Medical Pharmacology Question Bank

Chapter 1: General Pharmacology — Module 2: Pharmacokinetics Principles
Tier: Tier 2 — Conceptual Understanding

1. A drug is administered orally at 100 mg and produces a peak plasma concentration of 8 mg/L. When the same drug is administered intravenously at 50 mg, it produces a peak plasma concentration of 20 mg/L. Assuming linear pharmacokinetics, which of the following correctly calculates the oral bioavailability of this drug?

A) 20% — because the oral dose is twice the IV dose but produces less than half the plasma concentration
B) 40% — calculated as (AUC oral / AUC IV) corrected for the dose ratio: (8/100) / (20/50) = 0.08 / 0.40 = 0.20, which equals 20%
C) 40% — calculated as (Cmax oral / dose oral) / (Cmax IV / dose IV) = (8/100) / (20/50) = 0.08 / 0.40 = 0.20, meaning bioavailability is 20%
D) 20% — calculated as (Cmax oral / dose oral) / (Cmax IV / dose IV) = (8/100) / (20/50) = 0.08 / 0.40 = 0.20
E) 80% — because peak plasma concentration after oral dosing is 40% of IV despite twice the dose, implying 80% systemic availability after first-pass correction

ANSWER: D

Rationale:

Bioavailability is calculated as F = (AUC oral / AUC IV) × (Dose IV / Dose oral). When AUC data are not provided but Cmax values under linear kinetics are available, the dose-normalized Cmax can serve as a proxy. Dose-normalized Cmax(oral) = 8 mg/L ÷ 100 mg = 0.08 L¹. Dose-normalized Cmax(IV) = 20 mg/L ÷ 50 mg = 0.40 L¹. F = 0.08 / 0.40 = 0.20, or 20%. Option A arrives at the correct numerical answer (20%) but provides an imprecise qualitative explanation rather than the formal calculation. Option B states "40%" in the label but then correctly calculates 20% in the body — the label is internally inconsistent and therefore incorrect as written. Option C similarly labels the answer as 40% while calculating 20% — an internal contradiction making it incorrect. Option E is incorrect — the calculation described does not yield 80%, and the reasoning conflates Cmax ratio with bioavailability in an invalid way. The correct answer is D: 20% bioavailability, derived from dose-normalized Cmax comparison under linear pharmacokinetic assumptions.

2. A patient with severe hepatic cirrhosis (Child-Pugh Class C) is prescribed a drug that normally undergoes 90% first-pass hepatic extraction. Which of the following best predicts how cirrhosis will alter the drug's oral bioavailability and the clinical consequence of standard oral dosing?

A) Cirrhosis will have no effect on first-pass extraction because hepatic enzyme activity is upregulated as a compensatory response to hepatocellular loss
B) Cirrhosis reduces hepatic blood flow and functional hepatocyte mass, impairing first-pass extraction and substantially increasing oral bioavailability — standard oral doses may produce toxic systemic drug concentrations
C) is prescribed a drug that normally undergoes 90% first-pass hepatic extraction. Which of the following best predicts how cirrhosis will alter the drug's oral bioavailability and the clinical consequence of standard oral dosing? A. Cirrhosis will have no effect on first-pass extraction because hepatic enzyme activity is upregulated as a compensatory response to hepatocellular loss B. Cirrhosis reduces hepatic blood flow and functional hepatocyte mass, impairing first-pass extraction and substantially increasing oral bioavailability — standard oral doses may produce toxic systemic drug concentrations C. Cirrhosis increases renal clearance of the drug as a compensatory mechanism, offsetting the reduction in hepatic first-pass extraction and maintaining normal plasma concentrations
D) Cirrhosis reduces oral bioavailability further by impairing gastrointestinal absorption, because portal hypertension reduces intestinal mucosal perfusion
E) First-pass extraction is unaffected by cirrhosis because it depends on CYP enzyme affinity (Km), which is genetically determined and not altered by liver disease

ANSWER: B

Rationale:

First-pass hepatic extraction depends on two variables: hepatic blood flow (Q) and the intrinsic metabolic clearance of hepatocytes (CLint). In severe cirrhosis (Child-Pugh Class C), both are impaired: hepatic blood flow is reduced by portal hypertension and intrahepatic shunting, and functional hepatocyte mass is decreased by fibrosis and necrosis — reducing CLint. For high-extraction drugs (hepatic extraction ratio ≥ 0.7), first-pass extraction is normally so efficient that oral bioavailability is very low (e.g., morphine F 30%, propranolol F 25%, lidocaine F 35%). In cirrhosis, the dramatic reduction in first-pass extraction for these drugs can increase oral bioavailability to near-IV levels — a 2- to 4-fold or greater increase in systemic exposure from a standard oral dose. This carries serious toxicity risk and requires dose reduction or route change. Option A is incorrect — hepatic enzyme activity is not upregulated in cirrhosis; functional hepatocyte mass and CYP enzyme expression are reduced. Option C is incorrect — renal clearance does not compensate for lost hepatic metabolism in any meaningful pharmacokinetic sense for drugs primarily eliminated hepatically. Option D is incorrect — while portal hypertension can impair intestinal absorption to some degree, the dominant and clinically decisive effect of cirrhosis on high-extraction drugs is the loss of first-pass extraction, which increases rather than decreases oral bioavailability. Option E is incorrect — while Km is genetically influenced, first-pass extraction in vivo is determined by the overall hepatic extraction ratio, which is profoundly affected by both hepatic blood flow and functional enzyme activity, both of which are impaired in cirrhosis.

3. Drug A has a volume of distribution of 5 L and a plasma protein binding of 95%. Drug B has a volume of distribution of 600 L and a plasma protein binding of 40%. A patient develops acute renal failure requiring hemodialysis. Which drug is more likely to be effectively removed by hemodialysis, and what is the pharmacokinetic basis for this prediction?

A) Drug A, because its high protein binding increases the free drug fraction available for dialysis membrane filtration
B) Drug B, because its large volume of distribution means more drug is in the plasma compartment and therefore accessible to the dialysis membrane
C) Drug A, because its small volume of distribution means most of the drug resides in the plasma compartment, where it is accessible to the dialysis membrane, despite high protein binding limiting the free fraction
D) Drug B, because its lower protein binding means a higher free drug fraction, which combined with its large Vd makes it highly dialyzable
E) Neither drug is dialyzable, because hemodialysis only removes endogenous metabolic waste products and not exogenous drug molecules

ANSWER: C

Rationale:

The two key pharmacokinetic determinants of dialyzability are volume of distribution and plasma protein binding. Drugs with small Vd (< approximately 1 L/kg, or < 70 L in a 70 kg adult) are predominantly located in the plasma compartment and are therefore physically accessible to the dialysis membrane. Drugs with large Vd (> 5–10 L/kg) are predominantly sequestered in peripheral tissues; even if plasma drug is removed by dialysis, rapid redistribution from tissues replenishes the plasma compartment, making dialysis ineffective. Drug A, with Vd = 5 L, is almost entirely confined to plasma — the vast majority of total body drug is in the compartment dialysis can access. Drug B, with Vd = 600 L, has the overwhelming majority of drug in peripheral tissues, making dialysis essentially ineffective regardless of protein binding. The 95% protein binding of Drug A does limit the free fraction available for filtration at any instant, but the small Vd is the dominant and decisive factor — Drug A is far more dialyzable than Drug B. Examples of drugs with small Vd and clinically effective dialysis removal include lithium (Vd 0.7 L/kg) and salicylates. Option A is incorrect — high protein binding reduces, not increases, dialyzability. Option B is incorrect — a large Vd means most drug is in tissues, not plasma. Option D is incorrect — lower protein binding favors dialysis, but Drug B's enormous Vd (600 L) renders dialysis clinically ineffective regardless of its free fraction. Option E is incorrect — hemodialysis can and does remove many drugs; this is a clinically important and well-established application.

4. A patient is taking warfarin and is prescribed trimethoprim-sulfamethoxazole (TMP-SMX) for a urinary tract infection. Three days later, her INR rises from 2.4 to 4.8, and she develops minor bleeding. Warfarin is 99% protein-bound (primarily to albumin) and is a CYP2C9 substrate. Sulfonamides inhibit CYP2C9. Which of the following best explains the pharmacokinetic mechanism responsible for the elevated INR in this patient?

