
1) Usedinconjunctionwithbronchodilators
C) Sideeffects
1) Nausea
2) Diarrhea
3) Headache
D) Specificdrugs
1) Roflumilast
DrugsforCongestiveHeartFailure
I) Introduction
A) Compensatorymechanismstoheartfailure
1) Whencardiacoutputbeginstofall,bothsympatheticdischargeandreninreleaseincrease
2) IncreasedreninincreasedangiotensinIIseveraleffects
(a) Increasedaldosteroneincreasedfluidretentionincreasedpreload
(b) Vasoconstrictionincreasedafterload
(c) Increasedsympatheticdischargeprogressionofthecycle
3) Ultimately,ventricularremodelingoccurs,whichisgreatlydetrimental

B) Treatmentobjectives
1) Improvesurvival(obviously)
2) Improvecardiacfunctionwhilereducingsymptoms
3) Attenuatetheneurohormonalchanges
4) AttenuateprogressionofCHF
II) AngiotensinConvertingEnzyme(ACE)Inhibitors
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A) Mechanism
1) InhibitionofACEdecreased[angiotensinII]severaleffects
(a) Vasodilationdecreasedperipheralresistancedecreasedafterloadincreasedcardiacoutput
(b) Venodilation(minor)decreasedleftventricularenddiastolicpressure(LVEDP)
(c) Decreasedmyocardialoxygendemand
(d) Diuresisandnatriuresisdecreasedbloodvolumedecreasedbloodpressure
B) AdvantagesofACEinhibitors
1) Inhibitleftventricularremodeling
2) Increasesurvivalwhiledecreasinghospitalizations
3) Noneurohormonalactivation(e.g.,reflextachycardia)
4) Tolerancedoesnotdevelop
C) Sideeffects
1) Cough
(a) ACEalsodegradesbradykinin,whichinducescoughs(mechanismunknown)
(b) Thus,ACEinhibitorsincrease[bradykinin]bronchoconstrictiondrycough
(c) PresenceofthiscoughisakeyindicatorthatACEinhibitorsshouldbediscontinuedandARB
therapybeguninitsplace
2) Proteinuria
3) Hypotension
4) Hyperkalemia
D) Contraindications
1) Renalarterystenosis
2) Hyperkalemia
3) Pregnancy
E) Specificdrugs
1) Catopril
2) Enalapril
3) Lisinopril
4) Ramipril
III) AngiotensinReceptorsBlockers(ARBs)
A) Mechanism
1) CompetitiveantagonismoftheAT1receptorseveraleffects
(a) Vasodilationdecreasedperipheralresistancedecreasedafterloadincreasedcardiacoutput
(b) Venodilation(minor)decreasedleftventricularenddiastolicpressure(LVEDP)
(c) Decreasedmyocardialoxygendemand
(d) Diuresisandnatriuresisdecreasedbloodvolumedecreasedbloodpressure
B) AdvantagesofARBs
1) PatientswhocannottolerateACEinhibitorscantypicallyuseARBs
2) MayallowthefavorableinteractionofangiotensinIIandtheAT2receptor(entirelytheoretical)
C) Sideeffects
1) Proteinuria
2) Hypotension
3) Hyperkalemia
D) Contraindications
1) Renalarterystenosis
2) Hyperkalemia
3) Pregnancy
E) Specificdrugs
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1) Losartan
2) Valsartan
3) Irbesartan
4) Telmisartan
IV) DirectActingVasodilators
A) Nitroprusside
1) Nitricoxidedonoradministeredintravenously
2) Mechanisms
(a) NOreleasearterialdilationdecreasedafterload
(b) NOreleasecoronaryarterydilationincreasedmyocardialperfusion
(c) NOreleasevenodilationdecreasedpreloaddecreasedpulmonarycongestion
3) Sideeffects
(a) Headache
(b) Syncope
(c) Tolerance(sameasforantianginalnitrates,above)
4) Contraindications
(a) Mitralstenosis
(b) Increasedintracranialpressure
(c) Anemia
B) Sildenafil
1) PDE5inhibitoradministeredorally
2) Mechanism
(a) InhibitionofPDE5increased[cGMP]smoothmusclerelaxationvasodilation
3) Advantages
(a) Maybebeneficialincardiachypertrophy,asitmayhinderventricularremodeling
(b) Usefulinpulmonaryarterialhypertension
4) Sideeffects
(a) Headache
(b) Flushing
(c) Epistaxis
(d) Visionchanges
5) Contraindications
(a) Coadministrationwithnitrates
C) Hydralazine
1) NOpreservativedeliveredorallyinconjunctionwithanitrate
2) Mechanism
(a) Unknown,butsomehowstabilizesNOandprolongsitseffect
3) Sideeffects
(a) Lupuslikesyndrome
4) Contraindications
(a) Donotdeliverthisdrugalone,asitwillcauseaprofoundreflextachycardia
(i) Mustbecoadministeredwithanitrate,suchasisosorbidedinitrate(ISDN,above)
V) NatriureticPeptides
A) Mechanisms
1) Promotesnatriuresisdecreasedbloodvolumedecreasedpreloadreducedcongestion
2) Vasodilation:elevatescGMP
3) DecreasesaldosteroneinfluencedecreaseLVEDPandcongestion
B) Contraindications
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1) Hypotension
C) Specificdrugs
1) Nesiritide
(a) RecombinantBtypenatriureticpeptide(BNP)
VI) Diuretics
A) FirstlineoftherapyforthemajorityofpatientswithCHFaccompaniedbypulmonarycongestion
