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Mechanism of the cardiotoxic actions of terfenadine
R L Woosley1, Y Chen, J P Freiman
1Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007.
Objectives And Methods:
To gain insight into possible mechanisms of and predisposing factors for torsades de pointes during terfenadine therapy, spontaneous reports in the US Food and Drug Administration's Spontaneous Reporting System database were examined. Based on the characteristics of the cases, in vitro cardiac electrophysiologic studies were conducted to test the hypothesis that terfenadine, and not its major metabolite, has actions similar to those of quinidine and is responsible for this form of cardiac toxicity.
Design:
Spontaneous reports from the general medical community.
Results:
As of April 1, 1992, 25 cases of torsades de pointes had been reported to the Food and Drug Administration's Spontaneous Reporting System. Predisposing factors in these cases indicated that the parent drug, but not its metabolite, may have actions similar those of quinidine that are responsible for inducing arrhythmia. In vitro studies found that terfenadine is equipotent to quinidine as a blocker of the delayed rectifier potassium current in isolated feline myocytes. The metabolite, terfenadine carboxylate, did not inhibit this potassium current even at concentrations 30 times higher than the concentration of terfenadine producing a half-maximal effect.
Conclusions:
Since blockade of the potassium channel did not occur with the major metabolite of terfenadine, episodes of torsades de pointes are most likely the result of a quinidinelike action of the parent drug and of factors that impair the normally rapid metabolism of terfenadine. Dosage restriction and awareness of the clinical conditions and drug interactions capable of inhibiting the metabolism of terfenadine are essential for prevention of this serious reaction.
Insights
Terfenadine, not its metabolite, causes torsades de pointes by blocking potassium channels like quinidine. Awareness of metabolism-inhibiting factors is crucial for preventing this cardiac toxicity.
Area of Science:
- Cardiology
- Pharmacology
- Drug Safety
Background:
- Torsades de pointes is a potentially fatal arrhythmia associated with certain medications.
- Terfenadine, a widely used antihistamine, has been linked to cases of torsades de pointes.
Purpose of the Study:
- To investigate the mechanisms and predisposing factors of terfenadine-induced torsades de pointes.
- To test the hypothesis that terfenadine, rather than its metabolite, exhibits quinidine-like cardiac electrophysiologic effects.
Main Methods:
- Analysis of spontaneous adverse event reports from the FDA's Spontaneous Reporting System.
- In vitro electrophysiologic studies using isolated feline myocytes to assess potassium channel blockade.
Main Results:
- Twenty-five cases of torsades de pointes linked to terfenadine were reported.
- Terfenadine was found to be equipotent to quinidine in blocking the delayed rectifier potassium current.
- The major metabolite, terfenadine carboxylate, did not inhibit potassium current even at high concentrations.
Conclusions:
- Terfenadine's parent drug, not its metabolite, is likely responsible for torsades de pointes via a quinidine-like action.
- Factors impairing terfenadine metabolism contribute to this cardiac toxicity.
- Dosage restriction and awareness of drug interactions are essential for prevention.