PHARMACOLOGY
USMLE Step 1 Flash cards by Seetal K Dhaliwal H. S
1by Seetal K Dhaliwal H. S
Flash cards by Seetal K. Dhaliwal H. SSection I
2by Seetal K Dhaliwal H. S
Pharmacokinetics:
Vd:
Drugs with low Vd distribute in blood; medium Vd in
extracellular space or body water; high Vd distribute
in tissues.
t1/2:
A drug infused at a constant rate reaches ~94%
steady state after 4 t1/2 (FIRST ORDER ELIMINATION):
by Seetal K Dhaliwal H. S
Competitive
inhibitors
Non-competitive
inhibitors
Resemble substrate YES NO
Overcome by ↑ [S] YES NO
Bind active site YES NO
Effect on Vmax Unchanged ↓
Effect on Km ↑ Unchanged
Pharmacodynamics ↓ potency ↓ efficacy
3
# of half-lives 1 2 3 4
concentration 50% 75% 87.5% 93.75%
Pharmacokinetics:
Loading dose:
Cp x Vd/F (F=bioavailability is 1 when given IV)
Maintenance dose:
Cp x CL/F
In patients with renal or hepatic disorder, the loading dose remains unchanged although
the maintenance dose is ↓.
Metabolism of drug:
Phase 1 (reduction, oxidation, hydrolysis) usually yields slight polar, water-soluble metabolites
(often still active). CYP450. Geriatric patients lose phase 1 first.
Phase 2 (acetylation, glucuronidation, sulfation) usually yields very polar, inactive metabolites
(renally excreted). Conjugation phase.
Elimination of drugs:
Zero order constant amount of drug eliminated per unit time. Phenytoin, Ethanol & Aspirin
(high dose).
First order constant fraction of drug eliminated per unit time. Rate of elimination is
proportional to drug concentration. by Seetal K Dhaliwal H. S
4
Important Pharmacokinetics calculations:
Single dose equations:
Vd = D/C0
t1/2 = 0.7/k
CL = k x Vd
t1/2 = 0.7 x Vd/CL
by Seetal K Dhaliwal H. S
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Multiple dose equations:
k0 = CL x Css
LD = Vd x Css
MD = CL x Css x τ
Vd = Volume of distribution
k = elimination constant
D = Dose
C0 = concentration at time 0
t1/2 = half-life
CL = Clearance
Css = steady state concentration
LD = Loading Dose
k0 = infusion rate
MD = Maintenance Dose
τ = dosing interval
Flash cards by Seetal K. Dhaliwal H. SSection II
6by Seetal K Dhaliwal H. S
Central & Peripheral NS:
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ACh receptors:
Nicotinic ACh receptors are ligand-gated Na+/K+ channels; NN (found in autonomic
ganglia) and NM (found in NMJ) subtypes.
Muscarinic ACh receptors are G-protein-coupled receptors that act through 2nd messengers;
5 subtypes: M1, M2, M3, M4 and M5.
G-protein-linked 2nd messengers:
by Seetal K Dhaliwal H. S
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by Seetal K Dhaliwal H. S
9G-protein-linked 2nd messengers:
Receptor G protein class Major functions
α1 q ↑ vascular smooth muscle contraction, Mydriasis, ↑ intestinal &
bladder sphincter contraction.
α2 i ↓ sympathetic outflow, ↓ insulin release
β1 s ↑ HR, ↑ contractility, ↑ renin release, ↑ lipolysis
β2 s Vasodilation, bronchodilation, ↑ HR, ↑ contractility, ↑ lipolysis, ↑
insulin release, ↓ uterine tone
M1 q CNS, enteric nervous system
M2 i ↓ HR and contractility of atria
M3 q ↑ exocrine gland secretions (sweat, gastric acid), ↑ gut peristalsis, ↑
bladder contraction, bronchoconstriction, miosis, accomodation.
D1 s Relaxes renal vascular smooth muscle
D2 i Modulates transmitter release (especially in brain)
H1 q ↑ nasal & bronchial mucus production, contraction of
bronchioles, pruritus & pain.