B) Mechanism
1) Actinkidneytoreducewaterreabsorptiondecreasedbloodvolumedecreasedpreload
decreasedcongestion
C) Sideeffects
1) Incitesneurohormonalresponseincreased[norepinephrine]and[angiotensinII]
2) Potentiallyharmfulchangesinplasmaelectrolytes
(a) Hyponatremia,hypokalemia,metabolicalkalosis,etc.
3) Resistancemaydevelop
D) Specificdrugs
1) Furosemide(loopdiuretic)
2) Hydrochlorothiazide(thiazide)
VII) AldosteroneAntagonists
A) Mechanism
1) Antagonismofaldosteronereceptorseveraleffects
(a) Natriuresisdecreasedbloodvolumedecreasedpreloaddecreasedcongestion
(b) Potassiumretentionantiarrhythmic
(c) Hindersmaladaptiveremodeling
B) Sideeffects
1) Hyperkalemia
2) Gynecomastia
C) Specificdrugs
1) Spironolactone
2) Eplerenone
VIII) VasopressinAntagonists
A) Mechanism
1) Promoteswaterexcretioncorrectshyponatremiabyconcentratingsodium
B) Sideeffects
1) Hepatotoxicity
C) Specificdrugs
1) Tolvaptan
IX) Sympatholytics(AdrenergicReceptorAntagonists)
A) Mechanisms
1) Inhibitionof1receptorsintheheartdecreasedrateandcontractilitydecreasedmyocardial
oxygendemand
2) Inhibitionof1receptorsinthekidneydecreasedreninreleasedecreasedangiotensinactivation
severaleffects
(a) Vasodilationdecreasedperipheralresistancedecreasedafterloadincreasedcardiacoutput
(b) Venodilation(minor)decreasedleftventricularenddiastolicpressure(LVEDP)
(c) Decreasedmyocardialoxygendemand
(d) Diuresisandnatriuresisdecreasedbloodvolumedecreasedbloodpressure
B) Sideeffects
1) Nonselectivedrugsinduce2blockadevasoconstriction,bronchospasm,Raynaudsphenomenon
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2) Heartfailure
3) Bradycardia
4) AVblock
5) Fatigue,depression,andimpotencearerare
C) Specificdrugs
1) Bisoprolol
2) Carvedilol(bothandantagonism)
3) Nebivolol(mayactivateeNOS,furtheringvasodilation)
X) InotropicAgents
A) Cardiacglycosides
1) Mechanism
(a) InhibitionofNa+/K+ATPaseincreasedintracellular[Ca2+]increasedcontractility
2) Sideeffects
(a) Systemictoxicity
(i) Arrhythmia,SAblock,andAVblock
(ii) Nausea,vomiting,diarrhea
(iii)
Depression,disorientation,paresthesia
(iv)Blurredvision,scotomas
(v) Hyperestrogenism,gynecomastia,galactorrhea
3) Specificdrugs
(a) Digoxin
(i) Whiledigoxinincreasesfunctionalstatusinpatients,itdoesnotdecreasemortality
B) Sympathomimetics(adrenergicreceptoragonists)
1) Specificdrugs
(a) Dopamine
(b) Dobutamine
C) Phosphodiesteraseinhibitors
1) Specificdrugs
(a) Inamrinone
(i) PDE3inhibitorthatincreases[Ca2+]intheheart
AntimicrobialsI&II
I) Lactams
A) Mechanismofaction
1) Inhibitstranspeptidaseinhibitionofcellwallassembly
2) Bactericidal,butlesseffectiveagainstnondividingculturesastheyarenotsynthesizingnewcell
wallmaterialasfrequently
B) Pharmacokinetics
1) Oralabsorption,butbioavailabilityvarieswiththespecifictype
2) Mostareexcretedinurine
3) WidelydistributedthroughoutthebodyexceptfortheCNS
C) Resistancemechanisms
1) Manybacteriahaveevolvedpenicillinase,anenzymethatdegradesthelactamringandrendersthe
antibioticuseless
2) Alteredpenicillinbindingproteins,hinderingdruguptake
(a) Forexample,MRSAisresistantbecauseofitslowaffinitybindingproteins
D) Adversereactions
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1) Allergyanaphylacticshock
2) Toxicityisrelativelylowwithahightherapeuticindex
3) GIdisturbanceisseen(asitiswithmanyoralantibioticsthathavethepotentialtodisruptthenormal
gutflora)
E) Specificdrugs
1) PenicillinG
(a) EffectiveagainstG+andGcocci
(b) Oralbioavailabilityislow,soIVorIMadministrationispreferred
2) PenicillinV
(a) SimilartopenicillinG
(b) Oralbioavailabilityisimprovedsufficientlyfororaladministration
3) Oxacillin
(a) Replacedmethicillin
(b) Resistanttopenicillinase,makingitusefulforStaphyococciandStreptococcithatmayproduce
theenzyme
4) Ampicillin
(a) EffectiveagainstG+andGbacilli
(b) NotasubstituteforpenicillinGorV
(c) Resistanceisincreasing
5) Piperacillin
(a) ExtendedspectrumpenicillinthatistypicallyreservedforseriousG+andGinfections
6) Clavulanicacid
(a) Inhibitorofpenicillinasethatisadministeredalongsidelactamstoincreasetheirefficacy
(b) Hasnoantimicrobialpropertieswhenusedalone
(c) Amoxicillin+clavulanicacid=augmentin
II) Cephalosporins
A) Mechanism
1) Thesearelactamcontainingstructuresthatactsimilartopenicillin
B) Pharmacokinetics
1) Absorptionanddistributionvarieswithtype
