All Drugs

Class of Drug Drug Name Clinical Application
Corticosteroids
Used for persistent asthma
~ Improve pulmonary function
~ Reduced exacerbations and ED visits
~ Decreased asthma-related deaths
ICS = 1st Line treatment for persistent
asthma
Fluticasone Inhaled Corticosteroid
Prednisolone/Prednisone
Oral Corticosteroid
~ Used in ED for severe asthma attack
or for Step 6 trtmt
Beta-2 Agonists
Short-Acting (SABA) Albuterol
1.) Rescue medication for acute asthma
exacerbations
2.) Prevention of Exercise Induced
Bronchoconstriction (EIB)
Long-Acting (LABA) Salmeterol
*** Only use as adjunct therapy to
Inhaled Corticosteroids (synergistic)
Anti-muscarinics
Ipratropium
Tiotropium
PDE Inhibitors
Asthma, Allergy, and Smoking Medications
Only currently FDA approved for COPD,
but often used for asthma
Theophylline
Alternative therapy in step 2 and
beyond when ICS/LABA aren't effective
or tolerated
Leukotriene Antagonists Only work in 50% of patients
Montelukast
Zileuton
Anti-IgE Monoclonal Ab
Omalizumab
~ Use as adjunctive therapy in adult
pateints w/ allergen-induced asthma
that can't be controlled well with ICS
along (Steps 4-6)
Mast Cell Stabilizers
Cromolyn
Prevent asthma sx in unavoidable
exposure to known allergens
~ Doesnt work after attack begins
~ Alternative to ICS in Step 2, and EIB
First-Gen Antihistamines
Allergy, sleep, prevention of motion
sickness
Diphenhydramine
"Benadryl"
Anti-Parkinsonian effect
Chlorpheniramine
Promethazine Dental sedation
Dimenhydrinate
"Dramamine"
Motion-sickness
2nd-Gen Antihistamines Allergy only
Foxofenadine
"Allegra"
Once or 2x daily dosing (only one!)
Non-sedating
Cetirizine
"Zyrtec"
Sedating
Loratidine
"Claritin"
Non-sedating at therapeutic levels,
sedating at higher dose
Desloratadine
"Clarinex"
Non-sedating at therapeutic levels,
sedating at higher dose
Azelastine
"Astepro"
Other Drugs for Allergy
Phenylephrine/
Pseudoephedrine
Relief of histamine-mediated symptoms
"Phenylephrine is very ineffective"
Cromolyn Adjuvant therapy for rhinitis
Montelukast Adjuvant therapy for rhinitis
Ipratropium Reduces mucous production
Epinephrine Used to treat anaphylaxis
Fluticasone (intranasal)
Used intranasally for severe moderate-
severe rhinitis sx
Cimetidine
Used for GERD and peptic ulcer disease
to decrease HCl from stomach
Smoking Cessation Drugs
Histamine Receptors
H1 = mimics AChR, Gq coupled (increase IP3, DAG, Ca2+, NO)
~ SM (contraction), endothelium (release NO), perpipheral nerves (itch, sneeze) , CNS (wakefullness)
~ increase HR via baroreceptor reflex
H2 = Gs-coupled (increase cAMP)
~ gastric mucosa (increase HCl), heart (iono/chronotrope), mast cells, CNS
Nicotine replacement
Unlikely to cure addiction
E-cigarettes may work to remove
carcinogens, but still addictive
Buproprion
Varenicline Most effective addiction control
Mechanism
Metabolism/Pharmaco
kinetics
1.) Anti-inflammatory: decrease # and activity
of eosinophils, T-cells, mast cells,
macrophages, and dendritic cells
2.) Structural: decrease the response of
epithelial cells to cytokines and prevent
edema. Act on SM cells and mucous glands
~ Increase beta-2 receptor expression on
airway smooth muscle
stiumulate Beta-2 receptor
~ Gs coupled receptor = increase cAMP and
bronchodilation
Fast acting: 15 min
Slow Acting, chronic therapy
Block AChR, leads to decrease in cGMP
~ decrease bronchoconstriction and mucus
production
Receptor independent, prevents breakdown
of cAMP
~ Also blocks adenosine receptor which
prevents constriction
~ Bronchodilation, decreased mucus
Many drug interactions: uses
CYP450-1A2
Block LT-Rs
~ Prevent bronchoconstriction, chemotaxis,
mucous production, edema
Blocks CysLT-1 Receptor which binds LTC4,
LTD4, LTE4
blocks production of LTA4, precursor
molecule
IgG antibody that binds to IgE and prevents it
from binding to mast cells
Prevents release of inflammatory mediators
from mast cells
Mainly target H1 receptor, but also affect
mAChR, Serotonin receptors, and alpha-
adrenergic receptors
Cross BBB
~ Short 1/2 life, must take
every few hours
H1 antagonist
28 hour 1/2 life, but still take
every 4-6 hrs for therapeutic
benefit
Less cross of BBB, varying
degrees of sedation
Excreted in feces
Excreted via kidneys
~ Adjust for renal impairment
CYP3A metabolism, but NO QT
prolongation!
Metabolite of Loratadine
Alpha-1 agonist: vasoconstriction of arteries
and veins
~ Pseudoephedrine causes NE release,
activates alpha & beta receptors
1.) Alpha agonist: vasoconstriction
2.) Beta agonist: increase HR, contractility,
bronchodilation, and decreased mediator
release from mast cells
H2 antagonist
Histamine Receptors
H1 = mimics AChR, Gq coupled (increase IP3, DAG, Ca2+, NO)
~ SM (contraction), endothelium (release NO), perpipheral nerves (itch, sneeze) , CNS (wakefullness)
~ increase HR via baroreceptor reflex
H2 = Gs-coupled (increase cAMP)
~ gastric mucosa (increase HCl), heart (iono/chronotrope), mast cells, CNS
Antidepressant
~ increases synaptic DA and NE
~ Blocks nAChR
partial agonist of alpha-4-beta-2 nAChR
Adverse Effects Contraindications
Therapeutic
Considerations
1.) Adrenal suppression: don't take
off steroids quickly!
2.) Hyperglycemia
3.) HTN
4.) Cushing's sx
5.) Cataracts
6.) Osteoporosis
DO NOT reverse airway
remodeling, Nothing Does!
Don't stop therapy abruptly:
adrenal suppression
Increased risk of thrush (Candida)
with ICS only!
~ Chronic ICS causes stunted growth
in kids. 1/2 inch!
ICS take weeks for effects to
start
Only give for 5-10 days unless
Step 6
SABA > 2x/week = poorly
controlled
Don't give to kids!
~ Cardiac: increased HR, contractility,
CO
~ Hypokalemia: Beta-2R in skeletal
muscle retain K+
~ Skeletal muscle tremors
~ Hyperglycemia: Beta-2R in liver
dilate hepatic arteries and stimulated
gluconeogenesis
CI w/ arrythmias
~Increased risk of death
for LABAs when used
alone. (acute asthma
attack)
CNS: sedation
Heart: tachycardia (block PSNS)
Systemic: dry mouth, constipation,
urinary retention
Don't use in 70 year old
w/ BPH and difficulty
peeing
Lots
~ Heart: tachycardia/arrhythmia
~ CNS excitation: headache, insomnia,
seizures
~ Systemic: increased HCl in stomach,
diarrhea
Narrow TI
Very few! Only taken orally!
Significant risk of anaphylaxis
~ killed several young women
Very expensive $$$
~ Inject sub-Q 2x/month to
prevent IgE from getting to mast
cells
Very Safe!
No longer available via inhaler
due to flourocarbon regulations.
Nebulizer only
Lots: weight gain, dry mouth,
constipation, urinary retention (BPH),
glaucoma, blurry vision, orthostatic
hypotension
Use orally for allergic rhinitis,
allergic conjunctivits, and acute
urticaria
~ Use intranasal for allergic
rhinitis (oral don't relieve
congestion)
orthostatic hypotenstion due to alpha-
blocking effects
Beware of hypertensive effect!
~ Rebound hyperemia (if used
intranasally > 3-5 days)
Used to make amphetamines
CI with use of MAOI!
CI in pt with Seizure
disorder
Exacerbates psych sx
Pharmacology: Antivirals
Varicella Zoster Virus Vaccines:
Varivax
Zostavax
Anti-virals
Vidarabine
Acyclovir (Zovirax)
Valacyclovir (Valtrex)
Famciclovir (Famvir)
Cytomegalovirus Ganciclovir
Valganciclovir
Foscarnet
Cidofovir
Influenza Vaccines
Flumist (4 strains)
FluBok (RIV3)
Anti-virals
Amantadine/Rimantidine
Zanamivir
Oseltamivir (Tamiflu)
Respiratory Syncitial Virus (RSV) Vaccines
NO VACCINE AVAILABLE
Therapies
RespiGam
Palivizumab
Human Papilloma Virus (HPV) Vaccines
Gardasil
Cervarix
Hepatitis Vaccine:
Hep A (Havrix)
Hep B (Heptavax)
Anti-virals
Interferon-2-alpha
Lamivudine
Adefovir
Entecavir
Tenofovir
Ribavirin
Pegylated interferon (pegasus)
Boceprevir
Telaprevir
Human Immunodeficiency Virus
(HIV)
Nucleoside Reverse Transcriptase Inhibitors
Retrovirus (RNA to DNA to RNA) Abacavir
Reverse transcriptase Tenofovir
Targets CD4+ cells (mostly T cells) Lamivudine/Zidovudine (Combivir)
Non-nucleoside Reverse Transcriptase Inhibitors
Nevirapine
Efavirenz
Relpivirine
Etravirine
HIV Protease Inhibitors
Lopinavir/Ritonavir (Kaletra)
Atazanavir
Darunavir
Ritonavir
Entry Inhibitors
Fuzeon (T20)
Maraviroc
Integrase Inhibitors
Raltegravir
Primary Use Mechanism Clinical notes
Varicella Vaccine
Live guinea pig-attenuated vaccine
to prevent primary VZV infections
Can be used w/in 36 ours as post-
exposure prophylaxis. Does not
change frequency of getting shingles
Shingles vaccine
Live-attenuated vaccine for
prevention of shingles in patients
above 50-60
51% reduction in shingles, 67%
reduction in post-herpetic neuralgia
HSV/VZV antiviral
Prototypical HSV antiviral;
replaced by acyclovir
IV preparation only, M suppression
and neurotoxicity
Anti-viral for primary
varicella, shingles, and all
forms of HSV
Acyclic Guanine analog. Targets
viral DNA polymerase. Activated
by viral thymidine kinase (via
phosphorylation)
Low bioavailabilty and high Vd. 3-5hr
half-life
Approved for primary
varicella, shingles, and
acute/recurrent HSV
Prodrug form of acyclovir, 99%
activated by the liver
Higher bioavailability and longer
T1/2. Longer dosing interval
Shingles and
acute/recurrent HSV
Prodrug form of penciclovir: when
activated in liver becomes a
competitive inhibitor of viral DNA
polymerase
Only available orally
100x better vs CMV than
acyclovir
Phosphorylated by viral + cellular
kinases. Competitively inhibits
viral DNA polymerase
Oral bioavailability only 5-10%, IV use
only
CMV prodrug of ganciclovir 60% bioavailability
Treating resistant
viruses: CMV, HSV,
Influenza, HepB, HIV
directly inhibits DNA polymerase
by blocking pyrophosphate
binding site
used to treat acyclovir/gancyclor
resistant viruses. IV only
used to treat resistant
CMV retinitis
Nucleotide analogue of cytosine;
does not need viral TK
recommended for all > 6 months
recombinant HA vaccine useful for egg allergies
Influenza A
Concentration dpdt:
Low: Inhibits ion channel of M2
protein preventing viral uncoating
High: increase pH in lysosome to
inhibit viral membrane fusion
No longer recommended as >90% of
viruses are resistant
Influenza A + B Neuraminidase enzyme inhibitor inhaled powder
Influenza A + B Neuraminidase enzyme inhibitor Oral
prevent RSV in high-risk
infants
RSV Immune Globulin IV monthly
prevent RSV in high-risk
infants
RSV monoclonal antibody IM injection
prevent high risk HPV
16/18 for cancer and
6/11 for genital warts
Made from virus-like particles of
the major capsid (L1) of HPV,
stimulates humoral immune
response
recommended in girls age >9, can be
used in boys too
prevent high risk HPV
16/18 for cervical cancer
same ONLY recommended in girls
indicated for people traveling to
endemic areas
IM injection x3, recommended for
everyone
Hep B, Hep C
Increase NK and CD8+ T cell
activity, cytokine induction
resistance is common
Hep B
Nucleoside analogue,
competitively inhibits reverse
transcriptase
Prototype Hep B drug
Lamivudine resistant Hep
B
nucleotide analogue,
phosphorylated to inhibit viral
DNA polymerase and HBV reverse
transcriptase
2nd line therapy, not primary
Lamivudine resistant Hep
B
nucleoside analogue 30-100x more potent than limivudine
Hep B, HIV
nucleotide analogue, develoed for
HIV
superiro to Adefovir, no resistance
Hep C Used with Pegasus
Heb B, Hep C
Increase NK and CD8+ T cell
activity, cytokine induction
Used with Ribavarin
Hep C Protease inhibitor
Hep C Protease inhibitor-NS3
Used with interferon and ribavirin,
70-80% effective at CLEARING HCV
Greater affinity for reverse
transcriptase than DNA polymerase
HIV
nucleoside analogue, IC
phosphorylation, inhibits reverse
transcriptase
HIV
nucleoside analogue, IC
phosphorylation, inhibits reverse
transcriptase
HIV
Zidovudine is the commonly ref.
"AZT"
No phosphorylation needed, non-
competitive RT inhibitors
a single mutation can cause
resistance to the whole class
HIV
HIV
HIV mutation can cause etravirine to fail
HIV
most sensitive/effective, even with
mutations
inhibits HIV protease, prevents
assembly of viral core proteins,
prevents maturation of infectious
virus
These drugs are metabolized by and
inhibit the Cyt P450 system: impt
implications for other drug
interactions
HIV Use during pregnancy
HIV
HIV
HIV role as pharmacoenhancer
use with other drugs to slow down
metabolism, increase 1/2 life
HIV
Binds gp41, prevents
conformational change that allows
virus to fuse with cell membrane
HIV CCR5 inhibitor not effective vs. CXCR4 virus
HIV
Inhibit catalytic activity of HIV-1
integrase: prevents insertion of
linear HIV-1 DNA into host
genome. Effective vs. resistant
viruses
protype drug for this newest class of
antiretrovirals, take with food
(dramatically increases availability)
Side Effects
Nephropathy and
encephalopathy when
given high doses by IV
Very similar to acyclovir
Very similar to acyclovir
Bone marrow suppression,
renal toxicity, teratogenic
same as ganciclovir
Narrow TI: renal toxicity,
chelates divalent metal
ions (give Ca, K, Mg with
drug), seizures, numbness
renal toxicity
Side Effects
CNS toxicity
asthma exacerbation
Delirium, self-harm,
suicidal ideology
Side Effects
Side Effects
Side Effects
few
increase creatinine
GI, photosensitivity
hemolytic anemia, flu-like
sx, teratogenic
Flu-like sx from cytokines,
cytopenias
anemia
rash
Side Effects
~ All can cause potentially
fatal lactic acidosis with
hepatic steatosis
(mitochondrial toxicity)
- Central fat accumulation
and hyperlipidemia
FATAL hypersensitivity
rexn (screen for HLA
B5701 genotype) , liver
disease, lactic acidosis,
redistribution of body fat
renal toxicity, Fanconi-like
syndrome
Hematologic toxicity
(neutropenia, anemia),
lactic acidosis and
hepatomegaly
Rash and Cytochrome
P450 effects
(hepatotoxicity)
severe hepatotoxicity
psych/CNS sx, teratogenic
failure leads to resistance
of other NNRTIs,
depression
GI, insulin resistance,
hyperglycemia/lipidemia,
hepatotoxicity, drug/drug
interactions!
GI intolerance
asymptomatic
hyperbilirubinemia
rash
GI
MOA Class of Drug Drug Name
Inhibits synthesis or
damages the cell wall
Beta-Lactams
Penicillins
~ Natural Penicillins Penicillin G/V
~ Anti-Staph Penicillins
(Resistant to penicillinase!)
Nafcillin
~ Aminopenicillins
(Broad Spectrum, 2nd Gen)
Ampicillin/Amoxicillin
Anti-Microbials
Anti-Pseudomonas Penicillins
~3rd/4th Gen
Piperacillin
Cephalosporins
1st Gen Cefazolin
2nd Gen Cefoxitin
3rd Gen Ceftriaxone, Ceftazidime
4th Gen Cefepime
5th Gen Ceftaroline
Carbapenems
Imipenem, Meropenem,
etc
Monobactams
~Resistant to penicillinase, but
may be degraded by other beta-
lactamases
~ Not active against
enterococci
Aztreonam
Beta-Lactamase Inhibitor +
Beta-Lactam Combos
Amoxicillin/Clavulanate
(Augmentin)
Piperacillin/tazobactam
Glycopeptides Vancomycin
Bacitracins
Fosfomycin
Isoniazid Isoniazid (INH)
Ethambutol Ethambutol (EMB)
Echinocandins
Caspofungin
Micafungin
Anidulafungin
Inhibit synthesis/Damage
Cell Membrane
Polymyxins Colistin
Lipopeptides Daptomycin
Lipoglycopeptides Telavancin
Pyrazinamide Pyrazinamide (PZA)
Polyene Antifungals Amphotericin B
Azole Antifungals
Fluconazole
Itraconazole
Voriconazole
Posaconazole
Terbinafine Terbinafine
Cyclopirox Penlac
Inhibit Ribosomal
Transport and/or
Translation and/or
Protein Synthesis
Rifampin & derivatives
Rifampin (RIF)
Rifabutin
Aminoglycosides
Streptomycin
Gentamicin
Macrolides
Erythromycin
Clarithromycin
Azithryomycin
Fidaxomycin
Ketolides
Chloramphenicol Chloramphenicol
Clindamycin Clindamycin
Tetracyclines
Doxycycline
Tigecycline
Streptogramins
Quinupristin +
Dalfopristin (Synercid)
Oxazolidinones Linezolid
Mupirocin
Inhibit DNA
Synthesis/Metabolism
Fluoroquinolones
Non-Respiratory (older) Ciprofloxacin
Respiratory (newer)
Levofloxacin,
Moxifloxacin
Metronidazole
Flucytosine
Interfere with Microbial
Folic Acid Synthesis
Sulfonamides
Trimethoprim
Misc and/or Poorly
Understood Mechanisms
Griseofulvin
Pentamidine
Bedaquiline
General Class Notes
9 Mechanisms of Antibiotic Resistance (either Chromosomal or Plasmid)
1.) Production of enzymes that block or destroy antibiotics: e.g. penicillinase
2.) Develop membrane impermeability
3.) Active efflux of drug
4.) Alterations of ribosomal target so antibiotic can't bind
5.) Alteration of cell wall precursor target
6.) Alteration of target enzyme
7) Overproduction of target enzyme: overwhelms antibiotic
8.) Overproduction of competing substrate
9.) Auxotrophs that bypass the inhibited step: especially seen in using sulfonamides
Superbugs
~ Produce NDM-1 Beta-lactamase via plasmids: bacteria resistant to most/all available antibiotics
Anti-Tuberculosis Drugs
~ Always do quad therapy
1.) 1st line drugs: INH, RIF, PZA, EMB
2.) 2nd line drugs: aminoglycosides, capreomycin, cycloserine, entionaminde, FQs, Linezolid
Clinical Application Mechanism
Bactericidal
Active against aerobic and anaerobic
Gram(+) streptococci and some others
(Neisseria, Spirochetes,
Corynebacterium, Clostridium,
Actinomyces)
Antistaphylococcal, used to treat MRSA
~MRSA can also become resistant to
these penicillins via PBP mutations
Gram(+) infections
~Used to treat enterococcus faecalis
and Listeria monocytogenes
Anti-Microbials
Bind to Penicillin Binding Proteins
(PBPs) in the cell MEMBRANE (even
though site of action is the cell wall)
~ Most impt is transpeptidase which
strengthens peptidoglycan structure of
cell wall
~ Binding to transpeptidase triggers
autolysis of bacterial cell
Extended spectrum vs. Gram (-)
~Used for Pseudomonas aeruginosa
~ Administered via IV at high doses:
risk of CNS toxicity
Primary used for community acquired
enteric infections
Best vs. Staph (Gram+) and Gram(-)
enteric bacteria
Good vs. Gram+, Gram-, and some
anaerobes (EXCEPTION!)
Best against Gram(-) including
Pseudomonas aeruginosa (w/
aminoglycosides)
~Only cephalosporins to cross BBB-
treat meningitis
~ Less effective vs. Gram(+)
Even better vs. Gram (-) bacteria
~ Only cephalosporins good vs. PRSP,
MRSA, VRSA, VISA, and enterococci
Wide antibacterial spectrum including
Staph aureus and Pseudomonas. (Not
good vs. enterococci, MRSA, and PRSP)
~ Good for bone/soft tissue infections,
GYN infections, intra-abdominal sepsis
~ Good for CNS infections, pneumonia
and endocarditis (except enterococci)
~ Good alternative to multi-drug
therapies in polymicrobial infection
~ Used for A. baumannii
cell wall
Spectrum limited to Gram (-) aerobic
bacteria: Pseudomonas, Haemophilus,
Neisseria
~ Crosses BBB, good for meningitis
~ May be effective against NDM-1 beta-
lactamase producing bacteria
~Effective vs. beta-lactamase producing
strains of Staph, Haemo. Influenza, N.
Gonorrhea, E. Coli, and anaerobes
~Useful to treat diarrhea, C. difficile
enterocolitis, allergic rxns, and skin rash
Effective vs. Gram (+) strep, Gram (-)
enteric bacilli, Staph, and many
anaerobes
~ maybe vs. Pseudomonas aeruginosa
Primarily vs. Gram (+); includes MRSA,
PRSP, enterococci
~ Active vs. C. difficile
~ Does cross BBB: useful for meningitis
Bactericidal
Inhibits cell wall synthesis by blocking
incorporation of murein monomers
into peptidoglycan chain-Prevents
counteraction of osmotic gradient!
~ Synergistic w/ aminoglycosides vs.
enterococci and Staph aureus
1st line anti-mycobacterial
Bactericidal
~inhibits catG enzyme that makes
mycolic acids for cell wall
Bacteristatic
~Inhibits arabinosyl transferase
antifungal agents
~ Candida, Aspergillus, Cryptococcus
Bactericidal
Target Cell Wall
~ Blocks fungal glucan syntase
cell wall
Gram (-) only
Useful for Actinobacter baumannii
~ Brought off shelf for superbugs
Bactericidal
Bactericidal vs Gram (+) (MSSA, MRSA,
VRE)
~ Does NOT penetrate alveoli: NOT
used for pneumonia!
Attacks the cell membrane and causes
depolarizatoin of the membrane
potential. Causes leak of ions out of
cell which kills bacteria
~ Used to Treat TB
Bactericidal or static?
Unclear mechanism
Antifungal agent
~ Use against all fungi
~ Synergistic w/ flucytosine,
echinocandins, and voriconazole
~ Antagonistic w/other azoles
Bactericidal/static
Binds to ergosterol leading to ion
leakage through membrane
Antifungals
Block fungal CYP450, leads to
decreased ergosterol
For Candida, Crypto, Coccidiodes
~ Drug of choice for fungal meningitis
~ Not effective for Aspergillus
Use for endemic mycoses, Candida, and
Cryptococcosis
~ Not used for meningitis
Fluconazole + Aspergillus and yeasts
antifungal agent
~ Used for nail infections: Candida or
Trichophyton
Blocks ergosterol synthesis
topical antifungal agent
antimycobacterial agents
Bactericidal: blocks DNA dependent
RNA polymerase
Aerobic, Gram (-) bacilli (UTI,
pneumonia, sepsis)
~ Synergistic w/ penicillins and
vancomycin- allows use against Gram
(+)
Bactericidal
Passively enter Gram (-) bacteria by
passing through hydrophillic porin
protein channels in outer membrane
~Actively transported across inner
membrane: can be blocked by divalent
cations, hyperosmolarity, low pH, and
anaerobiasis
~ Used to Treat TB
~ Irreversibly binds 30S ribosomal
subunit
Most Gram (-) except Neisseria +
Legionella
~ Includes Pseudomonas, Klebsiella,
Proteus, Staphylococcus
~ Irreversibly binds 30S ribosomal
subunit
100x effective vs. Gram (+) than Gram (-
)
~ Also good for mycoplasma, legionella,
and chlamydia
Wider spectrum, including MAI,
toxoplasma gondii, and helicobacter
pylori.
~ Better absorption, tissue penetration,
and half-life than erythromycin
Best absorption, tissue penetration,
and 1/2 life.
~ Spectrum even broader, also includes
H. influenzae, N. gonorrhea, and
Campylobacter.
Best against C. difficile
Wide spectrum AB with lots of side
effects
~ meningitis in dvlping world
Bacteristatic
Inhibits 50S ribosomal
peptidyltransferase
Gram (+) anaerobes and aerobes
Gram (-) anaerobes (especially
Bacteroides)
~ NOT used for Gram (-) aerobes or
mycoplasma
~ Used for severe anaerobic infections
including lung abscesses and intra-
abdominal abscesses
~ Also used for Staph aureus
osteomyelitis
Bacteristatic
Binds 50S ribosomal subunit at same
site as macrolides
~ Binding bacterial 50S ribosomal
subunit: primarily bacteriostatic
~ Poor penetration into CSF/CNS
Many Gram (+) and (-)
~Agents of choice for Rickettsia,
Chalmydial pneumonia, psittacosis, and
early Lyme disease (Borrelia
burgdorferi)
Bacteriostatic
Treat B. anthracis, L. monocytogenes, N.
gonnorhea, R. rickettsii, T. pallidum
Useful for tetracycline resistant
bacteria as well as MRSA, PRSP, and VRE
~ May be effective vs. NDM-1 beta-
lactamase Gram (-) bacteria
Used to treat some species (not all) of
VRE, MSSA, and streptococi
Synergistic combination, bind to
bacterial 50S ribosomal subunit and
inhibit two different steps in bacterial
protein synthesis
~ Effective against ALL species of
resistance: VRE, MRSA, VRSA, VISA, and
PRSP, also mycobacterium
~ Also works vs. VRE meningitis b/c
crosses BBB
~ NOT effective vs. Gram (-)
BacterioSTATIC! (doesnt kill bacteria)
~ same mech as streptogramins
~ Also weak, non-selective MAO-i
Gram (-) bacteria (enteric bacilli,
Salmonella, Shigella, Campylobacter,
Hemophils, and Neisseria)
~ Active vs. IC bacteria (Chlamydia,
Mycoplasma, Legionella, Listeria),
Pseudomonas, S. aureus, and M. TB
Bactericidal
Reversibly inhibit 30S ribosomal
subunit: bacterioSTATIC
~ Often used for Bacillus anthracis
(anthrax)
~ Good for UTIs (Neisseria)
~ Active vs. streptococci, including PRSP
~Able to also treat respiratory infections
Antibacterial and antiprotozoal drug
~ Active vs. anaerobic Gram (+) and
Gram (-)
~ Best bactericidal effect of ALL DRUGS
vs. anaerobes (especially anaerobic
meningitis)
~ Also vs. Trichomonas, Amoeba, and
Giardia (protozoans)
Bactericidal
Enters bacteria and protozoa
~ Undergoes reductive activations:
binds and damages DNA, inhibits helix
Anti-fungal, Antibacterial and
antiprotozoal drug
Converted to 5-Fluorouracil inside
fungal cells, blocks DNA synthesis
Inhihibits dihydropteroate synthetase
in folic acid pathway (initial step)
Inhibits dihydrofolate reductase (2nd
step) in folic acid pathway
anti-fungal
~ 1st line drug for serious cutaneous
infection and T. rubrum
anti-protozoan
anti-mycobacterial: good for resistant
TB
Used together for synergistic effect
(Bactrim)
~ Broad spectrum: many GI, GU, and UR
infections
Inhibit bacterial DNA gyrase: impairs
DNA synthesis and causes rapid death
9 Mechanisms of Antibiotic Resistance (either Chromosomal or Plasmid)
1.) Production of enzymes that block or destroy antibiotics: e.g. penicillinase
2.) Develop membrane impermeability
3.) Active efflux of drug
4.) Alterations of ribosomal target so antibiotic can't bind
5.) Alteration of cell wall precursor target
6.) Alteration of target enzyme
7) Overproduction of target enzyme: overwhelms antibiotic
8.) Overproduction of competing substrate
9.) Auxotrophs that bypass the inhibited step: especially seen in using sulfonamides
Superbugs
~ Produce NDM-1 Beta-lactamase via plasmids: bacteria resistant to most/all available antibiotics
Anti-Tuberculosis Drugs
~ Always do quad therapy
1.) 1st line drugs: INH, RIF, PZA, EMB
2.) 2nd line drugs: aminoglycosides, capreomycin, cycloserine, entionaminde, FQs, Linezolid
Metabolism/Pharmacoki
netics
4-membered N-containing ring =
beta-lactam
CI in anyone with prior
allergic rxn
Excreted Renally with some
hepatic inactivation
~ Renal dose adjustment in
moderate renal failure
1.) Hypersensitivity: all
penicillins cross react allergically.
May also cross react with other
beta-lactams
2.) CNS toxicity-seizures
3.) GI (Clostridium difficile
outgrowth after ampicillin)
4.) non-allergic skin rash
CI in pt with CHF b/c
causes Na+ overload and
pulmonary edema. DO
NOT give with ACE-i
~ Hypokalemia can cause
arrythmias
~ High doses require
adjustment for renal
failure
Contain 6-membered sulfur ring
Renal Metabolism: Must dose
adjust with renal insufficiency
~ Resistant to penicillinase!
~ May cause seizures in pt w/
meningitis
~ 20% cross rx w/ penicillin
allergies
Excreted Renally with some
hepatic inactivation
~ Renal dose adjustment in
moderate renal failure
1.) Hypersensitivity: all
penicillins cross react allergically.
May also cross react with other
beta-lactams
2.) CNS toxicity-seizures
3.) GI (Clostridium difficile
outgrowth after ampicillin)
4.) non-allergic skin rash
~Mostly renal, some hepatic
~ Ceftriaxone is NOT excreted
renally and doesnt need dose
adjustment in renal failure
~ Can cross react with penicillins
~ Clostridium difficile outgrowth
~ 3rd Gen: Can precipitate in
lungs/kidneys when given with
Ca2+ solutions: CAN BE FATAL!
