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 Wrong. Histamine drives immediate allergic reactions, hives (urticaria), airway tightening (bronchospasm), and flushing. It does not cause the delayed dry cough seen with ACE inhibitors.
2. Prostaglandin E2 Wrong. Prostaglandin E2 may sensitize the airway in some lab models, but the mediator that builds up directly because of ACE inhibition is bradykinin. Switching to an ARB (angiotensin receptor blocker) fixes the cough exactly because ARBs do not change how bradykinin is broken down.
3. Aldosterone Wrong. Aldosterone is also reduced by the drug, which is why potassium went up. Aldosterone plays no part in triggering a cough.
4. Angiotensin II Wrong. The drug lowers angiotensin II, it does not raise it. This drop in angiotensin II explains the fall in blood pressure and the rise in potassium, but not the cough.
5. Bradykinin correct Correct. ACE (also called kininase II) breaks down bradykinin, on top of its main job of turning angiotensin I into angiotensin II. Blocking ACE lets bradykinin and substance P build up in the airway. This causes the dry cough seen in roughly 5 to 20% of patients, and rarely, swelling of the face or throat (angioedema).

The point: ACE inhibitor cough and angioedema (swelling) are caused by too much bradykinin. The rise in potassium (hyperkalemia) and creatinine happens because of lower angiotensin II, a separate, expected effect of the drug. Switching to an ARB fixes the cough, but the potassium effect stays, because that effect is part of how the drug class is meant to work.

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. A drug reaches steady state after about four to five half-lives, no matter what the dose is. So 4 to 5 times 8 hours is roughly 32 to 40 hours. The DOSE decides the drug LEVEL at steady state, while the HALF-LIFE decides how long it takes to get there.
2. Steady state is reached immediately with the first dose Wrong. Steady state is reached immediately only if a loading dose is given, and the question states no loading dose was used. A loading dose fills the whole volume of distribution, the space the drug spreads into, right away.
3. About 8 hours Wrong. 8 hours is only one half-life, at which point the drug has reached only about 50% of steady state.
4. Steady state depends on the maintenance dose, so it cannot be determined Wrong. This is a common misunderstanding. Raising the maintenance dose raises the drug CONCENTRATION at steady state, but it does not shorten the time it takes to get there.
5. About 16 hours Wrong. 16 hours is two half-lives, at about 75% of steady state, so the level is still rising by a meaningful amount.

The point: Time to reach steady state is four to five half-lives, and this does not depend on the dose. Loading dose equals target concentration times volume of distribution. Maintenance dose equals target concentration times clearance. Zero-order drugs, such as phenytoin at therapeutic levels, alcohol, and aspirin in overdose, do not follow 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 Wrong. Rifampin is a powerful CYP enzyme INDUCER, which speeds up drug clearance. It would LOWER the INR and raise the risk of blood clots (thrombosis), not bleeding.
2. Fluconazole correct Correct. Fluconazole strongly blocks CYP2C9, the liver enzyme that clears the more active (S) form of warfarin. Less clearance means more of the drug's blood-thinning effect stays active, so the INR, a measure of blood clotting time, rises.
3. St John's wort Wrong. St John's wort is an herbal CYP3A4 and P-glycoprotein inducer that reduces the effect of warfarin, birth control pills, and many antiretroviral drugs.
4. Carbamazepine Wrong. Carbamazepine is another CYP inducer, and it also speeds up its own breakdown over time (autoinduction).
5. Phenytoin at steady state Wrong. Phenytoin, once it reaches a steady level in the body, induces CYP enzymes and lowers the INR, though right after starting it, phenytoin can briefly raise the INR by displacing warfarin from the albumin protein it normally binds to.

The point: Enzyme inhibitors raise drug levels: azole antifungals, macrolide antibiotics (but not azithromycin), amiodarone, cimetidine, ciprofloxacin, isoniazid, grapefruit juice, and ritonavir. Enzyme inducers lower drug levels: rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort, and long-term alcohol use.

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