H2 s ↑ gastric acid secretion
V1 q ↑ vascular smooth muscle contraction
V2 s ↑ H2O permeability & reabsorption in CT of kidneys
Sym
pa
thetic
Para
-
sym
pa
thetic
Cholinomimetic agents:
Drug Clinical applications Action
- Direct Agonists
Bethanechol Postoperative & neurogenic
ileus & urinary retention
Activates bowel & bladder
smooth muscle; resistant to
AChE.
Carbachol Glaucoma, pupillary
contraction, & release of IOP
Pilocarpine Potent simulator of sweat, tears,
saliva
Contracts cilliary muscle of
eyes (open angle), pupillary
sphincter (narrow angle);
resistant to AChE.
Methacholine Challenge test for diagnosis of
asthma
Stimulates muscarinic
receptors in airway when
inhaled.
by Seetal K Dhaliwal H. S
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Cholinomimetic agents:
Drug Clinical applications Action
- Indirect Agonists
(anti-cholinesterases)
Neostigmine Postoperative & neurogenic
ileus & urinary retention,
myasthenia gravis, reversal of
NMJ block (post-operative)
↑ endogenous ACh; no CNS
penetration. NEO CNS =
NO CNS penetration.
Pyridostigmine Myasthenia gravis (long-
acting). Doesn’t cross BBB.
↑ endogenous ACh; ↑
strength.
Edrophonium Diagnosing myasthenia gravis
extremely short acting). If
+MG, symptoms disappear, if ACh
overdose, symptoms get worse.
↑ endogenous ACh.
Physostigmine Glaucoma (crosses BBB) &
atropine overdose
↑ endogenous ACh. PHYS for
EYES.
Echothiophate Glaucoma ↑ endogenous ACh.
by Seetal K Dhaliwal H. S
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Cholinesterase inhibitor poisoning:
Caused by parathion & other organophosphates. Irreversible inhibitors.
DUMBBELSS symptoms: Diarrhea, Urination, Miosis, Bradycardia, Bronchospasm,
Excitation of skeletal muscle, Lacrimation, Sweating, Salivation (also abdominal
cramps).
Antidote – ATROPINE (muscarinic antagonist) plus PRALIDOXIME (used to
regenerate active cholinesterase).
Atropine (muscarinic antagonist):
↑ pupil dilation (mydriasis), cycloplegia, ↓ airway secretions, ↓ acid secretion, ↓
motility, ↓ urgency & cystitis.
Blocks SLUD: Salivation, Lacrimation, Urination & Diarrhea.
Toxicity: ↑ body temperature, rapid pulse, dry mouth, dry flushed skin, cycloplegia,
constipation, disorientation.
Can cause acute angle-closure glaucoma in elderly, urinary retention in men with
prostatic hyperplasia, & hyperthermia in infants.
HOT as a HARE, DRY as a BONE, RED as a BEET, BLIND as a BAT, MAD as a
HATTER.by Seetal K Dhaliwal H. S
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Muscarinic antagonist:
Atropine, homatropine, tropicamide EYE produces mydriasis & cycloplegia.
Benztropine CNS Used in Parkinson disease (PARK my BENZ).
Scopolamine CNS Anti-motion Sickness.
Ipratropium bromide Respiratory used in Asthma & COPD.
Oxybutynin, glycopyrrolate Genitourinary used to reduce urgency in mild
cystitis & reduce bladder spasms.
Methscopolamine, pirenzepine, propantheline Gastrointestinal peptic ulcer
treatment.
Hexamethonium (Nicotinic antagonist):
Ganglion blocker. Used in experimental models to prevent vagal reflex responses
to changes in blood pressure – e.g., prevents reflex bradycardia caused by NE.
Toxicity: Severe orthostatic hypotension, blurred vision, constipation, sexual
dysfunction.
Put a HEX on smokers (nicotine) to help them quit.
by Seetal K Dhaliwal H. S
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Direct - Sympatomimetics:
Epinephrine α1,α2,β1,β2; low doses selective
for β1.
Used in anaphylaxis, glaucoma (open-
angle), asthma, hypotension.
NE α1, α2 > β1 Used in hypotension but ↓ renal
perfusion.
Isoproterenol β1 = β2 (isolated to β) Used in AV block (rare)
Dopamine D1 = D2 > β> α, inotropic &
chronotropic
Used in shock (to ↑ renal perfusion),
heart failure.