~ Clavulunate has no intrinsic
antibiotic activity. Only protects
vs. beta-lactamases
Renal dose adjust
~Poorly absorbed, must give IV
unless vs. C. Difficile
~ Ototoxicity: esp in renal pt.
Damage auditory nerve
~ Red neck/red man syndrome:
flushing of neck/face after IV
infusion
Metabolized by liver, renal
excretion (w/ Vit B6)
~ Renal + Liver Dose adjust
Early hepatotoxicity
Pyridoxine-associated peripheral
neuropathy
CI w/ OH and MAO-
inhibitors
CI with Pyridoxine
Renal
~ Decreased visual acuity (loss of
red/green vision)
Hepatic
Histamine Rxn: flushing, nausea,
face swelling
~ Liver, anemia, GI
Diarrhea, Clostridium difficile
outgrowth, allergic skin rxn
Neurotoxic
Renal tubular necrosis
~ Don't adjust for hepatic
insufficiency
~ GI toxicity, C. difficile
enterocolitis, myopathy,
peripheral neuropathy, CNS sx
(dizziness, headache, insomnia)
~ Increased risk of dyspnea,
cough, and eosinophyllic
pneumonia b/c of poor alveolar
penetration
CI in pt taking statins:
increased risk of
myopathy
~ CI for pneumonia
Renal
~ Hepatotoxic
~ Blocks Uric Acid excretion =
gout
Renal
1.) Nephrotoxic (80%)
2.) Anemia, hypokalemia,
hypomagnesemia, phlebitis
3.) Acute febrile reaction: N/V
Metabolized by CYP3A4 in liver
~ drug interactions with statins:
increase [ ] of both drugs
Renal
~ Good CNS penetration
Very few
Liver
~ poor CNS penetration
Hepatic and GI toxic
Very few
Liver and Renal
~ Dramatic increase in CYP-450
interactions
Headache, rash, GI
Bad Taste
~ Pancytopenia
~ Anaphylaxis
Liver
Hepatoxic
~ Urine/sweat/tears turn orange
Exclusively renal elimination: dose
adjustment necessary
Doesnt cross BBB
~ Permanent nephrotoxicity
~ Ototoxic (vestibular +
auditory)
~ neuromuscular blockade (can
cause respiratory paralysis)
CI in pregnancy:
accumulates in fetal
plasma and amniotic fluid
CI in myasthenia gravis:
respiratory paralysis
causes death
Ototoxic
Nephrotoxic
CNS Effects
GI (oral), thrombophlebitis (IV)
~ CYP450 interactions
CI in pt on 2nd Gen anti-
histamines: CYP450
interaction can cause
prolonged QT interval,
may progress to V Tach
(Torsades des Pointes),
Vfib, or death
CYP450 drug interactions
Does NOT inhibit CYP450
~ No dose adjustments needed
Only active in GI system, poorly
absorbed
~ Highly potent but can lead to
fatal aplastic anemia (-->
leukemia)
~ Gray baby sx (UDP glucorynyl
transferase)
Hepatic metabolism: dose adjust
as needed
~ Highly concentrated in
abscesses and bones
~ Doesnt cross BBB
~ 10% of pt develop C. difficile
enterocolitis
~ 20% get severe diarrhea
Inhibits CYP450 = drug
interactions
~ Erythromycin: metabolized by
liver
~ Clarithromycin: renally
metabolized
Hepatobilliary or fecal: no dose
adjustment needed
~ CYP450 induction can shorten
1/2 life when used with
barbiturates or phenytoin
Excreted in bile: dose adjust in
severe LIVER disease
CI in pregnancy and
nursing mothers
~ Inhibit CYP450 enzymes: drug
interactions!
~ Prolong QT interval at high
doses: may lead to V tach
(Torsades des Pointes) or V fib
No dose adjustments necessary
~ May cause GI toxicity,
reversible thrombocytopenia,
elevated liver enzymes, and
leukopenia
~Serotonin syndrome: reaction
with MAO-is and tyramine foods
can cause high fever, HT,
convulsions, and death
CI in pt taking other MAO-
Inhibitors or eating lots
of tyramine:
accumulation of serotinin
can be toxic
GI irritation, hepatic toxicity
~ Impaired bone/teeth
development
~ C. difficile enterocolitis
Renal EXCEPT Moxifloxacin
~ Wide tissue perfusion, including
CSF, brain, and placenta
~ Dose adjust for LIVER and
KIDNEY
Carcinogenic
~ GI irritation, neuropathy, CNS
toxicity
CYP450 interactions inhibit
warfarin metabolism
CI in Pregnancy:
mutagenic and
carcinogenic
Renal
BM Suppression
GI and Liver toxic
CYP450 drug interactions
~ Displace GABA from CNS
receptors: leads to seizures +
other CNS effects
~ Tendinopathy: ruptured
Achilles or diplopia
~ C. difficile enterocolitis
Renal, but no dose adjustments
necessary
Hypersensitivity rxn common
~ Hemolytic anemia via G6PD or
AI mechanisms
~Hyperkalemia may result since
trimethaprim inhibits Na-K
CI in pt on ACE-Is or ARBs
b/c of increased risk of
hyperkalemia
Resistance
Therapeutic
Considerations
Penicillin Allergies
1.) Type I Hypersensitivity:
rashes, hives, diarrhea (IgE +
mast cells)
2.) Type II hypersensitivity: bind
to RBCs, causes hemolytic
anemia
~ Can try to desensitize and
treat sx w/ diphenhydramine
~ Staph and some Gram(-)
produce penicillinase =
resistance
~ Penicillin resistant Strep
Pneumoniae (PRSP)-alteration
in PBP (Not penicillinase)
~MRSA-mechanism is altered
PBP
~ Resists penicillinase!
Susceptible to penicillinase
~ Good that they enter
CSF b/c they can treat
CNS infections
~ Safe for pregnancy
even though they cross
placenta
Susceptible to penicillinase
~ Agent of choice for Gonorrhea
(usually in combo with
Azithromycin or Doxycycline)
IV only, for life threatening
infections
Must be given parenterally
~ Good that they enter
CSF b/c they can treat
CNS infections
~ Safe for pregnancy
even though they cross
placenta
IM or IV only (except
inhalatation for P. aeruginosa in
Cystic Fibrosis)
~ Very little cross reactivity w/
other beta-lactams
~ Resistance is developing via
plasmids, especially in
enterococci. Also VRSA and
VISA are emerging.
~ Narrow TI! Monitor blood
levels
mutations in catG enzyme Always give w/ Vit B6
IV only
Prevent access to cell
membrane
Pyraminidase mutation
IV only
~ Must inject directly into CSF
for meningitis
Lipid formulations avaiable that
decrease side effects: VERY
expensive!
MIC increases with continued
use (NOT plasmid mediated)
1.) Increased efflux pumps:
~MDR for fluconazole
~ CDR for all azoles
2.) Change in EGR2 receptor
~ increase # or mutations
Minimum Inhibitory
Concentration (MIC): lowest
dose needed for effect
Oral or topical, 2 month half-life
in nail beds
RNA pol mutation
Plasmid-mediated inactivating
enzymes
~ sit in periplasmic space
~Terrible against abcesses b/c
of low pH, hyperosmolarity, low
pO2, etc
~ Bad vs anaerobes as well
~IV only
Narrow TI
Drugs of choice for mycoplasma
pneumoniae, legionella
pneumoniae, diptheria,
pertussis, chlamydia, bacillary
angiomatosis in AIDS pt, and
campylobacter traveler's
diarrhea
Plasmid-mediated
Acetyltransferase inactivates
compound
Drugs of choice for mycoplasma
pneumoniae, legionella
pneumoniae, diptheria,
pertussis, chlamydia, bacillary
angiomatosis in AIDS pt, and
campylobacter traveler's
diarrhea
Widespread resistance is
limiting utility
Parenteral administration only
DNA gyrase mutation: NOT
plasmid mediated
Agent of choice for Salmonella
and Typhoid as well as
traveller's diarrhea
Only given w/ Amphoterocin B
to prevent resistance
Pharmacology: NSAIDs
and Steroids
Primary Use
Acetaminophen
(Tylenol)
~ short term pain relief
Ketorolac
tromethamine
(Toradol)
Aspirin (and other
salicylates)
~ Unstable angina/post MI (low
dose)
Ibuprofen (Motrin,
Advil, Nuprin)
~ Good for primary dysmenorrhea
Analgesic Indication Only
Analgesic & Anti-Inflammatory
Naproxen (Naprosyn)
& Naproxen sodium
(Anaprox)
~ Good for primary dysmenorrhea
Ketoprofen
Diflunisal (Dolobid)
Rofecoxib (Vioxx)
Indomethacin (Indocin)
~ Patent ductus arteriosus in
neonates
Sulindac (Clinoril)
Celecoxib (Celbrex)
Prostaglandins (PGs)
Not a drug, key molecule in
inflammatory response
Steroids in General
~Endocrine disorders (Addison's)
~ Allergy, asthma, arthritis,
dermatitis, shock, leukemia
Cortisol
Steroids
~ Chemical group substitutions to
cortisol nucleus impact
pharmacokinetics
~ Fluorine at position 9 = greater
mineralo/glucocorticoid properties
~Methyl at position 16 = less
mineralocorticoid
~ Glucocorticoid potency = anti-
inflammatory potency
~ Useful for endrocrine disorders:
Addison's disease (adrenal or
pituitary insufficiency).
~Watch for withdrawl when
stopping steroids due to depressed
feedback: tapered drop off when
taking off meds
Analgesic & Anti-Inflammatory
Anti-inflammatory only
Aminoglutethimide
~ chemical adrenalectomy: used to
treat Cushings and stop all steroid
production
Metyrapone ~ reduce cortisol levels
Cortisone Short acting steroid (8-12 hrs)
Fludrocortisone
Replace aldosterone in Addison's
and salt-wasting adrenal
hyperplasia
Prednisone
Used for asthma, COPD,
autoimmune disorders, allergies, etc
Triamcinolone ~ Intermediate half life, 12-36 hrs
Dexamethasone ~ Long lasting, 36-72 hrs
Steroids
~ Chemical group substitutions to
cortisol nucleus impact
pharmacokinetics
~ Fluorine at position 9 = greater
mineralo/glucocorticoid properties
~Methyl at position 16 = less
mineralocorticoid
~ Glucocorticoid potency = anti-
inflammatory potency
~ Useful for endrocrine disorders:
Addison's disease (adrenal or
pituitary insufficiency).
~Watch for withdrawl when
stopping steroids due to depressed
feedback: tapered drop off when
taking off meds
NSAIDs target COX, but not LOX
~ Causes decrease in thromboxanes
(platelet
aggregation/vasoconstriction),
decrease in prostacyclin (vasodilation,
platelet inhibition).
~ No effect on leukotrienes (from LOX,
responsible for anaphylaxis)
COX-1 is in all cells
COX-2 is only inducible and only in
inflammatory cells
~ Not good in acute pain: only act in
the inflammatory response by
inhibiting PG production
~ COX potency does NOT predict
analgesic ceiling
Mechanism Clinical notes
~ Largely unknown: not a true NSAID
b/c it is only a very weak COX-inhibitor.
May bind COX-3 (speculative)
~ Weak base: not highly bound to
albumin and not efficiently delivered to
site of inflammation
~ not good for chronic arthritis b/c 1.)
you can't take it chronically and 2.) it
doesnt target COX1/2
~ Good to use in asthmatics: no risk
of hypersensitivity!
~ Safe for kids, pregnancy, renal
disease
IM Injection, similar effect to
morphine
~ No respiratory depression, good
alternative to narcotics
~ IRREVERSIBLE COX-1 inhibitor:
however endothelial cells will produce
more COX. Platelets are anucleated
and thus are permanently inhibited
~ First order kinetics at low doses but
zero-order at high doses: saturates
liver enzymes
~ propionic acid
~ analgesic ceiling similar to
aspirin+codeine
aspirin+codeine
12 hr half life
aspirin+codeine
short half life
~ Another type of salicylate: higher
analgesic ceiling and 1/2 life than
aspirin
COX-2 inhibitor
Removed from market due to CV
toxicity
~ Acetic acid
~Potent COX inhibitor
~ low dose b/c it is the MOST POTENT
of all NSAIDS
~ Slower onset of action b/c prodrug
~ Prodrug, prevents GI side fx
~ Renal sparing! Metabolized by
CYP450 in liver back to inactive form
before kidney
COX-2 Inhibitor Black box warning
vasodilation, increase vascular
permeability, chemoattractive,
pyrogenic, exacerbate pain response of
bradykinin, influence immune cell
interactions
PGs are common target for drugs b/c
of their ubiquitous role in
inflammation
~ Lipophylic, pass through membrane
and bind to IC receptors. Cross into
nucleus and modify gene transcription
of cytokines and PGs.
~ Inhibit phospholipase A2, decreasing
arachadonic acid (precursor to LTs,
PGs, and TXs)
~ Inhibits membrane adhesion of
leukocytes
~ Can be used in patients who are
hypersensitive to NSAIDs b/c
upstream of COX
~ Starting product is cholesterol:
shared enzyme synthesis with
gluco/mineralocorticoids and
androgens
~
~ Produced by adrenal cortex
~ Released with Circadian Rhythm:
highest in morning, declines in day,
increases in sleep
~ Lack of circadian rhythm =
Cushing's Disease
~ prevents conversion of cholesterol to
pregnenelone via competitive
inhibition
~ compensatory rise in ACTH due to
lack of feedback can overcome
aminoglutethimide
~ inhibits final conversion to cortisol
~ causes accumulation of inactive
substrate which should increase ACTH
levels.
~ useful diagnostic for pituitary
problem if no increase in ACTH
~ Potent mineralocorticoid, 250x
aldosterone, 10x cortisol
Synthetic corticosteroid, 4x stronger
than cortisol
~ Potent glucocorticoid, 30x effect of
cortisol, no mineralocorticoid effects
~ GI side effects: Gastric ulcers/bleeds,
heartburn, nausea, indigestion
~ 17,000 peple die from GI side effects of NSAIDs
every year
~ Renal toxicity: decreased RBF, necrosis,
hyperkalemia, blunting of AH and diuretic drugs
~Hypersensitivity: especially in asthmatics (not
acetaminophen). Shunt theory: increase LOX
causes more LT and vaso/brochoconstriction
~Pregnancy: risk of maternal/fetal hemorrhage,
not teratogenic
~ Bumping effects: when given with other drugs,
can "bump" them off serum proteins and cause
dramatic increase in serum concentration
(Coumadin, PHenytoin, Tolbutamide)
~ Gastric Ulcers: due to
concentration of NSAIDs by gastric
epithelial cells: inhibits mucus,
causes bicarb secretion.
~Methods to block this (H2
antagonists, gel coatings, GI sparing)
have all been ineffective
Side Effects
Liver toxicity (w/ prolonged use)
Acetaminophen overdose: toxic
metabolite (NAPQI) made by P450
can no longer be conjugated
because enzyme is overloaded.
Causes liver necrosis. Treat with N-
acetyl-cysteine immediately
~38% of all acute liver failure!
Reye's syndrome: can occur in children
who receive aspirin when recovering
from viral infection. Causes vomiting,
lethargy, elevated liver enzymes, and can
progress to coma/death
~ ASA poisoning: tinnitus, dizziness,
nausea, respiratory alkalosis. Can
lead to metabolic acidosis/ketosis
and coma/seizures/CV collapse.
~Treat by raising pH of urine to
increase excretion of salicylate
Cardiac toxicity (essentially opposite effect of
aspirin b/c platelets dont have COX-2)
Cardiovascular
~ GI (ulceration, hemorrage)
~ CV (HT, edema): compounded by
mineralocorticoid action and increased
cathecholamine synthesis
~ Contraindicated in peptic ulcers, HT, infection,
diabetes, glaucoma, psychosis, osteoporosis
Approved Therapeutic
Used for NSAIDS
NSAIDs vs. Narcotics
~ Together have additive
analgesic effect
~ NSAIDs do not cause
tolerance
~ NSAIDs aren't addictive
~No dependence liability
with NSAIDs
Inflammation
Acute/Chronic Pain
Fever
Primary Dysmenorrhea
Inflammation
Acute/Chronic Pain
Fever
Primary Dysmenorrhea
Pharmacology:
Oncology Drugs
All cytotoxic anti-cancer drugs
target All proliferating cells.
Cause of toxicity
Methotrexate
Leucovorin
5-Fluoro-Uracil
Doxorubicin (Adriamycin)
Irinotecan
Cyclophosphamide
Mechlorethamine
Cisplatin
Vincristine (Oncovorin)
Paclitaxel
Targeted Antibodies
DNA-Crosslinking
Mitotic Spindle
Topoisomerase inhibitors
Anti-metabolites
Growth Factor Antibody Bevacizumab
Cetuximab
Trastuzumab
Rituximab
Ipilimumab
Anti-PD1
Small-molecule signaling
inhibitors
Gefitinib/Erlotinib
Lapatinib
Sorafenib/Sunitinib
Imatinib
Vemurafenib
Bortezomib
Immunosuppressant Drugs
Small molecules
Cyclosporine
Tacrolimus
Sirolimus (rapamycin)
Growth Factor Receptor
Antibodies
T-cell Modulators
Azathioprine
Antibodies
Basiliximab
Daclizumab
Mechanism Primary Use
Acts on dihydrofolate reductase (DHFR) to
inhibit production of HF4, a necessary co-factor
for the conversion of dUMP to dTMP
an HF4 analogue, it enhances 5-FU and
diminishes effect of methotrexate
1.) used to enhance the effect of 5-FU by
inhibiting TS
2.) used to "rescue" bone marrow and GI
tissue from complete suppression via
methotrexate
Inhibitor of thymidylate synthase, prevents
coversion of dUMP to dTMP
used for colorectal cancer
used for breast cancer
used to treat colon cancer
prodrug, metabolized by liver: causes DNA
alyklyaton and crosslinking making replication
difficult
prodrug administered orally
~ Used in hematologic, breast, and Hodgkins
DNA cross-linking used in Hodgkin's lymphoma
Causes DNA adduct formation, otherwise
similar to Cyclophosphamide and
mechlorethamine
solid tumor breast cancer
Mitotic spindle poison, Inhibits Microtubules,
arrest cells in M-phase
Mitotic spindle poison, Enhances Microtubule
formation, arrest cells in M-phase
Cause DNA strand breaks during replication
~useful vs. solid tumors
Anti-VEGF Ab
~Angiogenesis Inhibitor
~ O2 deprived tumor cells activate HIF-1
(hypoxia induced trancription factor) to
upregulate VEGF
Used for macular degeneration
Anti-EGFR antibody
Treat EGFR colon cancer w/o KRAS mutation
~Used in many solid tumors w/o KRAS
mutation
Anti-HER2 Ab used in HER2+ breast cancer
Anti-CD20 Ab used in B-cell leukemias
Anti-CTLA-4 receptors on T-cells
~ encourages formation of CD8+ T cells
~ prevents binding of B7 ligand
Anti-PD1 targets PD-1L, a late co-inhibitory
signal in T-cell activation
metastatic melanoma, and many others
Less-specific targeting, more side fx
Anti-EGFR kinase
Used in many cancers: must treat T790M
lung cancer with erlotinib
Targets HER2 kinase
Anti-VEGFR, PDGFR and kit
Anti-ABL, kit, PDGFR Used to treat CML (BCR-ABL kinase)
Anti-BRAF kinase Used in metastatic melanoma
Proteosome Inhibitor
~ leads to apoptosis
Works well in multiple myeloma
used in prep for transplant
binds mTOR and interferes with T-cell signaling
Binds cacineurin and blocks IL production ,
prevents T-cell activation
prodrug metabolized to mercapto-purine,
inserted into DNA instead of purine, stops
replication of T-cells
Ab that bind CD25 receptor on T-cells, prevents
activation
Clinical notes Side Effects
used in colon cancer or
methotrexate overdose
used in AC combo for breast
cancer
Used in FOLFIRI combination
Principal component of CMF
~Nitrogen mustard from mustard
gas
~ Used in MOPP
renal side effect
Cardio-toxicity
peripheral neuropathy
~used as part of MOPP and CHOP
regimens
~ decreases blood supply to
neoplasms, but also decreases
other chemo delivery
~ can be injected locally in the
eye to prevent angiogenesis in
macular degeneration
Hypertension, decreased survival
time in breast cancer
GI and skin
restores prognosis to HER2(-):
85% survival
Cardiac toxicity (HER2 in heart)
Extremely promising: complete
cure in several cancers
Sx of autoimmune disease
~ T790 mutation makes cancers
resistant to Gefitinib
Skin toxicity (like Cetuximab [EGFR
Ab])
~ most specific of all kinase
inhibitors, fewer side fx
lots of side fx
~ Imatanib resistance almost
always develops. Impt to find
out and change treatment
downstream
Induction of squamous cell
carcinoma
Immunosuppression, nephrotoxic
ura
Immunosuppression, nephrotoxic
General Cancer Notes
Analysis of DNA mutation in
tumors helps decision making
for treatment: eg. HER2, KRAS,
TP53, BRAF, etc
HER2 biomarker is associated
with poor px in breast cancer,
but good target for
Trastazumab
KRAS mutation=bad px in lung
cancer
~EGFR mutations= good
response to TKIs
~BRAF/KRAS mutation = bad px
in colon cancer
~KRAS mutation makes colon
cancer resistant to EGFR Ab
p53 is the most commonly
mutated gene in all cancers
Pharmacology: Cholinergics
Primary Use
Agonists
Acetylcholine neurotransmitter (NT)
Muscarinic Agonists
Metacholine asthma challenge test
Bethanechol
used post-GI surgery to restart
peristalsis
Carbachol Glaucoma
Nicotinic Agonists
Nicotine
Antagonists
Muscarinic Antagonists
Atropine
prevents compensation of PSNS,
dilates pupils
Tolterodine (Detrol) overactive bladder
Nicotinic Antagonists
Curare relax muscles during surgery
Hexamethonium/Trimethaphan Hypertensive shock
Acetyl Cholinesterase Inhibitors
Reversible
Donepezil (Aricept) Alzheimers
Physostigmine Alzheimers and glaucoma
Neostigmine
reverse effects of curare post-
anesthesia
Pyridostigmine
treat myesthenia gravis (MG is
Ab vs NAChRs at the NMJ)
Edrophonium reverse curare effects
Irreversible Organophosphates
Parathion NONE: chemical weapon
Echothiophate Glaucoma
Antidote
Atropine + Pralidoxime Antidote to organophosphates
Mechanism Clinical notes
stimulates NAChRs and MAChRs
~NT for all pre-ganglionic synapses
(NnAChR) and for skeletal muscle
(NmAChR) and for adrenal medulla
(NnAChR)
~Post-ganglionic for PSNS (MAChRs),
Sweat glands (SNS, MAChRs), skeletal
muscleand Adrenal medulla
~ NAChRs require 2 ACh to activate:
more susceptible to blocking
stimulate MAChRs in bronchioles,
causes secretion and constriction
only used for asthma challenge test
opens canal of Schlemm
stimulates NAChRs
causes skeletal muscle contraction,
adrenal stimulation, gangionic
stimulation, and increased HR/BP
competitively blocks MAChRs
causes mydriasis (pupil dilation) and
cycloplegia (loss of accomodation)
when administered via eye drop
~ Used with pralidoxime for
organophosphate antidote
preferentially blocks MAChRs in genito-
urinary system
blocks NmAChRs in skeletal muscle
blocks NnAChRs in ganglia, blocks SNS
tone to blood vessels causing
vasodilation
AChEIs with tertiary N cross BBB,
quaternary N do not
blocks AChE in synapse, increases ACh
availability
tertiary N crosses BBB
increase ACh tertiary N
prevents AChE breakdown of ACh quaternary N
quaternary N
short acting
irreversibly blocks AChE at all synapses,
causes uncontrollable muscle
contraction and secretion
cause of death is usually respiratory
distress
irreversibly blocks AChE only in the eye,
is an ocular anti-hypertensive
given by eye drops
Atropine is a MAChR antagonist so it
inhibits some of the effects of the
excess ACh in the synapse.
Pralidoxime breaks the bond between
the organophosphates and AChE,
allowing them to return to function
administered via auto-injector
immediately after exposure to chemical
agents
Side Effects
Adrenergic Drugs
Agonists Drug Clinical Use
Epinephrine
NT, given following anaphylaxis to open
airways
Norepinephrine (NE) NT, drug of choice for cardiac arrest
Isoproteronol
used in bradycardia/heart block to
increase contractility
Albuterol asthma
Ritodrine asthma and premature labor
Phenylephrine
Clonidine
~Used to treat hypertension, touretts,
and drug withdrawal
~Dose dependent: low dose = lower BP,
high-dose = increase BP
Dopamine NT
L-Dopa Precursor to DA, treat Parkinson's
Dobutamine Increase contractility w/o increasing HR
Tyramine released by gut microbiota,
Ephedrine
weight loss drugs and nasal
decongestants. Starting material for
methamphetamine
Brimonidine
used for open angle glaucoma or ocular
HT
Antagonists
Metyrosine Pheochromocytoma treatment
Amphetamine ADHD and narcolepsy
Phenylzine Depression and Parkinson's
Selegiline
Cocaine drug of abuse
Desipramine tricyclic anti-depressant, ADHD
Theophylline
(Aminophylline)
Asthmatics on beta-blockers
Sildenafil (viagra) erectile dysfunction, pulmonary HT
Propranolol
Metoprolol exercise tolerance beta-block
Pindolol exercise tolerance beta-block
Carvedilol hypertension
Labetalol pregancy HT
Phentolamine Pheochromocytoma treatment
Phenoxybenzamine
Only used to block catecholamine effects
before pheochromocytoma surgery
Prazosin hypertension
Tamsulosin BPH
Mechanism Therapeutic Notes
stimulates all alpha/beta receptors
~DOSE Dependent!
~Low dose: primarily beta-2
~High dose; alpha/beta-1 effects
dominate
~ bronchodilation, glycogen breakdown,
vasodilation in skeletal muscle, increase HR
and contractility
~ Enhances effect of NE
stimulates alpha and beta-1, NOT beta-
2
selective beta-1/2 agonist greater beta effects than NE or Epi
Beta-2 selective agonist bronchodilation and decreased secretion
beta-2 agonist used for premature labor (several weeks)
selective alpha-1 agonist
~ causes vasoconstriction/increase TPR:
compensatory PSNS signal to heart causes
decreased HR and contractility to stabilize
BP
selective alpha-2 agonist, CNS activity
~ at low doses, it activates alpha-2A
receptors first, decreasing SNS tone
~ at high doses, it activates alpha-2B
receptors in vasculature and causes
vasoconstriction
risk of adaptation by increasing SNS
receptors. Quickly stopping drug can cause
dangerous hypertension
~Dose dependent
~ low dose: stimulates D1 in kidney
~ med dose: stimulates beta-1
~ high dose: stimulates alpha-1
low dose=increase blood to kidneys
medium dose=beta-1 effects, increase HR
and contractility
high dose=include vasoconstriction. Used
in show to increase CO and preserve kidney
function
crosses BBB before it is converted to DA
B-1>beta-2 and weak alpha-1
catecholamine releasing agent dangerous with MAOI's, can cause HT crisis
Activates alpha and beta receptors,
increases catecholamine release
Alpha-2 agonist, inhibits cAMP
decrease synthesis of aqueous humor in the
eye
inhibits tyrosine hydroxylase, decreases
all catecholamines
MAOI and blocks re-uptake at synapse.
Also facilitates release of
catecholamines
More potent and addictive than cocaine
MAOI, increase catecholamines at
synapse
watch levels of tyramine and dont take
with demerol.
MAOI-B inhibitor, less risk of tyramine
effects and HT crisis
MAO-A can still metabolise tyramine
serotonin/Epi/NE/DA reuptake inhibitor
increases catecholamines in the synapse.
Can cross BBB and cause addiction via
mesolimbic pathway
NE selective re-uptake inhibitor
Non-selective, competitive PDE
inhibitor. Increase cAMP leading to
bronchodilation
PDE normally removes cAMP. Non-specific
so we also get increased HR and
contractility
Selective PDE-5 inhibitor, increases
cGMP which is only in certain tissues
smooth muscle in penis relaxes allowing
erection, also decreases pulmonary HT and
increases cerebral blood flow
non-selective beta-blocker decrease CO
beta-1 selective blocker
greater exercise tolerace due to continued
beta-2 vasodilation, also better for
diabetics b/c glycogenolysis is less impeded
weak beta-blocker
doesnt slow HR as much but still blocks
increase in HR and CO: less likely to cause
severe bradycardia in pts with HT and low
HR (athletes). Good exercise tolerance
alpha-1 and beta blocker
decrease CO, vasodilation (from alpha-1
block). Decreases morbid/mortality in
heart failure. Antioxidant and decreases
size of heart wall
alpha-1 and beta blocker Uses to treat HT in pregnancy
non-selective alpha blocker
vasodilation. Not used in HT b/c drop in BP
too much. Causes tachycardia to
compensate for alpha block
alpha antagonist (blocker); non-
competitive, irreversible. Alkylates
receptors (including serotonin and
histamine)
alpha-1 antagonist
better than phentolamine because less
reflex tachycardia
alpha-1 antagonist
relaxation of prostate smooth muscle,
trigone muscle of bladder, and urethra.