2) Largelyexcretedinurine
C) Resistancemechanismsaresimilartopenicillin
1) Cephalosporinase
2) Penicillinase
3) Lowaffinitypenicillinbindingproteins
(a) CephalosporinsarenotreliablyeffectiveagainstMRSA
(i) Oneexceptionisarecentlydevelopedfifthgenerationcephalosporinthathasbeenapproved
forMRSAtreatmentincertainscenarios
D) Adversereactions(generallywelltolerated)
1) GIdisturbance
2) Allergy
3) Nephrotoxicity(maybeallergicresponse)
4) SuperinfectionduetoGinhibition
E) Generations
1) Therearefour(nowfive)generationsofcephalosporins
2) Asoneprogressesthroughthegenerations,thefollowingcharacteristicschange
(a) G+efficacydecreases
(b) Gefficacyincreases
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(c) CNSpenetrationincreases
3) Forexample,afirstgenerationcephalosporinwouldbeexpectedtobeeffectiveagainstG+bacteria,
ineffectiveagainstmanyGbacteria,andbeexcludedfromtheCNS
4) Afourthgenerationcephalosporin,however,wouldbeexpectedtobeeffectiveagainstanexpanded
rangeofGbacteria,havepoorG+efficacy,andreadilypenetratetheCNS
III) Carbapenems(Imipinem)
A) Mechanism
1) Thesearealsolactamcontainingantibioticsthatfunctioninasimilarmannertopenicillin
2) Relativelybroadspectrumofaction,includingGrods,G+organisms,andanaerobes
B) Pharmacokinetics
1) Parenteraladministration(i.e.,notoral)
2) Renalmetabolism
(a) Infact,theyaremetabolizedsoreadilybythekidneythatallcarbapenemsarecoadministered
withtherenaldehydropeptidaseinhibitorcilastatin(whichispreformulatedintothedrug)
3) Excretedinurine
4) PenetratesCNS
C) Resistancemechanismssimilartopenicillin
1) However,thesearegenerallyresistanttolactamase
2) StillnotusefulforMRSAorVRE
D) Adversereactions
1) Neurotoxicity(e.g.,seizures)
2) GIdisturbance
3) Superinfection
4) Allergy
IV) Vancomycin
A) Mechanism
1) Inhibitstransportofcellwallprecursorsacrosscellmembrane
2) Bactericidal(onlybacteristaticinEnterococci)
3) OnlyeffectiveagainstG+organisms
B) Pharmacokinetics
1) IVadministration
(a) Oraladministrationisusedtotreatgutinfections,butthepoorbioavailabilitymakesoral
deliveryinappropriateforsystemicinfections
2) Renalmetabolismandexcretion
C) Resistancemechanisms
1) Few,butVRE,MRSA,VISA,andVRSAstrainsareontherise
D) Adverseeffects
1) Allergy
2) Ototoxicity(hearingloss)andnephrotoxicityassociatedwithhighdoses
V) Daptomycin
A) Mechanism
1) Destabilizesthecellmembraneinbactericidalfashion
2) EffectiveagainstG+organisms
B) Pharmacokinetics
1) IVadministration
2) Renalelimination
C) Resistancemechanisms
1) Rarelyobservedandpoorlyunderstood
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2) CanbeusedtotreatMRSAbacteremia
D) Adverseeffects
1) Musclepain/weakness
VI) Aminoglycosides(Tobramycin)
A) Mechanism
1) Blockstheinitiationofproteinsynthesis
2) Rapidlybactericidal
3) EffectiveagainstaerobicGorganisms
(a) Ineffectiveagainstanaerobes
B) Pharmacokinetics
1) IMorslowIVadministration
2) Oraladministrationtotreatgutinfectionsonly,asoralbioavailabilityispoor
3) Topicalapplicationsinburnpatients
4) Renalexcretion
C) Resistancemechanisms
1) Transmembraneuptakerequiresoxygen,renderinganaerobes(andfacultativeanaerobes)resistant
2) Plasmidencodedenzymesgrantresistance
3) Ribosomalmutantsmayberesistanttooneaminoglycoside
D) Adversereactions
1) Ototoxicityandnephrotoxicity
2) Crossestheplacenta,potentiatingfetaldamage
VII) Tetracyclines(Doxycycline)
A) Mechanism
1) Inhibitionofthe30Sribosomalsubunitprohibitsproteinsynthesis
2) Bacteriostatic
3) DrugofchoiceforRockyMountainspottedfever,Qfever,Chlamydiaeinfection,andMycoplasma
pneumoniae
B) Pharmacokinetics
1) Goodoralbioavailability
(a) Coingestionofdairyproductsreducestheuptakeofsometetracyclines,butnotdoxycycline
2) Widedistribution,includingCNSandplacentaldiffusion
3) Renalmetabolismandexcretion
C) Adversereactions
1) GIdisturbance
2) Pseudomembranousenterocolitis
3) Toothdiscolorationinfetus(avoidinpregnancy)
4) Superinfection(Candidaalbicans)
VIII) Macrolides(Erythromycin)
A) Mechanism
1) Inhibitstranslocationofthe50Sribosomalsubunit,prohibitingproteinsynthesis
2) Bacteriostatic(thoughclinicaldosescanbebacteriocidal)
3) UsefulagainstG,G+aerobic,andsomeanaerobicorganisms
(a) NoteffectiveagainstMRSA
B) Pharmacokinetics
1) OralorIVadministration
2) DoesnotpenetrateCNS
3) Hepaticmetabolism
(a) MayprecipitateCYP450druginteractions
15

