Summary

The combination of chlorpromazine and fluconazole presents a significant drug interaction with increased risk of QT interval prolongation and potentially life-threatening cardiac arrhythmias. This interaction occurs through fluconazole's inhibition of CYP3A4 enzymes, leading to elevated chlorpromazine levels and enhanced cardiotoxic effects.

Introduction

Chlorpromazine is a first-generation antipsychotic medication (phenothiazine class) primarily used to treat schizophrenia, bipolar disorder, and severe behavioral problems. It works by blocking dopamine receptors in the brain and has notable anticholinergic and alpha-adrenergic blocking properties. Fluconazole is a triazole antifungal medication commonly prescribed for candidiasis, cryptococcal infections, and other fungal infections. It functions by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase, which disrupts ergosterol synthesis in fungal cell membranes.

Mechanism of Interaction

The interaction between chlorpromazine and fluconazole occurs through multiple mechanisms. Fluconazole is a potent inhibitor of cytochrome P450 enzymes, particularly CYP3A4 and CYP2C19, which are responsible for metabolizing chlorpromazine. When fluconazole inhibits these enzymes, it reduces chlorpromazine clearance, leading to increased plasma concentrations and prolonged half-life. Additionally, both medications independently possess the ability to prolong the QT interval on electrocardiograms. Chlorpromazine blocks cardiac potassium channels, while fluconazole can also affect cardiac repolarization. The combination creates an additive effect on QT prolongation, significantly increasing the risk of torsades de pointes and other serious ventricular arrhythmias.

Risks and Symptoms

The primary clinical risk of this drug interaction is severe QT interval prolongation, which can progress to torsades de pointes, a potentially fatal ventricular arrhythmia. Patients may experience symptoms including dizziness, fainting, palpitations, or sudden cardiac death. The risk is particularly elevated in patients with pre-existing cardiac conditions, electrolyte imbalances (especially hypokalemia or hypomagnesemia), or those taking other QT-prolonging medications. Enhanced chlorpromazine toxicity may also manifest as increased sedation, extrapyramidal symptoms, anticholinergic effects (dry mouth, constipation, urinary retention), and orthostatic hypotension. Elderly patients and those with hepatic impairment face heightened vulnerability to these adverse effects.

Management and Precautions

Chlorpromazine interactions with food and lifestyle

Alcohol: Chlorpromazine can significantly increase the sedative effects of alcohol, leading to enhanced central nervous system depression, increased drowsiness, and impaired motor coordination. Patients should avoid or strictly limit alcohol consumption while taking chlorpromazine. Sun Exposure: Chlorpromazine increases photosensitivity and the risk of severe sunburn. Patients should use broad-spectrum sunscreen with high SPF, wear protective clothing, and limit sun exposure, especially during peak hours. This photosensitivity can persist for weeks after discontinuing the medication. Heat Exposure: Chlorpromazine can impair the body's ability to regulate temperature, increasing the risk of heat stroke and hyperthermia. Patients should avoid prolonged exposure to high temperatures, stay well-hydrated, and seek air-conditioned environments during hot weather.

Fluconazole interactions with food and lifestyle

Fluconazole can be taken with or without food as food does not significantly affect its absorption. However, patients should avoid excessive alcohol consumption while taking fluconazole, as both substances can potentially affect liver function. While moderate alcohol intake is generally considered acceptable, patients with liver conditions or those taking fluconazole for extended periods should discuss alcohol use with their healthcare provider. No specific dietary restrictions are required with fluconazole therapy.