A patient with chronic stable angina well controlled on propranolol develops severe biventricular heart failure with markedly reduced cardiac output. Which pharmacokinetic change best explains the need to reassess propranolol dosing?

• A Reduced hepatic blood flow lowers clearance of this high-extraction drug ✓
• B Reduced albumin synthesis raises the free fraction and accelerates elimination
• C Increased volume of distribution raises the steady-state concentration
• D Induction of CYP2D6 by congestive hepatomegaly increases metabolism

Explanation

Propranolol has a high hepatic extraction ratio, so its clearance is flow-limited: the liver extracts nearly all drug presented to it, and clearance approximates hepatic blood flow. In low-output heart failure, hepatic perfusion falls, clearance drops, and concentrations rise disproportionately for a given dose. For high-extraction drugs, enzyme capacity and protein binding matter far less than perfusion. Option B applies mainly to low-extraction, highly bound drugs, where clearance depends on intrinsic capacity and free fraction.

Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 14th ed.

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