C) Resistancemechanisms
1) Roughly50%ofhospitalcasesofStaphylococciareresistanttoerythromycin
2) NoteffectiveagainstMRSA
D) Adversereactions
1) GIdisturbance
2) Sideeffectsarerare,anderythromycinisperhapsoneofthesafestantibioticsinuse
3) UsedforseriousG+infectionsinpenicillinallergicpatients
IX) Clindamycin
A) Mechanism
1) Proteinsynthesisinhibitor
2) Bacteriostatic(maybebacteriocidalinsomeorganisms)
B) Pharmacokinetics
1) Oral,IM,IV,andtopicaladministration
2) DoesnotdistributetoCNS
3) Hepaticmetabolism
C) Resistancemechanisms
1) Roughly50%ofhospitalcasesofStaphylococciareresistanttoerythromycin
2) NoteffectiveagainstMRSA
D) Adverseeffects
1) GIdisturbance
2) Pseudomembranousenterocolitis
X) Linezolid
A) Mechanism
1) Proteinsynthesisinhibitor
2) EffectiveagainstVRE,MRSA,etc.
B) Pharmacokinetics
1) Oraladministration
2) Hepaticmetabolism
3) Renalexcretion
C) Adverseeffects
1) GIdisturbance
2) Headache
XI) Sulfonamides(Sulfamethoxazole)
A) Mechanism
1) PABAanalogthatinhibitsfolatesynthesis
(a) Oftenusedinconjunctionwithtrimethoprim,whichinhibitsfolatesynthesisatadifferentstep
2) Bacteriostatic
B) Pharmacokinetics
1) Oraladministration
2) DistributestoCNS
3) Livermetabolism
4) Renalexcretion
C) Resistancemechanisms
1) Multiple
D) Adversereactions
1) Crystallizationinbladder
2) Acutehemolyticanemia
3) Aplasticanemia
16

