Pharmacology for USMLE Step 1

A 58-year-old man is started on a new antihypertensive. Two weeks later he develops a dry, persistent cough. Serum potassium has risen from 4.1 to 5.2 mEq/L and creatinine from 0.9 to 1.1 mg/dL. Which mediator most directly explains his cough?

1. Histamine Mediates immediate hypersensitivity, urticaria, bronchospasm, flushing, not the delayed dry cough of ACE inhibition.
2. Prostaglandin E2 Contributes to airway sensitization in some models, but the mediator ACE inhibition directly spares is bradykinin. Switching to an ARB resolves the cough precisely because ARBs do not affect bradykinin metabolism.
3. Aldosterone Also reduced, which is why potassium rose. It has no role in generating the cough reflex.
4. Angiotensin II Reduced, not increased, by the drug. Reduced angiotensin II explains the blood pressure fall and the potassium rise, not the cough.
5. Bradykinin correct Correct. ACE (kininase II) degrades bradykinin as well as converting angiotensin I to II. Inhibiting it lets bradykinin and substance P accumulate in the airway, producing the dry cough in roughly 5 to 20% of patients and, rarely, angioedema.

The point: ACE inhibitor cough and angioedema are bradykinin-mediated; the hyperkalemia and creatinine rise are angiotensin-mediated. Switch to an ARB for the cough, the potassium effect persists because it is on-target.

Source: USMLE Content Outline — pharmacology NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator

A drug is eliminated by first-order kinetics with a half-life of 8 hours. It is started at a fixed maintenance dose with no loading dose. Approximately how long until steady-state plasma concentration is reached?

1. About 40 hours correct Correct. Steady state is reached after approximately four to five half-lives regardless of the dose, so 4 to 5 × 8 hours is roughly 32 to 40 hours. The DOSE determines the level at steady state; the HALF-LIFE determines how long it takes to get there.
2. Steady state is reached immediately with the first dose Only if a loading dose is given, which the stem excludes. A loading dose fills the volume of distribution at once.
3. About 8 hours That is one half-life, at which the drug has reached only about 50% of steady state.
4. Steady state depends on the maintenance dose, so it cannot be determined A common misconception. Raising the maintenance dose raises the steady-state CONCENTRATION but does not shorten the time to reach it.
5. About 16 hours Two half-lives, about 75% of steady state, still climbing appreciably.

The point: Time to steady state is four to five half-lives and is independent of dose. Loading dose = target concentration × volume of distribution. Maintenance dose = target concentration × clearance. Zero-order drugs, phenytoin at therapeutic levels, alcohol, aspirin in overdose, break these rules.

Source: USMLE Content Outline — pharmacokinetics NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator

A patient on warfarin with a stable INR of 2.5 is started on a second drug. Two weeks later the INR is 6.8 with no change in warfarin dose or diet. Which added drug best explains this?

1. Rifampin A powerful CYP INDUCER. It would lower the INR and risk thrombosis, not bleeding.
2. Fluconazole correct Correct. Fluconazole is a potent inhibitor of CYP2C9, the enzyme that clears the more active S-enantiomer of warfarin. Less clearance means more anticoagulant effect and a rising INR.
3. St John's wort A herbal CYP3A4 and P-glycoprotein inducer that reduces the effect of warfarin, oral contraceptives and many antiretrovirals.
4. Carbamazepine Another inducer, and it autoinduces its own metabolism as well.
5. Phenytoin at steady state Chronic phenytoin induces CYP enzymes and lowers the INR, though the acute displacement from albumin can transiently raise it.

The point: Inhibitors raise drug levels: azoles, macrolides (not azithromycin), amiodarone, cimetidine, ciprofloxacin, isoniazid, grapefruit juice, ritonavir. Inducers lower them: rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort, chronic alcohol.

Source: USMLE Content Outline — pharmacokinetics NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator