Summary

Itraconazole significantly increases digoxin plasma concentrations through inhibition of P-glycoprotein and CYP3A4 metabolism. This interaction can lead to digoxin toxicity and requires careful monitoring and potential dose adjustments when these medications are used concurrently.

Introduction

Itraconazole is a triazole antifungal medication commonly used to treat systemic fungal infections, including aspergillosis, blastomycosis, and histoplasmosis. It works by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase. Digoxin is a cardiac glycoside derived from the foxglove plant, primarily used to treat heart failure and certain arrhythmias like atrial fibrillation. It works by inhibiting the sodium-potassium ATPase pump, increasing intracellular calcium and improving cardiac contractility.

Mechanism of Interaction

The interaction between itraconazole and digoxin occurs through multiple mechanisms. Itraconazole is a potent inhibitor of P-glycoprotein, a drug efflux transporter that plays a crucial role in digoxin elimination from the kidneys and intestines. By inhibiting P-glycoprotein, itraconazole reduces digoxin clearance and increases its absorption. Additionally, itraconazole inhibits CYP3A4, which may contribute to reduced digoxin metabolism. These combined effects result in significantly elevated digoxin plasma concentrations, potentially increasing levels by 50-70% or more.

Risks and Symptoms

The primary clinical risk of this interaction is digoxin toxicity, which can be life-threatening. Elevated digoxin levels may cause cardiac arrhythmias, including bradycardia, heart block, and ventricular arrhythmias. Patients may experience symptoms such as nausea, vomiting, visual disturbances (yellow-green halos), confusion, fatigue, and loss of appetite. The narrow therapeutic index of digoxin makes this interaction particularly concerning, as small increases in plasma concentration can lead to significant toxicity. Elderly patients and those with renal impairment are at higher risk for adverse effects.

Management and Precautions

When concurrent use of itraconazole and digoxin is necessary, close monitoring is essential. Digoxin serum levels should be measured before starting itraconazole and within 1-2 weeks after initiation. Consider reducing the digoxin dose by 25-50% when starting itraconazole therapy. Monitor patients closely for signs and symptoms of digoxin toxicity, including cardiac rhythm changes, gastrointestinal symptoms, and neurological effects. Regular ECG monitoring may be warranted. If possible, consider alternative antifungal agents with less potential for drug interactions, such as fluconazole at lower doses or echinocandins, depending on the indication.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.

Digoxin interactions with food and lifestyle

Digoxin has several important food and lifestyle interactions that patients should be aware of. High-fiber foods, including bran cereals and fiber supplements, can significantly reduce digoxin absorption and should be taken at least 2 hours apart from digoxin doses. St. John's wort, an herbal supplement, can decrease digoxin levels and reduce its effectiveness, so concurrent use should be avoided. Alcohol consumption can affect digoxin levels and increase the risk of side effects, particularly heart rhythm abnormalities. Patients should limit alcohol intake and discuss any alcohol use with their healthcare provider. Additionally, maintaining consistent dietary habits is important, as sudden changes in fiber intake or meal timing can affect digoxin absorption and blood levels. Patients should also be cautious with salt substitutes containing potassium, as changes in potassium levels can affect digoxin's effectiveness and safety.