Less orthostatic hypotension b/c alpha-1
selectivity
alpha-1
alpha-2a
alpha-2b
beta-1
beta-2
beta-3
SNS side effects throughout body
D-1
cardiac arrythmia
reflex tachycardia
vasculature, sphincter,
pilomotor smooth muscles,
prostate
Gq-protein coupled,
increase IP3/DAG
vasoconstriction and muscle
contraction
pre-synaptic SNS nerve
terminals
Gi-protein coupled,
decrease cAMP
decreased NE/Epi, DA, ACh
release, decrease HR
vascular smooth muscle vasoconstriction
heart and kidney
Gs-protein coupled,
increase cAMP
~heart: increase contractility and
nerve conduction velocity
~kidney: increase renin release
vascular, bronchi, uterus,
bladder, skeletal muscle
Gs-protein coupled,
increase cAMP
NOT innervated! Effects due to
Epi release from AM
~relaxes smooth muscles of
vessels and causes vasodilation
~stops secretions in bronchi
~delays labor
~ dilates skeletal blood vessels
Fat cells increase lipolysis
Kidney smooth muscle dilate renal blood vessels
Lipid Lowering Drugs
Atorvastatin (Lipitor)
Simvastatin (Zocor)
Pravastatin
(Pravachol)
Rosuvastatin
(Crestor)
Cholestyramine
(Questran)
Colesevalam
(WelChol)
Fenofibrate (Tricor)
Gemfibrozil (Lopid)
Niacin
~ Targets Adipose tissue to decrease
secretion of hormone-sensitive lipase
leading to decrease plasma free-fatty
acids
~ Decreased hepatic synthesis of LDL
Vitamin B3 ~ Vitamin, not FDA drug
Statins
~ HMG-CoA reductase inhibitors
(competitive)
~ Increased expression of SREBPs which
enhance LDL-R expression: causes liver to
remove LDL from blood
Bile Acid Sequestrants
~ "Bile Acid Binding Resins (BARs)
~ Prevents reabsorption of bile acids
from intestinal lumen which causes
increased LDL-Rs in liver: remove LDL
from blood
Fibrates
~ Fibric acids
~ Mechanism poorly understood, but act
through PPAR-alpha activation (which is a
transcription factor)
~ Upregulate lipoprotein lipase
(required for TG metabolism in blood)
~ Lowers LDL by 15-30%
~ Increases HDL by 3-5%
~ Increases TGs
~ Lower TGs which are
main fuel source of body
and high levels can lead to
heart disease/stroke
~ Decrease TGs 20-50%
~ Decrease LDL by 5-20%
~ Increase HDL by 10-35%
~ First line therapy for
lowering LDL
~ Reduce LDL by 60%,
increase HDL by 10%
~ Reduce TGs by 40%
~ Decreased thrombosis,
inflammation, and plaque
stabilization
Cholestorol Absorption Inhibitors Ezetimibe (Zetia)
~ Cholesterol absorption
inhibitor in GI
~ Mixed w/ statins can
lower LDL by 20-65%
~ No data showing
improved CV outcomes
alone
Fish Oils = Omega-3 Fatty Acids
Lovaza
~ EDA/DHA
~ Decrease total
cholesterol, LDL, TGs, and
increase HDL
~ FDA approved for very
high TGs
Statin +
BAR/Niacin/Ezetimib
e
Additional LDL-C reduction
Statin +
Fibrate/Niacin/Fish
Oil
Combined dyslipidemia
Main Concepts from Lecture
1
2
3
4
5
6
7
8
9
Combo-Therapies
Total Cholesterol: < 200 desirable, 201-239 = borderline high, >240 = high
Triglycerides: normal = < 150, high = 200-499, very high = >500
LDL: <100 = optimal, 100-129 = ok, 130-159 = borderline high, 160-189 = high, > 190 = BAD!!!
HDL: Anything >60 = Good! (Negative risk factor). <40 = low
5 Risk Factors for Heart Attack/Stroke: Family Hx, Smoker, Diabetes, Obesity, HT
Causes of elevated TriGs: Diabetes, renal failure, hypothyroid, OH excess, Px, Hep, Lupus
Causes of hypercholesterolemia: Hypothyroid, anorexia, nephrotic syndrome
~ High cholesterol in plasma = progression of atherosclerosis
Apolipoproteins: Made by liver, help keep cholesterol (hydrophobic) soluble in blood
~ Major Apo associated with LDL is ApoB100 - recognized by LDL receptor
LDL: When a cell has lots of LDL, LDL Receptor synthesis is blocked. These LDL molecules are oxidized by macrophages, leading to athersclerotic plaque formation. Plaques
provoke inflammatory response, leads to foam cell formation, leads to necrosis.
HDL transports cholesterol to liver for excretion. Helps remove cholesterol from bloodstream
Current normal levels may be higher than "optimal". Risk of atherosclerosis increases above optimal
Hyperlipidemia = elevated LDL, Triglycerides, total cholesterol, and low HDL
10
11
#1 Choice for Healthcare provider is ALWAYS therapeutic lifestyle changes (TLC)
~ Restrict diet, increase polyunsat. Fat, increase fiber, increase exercise, weight reduction
Must know this slide: when to consider drug therapy , etc! ------------>
Metabolism Adverse Effects Contraindications
~ Does NOT USE CYPs
at all
CYP-P2C9 and/or CYP-
P2C19
~ Skin flushing
~ Pruritis (itching)
~ GI
~ Niacin induced hepatitis
~ Blurred vision, fatigue,
glucose intolerance
CI with active liver
disease, peptic ulcer,
arterial bleeding
~ CI in biliary
obstruction and Type
III dyslipidemia
(elevated TGs)
~ Musculature: myopathy
(rhabdo, very rare)
~ Hepatic Side Effects (increase
LFTs)
~ Minor: sleep, memory, rash,
headache, insulin resist
GI
~ Hyper Na+/Cl-
~ Elevated TGs
GI
~Muscle and hepatic (rare)
~ Gall stones
~Potentiate oral anticoagulants
CYP-3A4
~ Lovastatin, Simvastatin,
Atorvastatin all use
~Same as grapefruit juice
~ CI in pt with Hepatitis
or decreased liver
function
~ CI in pregnancy
~CI in liver Pt
~ CI with oral anti-
coagulants: can
potentiate their
effects
~ CI w/ severe renal
impairment
GI (severe diarrhea)
~ Myalgia, Rhabdo, Hepatitis,
Pancreatitis (rare)
CI in active liver disease
~ Fishy burp
~ Increased bleeding risk
~ GI
~ Poor glycemic control
~ CI in Pt with fish
allergies
(hypersensitivity)
Therapeutic Considerations
~ Always give this with aspirin to
reduce flushing, pruritis, headache
~ Often used with other drugs but
MUST BE TAKEN SEPERATELY due to
drug binding. Give all vitamins 1hr
before or 4-6 hrs after
~ Taken orally only
Class of Drug Drug Name
Anti-Platelet Therapies
Aspirin
Dipyridamole
Thienopyridine compounds
~ Metabolism different for each
member of class
Clopidogrel (Plavix)
GP-IIa/IIIb therapies
~ block GPIIa/IIIb receptor
Abciximab
Eptifibatide
Heparin-derived Anticoagulants
Anti-Platelet and Anti-Coagulation Drugs
Indirect Thrombin Inhibitors (require AT)
Unfractionated
heparin (UFH)
LMWH Enoxaparin
Pentasaccharide analogs
Fondaparinux
(Ultra LMWH)
Factor Xa Inhibitors
Rivaroxaban
Apixaban
Vitamin K Antagonists
Warfarin
(Coumadin)
Hirudins Lepirudin
Argatroban
Dabigatran
Fibrinolytic Agents
"Clot Busters"
1st Gen Streptokinase
2nd Gen Alteplase
3rd Gen Reteplase
General Concepts from Lecture:
Direct Thrombin Inhibitors
Small molecule inhibitors
1
2
3
4
5
6
7
8
9
10
Pregnancy and Anticoagulation: Px = hypercoagulable state: increased levels of fibrinogen/Factors VII/VIII/IX, and X. Low levels of Protein S. Resistance to protein C
~ Venous stasis & blood pooling: compressed IVS and Progesterone-induced venous dilation
~ Elevated hormones
~ UFH, LMWH, Fondaparinux are all safe in Px
~ DO NOT USE Thenopyridines: teratogenic potential
~ DO NOT USE WARFARIN: known teratogen. Category X drug! Never a scenario
Aterial thrombosis = rupture of atherosclerotic plaque
Venous thrombosis = activated INTACT endothelium
~ COX-1 primarily produces TxA2 leading to platelet aggregation/ vasoconstriction
~ COX-2 primarily produces PGI2 and causes vasodilation/ platelet inhibition
Direct inhibitors bind directly to coagulation factors: no plasma co-factor is needed. All current meds target thrombin. Better activity against fibrin-bound thrombin
Indirect Inhibitors: mediate clotting by plasma cofactor. Most target anti-thrombin III (AT). Little/no intrinsic anticoagulation activity.
~ Reduce vascular death rates by 15% and non-
fatal events by 30%
~ Essential component of primary and
secondary prevention for stroke/MIs
~ Irreversible COX inhibitor: blocks TxA2
~ 50x affinity for COX-1
~ Low dose (75mg/day)= anti-thrombotic
(COX1>COX2)
~ Mid dose (650 mg/day) = analgesic &
antipyretic (COX1=COX2
~ High dose (4-8 mg/day) = anti-
inflammatory (COX2>COX1)
~ Vasodilator w/ anti-platelet properties
~ Use with aspirin for stroke prevention
Mechanism unclear, dilates arterioles,
increases adenosine
~ Used for Acute Coronary Syndrome
(ACS): ST-elevation MI or non-ST
elevation MI/unstable angina
~ Use in aspirin-intolerant patients
~ Prodrugs
~Irreversible inhibition of P2Y12 receptor
(lasts lifetime of platelet), blocks adenylyl
cyclase activity
~ Renal metabolism
Monoclonal antibody that is RENALLY
CLEARED
~ Reversible receptor inhibition (snake
venom derived)
~ Dose adjust for renal failure
Anti-Platelet and Anti-Coagulation Drugs
~ Given via continuous IV to treat active
clot or prophylactically
~ UFH Reversal: administer protamine
sulfate to reverse anticoagulant effect
~ Safe for Pt w/ renal impairment
~ Primary agent for prophylaxis in
medically ill Pt
~ Safe for Pregnancy: doesn't cross
placenta
~ Indirect inhibitor, binds to AT-III:
converts AT to rapid thrombin inhibitor
~ UFH inactivates Xa & IIa because of its
long polysaccharide tail - short heparins
only target Xa
~ Use for trtmt and prophylaxis: primary agent
for proph in medically ill Pt and ortho surgery
~ Primary agent in outpt bridging
~ Partial reversal w/ protamine sulfate
~ Less likely to cause HIT or bone loss
~ Safe for Pregnancy: doesnt cross placenta
~ Binds AT to enhance AT activity:
increased affinity to AT due to lower
weight gives longer 1/2 life
~ Reduced activity against thrombin IIa
compared to UFH
Renal Dose adjust in pregnancy
~ Great option for Pt w/ hx of HIT
~ Once daily dosing
~ Recommended trtmt for pregnancy with hx
of HIT
Synthetic analog of high affinity
pentasaccharide
~ High Xa affinity
~ Use in Atrial Fibrillation
~ Trtmt of DVT/PE
~Prophylaxis for DVT following hip/knee
replacement
~ Atrial Fib only
Dose adj for Hepatic and Renal, CYP3A4,
and Pgp inhibitors
~ Works on Vit K cofactors (II, VII, IX, X):
inhibits Vit K reductase
~ Also affects Protein C and S (risk of
thrombosis initially)
~ Warfarin is metabolized by many
CYP450 substrates = many drug-drug
rxns. Hepatic Clearance
~ Bivalent DTI: blocks both the active site
and exosite 1 of thrombin
~ RENAL CLEARANCE
~ Use in Pt w/ Hx of HIT
~ Univalent DTI: Binds only the active site
of thrombin
~ HEPATIC CLEARANCE (Only one)
Univalent DTI
~ Prodrug with peak concentration
reached in 2-3 hrs
~ Renal
~ Forms stable complex with plasminogen
~ Lacks fibrin specificity
~ Hepatic Metabolism
~ Binds to Fibrin and converts fibrin-
bound plasminogen to plasmin
~ Hepatic metabolism
~ Modestly increased efficacy to alteplase
~ Renal metabolism
ST elevation MI
~ NOT indicated in non-ST elev MI or
unstable angina
~PE/DVT
~ Thrombosed IV access
~ Elevated hormones
~ Tinnitus, hearing loss, GI
intolerance at high doses
~Thrombocytopenia
CI in pregnancy: premature closure
of ductus arteriosus and
prolongation of labor (only use for
specific risk of arterial clotting)
All Common:
~ Headache, hypotension,
bronchospasm, MI, Arrythmia,
Rash, etc
Coronary Steal: by dilating
coronary arterioles in both healthy
and unhealthy areas, it effectively
"steals" bloodflow from ischemic
areas (which are already maximally
dilated)
~ Aggrevates Angina
~ Severe Rash
~ Thrombocytopenia
~TTP
~ No risk of neutropenia
(contrast to ticlopidine)
~ CI in Pt with altered
metabolism of CYP2C19
(Black Box warning)
~ CI in Pt w/ severe renal
impairment
~ AV node block
~ Thrombocytopenia
~ Anti-abciximab antibody
CI in Pt with Renal Failure
~ Bleed, thrombocytopenia,
chest pain, bradycardia, angina
~UFH: bone loss, HIT, HI skin
necrosis, alopecia,
hypersensitivity rxn
~Protamine: hypotension,
bradycardia, allergy to fish
~ Protamine reversal is CI in pt
with fish allergies (derived from
fish sperm)
Bleeding CI in Pt w/ creat cl < 15 ml/min
Bleeding
CI in Pt w/ creatinine cl < 30 ml/min
~ CI in elderly (assumed renal
impairment)
~ Severe: epidural/subdural
hematoma, thrombocytopenia,
Stevens-Johnson syndrome
~ Px Category C
~ Rare risk of limb gangrene,
skin necrosis
~ Possible association w/
protein-C deficiency
~ Many meds interact/interfere:
especially antibiotics (b/c gut flora
affect Vit K absorption)
~ Known teratogen: Category X
drug! NEVER USE IN PREGNANCY
~ Risk of Ab formation and
anaphylaxis
CI in Pt w/ liver dysfunction
~ Severe bleeding events have been
reported in cases when capsule has
been opened prior to admin
~ DONT OPEN THE CAPSULE
Non-specific: risk of hemorrhage
is high
Risk for allergic reactions: fever
to anaphylaxis
~ Derived from streptococcus:
natural Ab may exist from prior
Strep infections
Less risk of hemorrhage due to
fibrin specificity
CI in Liver Failure
CI in Renal Failure
~ Elevated hormones
Therapeutic
Considerations
~ Stop givin aspirin 7-10 days
(platelet lifetime) before any
procedure
~ 1/2 life 10-20 minutes, but effect
for 7-10 days
~ No intrinsic anti-plt activity or
increase bleeding risk when used
alone
~ Must consider poor or over
metabolizers of CYP450 enzymes
~ Drug remains in circulation 10 days
~ Platelet function returns over 48
hrs
~ Recovery of plt function in 2-4
hours
~ Short 1/2 life (7 min)
~ Needs frequent dose adjustment
based on anti-Xa measurement
~ 1/2 life 3-6 hrs
~ Monitoring not necessary b/c of
predictable dose response (except
renal failure, Px)
~ Monitor anti-Xa levels in renal
impairment, obesity, and Px
~ reduce dose for Pt w/ creatinine
clearance < 30ml/min
~ Subcutaneous injection
~ 17 hr 1/2 life, greater anti-Xa
affinity
NO REVERSAL AGENT AVAILABLE
NO REVERSAL AGENT AVAILABLE
~ Adjust dose for renal impairment,
Hepatic impairment, and CPY3A4
and Pgp strong inhibitors
~ Oral administration
~ Very narrow Therapeutic Index:
start w/ low dose and adjust for
each patient by checking INR (aka
PT)
~ DO NOT LOAD PATIENTS
~Pills are color coded to help MDs
and Pt
~ Dose adjust in renally impaired Pt
~ NO REVERSAL AGENT- can use
activated Factor VIIa or prothrombin
complex in life-threatening cases
Improved efficacy, specificity, but
more expensive
~ Elevated hormones
Nitrates
Nitroglycerin, sublingual
Nitroglycerin, ointment
Nitroglycerin, slow release
(transdermal)
Isosorbide dinitrate
Isosorbide-5-mononitrate
(I5M)
Nitroprusside
Sildenafil
Tadalafil
Calcium Channel Blockers
Nifedipine
Amlodipine
Angina Medications
Dihydropyridines
PDE- Inhibitors
Verapamil
Diltiazem
Beta-Blockers
Atenolol
Metoprolol
Propranolol
Other
Ranolazine
General Concepts from Lecture
1
2
Non-DHP
3 Major Types of Angina Pectoris
1.) Typical angina (stable vs. unstable): caued by atherosclerotic stenosis of vessels
2.) Variant angina: caused by acute vasospasm of coronary arteries. Endothelial dysfunction! More common in women and at rest. No plaques!
3.) Microvascular angina: more common in women, caused by endothelial dysfunction in small cardiac vessels. No plaques!
Variant & microvascular angina can be challenged with ACh. Tests for endothelial response of N.O. No response = vasoconstriction = + test
3
4
5
6
7
8
9
10
5 Ways Drugs are Effective Against Angina
1.) Increased exercise test performance (time to onset of angina and time to 1mm ST depression)
2.) Frequency of angina attacks
3.) Number of NG tablets used
4.) Incidence of non-fatal MIs
5.) Incidence of CV related deaths
~ Beta-blockers are the only drugs that can do #4 and #5, thus 1st line drugs for angina!
Steps for treating angina:
1.) Use asprin and a beta-blocker
2.) Use sublingual NG for alleviation of sx and prophylaxis
3.) If angina > 2-3x weekly, add calcium channel blocker or long-acting nitrate (avoid tolerance)
4.) If angina persists w/ 2 anti-angina agents, add 3rd
Ischemia occurs when oxygen supply does not equal oxygen demand in the heart.
1.) Oxygen Supply is a POOR target for drugs because the vessels are already stenotic and increasing the aortic pressure will increase the O2 demand on the
heart as well! Additionally, increasing blood flow typically bypasses the already ischemic areas.
2.) You can decrease the O2 DEMAND by decreasing contractility/heart rate (via Beta blockers) or by decreasing the ventricular wall tension. This can be
accomplished in two ways: (a) decreasing preload via venous dilation (nitrates) or by (b) decreasing afterload via arterial dilation (Ca2+ channel blockers)
There are four ways to relax vascular smooth muscle:
1.) Calcium channel blockers: prevent influx of calcium and thus muscle contraction
2.) Beta 2 agonists: these drugs (isoproteronol) increase ATP to cAMP which then coverts MLCK to MLCK (P04)2. This "drains the supply" of MLCK needed for
contraction. Problem is that they also increase contractility and heart rate.
3.) Nitrates: these drugs increase cGMP which dephosphorylates MLC-PO4 causing SM relaxtation
4.) K+ channel openers: these drugs hyperpolarize the cell (only used in Europe)
~ The sub-endocardium is the most vulnerable to oxygen deprivation. This is for two reasons:
1.) The subendocardium is compacted during systole preventing circulation
2.) It is the most downstream from its coronary arterial supply. Less collateral circulation
Combination Therapy: ----------------------->
~ Used for HT emergency and for
Heart Failure: NOT USED FOR
ANGINA!
~ NO is released DIRECTLY from the nitroprusside
molecule: no mitochondria needed
Phosphodiesterase Inhibitor (PDE-I): prevents the
coversion of cGMP to GMP, extending the effects of
cGMP on SM relaxation
PDE5 Inhibitor
~ Blocks the CAv1.1-CAv1.4 channels (found in
cardiac, skeletel, SM, neurons, endocrine cells, and
bone)
~ Arterial dilation!
~ Don't target the heart!
Angina Medications
~Nitrates are converted to NO by SM
mitochondria. NO stimulates the conversion of
GTP to cGMP which in turn stimulates the
dephosphorylation of MLC-PO4 to MLC. MLC
causes SM relaxation
~ All of these can be thought of as "prodrugs" in the
sense that they have no affect on the endothelium
directly.
1.) Venodilation
2.) Decrease LV diastolic Pressure: = redistribution
of blood to ischemic areas
3.) Preferential dilation of collateral branches of
coronary arteries
~Angina, Variant Angina, HT,
Raynauld's phenomenon (Amlo)
~ Not indicated for MIs
~ Angina: stable and unstable
~ Variant (Printzmetal)
~ Microvascular angina (only one!)
~ Myocardial infarction
~ Can be used prophylactically
~ Sublingual NG for alleviation of sx
and prophylaxis
~ Angina, Variant Angina, HT,
Arrythmias, Migraine
~ Angina, Variant angina, HT,
Arrythmias, Raynaud's
~ Exertional angina
~ Unstable Angina
NOT indictated for Variant Angina or
MI
Inhibits late sodium current in the heart
~ Primary effect for benefit is improvement of
regional coronary blood flow in areas of ischemia
~Does NOT affect HR, contractility, or BV
~ Ischemic heart loses Na+ gradient and ability to
pump Ca2+ into sarc reticulum =
sustained/prolonged contraction = decreased
coronary blood flow
~ Arterial vasodilation
~ CV Effects: SA/AV nodes, myocytes
~ Hemo effects: arterial vasodilation (decrease
afterload), coronary dilation (relieves spasms),
decrease HR and contractility
~ Effect for angina is to decrease O2 demand by
decrease HR and contractility
~ Note: this causes increased LV end-diastolic
volume which increases wall tension. Net effect is
good though, especially with exercise
~ Angina
~ Unstable angina
~ MI
~ NOT indicated for variant angina!
5 Ways Drugs are Effective Against Angina
1.) Increased exercise test performance (time to onset of angina and time to 1mm ST depression)
2.) Frequency of angina attacks
3.) Number of NG tablets used
4.) Incidence of non-fatal MIs
5.) Incidence of CV related deaths
~ Beta-blockers are the only drugs that can do #4 and #5, thus 1st line drugs for angina!
Metabolism Adverse Effects
Prodrug: metabolized by liver to 2
metabolites: I2M and I5M. I5M is
active
I5M is active metabolite
~ Nitroprusside is broken down into
NO and Cyanide: Cyanide is
processed in liver and excreted.
Rapid onset, short duration
Longer onset
~ hypotension
~ All are highly metabolized to
inactive metabolites in liver.
Cannot give orally!
~ Reflex tachycardia/contractility after
stopping: increased O2 demand
~ Orthostatic hypotension
~ Worsening of endothelial
dysfunction
~ Flushing
~ "Case of the Mondays"
~ Headaches
~Tolerance:
1.) Thiol depletion in MAD: blocks
coversion to NO
2.) Neurohumoral activation: SNS and
RAAS system overpower
3.) Generation of free radicals
~Countered by Hydralazine
(antioxidant)!
Metabolized by CYP3A4, 5%
eliminated unchanged by kidney
~ 6-8hr duration of action
~ QT interval prolongation
~ Nausea, constipation, dizziness
~At high doses, can block the K+
repolarizing current and elongate
refractory period
~ bradycardia, heart block, heart failure
via negative ionotropic effects
~ hypotension
Verapamil = GI constipation
Diltiazem = gingival hyperplasia
~ Blood pooling in heart = hypertrophy
~ bradycardia, slow AV node
conduction = heart block
CYP3A4 Inhibitors!
Contraindications Therapeutic Considerations
Given 1-3x/day; eccentric schedule to
prevent tolerance
Given orally bid: must be given 7-8 hrs
apart to prevent tolerance
~ NO RISK OF TOLERANCE! Does not
need to be converted to NO by
mitochondria
~ Never give with nitrates.
Risk of severe hypotension
~ Not beneficial for Mis
~ Never give with PDE-Is!
Can cause severe
hypotension
Recommended for
COPD with
brochospasm or
asthma
~ Misc Ca2+ blockers
also hit heart, so are
recommended over
DHPs
~ Less effective monotherapy than
verapamil, diltiazem, or beta-blockers
~ Recommended in Pt with sinus
bradycardia or AV block
~ Use in pt with severe depression
~ Interactions with other drugs:
CYP3A inhibitors (such as Verapamil
and Diltiazem) increase ranolazine
concentration and duration of action
~ Necessitates dose adjustment
~ Don't give with beta-
blockers because non-DHP
Ca blockers have similar anti-
beta effects
~ CI with variant angina
(Beta 2 blocking)
~Don't give to Pt with
Asthma!
~ CI in pt w/ Raynaud's
phenomena b/c aggravates
peripheral vasospasms for
those sensitive to cold
~ Recommended for use in
supraventricular tachycardia, A Fib
~ Use in sinus tachycardia, ventricular
arrythmia, SV tachycardia, A Fib
~ Use in Heart Failure
~ Use for hyperthyroid
Recommended for
COPD with
brochospasm or
asthma
~ Misc Ca2+ blockers
also hit heart, so are
recommended over
DHPs
Coronary Steal Phenomenon
(Above)
Diuretic Drugs
Carbonic Anhydrase Inhibitors Acetazolimide
Minimally effective alone, doesnt
lower BP
~ Alkalinize the urine
Loop diuretics Torsemide
Furosemide
Thiazides
~ Always give with potassium-
sparing diuretic or ACE-i
Hydrochlorothiazide
(HCTZ)
Chlorthalidone
~ Should be #1 prescribed
drug (but it isnt). Better
efficacy & potency than
HCTZ in HT
~ ALLHAT Study showed
#1 drug fot HT
Metolazone
K+ sparing drugs Amiloride
Triamterene
Spironolactone
Eplerenone
Aldosterone Receptor
Antagonists
Most efficacious K+ sparing, can
be used as diuretic alone
Used in combo with thiazides,
prevent hypokalemia
Only use for CHF and edema
~ 1st line for people with edema
from CHF
Anti-Hypertensives
1.) Hypertension
2.) Heart Failure: too weak to be
effective
3.) Kidney stones (nephrolithiasis)
4.) Nephrogenic diabetes
insipidus: counterintuitive
Combos
Diazide
(Hydrochlorothiazide +
Triamterene)
Renin-Angiotensin-
Aldosterone Blockers
ACE Inhibitors
Captopril
~ prototype
Enalapril
~ 1st to show ACE-i for HT
Lisonopril
~ALLHAT study
Ramipril
~ HOPE study
ATII Receptor Blockers Losartan
Candesartan
Renin Inhibitors Aliskiren
Ca2+ Channel Blockers
Dihydropyridines Nifedipine
Amlodipine
Non-DHPs Diltiazem
Verapamil
Beta blockers
Beta + Alpha1 blockers Carvedilol
Lebatolol
Nebivolol
Non-selective beta blockers Propranolol
beta-1 selective blockers Atenolol increases type II diabetes!
Metoprolol
Esmolol
Alpha Blockers
Prazosin
Drugs that Act on Heart or Vasculature
Not used for HT: ALLHAT study
showed increase risk of CHF
Only 3 beta-blockers used for CHF
~ Do not give ACE-i alone to
African Americans: ineffective
b/c their HT is volume dpdt
~ Greatest effect on those with
low Na+ levels & older whites
Give ACE inhibitors for
1.) Diabetes
2.) CHF
3.) LV Hypertrophy
Doxazosin
Tamsulosin used in BPH
Direct vasodilators
Hydralazine
Minoxidil
Central sympatholytics
Clonidine
Sodium nitroprusside
~ Give after clonidine to prevent
rebound HT
alpha-Methyldopa
Prodrug alpha 2Aagonist. 6 hrs to
see effects but lasts 24 hours
PDE Inhibitors Sildenafil ED and pulmonary hypertension
General Class Notes
HT Risk Factors: Family hx, Black race, dx of pre-HT, age, obsesity, high Na+/low K+ intake, sleep apnea, low socioeconomic
status, excess OH
Not used for HT: ALLHAT study
showed increase risk of CHF
Use with isosorbide dinitrate for
CHF. Nitrate decreases preload
and direct vasodilators decrease
afterload
Blood Pressure Ranges
Normal = < 120/80
Prehypertension = 120-139/80-89
Stage 1 HT = 140-159/90-99
Stage 2 HT = > 160/>100 mmHg
Effects of AT1 Receptor Stimulation
1.) Vasoconstriction
2.) Aldosterone & ADH (vasopressin) synthesis/release
3.) Renal tubular sodium reabsorption
4.) Cardiac Growth
5.) Augment CNS activity
6.) Vascular smooth muscle proliferation
NO BENEFIT in combining ACE inhibitors with ARBs
A Change in the Renin-Angiotensin-Aldosterone System is equivalent to a change in the Sympathetic Nervous System
~ ATII normally stimulates SNS
~ Decreased Renin causes reflex increase in SNS
~ B1 adrenergic receptors on juxtaglomerular cells stimulate renin release
Central Sympathetic Response to HT
~ Normal reflex response; HT triggers baroreceptor reflex --> synapse in nucleus of solitary tract --> release of Glutamate -->
stimulation of inhibitory neurons which increase rate of GABA discharge --> GABA acts on vasomotor center in rostral ventro lateral
medulla to decrease SNS outflow and decrease BP
Mechanism
Metabolism/Drug
Interactions
Work at PCT to decrease Na+ and
H20 reabsorption
Inhibit Na+/K+/Cl- symporter in TAL
Excreted unchanged in urine
= longer 1/2 life
Hepatic and renal
metabolism = short 1/2 life
~ Effects may depend on PGs:
possible interaction with
NSAIDS
Synthetic steroids: Directly inhibit
aldosterone receptor in collecting
duct
Hepatic metabolism
~ Effects may depend on PGs:
possible interaction with
NSAIDS
Directs inhibits Na+ entry through
channels in collecting duct luminal
membrane
Interactions with NSAIDs,
aminglycoside antibiotics
~ Synergistic with other AH
drugs (doxazosin)
Inhibit thiazide-sensitive NaCl
symporter in the DCT
~ Enhance Ca2+ reabsorption in DCT
and K+ excretion
~ MOA for anti-HT action is related to
persistent reduction in body sodium
Renally metabolized
~Any drugs that prolong QT
interval increase risk of
ventricular tachycardia
~ Digitalis: increased binding
of digoxin to Na/K ATPase
due to hypokalemia
NOT a prodrug
Prodrug
NOT a prodrug
Prodrug
~ Directly binds to renin
~ Inhibit justaglomerular cells from
releasing renin
Fecal elimination
Blocks the AT1 receptor (receptor for
ATII)
~ Also prevents activity of alternate
pathway (chymase)
Alpha-1 blocking effect increases NO
synthase activity causing vasodilation
~ Beta-effects as well
Stricly arterial dilators
Arterial vasodliation + cardiac effects
similar to beta blockers
Block Angiotensin Converting Enzyme
(ACE) in epithelial cells (mostly
pulmonary)
~ Causes vasodilation and decreased
aldosterone/ADH/SNS release
~ Increased bradykinin : ACE also
breaks down BK. BK causes
vasodilation and increased PGs
Alpha-1 selective blocker
Increases cGMP to cause vasodilation
~ Reflex SNS outflow limits utility
alone
NO agonist and one of most powerful
arterial dilators
~ Also causes increased K+ conduction
in vascular smooth muscle, leading to
hyperpolarization and decreased
contraction
Binds alpha-2A receptors causing
hyperpolarization of vasomotor
center, decreased SNS outflow
~ At high doses (IV), also binds alpha-
2B receptors in periphery and causes
transient HYPERtension before
hypotension
Balanced arterial/venous dilation
Does NOT need mitochodrial
aldehyde dehydrogenase =
NO TOLERANCE!
alpha-2A agonist, converted to active
form by catecholamine pathway
PDE-5 selective inhibitor
HT Risk Factors: Family hx, Black race, dx of pre-HT, age, obsesity, high Na+/low K+ intake, sleep apnea, low socioeconomic
status, excess OH
Blood Pressure Ranges
Normal = < 120/80
Prehypertension = 120-139/80-89
Stage 1 HT = 140-159/90-99
Stage 2 HT = > 160/>100 mmHg
Effects of AT1 Receptor Stimulation
1.) Vasoconstriction
2.) Aldosterone & ADH (vasopressin) synthesis/release
3.) Renal tubular sodium reabsorption
4.) Cardiac Growth
5.) Augment CNS activity
6.) Vascular smooth muscle proliferation
NO BENEFIT in combining ACE inhibitors with ARBs
A Change in the Renin-Angiotensin-Aldosterone System is equivalent to a change in the Sympathetic Nervous System
~ ATII normally stimulates SNS
~ Decreased Renin causes reflex increase in SNS
~ B1 adrenergic receptors on juxtaglomerular cells stimulate renin release
Central Sympathetic Response to HT
~ Normal reflex response; HT triggers baroreceptor reflex --> synapse in nucleus of solitary tract --> release of Glutamate -->
stimulation of inhibitory neurons which increase rate of GABA discharge --> GABA acts on vasomotor center in rostral ventro lateral
medulla to decrease SNS outflow and decrease BP
~ Hyperkalemia
~ Hyperchloremic metabolic
acidosis (also prevents H+ from
being excreted in Na/H+
exchanger)
~ Gynecomastia, impotence, BPH
w/ spironolactone
~ Hypokalemia
~ Hyperuricemia (gout)
~ Hyperglycemia
~ Ototoxic
CI in patients with gout: excreted
by the same renal mechanism in
the proximal tubule as uric acid
~Hypokalemia, causes cardiac
arrythmias
~ Hyperuricemia: Gout
~ Impaired glucose tolerance:
hyperglycemia, but can be
corrected by fixing low K+
~ Hyponatremia: due to
hypovolemia: induced high ADH,
low kidney dilution, increased
thirst
~ Hyperlipidemia
Pregnancy: RAA blockers known
to cause fetal abnormalities
CI in pregnancy
CI in pregnancy: increased fetal
mortality
~ Hepatotoxicity
~ Dysgeusia
~ Rarely rhabdomyolysis
~ DOES NOT cause cough or
edema
~ CI in patients bilateral renal
artery stenosis: decreases GFR too
much and causes acute kidney
failure
~ CI in pregnancy! Teratogenic
~ Cough (bradykinin)
~ Dysgeusia (loss of taste)
Neutropenia
~ Hyperkalemia
~Angioneurotic edema
~ Rash
Hirsutism (now used as Rogaine!)