XII)
A)

B)

C)

XIII)
A)
B)

C)
D)

XIV)
A)
B)

C)

4) Bonemarrowsuppression
5) Allergy
Trimethoprim
Mechanism
1) DHFRinhibitorthathindersfolatesynthesis
(a) Oftenusedinconjunctionwithsulfamethoxazole,whichinhibitsfolatesynthesisatadifferent
step
Pharmacokinetics
1) Oraladministration
2) PenetratesCNS
3) Livermetabolism
4) Renalexcretion
Adverseeffects
1) Thrombocytopenia/leukopenia
2) Skinreactions
3) Renaldamage
Quinolones(Ciprofloxacin)
Mechanism
1) InhibitsbacterialgyraseandtopoisomeraseIV,destabilizingDNAreplication
2) Bactericidal
Pharmacokinetics
1) Oraladministration
(a) Uptakeishinderbycoingestionofantacids(oranymetalions)
2) Hepaticorrenalelimination
(a) CYP450druginteractionsarecommon
Resistancemechanisms
1) Many,whichgreatlylimitsuse
Adversereactions
1) Skinirritation
2) Headache,dizziness
3) Tendinopathy,tendonrupture
Metronidazole
Mechanism
1) ProdrugthatdamagescellularDNA
2) Effectiveagainstprotozoaandanaerobicbacteria
Pharmacokinetics
1) Oraladministration
2) Broadtissuedistribution
3) Livermetabolism
4) Renalelimination
Adversereactions
1) GIdisturbance
2) CNSeffects
3) Alcoholintolerance
Antiarrhythmics

I) Introduction
17

A) Antiarrhythmicdrugsaretraditionallygroupedintofourclasses,dependingonthephaseofthecardiac
actionpotentialtheyaffect
1) Phase0=rapiddepolarization
(a) Na+channelblockers
2) PhaseII=plateau
(a) Betablockers
3) PhaseIII=repolarization
(a) K+channelblockers
4) PhaseIV=pacemakerpotential
(a) Ca2+channelblockers
II) ClassIAntiarrhythmics
A) Mechanism
1) BlockvoltagegatedNa+channelsdecreasedrate
2) Exhibitusedependedchannelblockadewithspecificityforchronicallydepolarizedchannels
(a) Inthismanner,theywillspecificallytargetdamagedregionsoftheheartorectopicfoci
B) Indications
1) Ventricularfibrillation
2) Sustainedventriculartachycardia
C) Adversereactions
1) Proarrhythmiceffects
D) Specificdrugs
1) SubclassIA(lengthenactionpotential)
(a) Disopyramide
(b) Procainamide
(i) Hepaticacylationwithpotentialtodeveloplupuslikesyndrome
(c) Quinidine
(i) Elevatesserumdigoxintoxicity
2) SubclassIB(shortensactionpotential)
(a) Lidocaine
3) SubclassIC(noeffectonactionpotential)
(a) Flecainide
(b) Propafenone
III) ClassIIAntiarrhythmics
A) Mechanism
1) Antagonismof1receptorsdecreasedrateandcontractility
B) Indications
1) Atrialflutter
2) Atrialfibrillation(ratecontrol)
3) AVnodalreentrytachycardia(AVNRT)
C) Adversereactions
1) Bronchospasm
2) Cardiacfailure
D) Specificdrugs
1) Propranolol
2) Metoprolol
3) Pindolol
4) Esmolol
IV) ClassIIIAntiarrhythmics
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A) Mechanism
1) BlockvoltagegatedK+channelsprolongedrepolarizationincreasedrefractoryperiod
decreasedheartrate
B) Indications
1) Ventricularfibrillation(longtermsuppression)
2) Atrialfibrillation(rhythmcontrol)
C) Adversereactions
1) Bradycardia
2) Torsadesdepointes
D) Specificdrugs
1) Sotalol
2) Bretylium
3) Amiodarone
(a) Mostwidelyusedforrestoringandmaintainingsinusrhythminatrialfibrillation
(b) Quitetoxic,especiallytolungsandliver
4) Dronedarone
(a) Derivativeofamiodarone
(b) Lesstoxic,butalsolessefficacious
V) ClassIVAntiarrhythmics
A) Mechanism
1) BlockvoltagedependentCa2+channelsslowphaseIVdepolarizationdecreasedheartrate
B) Indications
1) Atrialfibrillation(ratecontrol)
2) AVNRT
3) Supraventriculartachycardia
C) Adversereactions
1) AVblock
2) Reducedcontractility
D) Specificdrugs
1) Verapamil
(a) Cardiacpreference
2) Diltiazem
(a) Bothcardiacandvascularmechanisms,butvascularpreference
VI) Adenosine
A) Mechanism
1) ActivatesGPCRsdecreasedCa2+permeabilityandincreasedK+permeabilityhyperpolarization
decreasedheartrate
B) Indications
1) Supraventriculartachycardia
C) Uniqueproperties
1) IVadministrationwithveryrapidelimination
VII) Digoxin
A) Mechanism
1) InhibitionofNa+/K+ATPaseincreasedintracellular[Ca2+]increasedcontractilityanddecreased
rate
B) Adversereactions
1) Systemictoxicity
(a) Arrhythmia,SAblock,andAVblock
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(b) Nausea,vomiting,diarrhea
(c) Depression,disorientation,paresthesia
(d) Blurredvision,scotomas
(e) Hyperestrogenism,gynecomastia,galactorrhea
2) Bindstoserumproteins
(a) Otherdrugsthatreleasedigoxinfromtheseserumproteinsmaypotentiatedigoxintoxicity
(i) Quinidine,verapamil,tetracycline,amiodarone,erythromycin,etc.
AntiClottingAgents
I) Introduction
A) Coagulationcascade

B) Platelets

20

II) AntiPlateletDrugs
A) Acetylsalicylicacid(aspirin)
1) Mechanism
(a) IrreversibleacetylationofCOXdecreasedTXA2(plateleteffect)anddecreasedPGI2
(endothelialeffect)decreasedplateletactivation
(b) EndotheliumcanresynthesizeCOX,butplateletsmustbeturnedover(1015%perday)
2) Adversereactions
(a) Generalizedbleeding
(b) GItoxicity
(c) Resistance(controversial)
B) Clopidogrel
1) Mechanism
(a) IrreversibleantagonismofADPreceptordecreasedplateletactivation
2) Pharmacokinetics
(a) Oralprodrug
(b) Livermetabolismtoactiveform
(c) Maximalplateletinhibitiontakes47days
(d) Additiveeffectwhenusedinconjunctionwithaspirin
3) Adversereactions
(a) Neutropenia
(b) Thromboticthrombocytopenicpurpura(TTP)
C) Ticagrelor
1) Mechanism
(a) ReversibleantagonismofADPreceptordecreasedplateletactivation
2) Pharmacokinetics
(a) Oraldosing
(b) Notaprodrug
(c) Fasteracting,butshorterdurationofeffectwhencomparedtoclopidogrel
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(d) Additiveeffectwhenusedinconjunctionwithaspirin
D) Abciximab
1) Mechanism
(a) InhibitionofglycoproteinIIb/IIIapreventionoffibrinogenbindingpotentinhibitionof
plateletaggregation
(b) Oneofthemostpotentplateletinhibitorsdeveloped
2) Pharmacokinetics
(a) IVadministration
(b) Usedasanadjuncttoheparin/aspirininpostsurgicalsituations
3) Adversereactions
(a) Mayincreasemortality
E) Esoprostenol
1) Mechanism
(a) SyntheticPGI2thatinhibitsplateletaggregation
2) Specializedapplication
(a) IVinfusioninhemodialysisifhepariniscontraindicated
F) Cilostazol
1) Mechanism
(a) InhibitsplateletPDE3increasedcAMPactivationofPKAinhibitionofplatelet
aggregation
2) Indications
(a) Peripheralarterydisease
(b) Claudication(paininlegsuponwalking)
III) Anticoagulants
A) Heparin
1) Mechanism
(a) BindsantithrombinIII(ATIII)andenhancesproteolyticactivityincreaseddegradationof
clottingfactors
(i) FactorsIIa(thrombin)andXaaremostsensitivetodegradationbyATIII
(ii) Degradationofthrombinisenhancedbyelectrostaticinteractionsbetweenitandheparin
2) Pharmacokinetics
(a) IVdosing
(b) Fastacting
(c) Polymerofvarioussize
(d) Therapeuticrangeisnonlinearandneedstobeindividualizedtoeachpatient
(e) Bindsproteinsunpredictably
(f) Maybecleavedbymacrophages
3) Adversereactions
(a) Bleeding
(b) Heparininducedthrombocytopenia
(c) Heparininducedosteoporosis
4) Relateddrugs
(a) Enoxaprin
(i) Lowmolecularweightheparin(LMWH)analogthatonlyinteractswithATIII,enhancingthe
degradationofXa(butnotthrombin)
(b) Fondaparinux
(i) PentasaccharidemoietythatbindsATIIIandenhancesthedegradationofXa(butnot
thrombin)
22