A) TMP-SMX displaces warfarin from albumin binding sites, acutely increasing the free warfarin fraction and causing a transient rise in INR that self-resolves as Vd expands to accommodate the displaced drug
B) TMP-SMX inhibits CYP2C9, reducing the hepatic metabolism of warfarin's S-enantiomer, increasing warfarin plasma concentrations and anticoagulant effect
C) TMP-SMX induces CYP2C9, increasing warfarin metabolism and paradoxically causing a rebound anticoagulant effect as the enzyme returns to baseline
D) TMP-SMX increases renal tubular secretion of warfarin's metabolites, reducing their urinary excretion and causing accumulation of active warfarin in the plasma
E) TMP-SMX competitively inhibits vitamin K epoxide reductase, directly augmenting warfarin's pharmacodynamic mechanism at its site of action

ANSWER: B

Rationale:

The clinically dominant mechanism of the warfarin-sulfonamide interaction is CYP2C9 inhibition. Warfarin is administered as a racemic mixture, but its S-enantiomer is approximately 3–5 times more potent as an anticoagulant than the R-enantiomer. S-warfarin is metabolized almost exclusively by CYP2C9. Sulfonamides, including the sulfamethoxazole component of TMP-SMX, are CYP2C9 inhibitors. Inhibition of CYP2C9 reduces S-warfarin clearance, increasing its plasma concentrations and anticoagulant effect — manifesting as a rising INR and bleeding risk. Option A describes protein binding displacement, which was historically considered a significant mechanism but is now understood to be clinically inconsequential in isolation: displacement transiently increases free drug, but the free drug is now also available for increased hepatic metabolism and renal clearance, so the net effect on steady-state total drug concentration is minimal and the free drug fraction rapidly returns to baseline. For drugs with narrow therapeutic windows like warfarin, the CYP interaction is the primary clinically meaningful mechanism. Option C is incorrect — sulfonamides are CYP2C9 inhibitors, not inducers. Option D is incorrect — warfarin is not significantly renally excreted; its metabolites are, but accumulation of inactive metabolites does not raise INR. Option E describes a pharmacodynamic rather than pharmacokinetic mechanism; while warfarin does inhibit vitamin K epoxide reductase, TMP-SMX does not share this mechanism of action.

5. A drug follows zero-order (Michaelis-Menten saturation) kinetics at therapeutic plasma concentrations. Which of the following best describes the clinical implications of this kinetic behavior compared to a drug following first-order kinetics?

A) At therapeutic concentrations, the drug is eliminated at a constant fraction of the plasma concentration per unit time, making dose-response relationships predictable and linear
B) Small increases in dose produce disproportionately large increases in plasma concentration, the half-life is not constant but increases with increasing plasma concentration, and the therapeutic window narrows dangerously at higher doses
C) The drug is eliminated faster at higher plasma concentrations because enzyme saturation increases hepatic blood flow and metabolic capacity
D) Zero-order kinetics apply only to renal excretion and imply that the drug is actively secreted by saturatable tubular transporters; hepatic metabolism remains first-order
E) At therapeutic concentrations, the drug's half-life is fixed and independent of dose, allowing standard nomogram-based dosing without plasma level monitoring

ANSWER: B

Rationale:

Zero-order (saturation) kinetics occur when drug plasma concentrations exceed the Michaelis-Menten Km of the metabolizing enzyme, such that the enzyme is operating at or near maximum velocity (Vmax) and can only eliminate a fixed amount of drug per unit time regardless of plasma concentration. This contrasts sharply with first-order kinetics, in which a constant fraction of drug is eliminated per unit time and the half-life is constant and dose-independent. The clinical consequences of zero-order kinetics are profound and dangerous: (1) small dose increments produce disproportionately large rises in plasma concentration — the relationship between dose and steady-state plasma level is non-linear; (2) the apparent half-life increases as plasma concentration rises, because the elimination rate (fixed at Vmax) becomes an ever-smaller fraction of the total drug load; (3) the drug accumulates unpredictably with dose escalation, dramatically narrowing the effective therapeutic window. Phenytoin is the classic clinical example: at low doses it follows approximate first-order kinetics, but at therapeutic concentrations (10–20 mg/L) its metabolism is near-saturated, so dose increases from 300 mg to 400 mg daily can raise plasma levels from 15 to 40 mg/L — well into the toxic range. Ethanol is another example of zero-order kinetics at intoxicating concentrations. Option A describes first-order kinetics, not zero-order. Option C is incorrect — enzyme saturation does not increase hepatic blood flow; it means the elimination rate is fixed at Vmax and cannot increase further regardless of concentration. Option D is incorrect — zero-order kinetics can apply to hepatic enzymatic metabolism (CYP saturation), not only renal tubular secretion. Option E describes first-order kinetics with a constant half-life, which is the opposite of zero-order behavior.