~ Rebound hypertension (can't
treat with beta blocker, use
sodium nitroprusside-no
tolerance and balanced
vaso/arterial dilation)
~ dry mouth
~ rare hemolytic anemia and
hepato-toxic
Prototype thiazide diuretic
Chlorothiadone has the highest
relative carbonic anhydrase
inhibition
~ Long 1/2 life, only give once every
few days
Only thiazide that works at GFR <
30ml/min
Triamterene and Spironolactone
effects may depend on
Prostaglandins.
~ Thus, high dose NSAIDs may
diminish effect
Used for HT in pregnancy
~ ACE inhibitors have been shown to
protect kidneys in diabetics!
Decrease urine protein excretion
Ca2+ channel blockers DO NOT
interact with NSAIDs and are
preferential arterial dilators.
Also has antioxidant properties: used
with Nitrates, reduces tolerance
~ issues with compliance
~ Safe for pregnancy!
Diuretics
Furosemide
Torsemide
Hydrochlorothiazide
Metolazone
Used in patients with
decreased renal function
Mannitol Not used in HF
Amlodipine
Triamterene
Aldosterone
antagonists
~ prolong life!
While AAs are used in HF, it is
not for their diuretic effect.
They protect the heart from
aldosterone.
Spironolactone
~ Low cost drug with great
cardioprotective effects. Side
effects because it blocks all
glucocorticoid receptors
Eplerenone
~ high cost drug with fewer
side effects because it ONLY
TARGETS aldosterone
receptor
Vasodilators
ACE Inhibitors
Captopril
ARBs
Prolong life!
Potassium-Sparing
Diuretics
Used synergistically with
Loop diuretics to prevent
hypokalemia
Congestive Heart Failure Pharmacology
Loop
~ Don't prolong life!
Thiazide
Important 1st line drugs for
CHF
~ Relieves SOB sx by
decreasing pulmonary edema
Losartan
Candesartan
Best ARB: binds more tightly
to AT1R and can't be
overcome
Direct vasodilator Hydralazine
Isosorbine dinitrate
Nitroprusside
Combos
BiDil
(Isosorbide dinitrate +
hydralizine
Decrease mortality in blacks
when added to std therapy
~ Alternative to not tolerated
ACEi/ARB
PDE Inhibitors
Milrinone
Only used in acute HF:
~ used when treated CHF pt
develops worse HF
~ chronic use leads to
increased mortality
Beta blockers
Metoprolol
Carvedilol
Bisoprolol
Cardiac
glycosides
Digoxin
Relief of Sx of HF: no effect
on improving mortality or
preventing disease
progression
Antidigoxin
immunotherapy
(Digibind)
Nesiritide
Nitrates
Prolong life!
Anti-arrythmia
drugs
Dopamine
Dobutamine
General Class
Points
1
2
3
4
5
6
7
Potential Roles of Aldosterone in Heart Failure
1.) Increased Na+ and H2O retention: edema, increased preload
2.) K+ and Mg2+ loss: arrythmogenesis
3.) Reduced myocardial NE uptake: increased NE causes myocardial remodeling and arrythmogenesis
4.) Reduced baroreceptor sensitivity; reduced PSNS in response to vasoconstriction, increased SNS stimulation
5.) Myocardial fibrosis, fibroblast proliferation: remodeling and ventricular dysfunction
6.) Alteration in Na+ channel expression: increased excitability and contractility of myocytes
Some drugs have different effects in Heart Failure than in Standard Hypertensive Therapy
1.) ACE inhibitors and ARBs: in HT they are strictly arterial dilators: in CHF they decrease both afterload AND preload!-new side effect of orthostatic HT
2.) Digoxin: In normal pt, it acts as arteriole constrictor and increases contractility; together no change in CO. In HF, TPR drops and CO dramatically increases
Dilated cardiomyopathy = systolic heart failure. Circular shape causes valvular incompetence, increased pre-load, thinner walls, etc. Treat with Ca2+ blockers, ranolazine, and aldosterone inhibitors
Hypertrophied heart = diastolic heart failure (or more correctly, HF w/ preserved Ejection Fraction)
Mechanisms of Heart Failure
1.) Ca2+ homeostasis derangement: the failing mycardium overexpresses the 2xCa/3xNa exchanger which leads to decreased levels of cytoplasmic Ca2+. In addition, the phospholamban protein is not phosphorylated by PKA on the surface of the
sarcoplasmic reticulum. This prevents activation of the SERCA Ca2+ pump and the coinciding re-uptake of Ca2+ into the sarcoplasmic reticulum and ultimately causes less Ca2+ to be available for myocardial contraction when necessary
2.) Contractile element dysfunction: cardiac remodeling causes the heart to revert from alpha-myosin to the fetal verision, beta-myosin. Beta-myosin promotes the release of growth factors, etc, but also is weaker at converting ATP to ADP and prevents
effective contraction of myocytes. In addition, the Ca2+ depletion prevents the deactivation of Troponin-I (which inhibits contraction). This will also decrease cardiac function.
3.) Adenylyl cyclase signaling pathway changes: In heart failure, the beta-arrestin protein expression is increased. This blocks Beta-receptors in the heart and prevents the conversion of ATP to cAMP. This in turn prevents the production of active PKA
which then prevents the phosphorylation of phospholamban (as described above).
Goals of CHF Therapy
1.) Relief of Sx: Diuretics + Digitalis: sx described by LV function curve ----->
2.) Counter maladaptive compensatory response: decrease HR, vasodilation, decrease inotropy
3.) Counter cardiac remodeling: prevents scarring and further decrease in cardiac function-ACE inhibitors and ARBs. Beta blockers also have this cardioprotective effect by increasing expressin of alpha-myosin.
Aldosterone antagonists prevent cardiac fibrosis.
4.) Prolong life: only a few drugs accomplish this: ACE-i's/ARBs/Aldosterone Antagonists/Beta blockers
In heart failure, there are three drugs poisoning the heart: NE, Angiotensin II, and Aldosterone
Heart failure results in an increase in fluid within the heart due to (a) decreased CO (b) activation of RAAS (c) SNS stimulation
8
Stages of Heart Failure
Stage A: no HF yet, but high risk! HTN, AS, diabetes, obesity, metabolic syndrome. Treat with ACEIs and ARBs
Stage B: structural heart disease but no sx of HF. Treat with ACEIs, ARBs, and beta blockers
Stage C: Sx of HF. Trtmt: ACEI/ARB, Beta blocker, diuretics
Stage D: Severe HF. Treat sx and consider bi-ventricular pacing and heart transplant.
Mechanism
Metabolism &
Pharmacokinetics
Up-regulates the thiazide transporter
in the distal tubule
Draws fluid from extravascular sites to
intravascular sites
~ Increases work for already failing
heart
arterial vasodilation
Block the aldosterone receptors in the
collecting duct.
~ More imporant effect may be to
block aldosterone receptors on the
heart
~ Eplerenone prevents cardiac
fibrosis
Inhibit Na+/K+/2Cl- cotransporter in
the TAL of kidney: destroys
hyperosmolar gradient
~ Also have direct vasodilatory effect
Resistance may develop!
~ noncompliance/excess Na+ intake
~ Decrease renal perfustion/GFR
~ NSAIDs
shortest half life (2hrs)
Inhibits cAMP degradation:
pre/afterload reduction
~ Acts "beyond" beta-receptros
Beta-1 selective
B1, B2, A1
Beta-1 selective Liver, CYP450
Activates both SNS and PSNS:
ionotropic (more Ca2+ in sarcoplasmic
reticulum), increases baroreceptor
sensitivity, electrical effect via Na/K
ATPase pumps (antiarrythmia)
Recombinant form of ANP, stimulates
cGMP and SM relaxation
Direct stimulation of B1 receptors
Therapeutic
Considerations
Short half-life: 1-2hrs
Longer lasting: only need to give
every 3-4 hrs
Synergistic w/ Loop diuretics and K-
sparing diuretics
CI in heart failure!
~Hyperkalemia
~ Gynecomastia
~ Sexual dysfunction
~ Urinary frequency
~Hyperkalemia
CI in severe renal
impairment
~ CI in patients with
hyperkalemia
~ Synergistic effect with ACE-
inhibitors (which increase
aldosterone), but risk of
hyperkalemia
~Synergism with K+ wasting
diuretics
Hypokalemia/natremia/chloremia/M
g2+
~Hyperuricemia and bicarb
Don't increase survival in
patients with HF: treats sx
only!
orthostatic HTN
hydralazine has antioxidants to
prevent nitrate tolerance
Patients feel better but
DIE SOONER!
Pronlong life
Causes arrythmias in high doses
~ Sinus bradycardia & heart block =
ventricular arrythmia
~ Paradoxical atrial arrythmia:
overrelease of ACh on atrial myocytes
~ Tachycardia: SNS + PSNS activation,
ventricles dont have PSNS
Pt with high K+ levels will
decrease effectiveness of
digoxin
Very narrow TI, Relief of Sx only
(no increase in lifespan)
Class I:
Na+ Channel Blockers
Procainamide
~ Drug of choice for
WPW!
(Only one really used today)
1.) SV Tachycardia
2.) Ventricular arrythmias
~ Use whenever there is QRS
widening (both SV and V)
Quinidine
Disopyramide
~ Only really used in pt w/
hypertrophic cardiomyopathy
2.) AFib
Lidocaine
Ventricular arrythmias (acute
use only)
~ Good post MI: preferenctially
affect ischemic areas
Mexiletine
Flecainide
(most POTENT anti-
arrythmic)
Subgroup 1C
~ Potent Na+ channel
blockers and weak K+
blockers
Subgroup 1B
(Lettuce, Tomato, Mayo)
(Tocainide not on our list)
~ Block Na+ channels only
Subgroup 1A
("Double Quarter
Pounder")
~ Block both Na+ and K+
channels: affects both
Phase 0 and Phase 3 of the
myocyte aP
Anti-Arrhythmics
Prolongs PR, QRS, and QT
1.) SV arrythmias
2.) Causes Ventricular
arrythmias in diseased heart
Propafenone
~ used to maintain
sinus rhythm w/ SVT
Class 2:
Beta-Blockers
Cardio-protective, decrease
mortality by 35%
Propranolol Abolish ventricular arrythmia
Esmolol
1.) Tachycardia
2.) Rapid Afib
Sotalol
1.) Afib/flutter
Acebutol
Metoprolol
Carvedilol CI for arrythmias!
Class 3:
Prolong Refractory
Period
Subgroup 1C
~ Potent Na+ channel
blockers and weak K+
blockers
Prolongs PR, QRS, and QT
1.) SV arrythmias
2.) Causes Ventricular
arrythmias in diseased heart
Amiodorone
~ Used to treat arrhythmias
that are resistant to other
treatment
~ Used to maintain sinus
rhythm for prolonged time
2.) SV arrythmias / AFib
3.) Hypertrophic
cardiomyopathy
Dronedarone
~ Similar to amiodorone w/o
sulfur or iodine!
1.) Acute A-fib and flutter
~ Use for persistent A-Fib
(ATHENA STUDY)
2.) Dont use in CHF
(ANDROMEDA study)
3.) Don't use in PERMANENT
Afib (PALLAS Study)
Vernakalant
May stop Afib and prevent risk
of Torsades
Dofetilide 1.) Afib to sinus rhythm
Ibutilide
Only FDA drug approved to
treat acute atrial fib by
conversion to sinus rhythm
Sotalol SV and V arrhythmias
Class 4:
Calcium Channel
Blockers
Used to treat "nodal"
arrhythmias (e.g. SVT)
Verapamil
Diltiazem
Other Antiarrhythmic
Drugs
Adenosine
Used for paroxysmal
supraventricular arrythmias
~ Also used to dx atrial
flutter/tachycardia
~ Used as vasodilator during
stress tests
Digoxin
Ventricular arrythmias, SVT,
and acute HF
Magnesium
Used IV to treat Torsades des
Pointes
Potassium
Give for digoxin toxicity due to
hypokalemia
Atropine
Anti-arrhythmic when heart is
too bradycardic
1
Drugs to treat Paroxysmal
SV Tachycardia (PSVT)
2
Drugs to treat Atrial
Flutter/Fib
3
Drugs to treat Ventricular
Tachycardia
4 Drugs to treat heart block
General Class
Points
Mechanism
Metabolism &
Pharmacokinetics
Decrease the slope of phase 0 of the
action potential
Increase AP duration
~ In WPW, it increases AP duration of
accessory pathway as well!
~ Active metabolite (NAPA) with K+
channel blocking activity (Type III)
2.) Quinidine: alpha-adrenergic
blockage and vagal inhibition,
increased AV nodal transmission
(DANGER!)
1.) Disopyramide: anticholinergic,
depresses myocardial contractility
Hepatic and renal metabolism
Given IV to avoid 1st pass metabolism
25% renal, 75% hepatic
Decrease AP duration
No net effect on AP duration
1.) potent Na+ channel blockers
(decrease AP duration) w/ slow
dissociation during diastole. Also have
K+ channel blocking activity (increase
AP duration)
~ Use-dependence: Slow dissociation
from Na+ channels leads to an
increase in their effect and an increase
in HR
Hepatically cleared
Decrease HR and conduction
~ Slow AV and SA nodal conduction
Non-selective
Beta-1 selective
Non-selective Beta blocker (Afib and V
arrhtyhmias) & K+ channel blocker!
K+ channel blockers that act on Phase
3 to delay repolarization, increase AP
duration, and increase refractory
period
Reverse use-dependence: greater
effect at slower HR
No net effect on AP duration
1.) potent Na+ channel blockers
(decrease AP duration) w/ slow
dissociation during diastole. Also have
K+ channel blocking activity (increase
AP duration)
~ Use-dependence: Slow dissociation
from Na+ channels leads to an
increase in their effect and an increase
in HR
Prolongs action potential phase 3
~ Structural analog of thyroid
hormone
Long 1/2 life: 13-103 days!
Hepatic metabolism: CYP450
= many drug interactions (CYP3A4,
CYP2C9, PGP)
~ Must 1/2 dose of other meds (dig,
Ca-channel blockers, beta blockers,
warfarin, etc)
Excreted in bile
~30% bioavailability
~ Highly lipophyllic: long 1/2 life
CYP3A4 metabolism
specifically targets the Ik(ur) current,
selective to atria
Blocks channel that carries the rapid
component of the delayed rectifier K+
current
Renal Metabolism
~ Drug interactions with verapamil,
cimetidine, trimethoprim,
ketoconazole, HCTZ
SAFE to use in Renal Failure!
Non-selective Beta blocker (Afib and V
arrhythmias) & K+ channel blocker!
~ Slows HR, prolongs AP, but no effect
on Na+ channels
Excreted unchanged in kidneys
Block L-type Ca2+ channel; decrease
HR and conduction at SA and AV nodes
Minimal Ca2+ blocking activity and
small sympatholytic activity: Reduces
Ca2+ curents
~ Extends AV Node Refractory Period
~ Prolongs PR interval
1/2 life = 10 seconds
~ Drug interactions: theophylline and
caffeine block effect. Dipyradimole
(anti-plt drug) increases its effect.
~ Enhanced effect on patients with
heart transplant (denervated)
Positive ionotropic effect: increased
contractility via increased IC Ca2+.
~ Reduces conduction through AV node
Drug interactions: increase system
digoxin levels EXCEPT...
1.) Rifampin: decreases digoxin
levels
~ Safe for renal impairment at
correct dosage
Anti-cholinergic, AChR antagonist
Non-DHP Ca-channel blockers have
potent SA/AV node effects that slow
sinus rate and depress LV function
Therapeutic
Considerations
1.) Lupus-like syndrome: arthritis,
arthalgia, inflammation of pericardium
Safe in pregnancy!
Digoxin interaction: increases
concentration of Dig
~ Excessive mortality or nonfatal
cardiac arrest
~ Anticholinergic effects (urinary
retention, glaucoma, constipation),
hypotension, CHF, Vtac, QT
prolongation, heart block, GI, CNS
(psychosis), hypoglycemia
ONLY USE IN LIFE-THREATENING
ARRYTHMIAS
1.) CNS effects: Seizures, Altered
consciousness, tremors, dysarthria,
nystagmus
Does NOT improve survival after
hospital discharge
Brady, heart block, V fib, Vtac, HF,
CNS, GI
~CI in structurally
abnormal hearts
~CI for asymptomatic
premature ventricular
contractions/rhythms
Should always be given with AV
node blocker to slow conduction
and prevent V tachy
Same, + metallic taste
CI in pt w/ bradycardia or
bronchospasm due to
beta-blocking effects
Never stop Beta-blockers quickly:
rebound HT, Tachycardia, angina,
arrhythmias
~ Give w/
Only 9 minute 1/2 life: useful IV
for quick on and off
Early afterdepolarizations and
Torsades des Pointes
Prolonged QT interval, risk of
~ (dose dependent)
Heart block, hypotension, HF,
bradycardia, bronchospasm,
depression, impotence
Pulmonary toxicity: pulmonary
fibrosis/ pneumonitis
~ Hepatotoxicity
~ Proarrythmic effects: brady, heart
block
~CNS: "glove and stocking" pattern
~ Hypo/hyperthyroidism
~ Skin: blue discoloration
~ DOESN'T HAVE GI EFFECTS
~ Most often drug used for tachy
arrhythmias
~ Start pt on huge loading dose
~ Reverse use-dependence (bind
K channels in resting state =
greater effect on slowing HR =
greater refractory period)
GI, photosensitivity, QT prolongation
~ Risk of liver failure
~ CI in pt on
antifungal/macrolide AB
~ CI in pt w/ symptomatic
heart failure (reduce EF)
~ Expensive drug!
~ Reduces CV mortality
Torsades des pointes
~ Pro-arrhythmic
CI in pt w/ prolonged QT
interval
CI in severe renal
impairment
Only give in hospital b/c of risks
Torsades des pointes in 4-8% (highest
risk of all drugs!)
IV only. Give by rapid infusion
Early afterdepolarizations and
~ Bronchospasm & Bradycardia
CI in renal failure!
Oral only
~ Reverse use-dependence
CI in Wolff-Parkinson-
White because they
suppress the normal AV
node pathway and induce
use of the alternate
pathway!
Heart block, hypotension, HF, asystole,
CNS (dizziness, headache), fatigue,
edema, nausea, constipation (worst of
all side effects as reported by
patients)
Heart block, hypotension, HF, asystole
Flushing, chest pain, hypotension
Effects blocked by caffeine
and theophylline
CI in pt who is actively
wheezing due to
bronchospasm
IV only (short half life): RAPID
BOLUS DOSE, otherwise it will be
metabolized before it reaches the
heart!
Bradycardia, AV block, arrythmias due
to delayed-after depolarization,
anorexia, nausea/vomit, diarrhea, ab
pain, CNS (headache, confusion,
abnormal vision (seeing yellow/green
halos)
Bad drug to use in active
patients. Good for "old
ladies" w/ minimal
exercise (low SNS)
DO NOT IMPROVE MORTALITY!
~ sympathetics override digoxin's
effect on AV node
~ Narrow TI
~ Very sensitive to electrolyte
imbalances
DigiBind: Ab to digoxin for acute
toxicity (remember that serum
Dig levels will be sky-high after
administration)
DO NOT IMPROVE MORTALITY!
Class of Drug Drug Name Clinical Application Mechanism Metabolism/Pharmacokinetics Adverse Effects Contraindications
1.) Supress excitatory
neurotransmisstion
Voltage-gated Na+
Channel Blockers
Stabilize the inactivated states of voltage-
gated Na+ channels: selectively impacting
only high-frequence neuronal firing (not ALL
firing as in local anesthetics)
Phenytoin
(Dilantin)
1st Line for Simple and Complex Partial
seizures
Generalized tonic-clonic seizures
Status epilepticus
~ fosphenytoin developed to increase water
solubility
~ CYP 2C9/2C19 metabolism is saturable =
NON-LINEAR: small differences in dose
cause huge changes in plasma []
~ Induces metabolism of contraceptives
(makes them not work as well!)
*** Purple glove syndrome
~ ataxia, sedation
~ Fetal hydantoin syndrome leads to
cleft palate
Carbamazepine
(tergretol)
1st Line for Simple and Complex
Partial seizures
Generalized tonic-clonic seizures
~ Mood stabilizer for bipolar disorder
CYP450 inducer, increased met of other
AEDs
Ataxia and sedation
~ Fetal hydantoin syndrome leads to
cleft palate
Lamotrigine
1st line trmt for generalized tonic-
clonic seizures
2.) Partial seizures
3.) Bipolar disorder
T-Type Ca2+ Channel
Blockers (Low Voltage)
absence epilepsy
T-type CCs impt in gen of rhythmic activity.
Drugs that block them prevent the "spike
wave" cycle produced by synchronized
inhibition of thalamic relay neurons
~ Highly expressed in thalamic relay neurons
(ventrobasal thalamus) which send excitatory
signals to the INHIBITORY neurons of the
nucleus reticularis.
Ethosuximide anti-absence seizure prototype blocks T-type CC
NOT a CYP450 inducer, levels reduced by
VPA or other CYP3A inducers
dizziness, lethargy, headache, GI
irritation, skin rash, bone marrow
suppression (aplastic anemia)
GABA Modulators
2.) Boost inhibitory
neurotransmission
Barbiturates
1.) Partial seizures
2.) Generalized tonic-clonic seizures
3.) Status epilepticus
4.) Withdrawal states
Increases the duration of GABA-R opening by
stabilizing the open state of the receptor
VPA, Phenytoin, and OH increase levels of
barbs and can cause respiratory depression
Drowsiness, ataxia, vertigo
** Suppression of respiration at high
levels (or with VPA and phenytoin,
OH)
Phenobarbitol
Most commonly used AED worldwide,
especially in NEONATES
~ 1st Line drug in pregnant women and
children
Primidone = phenobarb prodrug
Benzodiazepines
Increase the frequency of GABA-R opening,
not the duration
~ Positive allosteric modulators of GABAergic
neurotransmission
~ Subunit dependent: don't work at GABA-A
receptors w/ alpha4 and alpha6 subunits
Sedation, tolerance
~ Withdrawal (can cause seizures
too!)
Clonazepam
1st Line for Myoclonic Seizures
1.) Early status epilepticus
2.) Anti-absence effect: preferentially targets
alpha-3 GABA receptors which are highly
expressed in the nucleus reticularis (nRT), but
not other thalamic areas. Thus it reduces the
inhibitory effect of the nRT on the thalamic
relay nucleus and break the rhythmic cycle of
absence seizures
Diazepam
Highly lipophyllic = high volume of
distribution = low apparent duration of
action
Lorazepam Sublingual for premonitory status epilipticus
Shortest 1/2 life but longest duration of
action due to low liphophilicity
GABA reuptake
Inhibitors
Tiagabine partial seizures
blocks GABA transporter, high affinity for
GAT-1 transporter
*** Preferential activation of extrasynaptic
GABA-R create "tonic" currents
Sedation
GABA transaminase
Inhibitors
Vigabatrin
(Gamma-vinyl-GABA)
(Sabril)
Only effective treatment for West
syndrome (infantile spasms, severe
epilepsy in infants)
Irreversible suicide inhibitor of the enzyme
GABA transaminase
Visual field defects
~ Unmask psych conditions
Others 3.) Reduce Neuronal firing
Potassiumchannel
activator
Retigabine
Adjunct therapy for partial seizures in
adults
positive allosteric modulator of KCNQ
channels (which gen "Mcurrent", causes
repolarization)
~ shifts activation voltage to more negative
membrane potential
~Inhibits AP generation
not metabolized by CYP
~ Blue Skin and retinal pigmentation
with chronic use
~ Urinary retention
Others
Valproate
1st Line drug for Tonic-Clonic,
Myoclonic, and Atonic-Clonic
2nd Line for Absence
~ Also useful for partial seizures
~ Also used as mood stabilizer for
bipolar disorder
Blocks T-type CC, inhibits GABA
transaminase, increase GABA synthesis,
modify M-type K+ currents, blocks Na+
channels
Highly protein bound (80-90%): bumping
effects of caffeine, aspirin, etc may
increase free valproate in serum
Sedation, ataxia, tremor, weight gain,
allopecia
TERATOGENIC (neural
tube defects)
Levetiracetam
Effective against monoclonic, partia,
and tonic-clonic seizures in children
and adults
Binds SV2A synaptic vesicle adapter protein Excreted unchanged renally
Hyperactivity and aggression
~ Lacks common AED side fx
Gabapentin
1.) partial & mixed seizures
2.) Neuropathic pain
Off-label: bipolar, anxiety, restless leg,
multiple sclerosis
1.) Suicide
2.) Withdrawal
3.) dizziness, fatigue, weight gain,
drowsy, edema, hostility,
hyperactivity
High-voltage activated
CCBs
Glutamate receptor
blockers
Block Glutamate receptors, AMPA-R, and
NMDA-R, block excitatory neurotransmission
Ictal = during seizure
Interictal = between
seizures
Postictal = after seizure Prodrome = period before seizure
Aura = feeling/experience right before
seizure
Anti-Epileptic Drugs (AEDs)
Clinically defined Epilepsy
1.) at least 2 unprovoked seizures > 24hrs apart
2.) One unprovoked seizure + probabiliy of further seizures similar to the general recurrence risk of 2+ unprovoked siezures (>75%) ???
3.) At least 2 seizures in setting of reflex epilepsy
Types of Seizures
1.) Status Epilepticus: a life-threatening condition where seizure continues > 30min w/o interruption
2.) Partial seizures: start locally in confined region of brain (may later generalize
2a.) Simple partial: consciousness not altered, focal area (smell, sensory, motor)
2b.) Complex partial seizure: usually = temporal lobe epilepsy. Consciouness impaired, automatisms may occur
3.) Primary generalized seizures: no local onset, synchronized electrographic activity
3a.) Absence (petit-mal) seizures: brief disruption of consciousness, "staring spell"
3b.) Generalized tonic-clonic (grand-mal or convulsion): full body seizure
3c.) Others: myoclonic, clonic, tonic, atonic
Other Considerations
1.) Monotherapy: if first drug doesnt work, it is increasingly likely that 2nd/3rd/4th won't work
2.) Pregnancy and neonatal: valproate = NT defects, phenytoin and carbamazepine can cause "fetal hydantoin syndrome" leading to cleft palate.
~ AEDs in neonates can trigger neuronal apoptosis,permanent behavioral changes, and lower IQ
Prototype Drugs
L-Dopa Mainstay of anti-PD treatment
Carbidopa
Enhances the amount of L-dopa (1-10x)
that reaches the CNS and prevents
emesis by decreasing the amount of DA
that acts on the gut
~ Always used with L-Dopa, called
"Sinemet*" ("w/o emesis")
Antimuscarinics
Trihexyphenidyl Effective mainly for tremor and rigidity
Dopamine agonists
Bromocriptine
Long-acting DA-R agonist used for long-
term PD treatment.
1.) Delays need to start L-dopa
2.) Effective as monotherapy
3.) May be neuroprotective
MAO-B Inhibitors
Rasagiline
May be neuroprotective (DATATOP
study)
COMT Inhibitors
Parkinson's Drugs
Entacapone
Others
Amantadine
Normally an anti-viral agent, also used
for PD (treats tremor, bradykinesia,
rigidity, and dyskinesia)
Mechanical Interventions for PD
1.) Deep Brain Stimulation: high-frequency, pulsatile, electrical stimulation of specific brain nuclei
~ Stimulation of STN improved "off" sx by 60% and "on" sx by 10%
~ Reduced dyskinesia and reduced medicine reqmts
2.) Surgery: ablative, DBS, transplant
Impt Notes from Class
~ It takes 75-80% loss of dopamine neurons to see Parkinsonian Sx. Cell bodies are in the SNpc
~ Some people start w/ less DA neurons, some people undergo an exposure and lose neurons faster
~ 4 mechanisms of compensating for lost neurons
1.) Increased dopamine synthesis via activation of tyrosine hydroxylase
2.) Decreased DA reuptake via down-regulation of re-uptake channels
3.) Increased rate of firing of remaining DA neurons via lack of feedback inhibition
4.) Upregulation of post-synaptic DA receptors in the striatum (putamen specificically!)
Hallmarks of Parkinson's Disease
1.) Akinesia (Bradykinesia)
2.) Resting tremor ("pill rolling tremor")
3.) Rigidity and Postural instability
Treatment adjustments for Long-Term Therapy
1.) Delay initiation of L-dopa as long as possible
2.) Increase L-dopa/dose
3.) Increase frequency of dosing / use controlled release Sinemet*
4.) Add long-lasting DA-R agonist: bromocriptine, pergolide, pramipexole
5.) Add MAO-B inhibitor to slow degradation of DA in the brain: deprenyl (selegiline), rasagiline
6.) Add a catechol-o-methyl transferase (COMT) inhibitor to prolong availability of L-Dopa by slowing degradation of L-Dopa to 3-O-methyldopa in the periphery: entacapone, tolcapone
Mechanism Metabolism/Pharmacokinetics
Crosses BBB and is converted to DA via dopa-
decarboxylase (L-aromatic amino acid
decarboxylase, LAAD) within neurons and in
other brain areas
Less than 5% of L-Dopa survives 1st pass
hepatic metabolism to get to brain
~ 1/2 life = 90 min
Blocks Dopamine Decarboxylase (LAAD) in the
periphery
Doesn't cross BBB, thus preventing
peripheral breakdown of L-Dopa and
increasing the amount that reaches CNS
blocks action of ACh in striatum
Directly stimulates DA-Rs to compliment L-
dopa therapy
1/2 life > 8hrs
Slows degradation of DA in the brain
Parkinson's Drugs
Blocks COMT, slows the degradation of L-
dopa to 3-O-methyldopa (3-OMD) in the
periphery (so more is available to go to CNS)
Stimulates release of DA from presynaptic
neuron, inhibits reuptake, stimulates DA-R,
and blocks NMDA-R
~ Prolongs DA time in the synapse
Therapeutic
Considerations
Peripheral:
1.) N/V (via activation of DA-receptors
in the area postrema)
2.) Orthostatic hypoTN (via DA-
receptors in kidney)
CNS:
1.) Dyskinesias
2.) Psychosis
Long-term L-Dopa trtmt leads to a
shrinking therapeutic window.
= "Wearing-off Syndrome"
~ After one year, the benefits
fade before the end of dose.
~Additionally, the threshold for
dyskinesia is lowered
~ On-off Syndrome" - 5-7 yrs
Unpredictable fluctuations in the
ability & inability to move
Short half-life, must give multiple
doses per day
~ Don't use w/ high protein diet
Anticholinergic: dry mouth, sedation,
delerium, confusion, hallucinations,
constipation, urinary retention
Nausea, dizziness, somnolence,
confusion
~ Hallucinations/paranoia
~ Pulmonary and retroperitoneal
fibrosis; pleural effusion/thickening,
Raynaud's
Choice of agonist is an art: one
may fail, but doesnt predict
failure of other agonists
~ Reduce L-dopa dose when giving
agonists
Insomnia, hallucinations, nausea
(rare), OrthoHypoTN
Potential interactions
with TCA and SSRI
antidepressants
Diarrhea, orthostatic hypoTN,
dyskinesias, confusion
~Acute fulminant hepatic necrosis
(with Tolcapone only)
Always block COMT in both the
periphery and in the CNS
(vs. carbidopa which blocks LAAD
in periphery only)
autonomic, psychiatric
Protein from diet will
compete w/ L-dopa to
cross BBB
~ Protein re-distribution
diet: only eat high
protein before bedtime
Agonists
Morphine
Opioids and Other Pain Meds
~ Opiates = derived from opium (morphine, codeine)
~ Opioids = natural/synthetics that target opioid receptors
Hydromorphone
(Dilaudid*)
Codeine
(Methylmorphine)
Oxycodone
Hydrocodone
Meperidene
(Demerol*)
Fentanyl
Methadone
Heroin
(diacetylmorphine)
Levorphanol
Tramadol
Loperamide
(Imodium*)
Agonists/Antagonists
Pentazocine
Buprenorphine
Antagonists
Naloxone
Naltrexone
Methyl naltrexone
(Relistor*)
Neuropathic Pain Drugs
Tricyclic Anti-Depressants
(TCA)
Amitriptyline
Serotonin-Norepinephrine
Reuptake Inhibitors (SNRI)
Duloxetine
Antiepileptics
Gabapentin
Pregabalin
Valproic Acid (VPA)
Carbamazepine
Endogenous opioids and receptors are expressed in the:
Brain
Spinal Cord
Peripheral sensory nerves
GI Tract
Immune Cells
Important Class Notes
Classes of Opioid Receptors
~ Gi-protein coupled, decrease cAMP, suppress voltage-gated Ca2+ currents = decreased transmitter release from presynaptic terminals in sensory nerves
~ All partake in analgesia
1.) Mu: ALSO acativate K+ channel that hyperpolarizes and lowers excitability of postsynaptic neurons. Only one with RESPIRATORY effects. GI and Sedation
2.) Kappa: Sedation, Psychotomimesis effects (???)
3.) Delta
4.) ORL1-Orphanin
Pain Perception
~ A-delta nerve fibers are the "fast pain" fibers that sense noxious stimuli such as pressure, thermal, or chemical stimulation (burning hand on stove)
~ C-fibers are the "slow, second pain" fibers that carry dull and persistent pain informatation to the fibers. These are preferentially targeted by opioids via the mu receptor.
Types of Pain
1.) Nociceptive pain: somatic (localized, specific pain: arthritis, fracture, cellulitis, bone metastases) vs. visceral (poorly localized: pancreatitis, MI, peptic ulcer, etc)
2.) Neuropathic pain: results from injury to peripheral and/or central nerves. Causes neuronal hyperexcitability. Usually don't use opioids to treat
~ presents as burning, sharp, or electric pain
~ E.g. diabetic neuropathy, herpes zoster, phantom limb pain
Notes for Opioid Administration
~ Always give short acting opioids first to relieve pain quickly and establish dosing requirements/reactions
~ For persistent/constant pain, consider around-the-clock dosing or a long-acting formulation
~ Watch out for Tylenol #3 and #4! Doctors forget to tell their patients about the acetaminophen and patients often take with OTC tylenol at home which can lead to acetominophen overdose and
liver failure!
~ Dose increases less than 30-50% are unlikely to improve analgesia! Opioid responses increase linearly with the log of the dose
~ Opioid rotating: change from one opioid to another, consider reduction from equianalgesic dose due to non-cross tolerance (decrease 25-50% for most opioids)
Primarily for analgesia: reduces the
intensity of the pain and makes the
patient "care less" about the pain
~ Analgesia w/o loss of consciousness!
~ Anti-tussive (stops cough)
~ Analgesic effect is two fold
1.) Opioids produce "indifference to pain" in
the brain
2.) Opioids excite descending INHIBITORY
pathways
Relief of pain is selective: other sensory
modalities (heat, pressure, vibration, vision,
etc) are not affected
Morphine targets mu, kappa, and delta
receptors. Mu receptors are the primary
analgesic receptors are are preferentially
located on the C-fibers associated with slow,
persistent pain
Anxiolytic Effects: mu receptor inhibition of
NE release in the locus coeruleus
Analgesic: 6-10x more potent than
morphine
~ Potent antitussive agent
~ Given w/ NSAID or acetaminophen for
synergistic analgesic effect
10-15% converted to morphine via CYP2D6
~ No analgesic ceiling
9-10x more potent than codeine =
morphine
~ With acetaminophen = Percocet
6-8x more potent than codeine
~ With acetaminophen = Vicodin
Not used very much any more b/c of risk
of seizures
~ 1/6 potent as morphine
100x more potent than morphine
~ Used extensively in anesthesiology
~ Spinal admin: stays where you inject b/c
highly lipophylic
~ Transdermal patch: chronic cancer pain
~ Lollipop or lozenge: absorbed across
bucal mucosa for breakthrough pain
Intrinsic activity and activity as metabolites
(hydromorphone and oxymorphone)
~ Inhibition of CYP2D6 does NOT block
analgesic effect
Detoxification and maintenance trtmt for
opioid addicts
~ Equipotent as morphine
~ L-isomer acts at mu receptors
~ D-isomer also blocks NMDA receptors
which may give methadone some
neuropathic pain activity
Not used clinically
~Most often abused opioid in US
5x more potent than morphine, less N/V
Used for moderate pain and limited
respiratory depression & abuse potential
Partial mu agonist + NE/5-HT reuptake
inhibitor
~ This gives it several mechanisms for
analgesic effect
Anti-diarrheal Mu agonists that doesn't penetate the CNS
Used for moderate pain (1/5 potency of
morphine) with redu
Partial mu agonist + Kappa agonist
Widely used for moderate pain
~ less risk of abuse w/o psychotomimetic
effects of kappa agonism
~ Used for detox and rehabilitation of
alcoholics
Partial Mu agonist + Kappa antagonist
IV adminstration to treat opioid overdose Mu receptor antagonist
Oral administration used to treat opioid
addiction (relapse prevention)
~ Prevents the reward/euphoric effects of
taking an opioid
Mu receptor antagonist
Used to treat opioid induced constipation
~ Sub-Q injection
Mu receptor antagonist in gut
Used for neuropathic pain Blocks serotonin-NE uptake
Used for neuropathic pain
Brain
Spinal Cord
GI Tract
Immune Cells
Used for neuropathic pain
~Prevent neuronal hyperexcitability (just
like you want to do for seizures)
Not often used for pain because you have
to monitor plasma levels, high medical
burden
3.) Delta
4.) ORL1-Orphanin
Pain Perception
Types of Pain
liver failure!
Metabolism/Pharmacokinetics Adverse Effects
Liver metabolism, RENAL excretion (adjust
for renal failure!)
Oral, IM, IV, SC: 1/2 life 4-5 hours
Epidural/Intrathecal: up to 24 hrs
~ Morphine is transformed (liver, kidney,
brain) to two metabolites: morphine-3 (CNS
stimulant, not opioid) and morphine-6-
glucuronide (opioid)
~ Hydrophilic
~ Oral 1st pass metabolism: 25%
bioavailability
~ Tolerance: over time, drug loses
effectiveness. Tolerance to one opioid
leads to cross-tolerance to all other opioids
at that receptor
~ Physical dependence: reset the
homeostatic NT set point. Withdrawal
occurs when suddenly stopped.
~ Addiction: does NOT depend on
tolerance/physical dependence.
1.) Mood and reward: stimulations DA reward
pathways w/ nucleus accumbens
~ Euphoria, tranquility
2.) Miosis: pupillary constriction via PSNS
excitation in CNS
~ Doesn't reduce w/ tolerance
3.) Convulsions
4.) Hypothalamus/neuroendocrine: inhibits
release of GnRH and CRF. Leads to decreased
LH, FSH, ACTH, b-endorphins, testosterone, etc
5.) Respiration: depresses respiration center in
brainstem. Increased by other CNS
depressants (barbs, OH, benzos).
~ Cough: anti-tussive, indpt of respiratory
effects
6.) Smooth muscle:
~CONSTIPATION (doesn't improve w/
tolerance),
~N/V (chemoreceptor trigger zone for emesis in
the area postrema of medulla)
~decreased HCL in stomach, biliary tract
constriction, urinary retention
7.) CV: peripheral vasodliation (orthostatic
hypoTN), inhibits baroreceptors
8.) Skin: dilation leads to pruritis (itching) and
flushing (via histamine), diaphoresis (sweating)
9.) Immune system depression
More lipid soluble than morphine (ketone
groups), faster action
Metabolized to morphine by CYP2D6
Metabolite has much longer 1/2 life (15-
20hrs vs 2-3hrs), builds up and leads to
toxicity
Seizures/Convulsions
Peak analgesia in 5 min (vs. 15 min for
morphine)
~ Transdermal patch lasts 72 hours (steady
state after 16 hrs): stays in fat depot below
skin
~ Fever/hot water speed up reservoir
emptying
~ Over 50% hepatic excretion (Safe for
Renal impairment!)
1/2 life of 35-190 hours!
2-3x more potent than morphine, due to
higher lipid solubility (acetyl groups)
Metabolized slowly, 12-16 hour 1/2 life
Ceiling effect on analgesia due to partial
agonism
Psychotomimetic effects due to Kappa
agonism = hallucinations
Withdrawal sx due to partial mu agonism
Very short acting: 30 min to 1 hr. Must be
given repeatedly for overdose
Causes withdrawal in dependent people
24 hour duration of action
(Dr. Young says 3hr 1/2 life, duration 13hrs)
Extra methl group prevents crossing BBB
Potent anti-cholinergic side fx (ABCDs:
Anorexia, blurry vision, constipation, dry
mouth, sedation)
Brain
Spinal Cord
GI Tract
Immune Cells
3.) Delta
4.) ORL1-Orphanin
Pain Perception
Types of Pain
liver failure!
Contraindications &
Drug Interactions
Therapeutic
Considerations
Withdrawal: rapidly
stopping opioid use leads to
withdrawal sx.
~ Diarrhea
~ Sadness (dysphoria)
~ Anxiety
~ Oral, IM, IV, Epidural,
Intrathecal (into CSF)
administration
Simultaneous admin of
morphine at spinal and
supraspinal sites resuls in
synergistic analgesia: 10x less
morphine needed
~ Mu receptor polymorphism:
12% of Caucasians have an
A118G substitution in the N-
terminus of the Mu receptor -
requires 2x as much morphine
for same analgesia
CI with SSRIs such as
fluoxetine and paroxetine
(CYP2D6 inhibitors)
10% Caucasians have
polymorphism in CYP2D6 that
can't metabolize codeine
~ Keep in mind that codeine
allergy = morphine allergy!
Never give transdermal
patch to someone who
hasn't had opioids before:
lasts 72 hours and we dont
know their rxn
Safe for renal impairment
Limited respiratory depression
and abuse potential
Antagonizes respiratory
depression,
euphoria/sedation/miosis, GI
effects, analgesia of other
opioids
Life-changing drug for many
people with severe opioid
constipation
Prevents the anticholinergic side
effects of TCAs
Local Anesthetics
Cocaine
Procaine
Tetracaine
Bupivacaine
Etidocaine
lidocaine
Mepivacaine
Other (no tertiary nitrogen) Benzocaine
Anesthetics
Esters
Amides
( have 2 i's in them :)
Mechanism of Action for LA
~ Injected locally to area surrounding target nerve(s)
~ LAs are weak bases (pK range 7.5-9). In solution and in the injected LA, the drug is mostly in its salt form.
~ To cross the membrane into the nerve cell, only the drug in its base form (lipophylic) can cross. After crossing, the drug is recoverted to its
salt form in order to bind to the receptor w/in the Na+ channel (NB: abscesses are acidic surrounding the nerve. Thus more drug is in its salt
form and less is available to cross the nerve membrane, thus a higher concentration of drug is needed)
~ The LA can only bind to the receptor when both the voltage (M) and time (H) gates of the Na+ Ch are open
Decremental Conduction
~ When the LA is bound, less Na+ can cross through the open Na+ Ch in a given amount of time. Thus the AP has a slower rise (less steep slope)
and cannot reach its full depolarization before the time (H) gate closes. Thus, APs have a decreased velocity and magnitude.
~ All LAs are vasodilators EXCEPT cocaine! Often give with epinephrine to vasoconstrict.
Muscle Relaxants
Relaxants
Competitive (Non-depolarizers)
d-Tubocurarine
(Curare)
Vecuronium
Rocuronium
Atracurium
Cisatracurium
Non-competitive (Depolarizers) Succinylcholine
Antimuscarinic Agents
Atropine
Glycopyrrolate
Cholinesterase Inhibitors
~ Always check for blood (via aspirating w/ needle) before injecting LA. Systemic LA can cause arrythmias, bradycardia, convulsions and
seizures
Neostigmine
Edrophonium
General Anesthesia
Inhalation Agents
B/G = 12.0 Diethyl ether
B/G = 0.47
MAC = 105
Nitrous oxide
Potent Inhalation Agents
B/G = 2.3
MAC = 0.74 (most potent)
Halothane
B/G = 1.8
MAC = 1.68
Enflurane
B/G = 1.4
MAC = 1.15
Isoflurane
B/G =0 .69
MAC = 2.0
Sevoflurane
B/G = 0.42 (Fastest)
MAC = 6.0
Desflurane
Intravenous Anesthetics
Thiopental
Ketamine
Etomidate
Propofol
Midazolam
Dexmedetomidine
Narcotics
Fentanyl
Sufentanil
Respiratory Effects: (En > (Iso, Des, Sevo) > Halo)
CNS Effects: 1) Increase cerebral blood flow. (Halo > En > (Iso, Des, Sevo))
2) Increase neuromuscular drug effects. ( En > (Iso, Des, Sevo) > Halo)
Cardiac depression: H > E > (I, S, D)
Alfentanil
Remifentanil
Agent for malignant
hyperthermia
Dantrolene
Drugs for N/V
Ondansetron
Promethazine
Drugs to reduce stomach acid
??? -----> Remifentanil
H2 Blockers
(Ranatidine)
Proton pump inhibitors
(-azoles, Prilosec*)
Prokinetic agents
Metoclopramide
Prerequisites for a Good General Anesthetic
1.) Amnesia/Sedation: make patient unconscious with no memory of surgery
2.) Analgesia: pain control both during surgery and after regaining consciousness
3.) Immobility
4.) Decrease SNS activity (measures depth of anesthesia)
Blood gas solubility coefficient (BGC): the relative affinity a drug has for the blood phase compared to the gas phase when in equilibrium
~ In general, medications being used by a patient should be continued thoughout the perioperative period
~ Take meds w/ small cup of water in morning: actually decreases gastric fluid volume!
1.) Clonidine and propranolol are especially impt to prevent rebound HTN
2.) Supplemental steroids to patients on steroids due to adrenal suppression and risk of Addisonian crisis
3.) Diabetics require dosing modification
Qualities of Ideal IV Anesthetic
~ Rapid/smooth onset
~ Non-irritating & painless injection
~ Rapid metabolism to inactive metabolites
~Minimal CV and respiratory depression
~ Reduced cerebral blood flow, cranial pressure, and oxygen consumption
~ Rapid & smooth return to consciousness
~ No post-op side effects and no hypersensitivity reactions
Steps of Anesthesia
1. ) Pre-operative
2.) Monitoring
See below
Only clinically used as local anesthetic for
surgery in areas with extremely dense
vasculature (back of the eye/throat) due
to vasoconstrictive effect
Blocks NE reuptake: increases SNS
Used in topical preparations such as
Solarcaine*
Acts within the nerve cell membrane: increases
fluidity to compress Na+ channel
Anesthetics
Used to help us reduce the dose of
local/general anesthetic needed to stop
muscle action
Competitive antagonist of the ACh-R
Very commonly used MR
~ Intermediate duration w/ very few side
fx
60 sec onset, 30-40 min offset
One of the "rocks" of muscle relaxants
~ 90 sec onset of action makes it usable
for intubation if necessary
~ Fast enough to use for intubation
Fast onset (< 60 sec), lasts 25-30min
Used for intubation: Rapid onset and
short duration of action
Mimics the action of ACh at the NMJ producing
depolarization and muscle contraction, followed
by muscle relaxation
~ However, it remains at the muscarinic receptor
and prevents further depolarization
Must be given with AChE-I's to block
muscarine receptors and prevent reflex
bradycardia
Used to increase ACh at the NMJ and
restore muscle function
seizures
MR used in patients with renal
insufficiency
Onset 90 sec, lasts 30 min
Frequently used anesthetic, very
frequently used
~Causes amnesia, unconsciousness, and
analgesia but doesnt cause immobility or
SNS depression alone
6 - 25% N2O = Mild sedation and analgesia.
26 - 45% N2O = Moderate sedation and
analgesia.
46 - 65% N2O = Amnesia and significant
analgesia.
66 - 70% N2O = Unconsciousness and light
anesthesia is experienced by most patients.
most potent inhalation agent
Less CV risk and liver toxicity
Doesnt depress CO during surgery, mildly
irritates airway and pungent
Non-pungent, best induction agent for
children!
fastest onset inhalation agent, but
pungent and irritates airway
Quaternary Nitrogen prevents crossing the BBB
and limits action to periphery (like we want!)
~ Act at both nicotinic and muscarinic receptors
Induction agent
~ Works via (+) allosteric modulation of GABA-A
receptors
CNS Effects: CNS protectant! Decreased CBF, ICP,
and O2 consumption. Used to create barbiturate
coma in brain damaged pt
CV Effects: cardio depression and venous dilation
= decreased MAP, SV, and CO. Increased HR via
baroreceptor
Respiratory Effects: apnea! Must be on (+)
pressure ventilation
Induction agent for dissociative
anesthesia. Good for hypovolemic
patients
Maintains BP by direct SNS stimulation. Blocks
NMDA receptors and interacts with ACh signalling
Induction agent for patients with CAD
and/or hypovolemia
Short DOA
1.) Induction agent, antiemetic
2.) Maintenance anesthesia via IV
infusion. Used with vecuronium,
fentanyl, and NO (commonly)
~Works via GABA modulation
~Short DOA (4-8 min), patient comes out wide
awake
CNS: same as thiopental
CV: significant depression. Use IV fluids, alpha
and alpha/beta agonists, and SNS stimulation to
correct
Resp: Thiopental
Used in pre-operative anesthesia to
produce selective anti-anxiety effects w/o
excessive sedation, respiratory
depression, or adverse side effects
Benzodiazepine that acts at GABA receptors
Potent analgesia but unreliable amnesia
Potent opioid analgesic, can be used
preoperatively in anesthesia for patients
that require analgesia as well as sedation
75x as potent at morphine
Ultra-short acting opiod used for pain
during surgery or for sedation in
analegesia
Used in pre-operative anesthesia to
reduce risk of aspiration pneumonitis
increases gastric pH by blocking histamine
induced secretion of gastric fluid w/ high H+
~ doesn't decrease gastric volume
Gastrokinetic drug used to reduce risk of
aspiration pneumonitis
reduces gastric fluid volume by relaxing the
pyloric sphincter and promotic gastric motility.
~ No change in pH
3.) Immobility
Steps of Anesthesia
1. ) Pre-operative
2.) Monitoring
Euphoria
Addiction
~ Severe CV risks due to increased SNS
Without a tertiary N, it is not water soluble
pH-pKa=log(base/salt)
Anesthetics
Esters are broken down by free esterases in
the blood. All LAs are vasodilators except
cocaine, so Epi is often coadministered to
countervasodilation PABA metabolite of procaine causes skin
reactions (dermatitis) when administrator
doesnt use gloves
Amides are broken down by CYP450
enzymes in the liver
~ Hypotension: increased histamine release
~ HYPOTENSION: Ganglionic blockade
Very few, small ganglionic blockade
"Stable as a rock"- very few side effects
~ Slight tachycardia via mAChRs
Slight histamine release, decrease in BP
Almost none
Hydrolized by pseudochilinesterase in the
blood rather than by AChE.
~Bradycardia
~Hypotension (BV mAChRs)
~Cardiac arrhythmias (bradycardia, junctional
rhythms, sinus arrest
~ Hyperkalemia
~ Muscle fasciculations leading to myalgias
and myoglobinuria
~ Increased intraocular/cranial pressures
~ Trismus
~ Triggers malignant hyperthermia
seizures
All are primarily metabolized in the liver and
excreted in the kidney
"Spontaneous elimination" via plasma
cholinesterase in blood
Very few side fx
Hepatotoxic (fulminant form
has 50-75% mortality)
CV Effects:
Seizures at high doses
~ avoid w/ renal insufficiency
short, transient increase in HR and MAP
Short initial effect due to redistribution, 1/2
life of 11hrs
Doesn't lower BP
~ Myoclonus
Lowers BP
Given IV for rapid onset and titrated. DOA =
2-6 hrs
Very few!
respiratory depression, N/V, bradycardia,
hypoTN
3.) Immobility
Steps of Anesthesia
1. ) Pre-operative
2.) Monitoring
Contraindications &
Drug Interactions
Therapeutic
Considerations
Always put patients on MRs on
ventilator!
explosive!
Malignant Hyperthermia!
~ CV: maintain HR and SVR,
decrease MAP, CO, MVo2,
and myocardial O2
consumption
~Pulm: Dose related
respiratory depression
(decreased TV and sensitivity
to hypercarbia and hypoxia),
incrased RR, PaCO2,
bronchodilation, inhibits
mucocilliary function)
~ CNS: decrased O2
consumption and EEG
activity, increased blood
floow and NMJ blocking drug
effects
Analgesics
NSAIDs
~ Ibuprofen, Aspirin,
Actetaminophen
~ Excedrin (Asp, Acet, +
caffeine)
Vasoconstrictors
Triptans
Sumatriptan
Frovatriptan
Ergots
Ergotamine
Dihydroergotamine
Migraines
Others
Metoclopramide
Caffeine
Beta-blockers
(Propanolol and timolol)
Anti-epileptic drugs
(VPA, Topiramate)
TCAs
(amitriptyline,
nortriptyline, imipramine)
Strategies for treating migraines
1.) Abortive trtmt: stop active migraines. Mild = NSAIDs, Moderate-Severe = 1st line Triptans, 2nd line Ergots
2.) Preventative: Long-lasting triptans (frovatriptan), beta-blockers, anti-epileptics
Migraines are uni/bilateral, pulsating, 4-72 hr headaches, that always have other associated sx
~ Assoc. sx include nausea (90%), hypersensitivity to light/noise, and and aura (20%) before attacks occur
~ More common in women and during menstruation
Migraine etiology
~ Thought to be a primary neurological disease involving the hypthalamus and the brainstem. Altered brain activity leads to activation/inflammation of sensory nerves
~ In turn, these nerves release neuropeptides (CGRP) which relax vascular smooth muscle (vasodilate) and cause leakage of proteins, further irritating sensory nerves
~ There is a proposed trigeminovascular etiology involving the dorsal raphe nucleus and locus coeruleus and trigeminal nucleus in the brain stem
Analgesia in mild migraines
~ 1st line trtmt for mild migraines
Prevents sensory nerve activation and nerve
transmission by decreasing inflammation
5-HT-1B/D agonists (Gi coupled)
~ Direct vasoconstrictor on vascular smooth
muscle (via Gi mechanism)
~ Inhibits presynaptic release of vasodilator
peptides from sensory nerve terminals (CGRP)
(via Gi and decreased Ca2+ channel activity)
Abortive, rapid migraine relief
5-HT-1B receptors have much higher
concentration in cranial blood vessels
Prophylactic treatment of predictable
migraines
Non-selective 5-HT receptor agonists and
adrenergic agonist/antagonist
Sublingual, Long-lasting (24hr)
vasoconstriction
1.) 5-HT-1B agonist
2.) alpha 1/2 agonist (at low doses),
antagonist at high doses
3.) D2 agonist
Nasal spray, less potent than ergotamine
(less side fx)
~ Does NOT cause medicine induced
headaches with over use
Migraines
Prevention of migraine-associated N/V Enhances gastric motility
Aids in gastric emptying and promotes
drug absorption
Small anti-nausea effect as well
Xanthine binds adenosine receptors and
causes acute constrictoin of cranial vessels
Continuous migraine prophylaxis unknown
Continuous migraine prophylaxis Unknown
Migraine etiology
1.) Do not give Triptans and Ergots together
because of additive vasoconstriction
2.) Don't give Triptans and SSRIs together b/c of
risk of Serotonin Syndrome
Constricts cranial vessels with greater
potency and efficacy than 5-HT and doesnt
have same systemic effects
~ 1/2 life 2hrs
Metabolized by MAO-A
Bitter taste compared to zolmatriptan
1/2 life of 25hrs
~ Hepatic metabolism w/o P450 effects
CYP3A4 Inhibitors: beta blockers my
potentiate effects
Nausea in 10% of pts
Migraines
Poor GI absorption
VPA: nausea, fatigue, tremor, weight gain, hair
loss
Topiramate: paresthesias, fatigue, language
and cognitive impairment, taste, weight loss
Migraine etiology
Contraindications &
Drug Interactions
Therapeutic
Considerations
dont use NSAIDs in 3rd TM
of pregnancy (premature
closing of ductus arteriosus,
impairs contractions,
bleeding risk)
Often combined w/ NSAIDS to
enhance pain relief
~ Coronary or cerebral
vascular disease
~ Uncontrolled HTN
~ MAO-Is (serotonin
syndrome)
Available as tablets, nasal spray,
or injection. Nasal spray fastest
acting
~ Safe in pregnancy
1.) Coronary or cerebral
vascular disease
2.) CI in pregnancy: cause
abortions!
Less effective than Triptans, but
useful in unresponsive patients
1.) Decompensated heart
failure
2.) Asthma
CI in pregnancy
Gonadotropins
FSH
LH
hCG
Given in bolus to induce ovulation
~ Much more potent than LH
GnRH
Used to "reset" ovaries after
repeated administration of FSH and
LH causes desensitization
Menotropins
hMG
Urofollitropin
(Ferntinex*)
Purified FSH used in combo w/ hCG
to assist in ovulation and fertility
Leuprolide
Used in Polycystic Ovarian
Syndrome; prevents luteinization
~ Also can be used to "reset"
ovaries that become desensitized
to FSH/LH
Ganirelix
Keep ovaries from ovulating too
soon during fertility trtmt
Selective Estrogen Receptor
Modulators (SERMS)
Clomiphene
Drug of choice for infertility in
PCOS
Tamoxifen
Used for cancer, NOT fertility
- Menopause therapy
Reproductive Pharmacology
Given together to induce normal
follicular maturation and uterine
development
GnRH modulators
Raloxifene
Prevention of osteoporosis in
postmenopausal women
DA Receptor Agonists
Bromocriptine or
Carbegoline
Used for infertility due to high levels
of prolactin
~ 100% of women ovulate!