B) Warfarin
1) Mechanism
(a) CompetitiveinhibitionofvitaminKreductasedecreasedstoresoffactorsII,VII,IX,andX
2) Pharmacokinetics
(a) Oraldosing
(b) RapidlyabsorbedfromtheGItract
(i) Effectsstartafter1216hours(onceexistingcoagulationfactorshavebeenconsumed)
(c) HepaticmetabolismbyCYP450system
(i) P450inducerswillacceleratetheeliminationofwarfarin,requiringanincreaseddose
o Barbituates
o Rifampin
o Carbamazepine
o Phenytoin
(ii) P450suppressorswillslowtheeliminationofwarfarin,requiringadecreaseddose
o Trimethoprim
o Cimetidine
(d) DosesmustbeindividualizedandmonitoredbyINR
3) Adversereactions
(a) Bleeding
(b) Contraindicatedinpregnancy
Property
Structure
RouteofAdministration
SiteofAction
OnsetofAction
Mechanism
Monitoring
Antidote
Use
UseinPregnancy

ComparingHeparinandWarfarin
Heparin
Warfarin
Large,acidicpolymers
Small,lipidsolublemolecule
Parenteral(IV)
Oral
Blood
Liver
Rapid(seconds)
Slow(limitedbyhalflivesoffactorsbeingreplaced)
ActivatesantithrombinIII
InhibitssynthesisoffactorsII,VII,IX,andX
aPTT
PT/INR
Protamine
VitaminK,plasma
Acute(days)
Chronic(weekstomonths)
Yes
No

IV) Dabigatran
A) Mechanism
1) Directinhibitionofthrombin
B) Pharmacokinetics
1) Prodrug
2) Renalelimination
C) Indicatedforstrokepreventioninpatientswithatrialfibrillation
V) Rivaroxaban
A) Mechanism
1) DirectXainhibitor
B) Indicatedforstrokepreventioninpatientswithatrialfibrillation
VI) Fibrinolytics(Thrombolytics)
A) AlladministeredbyIVimmediatelytolyseaformedclot
1) Acutepulmonaryembolism
2) AcuteMI
3) Arterialthrombosis
4) Acuteischemicstroke
23

B) Adversereactions
1) Hemorrhage
C) Specificdrugs
1) Altepase
(a) RecombinanthumantPAthatactivatesplasmindegradationoffibrin
2) Streptokinase
(a) Bacterialproductthatcomplexeswithplasminogentodegradefibrinandfibrinogen
3) Urokinase
(a) Humanproductthatdegradesfibrinandfibrinogen
VII) Hemostatics
A) Protaminesulphate
1) Bindsheparintoinhibitanticoagulantactivity
2) AdministeredasanIVbolus
B) Tranexamicacid
1) Inhibitsplasiminogenactivation
2) OralandIVadministration

24