Chemical Structure

Arguably, any drug that shares a structural similarity with prenylamine is a candidate for a thorough preclinical and clinical evaluation of its potential to prolong the QT interval. Not surprisingly, terfenadine, terodiline, cisapride and pimo-zide all bear an obvious structural similarity to prenylamine and have all been associated with QT interval prolongation and torsades de pointes.

Apart from the study by Thomas et al. (1995), other studies have shown that adequate ECG monitoring of the patients during clinical trials ought to have identified the proarrhythmic risk. In the study by Yoshihara et al. (1992) in 109 Japanese patients receiving 24 mg daily of terodi-line for 4 weeks, side-effects such as orthostatic hypotension and arrhythmia were observed but these symptoms disappeared following discontinuation of the treatment. Of note is the prospective study of Stewart et al. (1992) in 8 elderly in-patients treated with terodiline for urinary incontinence. They found a significant increase in the QT interval by a mean of 29 ms, the QTc interval by 15 ms and a decrease in the resting heart rate by a mean of 6.7 beats per minute after 7 days treatment with terodiline 12.5 mg twice daily.

PHARMACODYNAMIC/ PHARMACOKINETIC PROPERTIES KNOWN TO BE ASSOCIATED WITH SUCH ADVERSE EVENTS

In an effort to further characterise the pharma-codynamics of the drug, in vitro studies with isolated tissue preparations are undertaken. In vitro electrophysiological studies should form part of this programme. Interestingly, when investigated in retrospect for their effect on potassium channels, prenylamine, terodiline, ter-fenadine, astemizole, pimozide and cisapride were all found to block these channels. As far as their metabolites are concerned, those of halofantrine and terfenadine are devoid of this activity. However, the desmethyl metabolite of astemizole blocks potassium channels with the same potency as the parent compound but it has a much longer elimination half-life, thereby increasing the risk from accumulation of this metabolite, especially following an overdose. Findings such as these during preclinical studies would require a detailed ECG evaluation of the drug during its clinical development. Among non-cardiovascular agents, such drugs would include all neuroleptics, antidepressants, H1-antihistamines, antimalarials and quinolone anti-bacterials.

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