Summary

The combination of hydrochlorothiazide (HCTZ) and dofetilide presents a significant drug interaction that increases the risk of serious cardiac arrhythmias. This interaction occurs primarily through hydrochlorothiazide-induced electrolyte imbalances, particularly hypokalemia and hypomagnesemia, which can enhance dofetilide's proarrhythmic effects.

Introduction

Hydrochlorothiazide (HCTZ) is a thiazide diuretic commonly prescribed for hypertension and edema management. It works by inhibiting sodium and chloride reabsorption in the distal convoluted tubule of the kidney, leading to increased urine production and reduced blood volume. Dofetilide is a Class III antiarrhythmic medication used to treat atrial fibrillation and atrial flutter. It functions as a selective potassium channel blocker, specifically targeting the rapid component of the delayed rectifier potassium current (IKr), which helps restore and maintain normal heart rhythm.

Mechanism of Interaction

The interaction between hydrochlorothiazide and dofetilide occurs through an indirect mechanism involving electrolyte disturbances. Hydrochlorothiazide can cause significant losses of potassium and magnesium through increased urinary excretion. These electrolyte imbalances, particularly hypokalemia (low potassium) and hypomagnesemia (low magnesium), create a proarrhythmic environment that enhances dofetilide's effects on cardiac repolarization. Low potassium and magnesium levels can further prolong the QT interval beyond dofetilide's inherent effects, significantly increasing the risk of torsades de pointes, a potentially fatal ventricular arrhythmia.

Risks and Symptoms

The primary clinical risk of combining hydrochlorothiazide with dofetilide is an increased likelihood of developing serious ventricular arrhythmias, particularly torsades de pointes. This risk is heightened when patients develop hypokalemia (serum potassium <3.5 mEq/L) or hypomagnesemia (serum magnesium <1.8 mg/dL). Additional risks include excessive QT interval prolongation, which can lead to sudden cardiac death. Patients with pre-existing cardiac conditions, kidney disease, or those taking other QT-prolonging medications face even higher risks. The interaction is considered clinically significant and requires careful monitoring and management to prevent potentially life-threatening complications.

Management and Precautions

Hydrochlorothiazide interactions with food and lifestyle

Hydrochlorothiazide may increase sensitivity to sunlight, increasing the risk of sunburn and skin reactions. Patients should use sunscreen, wear protective clothing, and limit sun exposure while taking this medication. Alcohol consumption may enhance the blood pressure-lowering effects of hydrochlorothiazide, potentially causing dizziness, lightheadedness, or fainting, especially when standing up quickly. Patients should limit alcohol intake and rise slowly from sitting or lying positions. Excessive salt intake may reduce the effectiveness of hydrochlorothiazide in lowering blood pressure, so patients should follow a low-sodium diet as recommended by their healthcare provider.

Dofetilide interactions with food and lifestyle

Dofetilide should be taken consistently with regard to meals - either always with food or always without food. Grapefruit juice should be avoided as it may increase dofetilide blood levels and risk of dangerous heart rhythm abnormalities. Alcohol should be used with caution as it may worsen heart rhythm problems. Patients should maintain consistent potassium and magnesium levels through diet, as low levels of these electrolytes can increase the risk of serious arrhythmias with dofetilide.