by Seetal K Dhaliwal H.

PHARMACOLOGY
USMLE Step 1 Flash cards by Seetal K Dhaliwal H. S

by Seetal K Dhaliwal H. S

Section I

Flash cards by Seetal K. Dhaliwal H. S

Pharmacokinetics:
Competitive inhibitors
Resemble substrate YES

Non-competitive inhibitors
NO

Overcome by [S]
Bind active site Effect on Vmax Effect on Km

YES
YES Unchanged

NO
NO Unchanged

Pharmacodynamics

potency

efficacy

Vd:

Drugs with low Vd distribute in blood; medium Vd in extracellular space or body water; high Vd distribute in tissues. A drug infused at a constant rate reaches ~94% steady state after 4 t1/2 (FIRST ORDER ELIMINATION):
# of half-lives 1
50%

t1/2:

2
75%

3
87.5%

4
93.75%
by Seetal K Dhaliwal H. S

concentration

Pharmacokinetics:
4

Loading dose:

Cp x Vd/F (F=bioavailability is 1 when given IV)

Cp x CL/F

Maintenance dose:

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. 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

Elimination of drugs:

Important Pharmacokinetics calculations:

5

Single dose equations:

Vd = Volume of distribution

k = elimination constant
Vd = D/C0 t1/2 = 0.7/k CL = k x Vd t1/2 = 0.7 x Vd/CL

D = Dose C0 = concentration at time 0

t1/2 = half-life
CL = Clearance Css = steady state concentration LD = Loading Dose

Multiple dose equations:

k0 = CL x Css LD = Vd x Css MD = CL x Css x

k0 = infusion rate MD = Maintenance Dose = dosing interval

by Seetal K Dhaliwal H. S

by Seetal K Dhaliwal H. S

Section II

Flash cards by Seetal K. Dhaliwal H. S

Central & Peripheral NS:

by Seetal K Dhaliwal H. S

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

G-protein-linked 2nd messengers:

Receptor
Sympathetic 1 2

G protein class Major functions

q i vascular smooth muscle contraction, Mydriasis, intestinal & bladder sphincter contraction. sympathetic outflow, insulin release

1
2 M1

s
s q

HR, contractility, renin release, lipolysis

Vasodilation, bronchodilation, HR, contractility, lipolysis, insulin release, uterine tone CNS, enteric nervous system

Para sympathetic

M2
M3 D1

i
q s

HR and contractility of atria

exocrine gland secretions (sweat, gastric acid), gut peristalsis, bladder contraction, bronchoconstriction, miosis, accomodation.

Relaxes renal vascular smooth muscle

D2
H1 H2

i
q s

Modulates transmitter release (especially in brain)

nasal & bronchial mucus production, contraction of bronchioles, pruritus & pain. gastric acid secretion

V1
V2

q
s

vascular smooth muscle contraction

H2O permeability & reabsorption in CT of kidneys
by Seetal K Dhaliwal H. S

Cholinomimetic agents:
Drug - Direct Agonists Bethanechol Postoperative & neurogenic ileus & urinary retention Glaucoma, pupillary contraction, & release of IOP Potent simulator of sweat, tears, Contracts cilliary muscle of saliva eyes (open angle), pupillary sphincter (narrow angle); resistant to AChE. Challenge test for diagnosis of asthma Stimulates muscarinic receptors in airway when inhaled. Activates bowel & bladder smooth muscle; resistant to AChE. Clinical applications Action

10

Carbachol

Pilocarpine

Methacholine

by Seetal K Dhaliwal H. S

Cholinomimetic agents:
Drug
- Indirect Agonists (anti-cholinesterases)

11

Clinical applications

Action

Neostigmine

Postoperative & neurogenic ileus & urinary retention, myasthenia gravis, reversal of NMJ block (post-operative) Myasthenia gravis (longacting). Doesnt cross BBB. Diagnosing myasthenia gravis extremely short acting). If
+MG, symptoms disappear, if ACh overdose, symptoms get worse.

endogenous ACh; no CNS penetration. NEO CNS = NO CNS penetration. endogenous ACh; strength. endogenous ACh.

Pyridostigmine Edrophonium

Physostigmine Echothiophate

Glaucoma (crosses BBB) & atropine overdose Glaucoma

endogenous ACh. PHYS for EYES. endogenous ACh.

by Seetal K Dhaliwal H. S

Cholinesterase inhibitor poisoning:

12

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

Muscarinic antagonist:

13

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

Direct - Sympatomimetics:
14

Epinephrine NE Isoproterenol Dopamine Dobutamine Phenylephrine

1,2,1,2; low doses selective for 1. 1, 2 > 1 1 = 2 (isolated to ) D1 = D2 > > , inotropic & chronotropic 1 > 2 , inotropic but NOT chronotropic 1 > 2

Used in anaphylaxis, glaucoma (openangle), asthma, hypotension. Used in hypotension but renal perfusion. Used in AV block (rare) Used in shock (to renal perfusion), heart failure. Used in shock, heart failure, cardiac stress testing (if treadmill cannot use) Used to dilate pupil, as a vasoconstrictor & nasal decongestant.

Metaproterenol, albuterol, salmeterol, terbutaline.

Ritodrine

Selective 2 agonists (2 > 1)

MAST: Metaproterenol & Albuterol for acute asthma, Salmeterol long-term tx, Terbutaline to reduce premature uterine contractions.
Reduces premature uterine contractions
by Seetal K Dhaliwal H. S

15

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, -methyldopa centrally acting 2-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.

by Seetal K Dhaliwal H. S

16

Drug Nonselective Phenoxybenzamine (irreversible) and pentolamine (reversible)

Application

Toxicity

Pheochromocytoma Orthostatic hypotension, reflex (use tachycardia phenoxybenzamine before removing tumor)

1 selective (-zosin) Prazosin, terazosin, Hypertension, urinary doxazosin. retention in BPH. 2 selective Mirtazepine

1st-dose orthostatic hypotension, dizziness, headache

Depression

Sedation, serum cholesterol, appetite

by Seetal K Dhaliwal H. S

17

Application HTN Angina pectoris MI SVT (propanolol, esmolol) CHF

Effect Cardiac output, renin secretion (due to -receptor block on JGA cells) HR & contractility, resulting in O2 consumption. -blockers, mortality AV conduction velocity (class II antiarrhythmics) Slows progression of chronic failure

Glaucoma (timolol) secretion of aqueous humor

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. 1-selective antagonists (1>2) Acebutolol (partial), Betaxolol, Esmolol (short acting), Atenolol, Metoprolol (A BEAM of 1 blockers). Nonselective & antagonists Carvedilol, Labetolol. Partial -Agonist Pindolol, Acebutolol by Seetal K Dhaliwal H. S

18 Drug Mechanism Side Effects

-agonist Epinephrine outflow of aqueous humor Mydriasis, stinging, do not use in closed-angle glaucoma

Brimonidine
-blockers Timolol, betaxolol, carteolol

aqueous humor synthesis

aqueous humor secretion

No pupillary or vision changes

No pupillary or vision changes

Diuretics
Acetazolamide 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.

aqueous humor secretion due to HCO3- (via CA inhibition)

No pupillary or vision changes

Miosis, cyclospasm

Prostaglandin
Latanoprost (PGF2) outflow of aqueous humor Darkens color of iris (browning)
by Seetal K Dhaliwal H. S