Dobutamine β1 > β2 , inotropic but NOT
chronotropic
Used in shock, heart failure, cardiac
stress testing (if treadmill cannot use)
Phenylephrine α1 > α2 Used to dilate pupil, as a vasoconstrictor
& nasal decongestant.
Metaproterenol,
albuterol,
salmeterol,
terbutaline.
Selective β2 agonists (β2 > β1) MAST: Metaproterenol & Albuterol for
acute asthma, Salmeterol long-term tx,
Terbutaline to reduce premature uterine
contractions.
Ritodrine β2 Reduces premature uterine contractionsby Seetal K Dhaliwal H. S
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by Seetal K Dhaliwal H. S
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Amphetamine indirect general agonist; releases stored catecholamines
used in Narcolepsy, obesity, attention deficit disorder (ADHD).
Ephedrine indirect general agonist; releases stored catecholamines used
in nasal decongestion, urinary incontinence, hypotension.
Cocaine indirect general agonist; uptake inhibitor causes vasoconstriction
& used as local anesthesia.
Clonidine, α-methyldopa centrally acting α2-agonists, ↓ central adrenergic
outflow.
Used in HTN especially with renal disease (does not ↓ blood flow to kidneys)
Celecoxib, Furosemide, Probenecid, Thiazides, TMP-SMX, Sulfasalazine,
Sulfonylureas, Sumatriptan.
Patients with sulfa allergy may develop fever, pruritic rash, SJS, hemolytic
anemia, thrombocytopenia, agranulocytosis, & urticaria (hives). Symptoms range
from mild to life-threatening.
Drug Application Toxicity
Nonselective
Phenoxybenzamine
(irreversible)
and pentolamine
(reversible)
Pheochromocytoma
(use
phenoxybenzamine
before removing tumor)
Orthostatic hypotension, reflex
tachycardia
α1 selective (-zosin)
Prazosin, terazosin,
doxazosin.
Hypertension, urinary
retention in BPH.
1st-dose orthostatic hypotension,
dizziness, headache
α2 selective
Mirtazepine Depression Sedation, ↑ serum cholesterol, ↑
appetite
by Seetal K Dhaliwal H. S
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Application Effect
HTN ↓ Cardiac output, ↓ renin secretion (due to β-receptor block on JGA cells)
Angina pectoris ↓ HR & contractility, resulting in ↓ O2 consumption.
MI β-blockers, ↓ mortality
SVT (propanolol,
esmolol)
↓ AV conduction velocity (class II antiarrhythmics)
CHF Slows progression of chronic failure
Glaucoma (timolol) ↓ secretion of aqueous humor
by Seetal K Dhaliwal H. S
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Toxicity: Impotence, exacerbation of asthma, CVS effects (bradycardia, AV block, CHF),
CNS effects (sedation, sleep alterations); USE WITH CAUTION IN DIABETICS (masks
hyperglycemia)
Selectivity: Nonselective antagonist – Propanolol, Timolol, Nadolol, Pindolol &
Labetolol.
β1-selective antagonists (β1>β2) – Acebutolol (partial), Betaxolol,
Esmolol (short acting), Atenolol, Metoprolol (A BEAM of β1 blockers).
Nonselective α & β antagonists – Carvedilol, Labetolol.
Partial β-Agonist – Pindolol, Acebutolol
by Seetal K Dhaliwal H. S
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Drug Mechanism Side Effects
α-agonist
Epinephrine ↑ outflow of aqueous humor Mydriasis, stinging, do not use
in closed-angle glaucoma
Brimonidine ↓ aqueous humor synthesis No pupillary or vision changes
β-blockers
Timolol, betaxolol,
carteolol
↓ aqueous humor secretion No pupillary or vision changes
Diuretics
Acetazolamide ↓ aqueous humor secretion due to ↓
HCO3- (via CA inhibition)
No pupillary or vision changes
Cholinomimetics
Pilocarpine,
carbachol,
physostigmine,
echothiophate
↑ outflow of aqueous humor (echothiophate,
physostigmine); contract cilliary muscle &
open trabecular meshwork (pilocarpine,
carbachol); use pilocarpine in emergencies
very effective at opening canal of Schlemm.
Miosis, cyclospasm
Prostaglandin
Latanoprost (PGF2α) ↑ outflow of aqueous humor Darkens color of iris (browning)