Digoxin toxicity is markedly worsened by hypokalemia. The mechanism is:

• A Hypokalemia increases digoxin renal clearance, paradoxically raising plasma levels
• B Hypokalemia activates the renin-angiotensin system which amplifies digoxin's toxic myocardial effects
• C Low potassium impairs hepatic glucuronidation of digoxin metabolites
• D Potassium and digoxin compete for the same binding site on Na+/K+-ATPase; low extracellular K+ increases digoxin binding affinity to the pump, enhancing toxicity ✓

Explanation

Digoxin and K+ compete for the same extracellular binding site (E2-P conformation) on Na+/K+-ATPase. When extracellular K+ is low (hypokalemia), less K+ competes with digoxin for the enzyme, allowing increased digoxin binding and greater pump inhibition. This potentiates both the therapeutic and toxic effects of digoxin. Conversely, hyperkalemia reduces digoxin binding. Loop and thiazide diuretics (commonly co-prescribed with digoxin in heart failure) cause hypokalemia, making K+ monitoring essential.

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

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