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Difficulty: MediumPharmacokinetic and Pharmacodynamic Principles

A 68-year-old man with a history of heart failure with reduced ejection fraction and atrial fibrillation comes to the emergency department reporting severe nausea, vomiting, blurred vision, and seeing yellow-green halos around objects for the past two days. His medications include lisinopril, metoprolol succinate, furosemide, and digoxin. Two weeks ago, oral amiodarone was added to his regimen by his cardiologist for recurrent, symptomatic atrial fibrillation. His pulse is 48/min and blood pressure is 110/70 mm Hg. An electrocardiogram shows sinus bradycardia with first-degree atrioventricular block. Laboratory studies show:

Serum potassium: 4.1 mEq/L4.1 \text{ mEq/L}
Serum creatinine: 1.1 mg/dL1.1 \text{ mg/dL}
Serum digoxin: 3.4 ng/mL3.4 \text{ ng/mL} (therapeutic range: 0.50.5 to 2.0 ng/mL2.0 \text{ ng/mL})

Which of the following pharmacokinetic mechanisms best explains this patient's current presentation?

  1. Inhibition of P-glycoprotein-mediated drug effluxAnswer
  2. B
    Inhibition of cytochrome P450 3A4 metabolism
  3. C
    Displacement of the drug from plasma albumin
  4. D
    Inhibition of organic anion transporter 1 (OAT1) in the kidney
  5. E
    Induction of hepatic UDP-glucuronosyltransferase

Answer

Inhibition of P-glycoprotein-mediated drug efflux
The patient is exhibiting classic signs of digoxin toxicity (nausea, vomiting, visual changes, bradycardia, and first-degree AV block) precipitated by the recent addition of amiodarone. Amiodarone is a potent inhibitor of P-glycoprotein (P-gp), an efflux transporter located in the intestinal mucosa, renal proximal tubules, and biliary system. Digoxin is a primary substrate for P-gp. Inhibition of P-gp by amiodarone reduces the renal and biliary clearance of digoxin and increases its intestinal absorption, leading to elevated serum digoxin levels and subsequent toxicity. Because of this interaction, the dose of digoxin should typically be reduced by 50% when amiodarone is initiated.

Step-by-Step Solution

1
Analyze the clinical presentation and laboratory findings.
The patient has nausea, visual disturbances, bradycardia, AV block, and an elevated serum digoxin level (3.4 ng/mL3.4 \text{ ng/mL}), confirming digoxin toxicity.
Identifying the active clinical problem is the first step to determining its etiology.
2
Identify the precipitating factor for the toxicity.
The recent addition of amiodarone to a stable digoxin regimen is the precipitating event.
Amiodarone is known to have significant drug-drug interactions that can rapidly alter the pharmacokinetics of concurrent medications.
3
Determine the specific pharmacokinetic mechanism of the interaction.
Amiodarone inhibits P-glycoprotein, decreasing digoxin clearance and increasing its levels.
Understanding the specific transporter involved in the amiodarone-digoxin interaction is required to answer the question.

Key Concept

Amiodarone causes digoxin toxicity by inhibiting P-glycoprotein (P-gp), which decreases the renal and biliary clearance of digoxin and increases its intestinal absorption.
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Topics

Pharmacokinetic and Pharmacodynamic Principles

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