Tocolytic Drugs
used to prevent premature
contractions (<37 weeks) by 2-7
days
~ allow lungs to fully mature
Beta-adranergic agonists Ritrodine/terbutaline
Ca2+ Channel Blockers or Ca2+
blockers
Magnesium Sulfate
COX inhibitors Indomethacin
Oxytocin receptor antagonists
Best used later in pregnancy when
oxytocin receptors are upregulated
NO donors Nitric oxide
Inducing Labor
Oxytocin Stimulate uterine contractions
Prostaglandins Misoprostol
Cervical ripening and labor
induction
Contraceptives
Estrogens Ethinyl-estradiol
Mestranol
Progestins
Drospirenone
(YAZ* and Yasmine*)
Medroxyprogesterone
(Depoprovera*)
Used for 3 months of birth control,
IM injection
Norethindrone
(Minipill*)
Oral contraception with minimal
side effects
Levonorgestrel
(Plan B*)
Emergency contraception w/in 72
hours of sex
Combos
Abortion
Mifepristone
(RU-486)
Terminate pregnancy in 1st
trimester
Post-Menopausal Therapies
Estrogen Replacement Therapy Used for women w/ hysterectomy
Premarin*
Estrone sulfate
(Ogen*)
Estradiol
HRT for post-menopausal women.
Vaginal cream or transdermal patch
Combo HRT Estrogen + Progestin
Used w/ women that still have
uterus
SERMs Tamoxifen, Raloxifene
Tamoxifen acts as ER agonist in
bone (good) and uterus (bad).
Antagonist in breast = good
Review of Female Menstrual Cycle Hormones
1.) Hypothalamus normally secretes GnRH in a pulsatile manner to act on the anterior pituitary (AP). GnRH travels via the pituitary portal vasculature to activate G-protein receptors in AP
~ Opioid neurons inhibit GnRH release, NE neurons stimulate it
~ Over-release of GnRH will cause the body to down-regulate
1st half of Cycle = low amplitude, high frequency GnRH release
2nd half of Cycle = high amplitude, low frequency
2.) Anterior Pituitary: stimulated by GnRH, will release FSH and LH
3.) Ovaries: stimulated by FSH and LH will produce estrogen (E) and progesterone (P)
~ Both E and P normally exert (-) feedback on AP and hypothalamus
~ FSH stimulates the follicles to grow in the ovaries
~ During middle of cycle, E rapidly increases and causes a rapid release of LH (instead of inhibiting it). The massive LH release stimulates ovulation.
~ LH stimulates the corpus luteum (remnants of follicle) to release lots of Progesterone. If implantation doesn't occur, LH will drop and the corpus luteum will atrophy, decreasing P release
~ When P drops below critical level, menstruation occurs
4.) Uterus: during 1st half of cycle, Estrogen causes the endometrium to proliferate.
~ When Progesterone dominates in 2nd half of cycle, the endometrium becomes secretory to prepare for implantation
5.) Cervix: during 1st half of cycle, Estrogen causes the cervix to secrete thin, alkaline substance that is pro-sperm
~ During 2nd half of cycle, increased Progesterone cause thick and viscous, anti-sperm secretions from cervix
Stimulation of Ovulation
1.) Give bolus doses of LH and FSH to stimulate follicle growth
2.) Give bolus dose of hCG (more potent than LH) at proper time to induce ovulation
~ Use test doses to avoid release of too many eggs
~ Don't need a functional hypothalamus or AP to be effective
~ If patient becomes desensitized to FSH and LH, administer continuous GnRH agonists to shut down FSH and LH production in the AP and allow ovaries to "reset"
Role of Prolactin
~ Normally prolactin plays important role in breastmilk production and is high after babies are born
~ In some women, circulating prolactin is high while not breastfeeding, causing abnormal milk production and amenorrhea
~Causes of hyperprolactinemia:
1.) Hypothyroidism: decreased thyroid activity leads to incrased thyrotropin-releasing hormone (TRH) which stimulates prolactin release.
2.) Drugs: Reserpine, a-methlydopa, anti-dopaminergics
3.) Pituitary tumor
~ Prolactin release results in low estrogen affecting fertility
~ Dopamine acts as a prolactin inhibitory factor on lactotrophs
Contraceptives
~ Originally gave high estrogen and progesterone
- High E and P feedback on pituitary and decrease FSH and LH release. Low FSH suppresses follicle development. Low LH prevents ovulation
- High progesterone will keep the endometrium in the "secretory" state and prevent implantation and it will maintain viscous, acidic cervical secretions which are anti-
sperm
- High E interferes with fallopian tube movement
Extracted from pregnancy urine
High FSH:LH level
~ Extracted from urine of postmenopausal
women
GnRH agonist on pituitary; downregulates
GnRH-R and decreases endogenous LH/FSH
GnRH antagonist on the pituitary, suppress
LH and FSH production
High affinity Estrogen receptor antagonist in
the Anterior Pituitary
~ Blocks normal Estrogen action and causes
massive release of LH and FSH
~ Requires intact hypothalamus-pituitary
axis
Reproductive Pharmacology
Acts on the D2/D3 dopamine receptors on
lactotrophs to inhibit prolactin release
Antagonizes SNS, causing decreased NE
release
Hyperprolactinemia leads to amenorrhea,
usually assoc w/ low E
Increase cAMP which inhibits myosin light-
chain kinase
Blocks influx of Ca2+
Blocks synthesis of prostaglandins
Increases cGMP which inhibits myosin light-
chain kinase
Binds to receptors in the myometrium
causing uterine contraction through cAMP-
independenent release of Ca2+ in SM cells
Synthetic PGE1 given intravaginally to cause
cervical ripening and uterine contractions via
upregulation of Ca2+ in the myometrium
~ Increases Ca2+ and decreases cAMP
Ethinyl group increases bioavailability of oral
estrogen by 40-50%
Metabolized to ethinyl-estradiol in the liver
Analogue of spironolactone, this drug has
both anti-androgenic and mineralocorticoid
effects
Prevents fertilization via maintenance of anti-
sperm cervical secretions
Single 1.5mg dose or two 0.75mg doses of P.
Stops ovulation, inhibits sperm capacitation,
fallopian tube motility, and blastocyst
implantation
Estrogen activity maintains proliferative
endometrium (until withdrawal bleeding) and
Progesterone maintains anti-sperm cervical
secretions
Progesterone receptor angatonist
~Blocks's progesterone effects at its receptor
and causes detachment of the uterine lining
~ Used with Misoprostol (PGE1) to cause
uterine contractions
Good effects: regulated cycles, decreased menstrual blood loss/cramps, correction of anemia, decreased tension, increased
libido, decreased ovarian cysts, decreased acne
Bad effects (Estrogen related): N/V, headache, tension, breast discomfort, anxiety, fatigue, depression, weight gain, adenitis,
amenorrhea, cholasma (brown spots on face)
Really Bad: CARDIOVASCULAR!
Decreased glucose tolerance (P effects insulin), reversible HTN (excess renin, AT2, aldo), benign hepatomas, cervical cancer,
breast cancer, venous thrombosis (increases w/ smoking too)
High estrogen exerts (-) feedback on the AP
Conjugated equine estrogen
SERMS have different effects in different
types of tissue depending on which receptors
they target and which proteins are activated
(normally you'd expect them to WORSEN
osteoporosis!)
1.) Hypothalamus normally secretes GnRH in a pulsatile manner to act on the anterior pituitary (AP). GnRH travels via the pituitary portal vasculature to activate G-protein receptors in AP
~ LH stimulates the corpus luteum (remnants of follicle) to release lots of Progesterone. If implantation doesn't occur, LH will drop and the corpus luteum will atrophy, decreasing P release
~ During 2nd half of cycle, increased Progesterone cause thick and viscous, anti-sperm secretions from cervix
Role of Prolactin
~ Normally prolactin plays important role in breastmilk production and is high after babies are born
~ In some women, circulating prolactin is high while not breastfeeding, causing abnormal milk production and amenorrhea
~Causes of hyperprolactinemia:
1.) Hypothyroidism: decreased thyroid activity leads to incrased thyrotropin-releasing hormone (TRH) which stimulates prolactin release.
2.) Drugs: Reserpine, a-methlydopa, anti-dopaminergics
3.) Pituitary tumor
~ Prolactin release results in low estrogen affecting fertility
~ Dopamine acts as a prolactin inhibitory factor on lactotrophs
Contraceptives
- High progesterone will keep the endometrium in the "secretory" state and prevent implantation and it will maintain viscous, acidic cervical secretions which are anti-
sperm
Adverse Effects
Contraindications &
Drug Interactions
Hyperstimulation of ovaries
Multiple births
Hyperstimulation of ovaries
Multiple births
Safe
~ 75% ovulation, 33% pregnancy
~ 8% multiple births (usually twins)
~ Decreases breast cancer
~ Increases hot flashes, strokes, endometrial cancer
risk, DVTs
Reduces breast/endometrial cancer risk and
osteoporosis
~ Increased hot flashes, MSK problems, DVTs
Postural hypotension (decreased SNS)
N/V
Minor
~ Cardiac side fx (decreased NE)
~ CNS effects: hallucinations and psychosis (rare)
HTN, tachycardia
CI in patients with CV
problems
N/V, visual defects, pulmonary edema, fetal death? CI w/ mysethenia gravis
Causes premature closure of the ductus arteriosus
(PGs keep it open!)
CI w/ plt dysfunction or
bleeding disorder
Effectiveness may be
decreased by P450 inducers
or AB use
CI in patients with hx of
DVTs, MI, hyperlipidemia,
cancer
Long-term, high doses can cause hypothalamic and
pituitary atrophy
hypotension, but less edema
Decreased bone density and possible future fertility
issues
Breakthrough bleeds and irregular menses for first few
months (body needs time to dampen down cycle)
N/V, headache, ab pain, dysmenorrhea, dizziness
Menopause causes hot flashes, vasomotor effects,
osteoporosis, urogenital atrophy
~ Decrease risk of colon cancer!
Good effects: regulated cycles, decreased menstrual blood loss/cramps, correction of anemia, decreased tension, increased
libido, decreased ovarian cysts, decreased acne
Bad effects (Estrogen related): N/V, headache, tension, breast discomfort, anxiety, fatigue, depression, weight gain, adenitis,
amenorrhea, cholasma (brown spots on face)
Really Bad: CARDIOVASCULAR!
Decreased glucose tolerance (P effects insulin), reversible HTN (excess renin, AT2, aldo), benign hepatomas, cervical cancer,
breast cancer, venous thrombosis (increases w/ smoking too)
E causes endometrial
proliferation and cancer risk
Good: Reduced breast cancer, endometrial cancer (R),
and osteoporosis (R)
Bad: Increased hot flashes, strokes (T), increased
endometrial cancer (T), increased DVT
~ Decreased risk of colon cancer!
~ Decreased osteoporosis
~ Decreased vaginitis and vasomotor sx
~ Cardiovascular effects (stroke, MI, Venous
thrombosis)
~ dementia/cognitive loss, endometrial cancer (only
w/ uterus)
Therapeutic
Considerations
Useful in pt w/o intact HPA axis
Sub-Q injection
requires continuous
administration
Given alone or synergistically
with PGE1
Biggest problem is user error
Depot shots are more effective
than oral contraceptives
Not quite as effective as others,
but good for people who can't
tolerate Estrogen
60-80% effective at preventing
high-risk pregnancy
~ Available OTC for women over
17yo
Monophasic (same levels of
drugs throughout course)
Biphasic (vary the dose of E
throughout cycle)
Given with PGE1 to cause
contraactions and expel the
uterine lining
More effective at higher doses,
but increases side effects
Cream can be used in women
on aromatase inhibitors for
breast cancer because of its
local effects
Drug Name Clinical Application
Alcohol
ACEis and ARBs HTN
Antithyroid Drugs
(Propylthiouracil & methimazole)
Hyperthyroidism
Carbamazepine Anti-epileptic
Cocaine Drug of abuse
Diethylstilbestrol (DES)
Used in 1940's to 70's to
prevent miscarriage
Hypoglycemic drugs Diabetes
Lithium Bipolar disorder
Phenytoin
Psychoactive drugs
(barbs, opioids, benzos)
Smoking
Systemic Retinoids
(Acutane*)
Thalidomide
Used in 50's and 60's for
nausea in pregnant
women
VPA
Anti-epileptic, refractory
mood disorders
Warfarin anti-coagulant
Teratogenic Drugs
Almost all human teratogens are animal teratogens too (except misoprostol), but not vice versa
Untreated diseases that may also harm fetuses: Diabetes, HTN (anoxia, respiratory distress, growth retardation), Epilepsy
FDA Pregnancy Categories:
A: Controlled human studies = no risk (e.g. Beta-2 agonists)
B: No evidence of risk in humans (e.g. methyldopa)
C: Risk cannot be ruled out (most drugs)
D: Positive evidence of risk, but benefits may outweigh risk (e.g. ACE-Is and ARBs in 2nd/3rd trimester)
X: Contraindicated in pregnancy (e.g. thalidomide)
Criteria for Establishing Teratogenicity
1.) Genetics: fetal susceptibility depends on the genotype and interaction w/ envmt
2.) Timing: Fetal susceptibility depends on developmental stage at exposure
3.) Specificity: drugs act on specific cells in specific ways to cause characteristic malformations
4.) Dose effect: higher doses = greater effects on fetus
Drug Studies
1.) Animal studies: very useful, but may not always translate to humans
2.) Case reports: very useful, but we dont know the denominator to determine prevalence
3.) Case-control studies: retrospective studies, better than case-reports, may have bias. Best for moderate risk teratogens
4.) Cohort studies: prospective studies, difficult to do for high risk teratogens, best done with registries. Limitations include IDing long term effects and less obvious effects (mental)
Inadvertent exposure: 50% of pregnancies are unplanned and most birth defects occur in 1st TM
Adverse Effects
Contraindications & Drug
Interactions
CNS effects, Facial changes (FAS), long
filtrum, low set ears, small stature, mental
retardation
30-50% risk in chronic bingers
CV Malformations (1st TM)
renal failure, decreased skull ossification,
renal tubular dysgenesis (2nd/3rd TM)
Fetal & neonatal goiter and
hypothyroidism
12% goiter
NT defects
Small for gestational age (SGA) babies
Vaginal carcinoma, other GU defects in
boys and girls
50% risk in females
Neonatal hypoglycemia
Ebstein's anomaly (tricuspid valve) 8.2% risk
Facial and CNS defects (fetal hydantoin
syndrome)
10% full blown
30% some features
Neonatal withdrawl syndrome when drug
used late in pregnancy
SGA babies
CNS, craniofacial, CV, and other defects
25% anomalies
40% miscarriage
Phocomelia (no limbs), ear changes,
internal organ defects
20% risk
NT defects 1-2% spina bifida
Skeletal and CNS defects
Dandy-Walker Syndrome
17-30%
Teratogenic Drugs
Drug Studies
All drugs w/in these classes are equally bad
NB: hyperthyroidism MUST be treated in
pregnancy. Use PTU in 1st TM and then
switch to Meth in 2nd/3rd TMs
For DM Type 2, switch to insulin during
pregnancy (best control of sugars)
Withdrawal from barbs and OH can be fatal
Smoking causes vasoconstriction, nicotine
alone is not teratogenic
Women can switch to LMW Heparin during
pregnancy
Teratogenic Drugs
Drug Studies
SERMs
Tamoxifen
1.) Adjuvant therapy of resected
ER+ breast cancer
2.) Metastatic breast cancer
3.) Chemopreventative agent for
high risk breast cancer
Fulvestrant
Used for ER+ breast cancer in
post-menopausal women
after tamoxifen
~ Trmt of osteoporosis
Raloxifene
Risk reduction of invasive breast
cancer (BC) (from DCIN) and
prevention of BC in high risk
women
Aromatase Inhibitors
1st line adjuvant therapy for ER+
breast cancer
Non-Steroidals Anastrozole
Letrozole
Hormone Therapy for Cancer
Used either instead of or after
Tamoxifen as adjuvant therapy in
ER+/PR+ BC.
~ Postmenopausal only!
Steroidals Exemestane Effective in PREVENTING BC!
GnRH Analogues
Metastatic prostate and breast
cancer
Leuprolide
Goserelin
Anti-Androgens
Flutamide
Bicalutamide
BPH Trtmt
Finasteride
1.) Alternative to surgery for BPH
2.) Male pattern baldness
Glucocorticoids Prednisone
Adjunct Trtmt for Leukemia and
Lymphoma
~ ALL, CLL, MM, and H/NH-
Lymphoma
1st Line therapy for advanced,
metastatic prostate cancer
~ Used with GnRH analogues to
prevent surge in LH/FSH
1.) Hypothalamus normally secretes GnRH in a pulsatile manner to act on the anterior pituitary (AP). GnRH travels via the pituitary portal vasculature to activate G-protein
receptors in AP
~ LH stimulates the corpus luteum (remnants of follicle) to release lots of Progesterone. If implantation doesn't occur, LH will drop and the corpus luteum will atrophy, decreasing
P release
Contraceptives
- High progesterone will keep the endometrium in the "secretory" state and prevent implantation and it will maintain viscous, acidic cervical secretions which are anti-sperm
Binds to ER active site and prevents
the rotation of helix 12: prevents co-
activator function
1.) Breast: blocks proliferation, Progesterone
Receptor (PR) synthesis, and DNA polymerase
2.) Partial agonist at ER
3.) Stimulates production of TGF-Beta (growth
inhibitory factor)
Agonist in bone (good) and uterus (bad).
Antagonist in breast (good)
1.) CYP3A4: removes methyl group: converts
tamoxifen to desmethyltamoxifen and 4-
hydroxytamoxifen to endoxifen
2.) CYP2D6: adds hydroxyl group: converts
desmethyltamoxifen and 4-
hydroxytamoxifen to endoxifen
~ Endoxifen is the main active metabolite
with the major anti-cancer effect
1.) Estrogen antagonist in breast tissue
2.) Estrogen agonist in bone: trtmt of
osteoporosis
Steroidal complete ER-alpha antagonist
1.) Competetive antagonist
2.) Proteosomal degradation of ER
Block the conversion of
Androstenedione/Testosterone to
Estrone/Estradiol
~ Preferentially works in peripheral fat (also
likely w/in tumors)
Hormone Therapy for Cancer
Reversibly interacts with the heme group of
CYP enzymes
Suicide inhibitors that irreversibly inactivate
aromatase
Increased affinity (80-100x) for GnRH
receptors in the anterior pituitary to cause
long-term occupancy and down-regulation of
receptors
Met to hydroxyflutamide = high affinity
Competitively inhibits 5-alpha reductase in
prostate and hair follicles
~ Prevents conversion of T to DHT
Leads to decreased serum DHT, but normal
T and LH levels
Given at VERY high doses (20-80 mg/day)
1.) Directly lymphocytolytic
2.) Stimulates programmed cell death
(apoptosis): esp. T-cells
3.) Receptor mediated
Chemical castration/oophorectomy
~ Decreased plasma FSH and LH
~ Decreased estrogens & progestins
1.) Potent inhibitor of testosterone and DHT
binding to androgen receptor
2.) Regression of androgen target tissue
1.) Hypothalamus normally secretes GnRH in a pulsatile manner to act on the anterior pituitary (AP). GnRH travels via the pituitary portal vasculature to activate G-protein
receptors in AP
~ LH stimulates the corpus luteum (remnants of follicle) to release lots of Progesterone. If implantation doesn't occur, LH will drop and the corpus luteum will atrophy, decreasing
P release
Contraceptives
- High progesterone will keep the endometrium in the "secretory" state and prevent implantation and it will maintain viscous, acidic cervical secretions which are anti-sperm
Adverse Effects
Contraindications &
Drug Interactions
Bad
1.) Increased endometrial cancer
2.) DVTs, Thrombocytopenia, Stroke
5.) High doses: retinal opacity, cataracts
Good!
1.) Slows osteoporosis
2.) Decrease in serum cholesterol, LDL, etc
SSRIs: block CYP2D6 and
prevent production of active
metabolites
~ Exception: Venlafaxine is ok
to use
hot flashes, leg cramps, DVT, PE
Good: no risk of endometrial proliferation/cancer
GI, headache, back pain, hot flashes
Don't use in premenopausal women unless they have
ovaries removed due to ovarian stimulation
~ No risk of endometrial cx
Bad: Hot flashes, bone loss, dryness, arthralgias,
asthenia
Tumor Flare: initial administration may cause
stimulation of GnRH axis and cause intense tumor pain:
give w/ hormone antagonist to avoid
~ Hypogonadism, loss of libido, hot flashes, vaginal
dryness/atrophy, altered lipid metabolism
Hepatotoxic: can lead to liver failure
~ Decreased libido
~ Gynecomastia
~ GI side fx
Decreased libido, impotence
LOTS of side fx:
CV: HTN and CHF
GI: peptic ulcer disease
Endocrine: Cushing's sx, hyperglycemia, growth
inhibition in children, high Na+, Low K+, low adrenal
SkeletoMuscular: myopathy, osteoporosis
Neuro: convulsions, psychosis
Immune: infections
Therapeutic
Considerations
Tamoxifen may be less effective
in women with polymorphic low
activity of CYP2D6
Resistance: changes in the ER
and in HER2 signaling
IM admin 1x/mo
Shown to increase disease-free
and overall survival
most widely used, better side fx
profile
Improves urinary flow and
decreases prostate size
Resistance develops due to
glucocorticoid receptor
modification
Antidepressants
SSRIs
Can also be used for
premature ejaculation
Fluoxetine
Only SSRI approved for
use in children < 18yo
~ All antidepressants have equal
efficacy and delay of effect
Sertraline
Citalopram
Fluvoxamine
5-HT and NE Reuptake Inhibitors
Venlafaxine
Desvenlafaxine
Duloxetine
Other Buproprion
Used as add-on drug for
SSRIs
~ Less likely to decrease
libido
Mood Disorder Pharmacology
TCAs
Desipramine
2nd line trtmt for patients
that dont respond to SSRIs
~ Best to use in elderly
Amitryptyline
Used to treat neuropathic
pain & depression
Non-reuptake Inhibitors
Mirtazapine
Add-on drug for SSRIs
~ Faster onset than SSRIs
Ketamine
Rapid AD response in
severely depressed/
suicidal patients
MAO Inhibitors
Phenylzine,
tranylcypromine
3rd line drugs due to side
effects and drug
interactions
Non-Pharm Treatments
Electroconvulsive
Therapy
Most effective and fastest
therapeutic effect to treat
depression & mania
Drugs for Bipolar Disorder
Lithium
1.) Effective prophylactic
agent for bipolar disorder
2.) Can be used for acute
manic episodes w/
neuroleptic drugs or
benzodiazepines
Valproic Acid
Carbamazepine
Lamotrigine
Anti-epileptics
Combine w/ Li+ in
refractory bipolar
Depression Biology
1.) Biogenic Amine Hypothesis: low levels of neurotransmitter activity result in depressed mental status. Implicates 5-HT, NE, and DE as the critical NTs
~ Drugs that reduce release of these chemicals (e.g. resperine, clonidine, beta-blockers) may CAUSE depression
~ Clonidine stimulates alpha-2 receptors which are inhibitory in NE neurons
~ Reserpine disrupts NE vesicle storage. Amphetamines block NE release. Amphetamine/cocaine/TCA block NE reuptake (and treat depression)
~ All do the same to DA neurons EXCEPT TCAs
~ 5-HT and NE have wide distributions to most areas of the brain while DA is limited to the basal ganglia and prefrontal cortex
2.) Neurotrophic Hypothesis: Neuronal growth factors (e.g. BDNF) are important to neural plasticity and maintenance and neurogenesis
~ Neurotrophic activity is diminshed in depression
Neurotransmitters
1.) Serotonin (5-HT): produced in cell bodies of the midbrain (raphe nuclei), projects to entire cortex and basal ganglia, excitatory
~ Serotonin receptors: 14 different types, only 1A and 2A are impt for depression.
2.) NE: generated in locus coeruleus neuronal cell bodies, diffuse innervation, excitatory
3.) DA: produced in the substantia nigra pars compacta, limited to the limbic system and basal ganglia
All antidepressants have been shown to have equal efficacy!
Possible mechanism for delay of SSRI effect is due to the effect of SSRIs on the 5-HT-1A autoreceptor and SNRIs on the alpha-2a autoreceptor (locus coeruleus): inhibits
transmission at the neuronal cell body. Eventually these receptors are desensitized
No adrenergic, muscarinic, or Na+, K+, or
Ca2+ blocking effects
~ No H1 blocking = less weight gain
All SSRIs are highly protein bound and can
affect free levels of other drugs (warfarin)
30 days before reaches steady state levels
~ Takes 4+ weeks to change meds
CYP3A4
Blocks NE and DA reuptake
~ Primarily acts by blocking DA reuptake
Mood Disorder Pharmacology
Increase [] of 5-HT in the synaptic cleft by
selectively inhibiting 5-HT reuptake
~ 1A receptor: located on recurrent collateral
neurons that INHIBIT the neuronal cell body.
~ Initial SSRI use actually turns off the
neurons and worsens depression
Tightly bound to plasma proteins
Most selective NE reuptake inhibitor (+++)
~ Minimal muscarinic, histamine, and alph-1
NE effects
Tertiary amine: gives it greater selectivity at 5-
HT reuptake than at NE reuptake
Possible block of alpha-2A adrenergic or 5-HT-
1A autoreceptors
may involve blockade of glutamatergic NMDA
receptors
Increase NE, DA, and 5-HT release: reverses
the re-uptake pump!
~ Increased NE in cytoplasm inhibits tyrosine
hydroxylase (feedback) leading to decreased
NE synthesis
~ Inhibits phosphatase enzymes necessary to
regenerate IP3, blocks effect of alpha-1 NE
and 5-HT-2A receptors
~ Inhibits adenylyl cyclase function
~ Increase 5-HT release and 5-HTR sensitivity
Inhibits ADH stimulated cyclic AMP
production causing diuresis.
Li+ competes with Na+ and K+ for
reabsorption in proximal tubule. Therefore
changes in Na+ and K+ levels affect Li+ levels
Depression Biology
1.) Biogenic Amine Hypothesis: low levels of neurotransmitter activity result in depressed mental status. Implicates 5-HT, NE, and DE as the critical NTs
~ Drugs that reduce release of these chemicals (e.g. resperine, clonidine, beta-blockers) may CAUSE depression
~ Clonidine stimulates alpha-2 receptors which are inhibitory in NE neurons
~ Reserpine disrupts NE vesicle storage. Amphetamines block NE release. Amphetamine/cocaine/TCA block NE reuptake (and treat depression)
~ All do the same to DA neurons EXCEPT TCAs
~ 5-HT and NE have wide distributions to most areas of the brain while DA is limited to the basal ganglia and prefrontal cortex
2.) Neurotrophic Hypothesis: Neuronal growth factors (e.g. BDNF) are important to neural plasticity and maintenance and neurogenesis
~ Neurotrophic activity is diminshed in depression
Neurotransmitters
1.) Serotonin (5-HT): produced in cell bodies of the midbrain (raphe nuclei), projects to entire cortex and basal ganglia, excitatory
~ Serotonin receptors: 14 different types, only 1A and 2A are impt for depression.
2.) NE: generated in locus coeruleus neuronal cell bodies, diffuse innervation, excitatory
3.) DA: produced in the substantia nigra pars compacta, limited to the limbic system and basal ganglia
All antidepressants have been shown to have equal efficacy!
Possible mechanism for delay of SSRI effect is due to the effect of SSRIs on the 5-HT-1A autoreceptor and SNRIs on the alpha-2a autoreceptor (locus coeruleus): inhibits
transmission at the neuronal cell body. Eventually these receptors are desensitized
Adverse Effects
Contraindications &
Drug Interactions
May induce mania in bipolar patients
~ Acute worsening of depression/anxiety (via 5-HT-1A
receptor action)
~ Loss of libido
~ Moderate Weight gain
CI with MAOIs: risk of
Serotonin Syndrome (HTN,
clonus, coma)
~ CI w/ TCAs, meperidine
(Demerol*), St. John's wort,
dextromethorphan
~ CI w/ even moderate
alcohol: risk of coma
~ CYP2D6 inhibitor (codeine,
beta blockers)
CYP3A4 (interactions with
oral contraceptives, CCBs,
PDEis, protease inhibitors
(AIDS)
Only antidepressant with abuse potential (due to DA
action)
~ Only AD associated seizures (at high doses)
Can be used for suicides in overdose
CI in patients w/ cardiac
conduction problems or w/in
one year of MI
Weight gain
Acute euphoria/CNS excitation, suppress REM sleep
Interacts w/ tyramine foods
~ Inhibit metabolism of other
drugs that use MAO (e.g.
meperidine (Demerol*) may
cause Serotonin Syndrome
Safe in pregnancy
"Nephrogenic diabetes insipidus" that is reversible
(due to ADH block)
~ Reduce thyroid function
~ Weight gain
~ Sinus note depression
~ Lethal with overdose
~ Teratogenic (Ebstein's anomaly = tricuspid valve
malformation)
~ NSAIDs increase Li levels
~ Thiazide diuretics reduce
Na+ reabsorption at distal
tubule and increase Na+ and
K+ excretion which allow
more Li+ to reabsorb
~ Exercise, dehydration, and
sweat loss can alter Li+
~ CI in pt with SA node
dysfunction
~ Cardiac excitability & arrhythmias (block of Ca2+ and
Na+ channels
~ Overdose risk of lethality
Anti-Muscarinic: blurred vision, dry mouth,
constipation, urinary retention, sinus tachycardia
~ Anti-Histamine: Weight gain, sedation, drowsiness
~ Alpha blockade: hypoTN, dizziness, reflex tachycardia
Teratogenic: NT defects
~ Impaired fetal cognitive dvlpmt
Decrease levels of oral
contraceptives
Therapeutic
Considerations
Usually not fatal overdose,
unless taken with MAOIs or
other Ads
Assessing efficacy is tricky, takes
4-12 weeks to have therapeutic
effect + large placebo effect
~ Difficult to change therapy
~ Very effective when combined
with psychotherapy
Never prescribe WITH other Ads
Not useful alone to treat
depressive bipolar episodes, can
be used for refractory
depression w/ SSRIs
Barbiturates
Pheno/Pentobarbitol,
Thipental
Insomnia, Epilepsy,
Anesthesia
~ Not used as anxiolytics
anymore
Benzodiazepines
Long-Acting Diazepam
Flurazepam
Intermediate Acting Nitrazepam, Alprazolam
Anxiolytic and Hypnotic Pharmacology
Short-Acting Oxazepam
Ultra-Short Acting Midazolam, temazepam
Reversal Agents Flumazenil
Benzodiazepine overdose,
non-benzo reversal
~ Also would block beta-
carbolines
Beta-Carboline
Non-Benzodiazepine
Anxiolytics
Buspirone
(Buspar*)
Generalized anxiety
disorder
Zolpidem Insomnia
Hydroxyzine
Antihistamine and
anxiolytic
Benzodiazepines vs. Barbiturates
1.) Benzodiazepines have a much larger Therapeutic Index for anxiolysis: they less toxic, less sedative, cause less dependence, take longer for tolerance to develop (no anxiolytic
tolerance), less addictive, less depression of REM sleep
2.) Benzos take longer before withdrawal sx are seen, but the sx are the same as Barbs: anxiety, tremor, weakness, psychosis, seizures, death!
