A patient with severe hepatic cirrhosis (Child-Pugh Class C) is prescribed propranolol for portal hypertension. The dose must be reduced substantially. Which pharmacokinetic parameter most importantly explains propranolol's substantially increased bioavailability in cirrhosis?

• A Cirrhosis increases gastric acid production enhancing propranolol absorption from the gut
• B Hypoalbuminemia in cirrhosis reduces propranolol protein binding, increasing free drug fraction
• C Reduced first-pass hepatic extraction due to decreased hepatic blood flow and reduced CYP2D6 activity in cirrhotic liver ✓
• D Portosystemic shunts reduce volume of distribution concentrating propranolol in plasma

Explanation

Propranolol undergoes extensive first-pass hepatic metabolism (hepatic extraction ratio approximately 0.6-0.7), with bioavailability normally only 25-35%. In hepatic cirrhosis, two factors combine to markedly increase bioavailability: reduced hepatic blood flow (less drug presented for extraction per unit time) and reduced CYP2D6 and CYP1A2 activity in the damaged hepatocytes reducing extraction efficiency. Additionally, portosystemic shunts divert intestinal blood containing absorbed propranolol directly to systemic circulation, completely bypassing the liver. Together these can raise bioavailability 3-4 fold, necessitating major dose reductions.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.