3.) Both cross the placenta: Benzo's however have risk of birth defects in 1st 6 wks and Barbs cause neonatal withdrawal in 3rd TM
SSRIs for Anxiety
~ May cause acute anxiogenesis until post-synaptic receptors are down-regulated / desensitized
Subunits determine Benzo binding!
The Longest Acting Metabolite determines the effective duration of action of the drug!
Benzodiazepines are safer when used alone: but together with barbs or OH, they lose their safety margin
Brain circuits affected by Benzodiazepines
1.) Amygdala: 5-HT mediated anxiolysis
2.) Hippocampus: memory (amnesia)
3.) Cerebellum: motor (ataxia)
4.) Basal ganglia: motor
5.) Ascending Reticular Activating System: NE mediated, sedation and sleep
6.) Spinal cord: augments GABA mediated presynaptic inhibition, decreases spinal reflexes
Non-specific depression of membrane
excitability
~ Supressed Glutamate-mediated excitation
~ Especially in Ascending Reticular Activating
System (ARAS)
~ Increase the open time of the Cl- channel
Binds to BZ1 receptor, Facilitatate GABA-A
action by increasing the frequency of Cl-
channel opening
1.) Diazepam (20-50hr)
2.) Desmethylated to desmethyldiazepam
(60hr)
3.) Hydroxylated to oxazepam
4.) Glucuronidated for excretion
~ Highly lipophylic = absorbed quickly
~ Active metabolites can accumulate and
slow metabolism of parent drug
1.) Flurazepam (1hr)
2.) Desalkylated to desalkylflurazepam (60
hr T1/2)
3.) Conjugated for excretion
Anxiolytic and Hypnotic Pharmacology
1.) Oxazepam is already alpha-hydroxylated,
so it is NOT metabolized in the liver and it
has a much shorter T1/2 (6-18 hrs)
2.) Highly hydrophilic, so it is absorbed
slowly and poorly distributed in peripheral
tissue
3.) Highly protein bound = why its not ultra-
short acting
Competitive antagonist of the GABA Benzo
receptor
Inverse agonist, decreases normal GABA
response
Stimulates pre-synaptic 5-HT-1A receptors
(inhibits 5HT)
Act via the BZ1 receptor on GABA-A CYP3A4 metabolism
Antagonist at 5-HT-2A receptors (post-
synaptic)
~ H1 inverse agonist
Its active metabolite (cetirizine = Zirtec) has
no 5-HT activity and is not anxiolytic
Benzodiazepines vs. Barbiturates
1.) Benzodiazepines have a much larger Therapeutic Index for anxiolysis: they less toxic, less sedative, cause less dependence, take longer for tolerance to develop (no anxiolytic
tolerance), less addictive, less depression of REM sleep
2.) Benzos take longer before withdrawal sx are seen, but the sx are the same as Barbs: anxiety, tremor, weakness, psychosis, seizures, death!
3.) Both cross the placenta: Benzo's however have risk of birth defects in 1st 6 wks and Barbs cause neonatal withdrawal in 3rd TM
SSRIs for Anxiety
~ May cause acute anxiogenesis until post-synaptic receptors are down-regulated / desensitized
Subunits determine Benzo binding!
The Longest Acting Metabolite determines the effective duration of action of the drug!
Benzodiazepines are safer when used alone: but together with barbs or OH, they lose their safety margin
Brain circuits affected by Benzodiazepines
1.) Amygdala: 5-HT mediated anxiolysis
2.) Hippocampus: memory (amnesia)
3.) Cerebellum: motor (ataxia)
4.) Basal ganglia: motor
5.) Ascending Reticular Activating System: NE mediated, sedation and sleep
6.) Spinal cord: augments GABA mediated presynaptic inhibition, decreases spinal reflexes
Adverse Effects
Contraindications &
Drug Interactions
Anesthesia, Coma, and Death due to strong respiratory
depression
~ "REM Rebound" due to depression of REM and Stage
4 sleep
Withdrawal
Tolerance: to both anxiety and hypnotic
Withdrawal in newborn if
taken in 3rd TM
Confusion, delerium, ataxia, unconsciousness
~ Depression of Stage 4 Sleep (good for sleep walking
and night terrors). No "REM Rebound"
~ Tolerance is much more pronounced to hypnotic
effects than anxiety effects
Causes birth defects if taken
in 1st 6 weeks of pregnancy
Does not cause sedation, addiction, or tolerance!
Doesn't interact w/ OH
Unpleasant taste (over 75% of patients), amnesia,
hallucinations, depression
Therapeutic
Considerations
Drugs of abuse
Both diazepam and
desmethyldiazepam persist in
blood for weeks after last dose
Must be regularly administered,
even after overdose sx decrease
because it has such a short T1/2
Typical Antipsychotics
Treat the (+) sx of
schizophrenia and
exacerbate (-) sx
Chlorpromazine
Thioridazine
Haloperidol
Atypical Antipsychotics
Somewhat Atypical
Risperidone
Olanzapine
Truly Atypicals
Clozapine
Used for refractory
schizophrenia
~ Can be used to suppress
TD
Antipsychotic Pharmacology
1st Line drug for
schizophrenia b/c most
can achieve therapy w/o
EPS
Quetiapine
(Seroquel*)
1st Line drug for
schizophrenia
Other Atypicals
Aripiprazole
(Abilify*)
Pathophysiology of Schizophrenia
~ Limbic system has hyperactive DA circuits (+ symptoms) and cortex has hypoactive DA circuits (- symptoms)
Symptoms of Schizophrenia
Positive Symptoms: delusions, hallucinations, disorganized speech, disorganized & catatonic behaviors
Negative Symptoms: Blunted affect, alogia (reduced speech), avolution (no motivation), anhedonia (lack of pleasure), attention deficit. ALWAYS PRESENT!
Typical antipsychotics dont alter levels of DA and NE, but rather they lower levels of DA and NE metabolites: prevent
conversion via COMT
Evidence for DA receptor blockade being the mechanism for therapeutic potency of typical antipsychotics?
1.) Increase DA turnover in basal ganglia
2.) Increased firing of DA neurons in substantia nigra: more potent the drug for increased DA firing in SN = more potent schizophrenia trtmt. DA firing as a
result of lack of feedback from metabolites and b/c of blockade of pre-synaptic inhibitory DA receptor
3.) Increased prolactin release: amount of prolactin released is directly related to therapeutic effect (not so for atypicals!)
Long-term Treatment of Schizophrenia
1.) Enhancement of drug efficacy and NO tolerance to relief of (+) symptoms
2.) No tolerance develops to prolactin release :(
3.) Tolerance develops to EPS/parkinsonian sx: overcorrection leads to Tardive Dyskinesia
~ TD may not go away w/ removal of drug; treat w/ higher dose to occupy hypersensitive DA receptors
4.) Tolerance develops to sedation
Major Brain Areas Affected by Antipsychotics
1.) Basal Ganglia (caudate, putamen, globus pallidus): EPS, Parkinson-like sx
2.) Amygdala & Nucleus accumbens/Mesolimbic pathway = reward (anhedonia)
3.) Neocortex: (-) effects on cognition, (+) effects of helping w/ disordered thoughts and delusions. (-) affects on attention
4.) Hypothalamus: prolactin release can cause severe endocrine dysregulation: blocks GnRH release and thus LH/FSH and Testosterone/Estrogen/Progesterone
Never give antipsychotics to elderly patients w/ dementia: mega increase in mortality!
Side Effects of Antipsychotics
1.)D2 Blockade related Side Effects: Extrapyramidal side fx: parkinsonian sx, dystonia, akathisia (restlessness)
~ Parkinsonian side effects develop tolerance over a few months!
~ Akathisia = can't sit still, very aggrevating to do so!
~ Emotional, Cognitive, & Neuroendocrine
2.) Alpha-blockade (anti-NE): sedation, hypoTN, seizures
3.) Antimuscarinic sx (dry mouth, urinary retention, constipation, etc): develop tolerance over time!
4.) Metabolic sx: DM, obesity, HTN, dyslipidemia - related to 5-HT2 blockade in pancreas = decreased insulin production + insulin resistance
Block D2 dopaminergic receptors.
Most potent anti-muscarinic effect
Most potent anti-DA effect, least sedation
Block lots of various receptors: D2, 5-HT2, H1,
etc
1.) 5-HT-2 Receptor activity in pancreas leads
to insulin resistance
Antipsychotic Pharmacology
Partial agonist of the D2 receptor
Pathophysiology of Schizophrenia
~ Limbic system has hyperactive DA circuits (+ symptoms) and cortex has hypoactive DA circuits (- symptoms)
Symptoms of Schizophrenia
Positive Symptoms: delusions, hallucinations, disorganized speech, disorganized & catatonic behaviors
Negative Symptoms: Blunted affect, alogia (reduced speech), avolution (no motivation), anhedonia (lack of pleasure), attention deficit. ALWAYS PRESENT!
Typical antipsychotics dont alter levels of DA and NE, but rather they lower levels of DA and NE metabolites: prevent
conversion via COMT
Evidence for DA receptor blockade being the mechanism for therapeutic potency of typical antipsychotics?
1.) Increase DA turnover in basal ganglia
2.) Increased firing of DA neurons in substantia nigra: more potent the drug for increased DA firing in SN = more potent schizophrenia trtmt. DA firing as a
result of lack of feedback from metabolites and b/c of blockade of pre-synaptic inhibitory DA receptor
3.) Increased prolactin release: amount of prolactin released is directly related to therapeutic effect (not so for atypicals!)
Long-term Treatment of Schizophrenia
1.) Enhancement of drug efficacy and NO tolerance to relief of (+) symptoms
2.) No tolerance develops to prolactin release :(
3.) Tolerance develops to EPS/parkinsonian sx: overcorrection leads to Tardive Dyskinesia
~ TD may not go away w/ removal of drug; treat w/ higher dose to occupy hypersensitive DA receptors
4.) Tolerance develops to sedation
Major Brain Areas Affected by Antipsychotics
1.) Basal Ganglia (caudate, putamen, globus pallidus): EPS, Parkinson-like sx
2.) Amygdala & Nucleus accumbens/Mesolimbic pathway = reward (anhedonia)
3.) Neocortex: (-) effects on cognition, (+) effects of helping w/ disordered thoughts and delusions. (-) affects on attention
4.) Hypothalamus: prolactin release can cause severe endocrine dysregulation: blocks GnRH release and thus LH/FSH and Testosterone/Estrogen/Progesterone
Never give antipsychotics to elderly patients w/ dementia: mega increase in mortality!
Side Effects of Antipsychotics
1.)D2 Blockade related Side Effects: Extrapyramidal side fx: parkinsonian sx, dystonia, akathisia (restlessness)
~ Parkinsonian side effects develop tolerance over a few months!
~ Akathisia = can't sit still, very aggrevating to do so!
~ Emotional, Cognitive, & Neuroendocrine
2.) Alpha-blockade (anti-NE): sedation, hypoTN, seizures
3.) Antimuscarinic sx (dry mouth, urinary retention, constipation, etc): develop tolerance over time!
4.) Metabolic sx: DM, obesity, HTN, dyslipidemia - related to 5-HT2 blockade in pancreas = decreased insulin production + insulin resistance
Adverse Effects
Contraindications &
Drug Interactions
1.) Nigro-striatal = Extrapyramidal Sx (akathisia = can't
sit still), Parkinsonian, Tardive Dyskinesia
2.) Hypothalamus = prolactin release
3.) Mesolimbic system (amygdala/nucleus accumbens)
= anhedonia
4.) Mesocortical system (neocortex) = cognitive
function
Exacerbation of (-) sx
~ Neuroleptic Malignant Syndrome: see below
Least parkinsonian sx at therapeutic dose (b/c it has
greatest anti-muscarinic effect)
Least sedating of all the typicals
~ Worst Parkinsonian sx (no anti-ACh effect)
~ Metabolic side fx: DM, hyperglycemia, HTN,
dyslipidemia, weight gain
~ Very few ExtraPyramidal sx (EPS) due to lower DA
antagonism
~ No Tardive Dyskinesia (TD)
~ No prolactin elevation
20% incidence of EPS, TD
Prolactin Elevation (decreases GnRH and thus FSH/LH,
test/estrogen/progesterone)
Prolactin sparing (only releases prolactin at HIGH
dose)
~ High incidence of weight gain
No EPS, No TD, No prolactin release
~ Agranulocytosis (neutropenia): occurs w/ Clozapine,
can cause life threatening infections
Sedation
HypoTN
* Fewer side effects for patients and equally effective
~No prolactin release reported
~Less anhedonia
~ Agranulocytosis (neutropenia): occurs w/ Clozapine,
can cause life threatening infections
Sedation
HypoTN
1.) Most potent muscarinic antagonist = Thioridazine (ACh)
2.) @ Therapeutic dose, least sedating = Haloperidol (NE)
3.) @ therapeutic dose, least Parkinsonian = Thioridazine (DA + ACh)
4.) @ therapeutic dose, most Parkinsonian = Haloperidol (DA w/o ACh)
Therapeutic
Considerations
All typicals have = efficacy
Often called "miracle drug" that
works when no others will
1.) Most potent muscarinic antagonist = Thioridazine (ACh)
2.) @ Therapeutic dose, least sedating = Haloperidol (NE)
3.) @ therapeutic dose, least Parkinsonian = Thioridazine (DA + ACh)
4.) @ therapeutic dose, most Parkinsonian = Haloperidol (DA w/o ACh)
Anti- H. pylori
Bismuth subsalicylate
(*Pepto-Bismol)
Controls acid secretion and has
bactericidal properties
Metronidazole
Antibacterial with PROKINETIC
properties
Tetracycline antibacterial
Amoxicillin
Clarithromycin
(*Biaxin)
H2 Blockers
1st line Trtmt of GERD and PUs
~ Decreases pain, promotes healing, but
DOES NOT prevent relapse of PUs
Cimetidine
(*Tagament)
Ranatidine
(*Zantac)
Famotidine
(*Pepcid)
Anti-Cholinergics
Atropine
Proton Pump Inhibitors
(PPIs)
Trtmt of GERD & PUs
~ 1st Line Drugs for PUs
~ Alleviate pain and promote healing
Omeprazole
(*Prilosec)
Esomeprazole
(*Nexium)
GERD & Peptic Ulcers & GI Motility Drugs
Antibiotic alternative for peptic ulcer
therapy
Lansoprazole
(*Prevacid)
Antacids
Adjunct Trtmt of GERD & adjuct for
Ulcers
Sodium Bicarbonate Baking soda, cheap
Calcium Carbonate Major ingredient in TUMS
Magnesium Hydroxide
(Milk of Magnesia)
Antacid + Laxative
Aluminum Hydroxide Major ingredient in Rolaids
50/50 Mg2+ and Al+ Salts Most antacids
Cytoprotection Used for PUD
Sucralfate
(Sucrose Al+ Sulfate)
Misoprostol
(PGE1, *Cytotec)
Useful in older pt on chronic NSAID
therapy (for arthritis)
Combo Therapy
Used to Eliminate H. pylori infection
~ 2nd line therapy if H2 blocker or PPI
alone for 2 wks doesnt work
Triple Therapy
Clarithromycin +
Amoxicillin/Metro + PPI
LAC Therapy: Lansoprazole (PPI for
healing and pain), Amoxicillin, +
Clarithromycin
Quad Therapy
Bismuth sub., Metro,
Tetra, + PPI/H2 blocker
Other Drugs
Metoclopramide Anti-emetic and Prokinetic
Not on drug list, but in
handout
Bethanechol
Prokinetic, increases gastric motility
~ Used for GERD
Not on drug list, but in
objectives
Simethicone
(*Mylanta)
Anti-foaming agent (in beer, wine, ice
cream, carbonated beverages) used to
reduce bloating
Emetics
Ipecac
Apomorphine
Commonly used in ER for poisoning
Sub-Q injection
Anti-Emetics
Phenothiazines
(Chlorpromazine)
anti-emetic
~ May be given rectally in vomiting pt
Ondansetron
anti-emetic for severe nausea after
surgery or cancer therapy
Metoclopramide See above
Cannabinoids Anti emetic
Motion Sickness
Demenhydrinate
(*Dramamine)
*Benadryl
Scopolamine
Transdermal patch, orally, or injected
antimuscarinic
Anti-Diarrheal
oral rehydration solutions Used for severe diarrhea
Lamotil
(Diphenoxylate and
atropine)
Loperamide
(*Imodium)
Most commonly used today
Laxatives
Bulking agents
(Psyllium, Sorbitol,
*Miralax)
Safest class of constipation therapy,
used for chronic constipation (opioid
induced)
~Anthraquinones
~Castor Oil
~Dephenylmethanase (*Ex-
Lax)
Salines (Mg Citrate),
Milk of Magnesia
Used pre-colonoscopy
Colace Stool softener
Causes of Peptic Ulcers
1.) H. pylori: invades stomach and resides between mucous layer and epithelial lining. Secretes urease to break down urea into CO2 and ammonia. Ammonia (a) neutralizes H+ for H. pylori to survive and (b)
breaks down mucous to expose epithelial layer.
2.) Smoking: nicotine binds ganglionic nerve receptors at the synapse and potentiates their effects. Since the vagus plays a primary role in the peptic ulcer cycle, this enchances HCl release from parietal cells
3.) NSAIDs: blocking prostaglandins results in decreased mucous production
GERD
~ Factors that reduce lower esophageal sphincter (LES) pressure: fatty foods, anticholinergics, progesterone, caffeine, chocolates, obsesity, preganancy
~ Stepwise therapy approach: elevate head, stop smoking (stimulates vagus nerve), don't overeat (increased stomach volume causes reflux), avoid meals at bedtime, avoid drugs that decrease LES pressure, Add
H2 blocker or PPI w/ antacid. Add metoclopramide or bethanechol
1.) Chronic GERD may lead to Barrett's Esophagus = pre-malignant metaplasia of glandular stomach tissue into the normal squamous esophagus: increased risk of adenocarcinoma
Goals of GERD Therapy
1.) Decrease reflux
2.) Neutralize contents of reflux
3.) Enhance esophageal clearance to the stomach
4.) Protect the esophagus from damage
Peptic Ulcer Cycle
1.) Breech in mucosal barrier allows H+ ions through to epithelium
2.) Vagus nerve is stimulated by H+, producing (a) pain and (b) more HCl from Parietal cells
3.) Increased acidity produces more capillary injury and bleeding
4.) Blood and vagus nerve input stimulate Histamine release from ECL cells, which stimulate Parietal cells to produce even more HCl.
Emesis
~ Controlled by emetic center in the medulla which receives inputs from the cerebellum (motion), higher brain centers (sensory and memory), and from the chemoreceptor trigger zone (CTZ) of the area
postrema.
~ Inputs to the emetic center use 5-HT3 and D2 receptors
~ Blood borne emetic agensts can act directly at the CTZ or indirectly on 5-HT3 receptors in the stomach and small intestine
~ Cerebellar inputs for emesis are relayed via H1 and muscarinic receptors, requiring different drugs to treat.
Constipation Therapy
1.) Increase fiber, fluids, and exercise
2.) Do not ignore urge to defecate
3.) Therapy aims to increase fluids in GI lumen allowing for increased "bulk" of stool, decrease absorption of water and electrolytes from stool, and increased intestinal motility
Mechanism
Metabolism &
Pharmacokinetics
Competitive antagonist of H2 receptos (histamine)
on basal surface of parietal cells
~ H2 Selective: decreases heart rate and inhibits
release of HCl
Blocks 80% of H2 receptors Dosed 2x/day, acts 4-5 hours
Polar structure makes it less liver
toxic
Even more polar = least liver toxicity
Suppress vagal nerve stimulation
1.) ECL-cells: decreased ACh prevents histamine
release
2.) Parietal cells: decreased ACh reduces Ca++
influx required to activate proton pump
Taken up into parietal cells an converted to
sulfhydryl compounds by acidic pH
~ SH groups inhibit the H+/K+ pumps
Normal dose hits 80-90% of proton
pumps and lasts up to 12 hours
Isolated "S" isomer of Omeprazole
GERD & Peptic Ulcers & GI Motility Drugs
Weak bases that neutralize stomach acids
Produces highest amount of CO2 fast
fast
slow
slow
Pairs laxative with constipation agent and
maintains acid neutralization
slow
Ionically bond to exposed Nitrogen groups in the
exposed epithelium and protect from further acid
damage
1.) Stimulates a Gi coupled receptor on the basal
side of parietal cells, decreasing the cAMP
dependent pathway of activating the H+/K+
exchanger
2.) Enhances mucous production
D2 receptor antagonist (anti-emetic at area
postrema)
Mixed 5-HT receptor agonist/antagonist
Muscarinic activity
~ Increases tone of lower esophageal sphincter
(LES)
Muscarinic agonist
Long acting b/c NOT broken down by
cholinesterase
Causes decreased surface tension of gas bubbles,
allowing them to combine into larger bubbles in
the stomach that may pass easier
contains emetine which stimulates emesis
Similar structure to morphine, causes N/V but no
euphoria or analgesia
D2 receptor antagonist rapid effect
5-HT3 receptor antagonist
D2 antagonist, 5-HT3 antagonist, mACh agonist
Direct inhibition of emetic center
mediated by H1 and muscarinic relay signals to
emetic center
blocks H1 receptor
blocks H1 receptor fast acting, short lasting
Anticholinergic
High osmotic load solution that pushes water
across the gut by osmosis
~ promote water & ion absorption in the GI
Form gelatinous mass in stomach that increases
bulk and puts pressure on intestines to prompt
peristalsis
Takes 1-3 days to work
Narcotics that decrease peristalsis, increase
muscle tone, increase transit time through GI
allowing more fluid absorption
Irritants that produce a semi-fluid stool Takes 6-8 hours
Hyperosmotic solutions that cause watery
evacuation of bowels
1-3 hours
GERD
1.) Decrease reflux
Peptic Ulcer Cycle
Emesis
postrema.
Black tongue
Black, tarry stool
~ Bradycardia
~ Mental cloudiness/confusion
~ Androgen receptor antagonist (decreased sperm
count, gynecomastia + tenderness
~ CYP-3A4 inhibition: increases serum [ ] of
theophylline, diazepam, etc.
Less CYP3A4 inhibition
Least CYP3A4 inhibition
~ Photophobia (dilated pupils)
~ Lack of nasal secretions + dry mouth
~ Urinary retention
~ Increased body temperature
1.) Hip and thigh fractures (especially women)
2.) CYP2C19 inhibition: impt for pt on Clopidogrel
(anti-platelet drug)
3.) Predisposition to opportunistic infections (C. diff)
Excess CO2 production = lots of gas
Possible risk of INCREASING acid production! Theory
is that rise in serum Ca++ would stimulate gastrin
release = acid rebound!
Laxative causes diarrhea
Causes severe constipation
Constipation (due to Al+)
Diarrhea
Abortion
Can NEVER be used in
women of childbearing
age!
1.) Hip and thigh fractures (especially women)
2.) CYP2C19 inhibition: impt for pt on Clopidogrel
(anti-platelet drug)
3.) Predisposition to opportunistic infections (C. diff)
dry mouth, mydriasis, photophobia
GERD
1.) Decrease reflux
Peptic Ulcer Cycle
Emesis
postrema.
Therapeutic
Considerations
Must abstain from alcohol
Antibiotics
Macrolide Abs
Azithromycin, Tobramycin,
Gentamycin
Used for CF pt w/ Pseudomonas
infection
~ mainstay of current therapy
Cephalosporins
Cefatazdime,
Cephtriaxone
Quinolones
Penicillins
Decreasing viscosity
Recombinant human
doxyribonuclease enzyme
Dornase alpha
Used to decrease viscosity of mucous
in CF
~ 6% improvement of FEV1
~ Reduction in hospital days
7% hypertonic saline
Increases mucociliary clearance in CF
~ Improves lung function in CF pt
Gene Therapy
Ivacaftor
(Kalydeco*)
1st available treatment of underlying
defect in CF
~ Approved for CFTR mutation G551D
(Class 3 mutation)
Anti-Inflammatory
Systemic steroids
Used in CF patients w/ concomitant
astha or ABPA
Inhaled steroids No improvement in FVC or FEV1
NSAIDS Ibuprofen
High doses lead to halted progression of
pulmonary function decline in CF pt w/
mild disease under 13 yo
Transplant
Cystic Fibrosis Treatment
Lung Transplant
Last resort for irreversible respiratory
failure
GI management
Pancreatic enzyme therapy
Vitamin supplementation ADEK
Increased calorie intake
Physiotherapy
physical means to
promote clearance of
secretions
Postural drainage
Airway clearance devices PEP mask/device
Flutter device
Acapella
Percussive vest
Mechanism
~ Cleaves the extracellular DNA from the neutrophils
in sputum to make it less viscous
Increases the time that activated CFTR channels at the
cell surface remain open
Decreased migration of neutrophils to lung
Survival rates similar to other transplants
~ 1 yr = 84%, 3 yr = 61%, 5 yr = 40-60%
Metabolism & Pharmacokinetics Adverse Effects
minimal side effects
Good tissue penetration
Contraindications
Therapeutic
Considerations
Antispasmodic Scopolamine
Dipyridamole Vasodilator w/ anti-plt properties
Anti-infective Nitrofurantoin Used for urinary tract infections
Alpha-1 Blocker Prazosin Hypertension
Amiodarone Anti-arrythmic
Spironolactone
used for fluid retention in CHF and for
HTN (blocks aldosterone)
Barbiturates Phenobarbital
Benzodiazepines Clonazepam
Non-benzo hypnotic Zolpidem
Synthetic progesterone Megestrol
Treat malnutrition in patients with
cancer
Sulfonylurea Glyburide
Treat diabetes: increase insulin release
from pancreas
Metoclopramide
Anti-emetic and pro-motility agent in GI
system
Aspirin
Atypical Antipsychotic Quetiapine 1st line for schizo
Guanfacine
Drugs in the Elderly
Why to avoid in Elderly
highly anticholinergic
may cause orthostatic hypertension
lack of efficacy in patients with CrCl < 60 ml/min due
to inadequate concentration in urine
may cause orthostatic hypertension
QT-interval prolongation (along with thyroid disease
and pulmonary disorders)
Increased risk of hyperkalemia
High rate of physical dependence with tolerance to
sleep benefits
Increased sensitivity and decreased metabolism of
benzodiazepines in elderly
Minimal improvement in sleep w/ increased risk of
delerium, falls, and fractures
Increased risk of thrombotic events and possibly
death in adults > 65yo
Greater risk of severe, prolonged hypoglycemia in
adults > 65yo
increased risk of extrapyramidal effects in frail adults
> 65yo
Lack of evidence for primary prevention of cardiac
events for those > 80yo
increased risk of CVA and mortality in dementia
Can cause bradycardia, orthostatic hypoTN, and CNS
depression
Exceptions
only use in palliation to decrease secretions
May use for gastroparesis
Thyroid Hormone
Thyroxine, Levothyroxine
(T4)
Trtmt of choice for hypothyroidism
Liothyronine (T3)
(Cytomel*)
NOT routinely used for hypoTH
Methimazole (tapazole) 1st line for hyperthyroid
Propylthiouracil (PTU) Never 1st line (except 1st TM preg)
Growth Hormone
Excess GH in childhood causes gigantism
Excess GH in adults = cretinism
~ Usually caused by pituitary tumor:
must remove surgically, not medically!
Somatostatin analogs
(Octreotide/lanreotide)
GH-Receptor
antagonists
Pegvisomant (somavert)
GHRH
GHRH agonist
(Sermoreline/Geref*)
Used for diagnosis of GH deficiency
Endocrine Pharmacology
Thionamides
Used for pituitary tumors that cannot
be surgically resected
Growth Hormone
Treatment of children and adults w/ GH
deficiency
Testosterone /
Androgens
Testosterone
Used to treat low testosterone /
androgen deficiency.
Many preparations: pure Test, DHT,
DHEA, etc
GnRH agonists, FSH, LH diagnostic and to treat infertility
Anti-androgens
flutamide (receptor
blockers)
finasteride (5-alpha
reductase inhibitors)
Prevent generation of DHT, used for
BPH and prostate cx treatment
Mechanism
Metabolism &
Pharmacokinetics
T3 affects nearly every cell and regulates gene
transcription and protein synthesis
~ Required for normal CNS development
~ Required for normal linear growth &
pubertal development
~ In adults, needed for metab. homeostasis
Steroid-like hormone
T4= 4 iodines, 7 day half-life, 99.6%
protein bound
T3 = 3 iodines, ACTIVE hormone. 15%
from thyroid, 85% from liver/kidneys. 1
day half-life, 99.3% protein bound
Given orally. Takes 4-6 weeks to reach
steady state (half-life = 7 days)
Must give multiple times a day b/c half-
life = 1 day. Hard to do and results in
fluctuating levels
T1/2 = 4-6 hrs (qd dosing), concentrated
in thyroid tissue
T1/2 = 75 min, slower effect
GHRH from hypothalamus stimulates release
of GH from anterior pituitary. Inhibited by
somatostatin, IGF-1 (from liver), and
nutritional factors (ghrelin, leptin)
~ Essential for linear growth, fat storage, and
glycemic control
~ In adults, it maintains body composition,
improves lipid profile, and supports bone
density
GH drugs are all peptides and thus
CANNOT BE TAKEN ORALLY! (they are
quickly broken down in liver)
Mutated GH molecule that binds/blocks
receptor
Endocrine Pharmacology
Lower thyroid hormones by interfering with
thyroid peroxidase which is necessary for TH
synthesis.
~ Inhibit addition of Iodine to tyrosine and
decreases thyroglobulin
Good effects:
~ Body fat redistrobution, improved bone
density & muscle mass, better lipid profile,
and improved sense of "well-being"
Given by SC injection, dose based on IGF-
1 levels, growth (children), and sx
(adults)
Hypothalamus releases GnRH which acts on
pituitary to release LH and FSH which
stimulate testosterone
~ Androgens are required for virilization and
normal puberty
~ Also maintain libido, sexual function, bone
density, muscle mass, and sexual hair
~ Androgens also stimulate erythropoeiesis
1.) Alkylated androgens: abused by
athletes
2.) Testosterone esters (IM) every 2-3
weeks
3.) Transdermal testosterone: patches &
gels, allows steady serum levels
1.) Iatrogenic hyperthyroidism
2.) Palpitations
ONLY safe during 2nd and 3rd TM for pregnancy
~ Embryopathologies in 1st TM
~ SE are dose related: rash, GI, joint stiffness
~ Rare = Hepatitis & agranulocytosis
SE are NOT dose related
Safe during 1st TM for pregnancy!
~ Hepatotoxicity, especially in kids
May increase risk of malignancy: colon polyps/cx,
esophageal cx, stomach cx, maelanoma
1.) Assoc w/ hepatotoxicity
2.) High estrogen = gynecomastia
3.) Must monitor to avoid erythrocytosis (stroke)
4.) Acne
5.) Premature epiphyseal closure (kids)
6.) Poor lipid profile (decreased HDL, increased LDL)
7. ) increased risk of prostate cx
Therapeutic
Considerations
Must check TH levels 6 wks after
starting or changing trtmt
better compliance
worse compliance, useful for 1st
TM pregnancy and thyroid storm
Base dose on IGF-1 levels
Must try to keep testosterone
w/in age-adjusted normal range
~ Monitor CBC for erythrocytosis
Insulins
Insulin is the only option
for Type 1 Diabetes
1.) Stimulates glucose uptake by muscle,
adipose, etc
~ Increased glycogenesis
~ Decreased gluconeogenesis
2.) Stimulates uptake of amino acids
~ > protein synthesis, < proteolysis
3.) Lipids: > lipogenesis, cholesterol syn,
esterification & utilization of lipids
~ < lipolysis, < ketogenesis, < fatty acid
4.) Regulates gene transcription
Rapid-Acting
Lispro
(Humalog*)
Aspart
(Novolog*)
Short Acting Regular Insulin
Long-Acting
Glargine
(Lantus*)
Taken 1x per day to maintain basal
levels of insulin
Injectible Agents
Incretin Mimetics
Exanatide
(Byetta*)
Adjunctive therapy for DM Type 2
taking metformin, sulfonylureas, or
combo
~ Don't use in Type 1 DM!
Liraglutide
(Victoza*)
Once daily injection for DM2
Diabetes Medications
Taken as short-acting agent 5-10 min
before meals
GLP-1 Agonists
Amylin Analogs
Pramlintide
(Symlin*)
Injectible analog of IAPP
~Must be used WITH insulin!
Oral Agents
Biguanides
Metformin
(Glucophage*)
Insulin Sensitizing Agent
Glipizide
(Glucotrol*)
Glyburide
(Micronase*)
Meglitinides
(not on objectives)
Repaglinide Insuline secretagogue
Alpha-glucosidase
inhibitors
Acarbose
(Precose*)
Very modest decrease in serum glucose
Thiazolidinediones
(TZDs)
Pioglitazone
(Actos*)
Insulin Sensitizers
DPP-4 Inhibitors
Sitagliptin
(Januvia*)
1x Daily monotherapy or combo w/
TZD/metformin to lower fasting and
postprandial glucose levels
SGLT2 Inhibitors
Canagliflozin
(Invokana*)
Adjunct to diet & exercise to improve
glycemic control in Type 2 DM
Sulfonylureas
Glucagon: secreted by pancreated ALPHA-cells, opposes insulin: > glycogenolysis, > gluconeogenesis
Islet Amyloid Polypeptide (IAPP): secreted w/ insulin by BETA-cells during meals. CNS receptor, doesnt stimulate insulin release
Incretins: secreted by entero-endocrine cells of GI tract: help glucose-stimulated insulin release, inhibit glucagon release
~ GLP -1: promotes pancreated endocrine cell growth and inhibits apoptosis
~ Short half-life (2min): degraded by dipeptidyl peptidiase (DPP-IV)
Glucose Transporters
~ GLUT2 = low affinity, islet cell glucose sensing
~ GLUT 4 = insulin responsive
~ SGLT = sodium-dependent glucose co-transporters: mediate glucose transport against concentration gradient (intestine, kidneys)
Mechanism
Secreted by pancreated Beta-islet cell
~ 51 amino acid peptide w/ two polypeptide chains:
alpha and beta
~ Stimulated primarily by glucose via GLUT2
transporter: inhibits ATP-dep K+ channels which >
intracellular Ca2+
~ Acts via surface tyrosine kinase receptor
Mimics actions of GLP-1
1.) Restores 1st phase insulin response & second
phase: CRITICAL!
2.) Lowers glucagon during hyperglycemia
3.) Slows gastric emptying, reduces food intake
1.) Slows gastric emptying w/o affecting nutriet
absorption
2.) Reduces post-prandial glucagon
3.) Suppresses appetite: CNS receptors
Doesn't require good Beta-cells, no insulin release
~ Decreases hepatic gluconeogenesis
~ Increases insulin-stimulated glucose uptake
~ Decreases intenstinal glucose absorption
Same mech as sulfonylureas, but different chemically
Reduces/slows intestinal absorption of complex carbs
by competitive inhibition of alpha-glucosidance,
glucoamylase, and sucrase
~ Blunts the post-prandial glucose rise
Selective agonists for PPAR-gamma receptors in liver,
skeletal muscle, and adipose tissue
~ No need for good beta cells, no insulin release
*** Enhances systhesis and translocation of GLUT4
Blocks degradation of incretins like GLP-1
~ Augments secretion of insulin from beta cells and
inhibits glucagon secretion
Block reabsorption of glucose in the kidney, increase
excretion, and lowers blood glucose levels
~ SGLT2 transporter in the S1 segment of proximal
tubule
Stimulates insulin release from Beta-cells (requires
functioning beta cell!)
~ Binds to beta-cell high affinity receptor to block K+
channel
~ Reduces glucagon release w/ chronic use
Synthesized as a single chain = preproinsulin
1.) Loses 19 amino acid sequence at the ER = proinsulin
2.) Loses 33 amino acid C-peptide at the Golgi complex
Kinetics: low basal secretion + biphasic respose to
glucose
~ 1st phase peak at 1-2 min
~ Delayed 2nd phase
Degraded by liver, kidney, and muscle
Half-life = 3-5 min unless given w/ buffer (protamine or
Zinc)
Onset: 30-60 min
Peak: 2-4 hrs
Duration: 6-10 hrs
Onset: 1-2 hours
Peak: FLAT
Duration: 20-26 hrs
Administer dose 60 min before meals
Peak: 1.5-3.5 hrs
Half-life = 1.5-4.5 hours
Elimination: glomerular filtration + proteolytic
degradation
Onset 5-15 min
Peak: 1-2 hrs
Duration: 4-6 hrs
1.) Hypoglycemia: most common
~ Repeated episodes many cause
"hypoglycemia unawareness" where body
loses its normal counter regulatory
responses. Very dangerous
2.) Insulin antibodies: rare
3.) Lipodystrophy: at injection site
1.) Risk of Thyroid C-Cell Tumors &
medullary thryoid carcinoma for
Liraglutide only
~ CI in patients w/ family hx of MTC or
MEN2
2.) GI: N/V, diarrhea
3.) Antibody formation in 38%
Cannot be mixed directly with insulin b/c pH = 4.0
Good: weight loss
Bad:
~ Severe hypoglycemia (only w/ insulin)
~ GI: N/V
Excreted unchanged in urine
*** Lactic acidosis: very rare but 50% fatal.
Increased risk w/ age and renal dysfunction
~ GI: N/V, diarrhea, bloating, anorexia
~ Hypoglycemia w/ sulfonylureas
~ > CV mortality
90% excreted in bile Less hypoglycemia than sulfonylureas
< 2% absorption, extensive GI metabolism, excr. In urine
GI: flatulence, diarrhea, ab pain
Increased liver transaminases w/ high dose
~ No risk of hypoglycemia!
Hepatic metabolism w/ active metabolites
T1/2 = 3-7 hrs, Action = 12-24 hrs
1.) Idiosyncratic hepatotoxicity
2.) Fluid retention / weight gain
3.) Lipid problems: increase in HDL w/o
change in TC or LDL
Must modify dose for renal insufficiency
Nasopharyngitis, Headache (very well
tolerated!)
Metabolized in liver, excreted in urine
1.) Glipizide: INACTIVE metabolites, t1/2 = 2-4 hrs
2.) Glyburide: mildly active metabolites, t1/2 = 3-5hrs
~ Both have duration = 10-24 hrs
1.) Hypoglycemia: long-duration of action
~ Cautious in elderly, debilitated,
malnourished
~ Cautious in pt w/ hepatic/renal
dysfunction
2.) Disulfuram-like rxn: flushing w/ EtOH
Contraindications
Therapeutic
Considerations
Contraindications:
1.) Renal dysfunction: Cr > 1.5 in
men, 1.4 in women
2.) Congestive Heart Failure
3.) Use of iodine contrast
4.) Hypersensitivity to metformin
5.) Acute or chronic metabolic
acidosis or ketoacidosis
Start low, go slow
Least popular oral medication
~ Approx 50% of newly dx Type 2
DM have acceptable glycemic
control w/ Sulfonylureas alone
~ 10-20% have no glycemic
response
Prevention
Calcium
1200 mg/day for women over 50 and
men over 70; dietary source preferred
Vitamin D 1000 IU/day for men and women over 50
Antiresporptive Agents
Bisphosphanates
1.) PMOP and male OP prevention (men
and women)
2.) Glucocorticoid-Induced OP
Risedronate
Low-affinity bisphosphonate
~ Reduced risk of vertebral, hip, and
nonvertebral fractures
Ibandronate
Reduced risk of Vertebral fractures
~ No change in hip/nonvertebral
Alendronate
High-affinity bisphosphonate
Zoledronic Acid
High-affinity bisphosphonate
Estrogen
Agonist/Antagonists
Raloxifene
Prevention and Treatment of
postmenopausal osteoporosis
~ Reduces new vertebral fracture
~ No reduction in hip/nonvertebral
Estrogens
Prevention of osteoporosis in
postmenopausal women
~Reduces the risk of vertebral, hip, and
non-vertebral fractures
Osteoporosis (OP) Pharmacology
Calcitonin Calcitonin
Treatment of postmenopausal OP in
women > 5yrs post menopause and those
who can't take estrogen
~ Last line therapy (not very effective)
~ Reduces new vertebral fractures
~ No effect on hip/nonvertebral
Antibodies Denosumab
Indicated for men and PM women w/
osteoporosis @ high risk of fracture
~ Great option for men on androgen
deprivation therapy for prostate cx and
women on aromatase inhibitors for
breast cx
~ Reduces vertebral, hip, and non-hip
fractures
Anabolic Agents
Synthetic PTH
Teriparatide (PTH 1,
34)
Indicated for PM women w/ OP @ high
risk of fracture and men w/ primary or
hypogonadal OP @ high risk of fracture
~Decreased risk of all fractures
Very IMPT Slide
---->
Fracture Risk Factors
~ Age, Sex, Height, Weight, Previous fracture, parental hip fracture, smoking, rheumatoid arthritis, any use of glucocorticoids EVER, EtOH
Universal Prevention Strategies and Treatment Recommendations
1,) Calcium: Women > 50yo and men > 70yo: 1200 mg/day of Ca2+ (dietary)
~ Ca2+ absorption decreases w/ age. Best to take w/ evening meal. Calcium citrate inhibits Ca-oxalate crystals and is the choice for those at risk for kidney stones
2.) Vitamin D: Women and men > 50yo: 1000 IU/day of Vitamin D
~ Risk factors for Vit D deficiency: age, malabsorption, obesity, chronic renal prob, limited sun exposure, dark sin, osteoporosis
3.) Weight-bearing exercise
4.) Avoid smoking and excess EtOH
5.) Fall prevention
Mechanism
Metabolism &
Pharmacokinetics
Suppress bone resportion via osteoclast
interference
~ 2 side chains: one binds to bone mineral,
one determines potency (via nitrogen)
Very poor bioavailability
Deeper bone penetration due to low
affinity
~ Most potent osteoclast inhibitor
~ Most affinity to bone minerals
Agonist in Bone, Antagonist in Breast and
Uterus
Inhibits the expression of RANK ligand and
stimualtes OPG expression
~ Stimulates collagen synthesis
~ Enhances GI Ca2+ absorption
Osteoporosis (OP) Pharmacology
Stonger uptake, slower offset, higher
reattachment
~ Long T 1/2
Anti-osteoclast: blocks osteoclast brush
borders, inhibits cytoplasmic motility,
decreases rate of osteoclast formation
Made naturally by parafollicular C cells
of thyroid
Monoclonal Ab, RANK-L inhibitor
Does not require renal clearance: GOOD
FOR RENAL IMPAIRMENT!
1.) Decreases osteoblast apoptosis
2.) Stimulates bone lining cells to form
osteoblasts/cytes
~ Together = net increase in osteoblasts
5.) Fall prevention
Short term: GI sx, acute phase rxn (flu-like sx), ACUTE
RENAL FAILURE (IV only)
Long Term: Osteonecrosis of the jaw (IV only),
atypical fractures (subtrochanteric fractures)
Uncorrected Hypocalcemia
Esophageal stricture (oral)
*** 28% decreased mortality after hip fracture
Increased frequency of hot flashes
Venous thromboembolism
Lowers total and LDL (no effect on CV death)
Reduces breast cx risk
Pregnancy
Thromboembolic dx
Vaginal bleeding & candidiasis
Breast tender/enlarged
Venous thromboembolism
Headache
Elevated BP and Triglycerides
Pregnancy
Breast CX
Migraine w/ aura
Thromboembolic dx
^
|
Nasal sx
Back pain, arthralgias, headache
May have analgesic effect
Skin changes (eczema, dermatitis, rash)
Flatulence
Cellulitis
Back/Musculoskeletal pain
Hypercholesterolemia
Cystitis
Hypocalcemia
Pregnancy
Black box warning: risk of osteosarcoma
~ N/V, headache, dizzy, cramps, neck pain, asthenia
Anyone w/ increased risk of
osteosarcoma: Paget's, peds,
prior radiation
~ Pt w/ bone metastases
~ Hypercalcemia
5.) Fall prevention
Therapeutic
Considerations
Take w/ water upon arising for the
day >30 min before food
~ VERY long T 1/2 may suggest
need for "Drug Holiday"
IV only!
Can be given intranasally or
injectable
Daily sub-Q injection for MAX of 2
years
Acute Gout Attacks
NSAIDs
1.) 1st Line Therapy for Acute Attacks
2.) Flare prophylaxis during initiation of
urate lowering therapy
Naproxen
Colchicine
(Colcrys*)
1.) 1st Line Therapy for Acute Attacks
2.) Flare prophylaxis during initiation of
urate lowering therapy
Glucocorticoids Prednisone ~ Best for monoarticular gout
Gout Prevention:
Urate Lowering Trmt
Xanthine Oxidase Inhibitors Allopurinol
Used for hyperuricemia
(Zyloprim*)
Febuxostat
Treatment of hyperuricemia in patients
w/ gout
Uricase Agent Pegloticase
Used for chronic gout refractory to
other treatments
~ Lowers urate levels and tophi
Uricosurics
(Probenacid,
Sulfinpyrazone, etc)
Gout Medications
1.) Rapid lowering of urate levels is associated w/ acute gout flares: use cochicine or NSAID prophylaxis when starting urate lowering therapy
2.) Excessive meats/seafoods and sugar-sweetened drinks may contribute to elevated urate levels
3.) HCTZ may increase urate levels, but must balance w/ HTN risks (might try losartan instead)
Under excretors vs. Over producers of Uric Acid
1.) Under excretors (85% of gout pt): usually renal insufficiency, these patients may benefit more from uricosurics, but are CI w/ hx of stones
2.) Over producers: genetic enzyme partial deficiency or hypermetabolic state: cancer, psoriasis
Mechanism
Inhibition of cyclooxygenase 1/2
Disruption of microtubules in PMN cells needed for
degranulation and acute intense inflammation
Intranuclear steroid receptor blocks protein synthesis
Competitive inhibitor of xanthine oxidase:
Block the synthesis of uric acid
Competitive purine metabolite inhibitor of xanthine
oxidase: blocks conversion of hypoxanthine and
xanthine to uric acid
Converts uric acid to soluble protein allantoin
Block renal tubular urate reabsorption
Gout Medications
1.) GI
2.) Renal
3.) Anti-platelet
4.) Cytopenia (rare)
Renal + Hepatic metabolism: must be adjusted/stopped
for renal insufficiency
1.) GI sx (diarrhea)
2.) Myotoxicity/Nerve toxicity (rare)
3.) Blood dyscrasias (rare, inhibits mitosis
in marrow cells
~ Good to use for moderate to severe renal impairment
Long-Term Effects
1.) Infection
2.) Osteoporosis
3.) Glucose intolerance
4.) Central obesity
5.) Acne
6.) Cataract formation
Interacts w/ azathioprine and 6-mercaptopurine: dose
adjust
1.) Hepatotoxic
2.) Allergic rxn: from mild rash to Stevens-
Johnson syndrome (rare)
better for pt w/ renal impairment than allopurinol 1.) Hepatotoxic (rare)
1.) Infusion rxns (IV rqmt)
Ineffective in pt w/ renal impairment
Gout Medications
Contraindications
Therapeutic
Considerations
1.) Renal/hepatic insufficiency
2.) CHF
3.) Allergy
4.) Bleeding disorder
1.) Renal/hepatic dysfunction
2.) Known GI sx
3.) W/ other CYP3A4 inhibitors or P-
glycoprotein
1.) Hyperglycemia
2.) CHF
1.) Patients w/ G-6-PD deficiency
IV only
~ Give prophylaxis before therapy
to prevent flares
1.) History of nephrolithiasis
Inflammatory
Dermatoses
Topical Corticosteroids
Mainstay of dermatology for
inflammatory dermatoses
Triamcinolone acetonide
Clobetasol propionate Great for psoriasis and eczema
Calcineurin Inhibitors Tacrolimus
Pimecrolimus
Non-melanoma skin
cancer
5-Fluorouracil
Used for treatment of non-melanoma
skin cancer: SCC and actinic keratoses
Imiquimod
Immune-response modifier
~ Actinic keratosis, superficial basal cell
cx, and external genital warts
~ Great for viruses: mulloscolum
contagiosum, HPV, etc.
Cutaneous Infections
Antifungals
~ Allylamines / Benzylamines Terbinafide
~ Azoles Ketoconazole
~ Polyenes Nystatin Anti-candida
Antibacterials
Bacitracin
Best vs. staph aureus and strep
~ Doesnt work vs. MRSA and Gram (-)
Topical Medicines for Dermatologic Disorders
Immunomodulators: anti-inflammation
w/o as many side effects as steroids,
but less potent
~ very effective
Mupirocin
Anti-Gram (+) only!
~ Trmt of MRSA
Polymyxin
Gram (-) only
~ Pseudomonas, E. Boli, Klebsiela, etc
Neomycin
Aminoglycoside
~ Good for Gram (-), +/- for Gram (+)
Antivirals
Imiquimod (see above)
Podophyllin Condyloma (Genital warts)
Salicylic acid Warts
Acne Medications
Topical antimicrobials
Benzoyl peroxide
Comedolytic agent which blocks the
formation of comedones
Topical Retinoids (adapalene, tazarotene)
Standard for opening pores /
inflammatory acne
Tretinoin
(Accutane*)
Used for
recalcitrant/nodulocystic/scarring acne
Vehicles for Topical Delivery
1.) Ointments: most potent (lipids give better penetration), least irritation, but they are GREASY and patients don't like them
2.) Creams: better tolerated, but more irritating (additives) and less potent
3.) Foams, gels, etc = no residue (patients like)
Acne/Acneiform Eruptions
1.) Acne vulgaris: main type. Black, dead, oxidized skin scells clump and can form pustules (comedones = oil/skin trapped in pore)
2.) Rosacea: redness in older patients
Mechanism
Intranuclear steroid receptor blocks protein synthesis
Preferential targeting of DNA/RNA of sun-damaged cells,
preventing their growth
Uses TLR7 signaling to recruit natural killer cells
~ Induces IFN-alpha, TNF, and Ils
Blocks squalene epoxidase: prevents lanosterol synthesis
(precursor to ergosterol)
Blocks 14-alpha demethylase
~ Prevents ergosterol synthesis
Irreversibly binds membrane sterols
Interferes w/ cell wall synthesis
~ Prevents hydrolysis into undacaprenyl phosphate
Block inflammation cascade by binding to FK506-BP:
~ prevents NFATc dephosphorylation and depletes
dendritic cells. Prevents transcription of IL-2 activation of
Th1 and Th2 cytokines + Histamine release from mast cells
Inhibits bacterial isoleucyl-tRNA synthetase
Lipopeptide, punches holes in cytoplasmic membrane
Binds 30S ribosomal subunit
Derivative of American Mayapple: arrests mitosis ?
Causes epidermal cells to shed more rapidly
Work at 2 classes of nuclear receptors to
1.) reduce corneocyte cohesion
2.) reduce follicular hyperkeratosis
3.) reduce inflammation
Classifed based on strength:
Class I (ultra-potent) to Class VII (weak, OTC)
1.) Long term trtmt: atrophy, striae,
neovascularization, and steroid acne
2.) HPA suppression: especially in kids, over
time
Class III-IV
Class I
Skin becomes red, crusty, bubbly, painful
(but this is the medication working)
Skin becomes red, crusty, bubbly, painful
(but this is the medication working)
1.) Can "sting" w/ application
Natural product of pseudomonas!
Nephrotoxic
~ Allergies
Irritating
Vitamin A derivatives
Irritation
~ Photosensitivity
1.) Teratogen (ear, thymus, scalp, CV)
2.) Psych effects
3.) GI side fx
4.) Severe dryness
Contraindications
Therapeutic
Considerations
1.) Tachyphylaxis: tolerace
develops to one steroid over time
Pregnant or lactating
Use cream as "field therapy"
~ Comes as cream or solution
Only use for adults w/ normal
immune system
~ Pregnancy
~ Risk of lymphoma at HIGH doses
Stains clothes/towels
TNF-alpha inhibitors
Etanercept
Adalimumab
Infliximab
Certolizumab pegol
Golimumab
Recombinant IL-1 receptor antagonist Anakira
Anti-CD20 Rituximab
Anti-CTLA4 Abatacept
DMARDs & Biologic Therapies for Rheumatoid Arthritis
~ All are equally effective for RA
~ RA = rheumatoid arthritis
~ CD = Crohn's disease
~ Psoriasis
~ AS = Ankylosing spondylitis
~ Monoclonal Abs are better for extrajoint
manifestations of disease
Anti-IL6 Tocilizumab
B-Lymphocyte Stimulator (BLyS) / BAFF
Inhibitor
Belimumab
JAK Inhibitor Tofacitinib
IVIG
Uricase Agent Pegloticase
Disease Modifying Anti-
Rheumatics
(DMARDS)
Hydroxychloroquine
(Plaquenil*)
Sulfasalazine
(Azulfidine*)
Methotrexate
Azathioprine
(Imuran*)
Leflunomide
(Arava*)
Cyclophosphamide
(Cytoxan*)
Cyclosporine
(Neoral*)
Mycophenolate Mofetil
(CellCept*)
Biologic agents do NOT come in tablet form. They are proteins derived from living materials with specific targets. They have to be injected to avoid 1st pass metabolism
~ ACR 20 criteria: to be beneficial to patients, therapeutic agents must show at least a 20% improvement in swollen joints, improvement in tender joints and a least three of the following: patient/physician global
assessment, patient reported pain, ESR/CRP, or disability. This must occur in at least 20% of patients
~ RAPID3: improvment in patient function, pain, and global perception of their condition
Tumor Necrosis Factor Effects
1.) Crohn's Disease: T-cell proliferation and granuloma formation
2.) RA: Bone destruction, carliage degradation, Fibroblast proliferation
3.) Psoriasis: T-cell proliferation, keratinocyte proliferation, DC/Langerhans migration
~ Protective in tuberculosis!
Risk Factors for Anti-Drug Abs: low dosing, intermittent dosing, non-use of immunosuppressants, certain IL-10 polymorphisms
~ Always give DMARDs with TNF-alpha inhibitors to minimize ADAbs.
"Treat to Target" = treat each patient individually with step-wise approach
1.) Make the right dx
2.) Start trtmt (RA start w/ cheaper DMARDs)
3.) Measure response: if good, STOP
4.) Change therapy until things are better. If drug didnt work at all, switch class. If drug used to work, increase dose or change w/in class
5.) Goal is to provide consistent suppression of dx activity
Inhibition of TNF signalling between cells
RA, CD arthritis, Psoritic arthritis, AS joint pain
~ Moderately effective in RA
(Good for people w/o metalloproteinases = TRAPS)
~ Good for gout
IL-1 R antagonist
~ Indicated for those who dont respons to anti-TNF
1.) Good for RA (not for psoriasis or AS)
2.) Good for granulomas (Wegener's)
3.) Effective for inflammatory muscle dx: polymyositis
and dermatomyositis
4.) Good for Lups, myasthenia gravis, Grave's, ITP,
pemphigus
Targets B-cells and causes mature B-cell
death. Doesnt kill stem cells or plasma cells.
~ Results in low B-cells for 6+ months
RA, CD, Psoriasis skin lesions, psoritic arthritis, AS
uveitis
~ Better for extra-articular sx
RA refractory to anti-TNFs
~ good for Juvenile RA & Castleman's disease (rare B-
cell dx)
Only indicated for Lupus (SLE) w/o kidney disease
BLyS/BAFF inhibitor: BLyS/BAFF normally
keeps B-cells alive
Janus Kinase 3 Inhibitor
~Prevents cytokine production and other
immune functions
1.) Replacement for Immune Deficiency
2.) IVIG for idiopathic thrombocytopenia of Childhood
3.) Kawasaki Disease: life saving reduction in
formation of coronary artery aneurysms
4.) Inflammatory muscle disease unresponsive to
other therapy
Unclear
~ may stimulate Ig feedback mechanism
Used for chronic gout refractory to other treatments
~ Lowers urate levels and tophi
Converts uric acid to soluble protein
allantoin
Inflammatory skin/joint conditions: RA and SLE Alters lysosomal pH in antigen presenting cells
Used in RA, IBD, spondyloarthritis
1st line for Polyarticular JRA
~ Approved for adult RA
Interferes w/ methylation of DNA base pairs.
Impact on lymphoid cell line
~ Can be reversed by folinic acid
Used for RA
~ Initially for transplant rejection
Interferes w/ DNA in rapidly dividing cells
Blocks dihydro-orotate pathway in
lymphocytes
Front line therapy for severe SLE Alkylation of DNA of rapidly dividing cells
Inhibits T lymphocytes (mech ?)
good for SLE nephritis Inhibits T and B cell proliferation
Metabolism &
Pharmacokinetics
Adverse Effects
1.) Increased risk of infections (due to
macrophage inhibition)
2.) Significant risk for TB reactivation
3.) Possible increased risk of cx (lymphoma)
4.) Reactivation of Hep B (not C)
5.) Safe in pregnancy?
soluble TNF receptor stuck on Ig
constant region
~ "fusion" molecule
Enitrely human protein directed at
Mouse/human chimeric monoclonal
antibody
Causes welts w/ injection!
~ Neutropenia, TCP, cx?
Mild to severe infusion rxn
~ Reactivation of JC virus leading to progressive
multifocal leukoencephalopathy (PML)
~ Reactivation of Hep B
anaphylaxis, pneumonia, cellulitis, pyelonephritis
~ Hypercholesterolemia
~Increased infections, reactivation of TB,
elevation in blood pressure, elevated liver
enzymes
infection, anaphylaxis, leukopenia, pyrexia
~ Hypercholesterolemia
~ Immune suppression, diverticulitis, TB, sepsis,
leukopenia, TCP
~ Malignancy potential (EBV assoc lymphoma),
hematologic suppression, GI performation
Solubilized preparation of human
gamma globulin given IV
1.) Allergic rxn (very rare)
2.) Headache / serum sickness of IgA deficiency
3.) Fluid overload, renal problems
4.) $$$$
1.) Infusion rxns (IV rqmt)
1.) Need to see opthamology every 6-12 months
b/c risk of retina damage
2.) Tinnitus, balance disorders
3.) Deposit in pigmented tissues
GI distress
Reversible azospermia
Rash if sulfa allergic
Long term effect: expect results in 5-6
weeks and lasts months
N/V, memory loss, hair thinning, hepatic fibrosis,
acute pulmonary reaction/fibrosis, Cytopenias
~ Must monitor liver enzymes every 2-3 mo
GI, cytopenias, lymphoma (?)
Very long t1/2 due to hepatobiliary re-
circulation.
~ Must be cleared in women before pregnancy!
Teratogenic
~ Cytopenia, GI, rarely hepatotoxic
1.) Infection, leukopenia, hair loss, N/V
2.) Cancer: risk of bladder cx and lymphoma
(Give w/ Mesna to protect bladder)
3.) premature ovarian failure
Renal toxicity, hirsutism, gingival hyperplasia,
HTN, pseudotumor cerebri, gout
Cytopenias, BK virus associated neuropathy, GI dx,
lymphomas, lymphoprolif. Dx
Contraindications
Therapeutic
Considerations
Meets ACR 20 Criteria
~ Lowest rate of ADAb rxns!
Meets ACR 20 criteria
1.) Patients w/ G-6-PD
deficiency
IV only
~ Give prophylaxis before therapy
to prevent flares
Give with pre-hydration and
bladder protection b/c of
carcinogenic effect
Pregnancy: increased
preg loss and
malformation risk

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