Preclinical in vitro cardiac electrophysiology - A method of predicting arrhythmogenic potential of antihistamines in humans?

The cardiac action potential results from a dynamic balance between inward depolarising Na+ and Ca2+ currents and outward K+ repolarising currents. Du ring a cardiac cycle, the resultant of repolarisation phase from all ventri cular cells is represented by the QT interval of the surface EGG. Congenita l long QT syndrome (LQTS) is characterised by polymorphic ventricular tachy cardia sometimes with twisting QRS morphology (torsade de pointes) which, a lthough usually self-limiting, can result in sudden cardiac death. Acquired LQTS can be induced by a variety of drugs, including some nonsedat ive histamine H-1 receptor antagonists (astemizole, terfenadine). The Commi ttee for Proprietary Medicinal Products of the European Union has recently proposed studying the action potential in in vitro heart preparations as a preclinical test for predicting the propensity of noncardiovascular drugs t o induce malignant QT prolongation in humans. The effects of several histamine H-1 receptor antagonists on the electrical ly evoked action potential have been evaluated in rabbit Purkinje fibres. I n this preparation, astemizole (0.3 to 10 mu mol/L) prolongs the duration o f the action potential measured at the level where repolarisation is 90% co mplete (APD(90)). This effect is dependent on drug concentration, incubatio n time, pacing frequency and K+ or Mg2+ concentration. Astemizole also mark edly depresses the rate of rise of the action potential (V-max). Terfenadin e showed qualitatively similar, but quantitatively smaller, effects in this model. The histamine H-1 receptor antagonists cetirizine, ebastine, careba stine, loratadine and fexofenadine do not significantly affect APD(90) at 1 mu mol/L, but cetirizine and carebastine prolong it slightly at 10 mu mol/ L. In conclusion, in rabbit Purkinje fibres, astemizole and terfenadine produc e adverse electrophysiological effects at concentrations which may be achie ved in the human myocardium in certain clinical situations. APD(90) lengthe ning induced by carebastine and cetirizine is minor and occurs at concentra tions that are very unlikely to be encountered clinically, since these drug s, in contrast to astemizole and terfenadine, do not accumulate in the myoc ardium. Direct extrapolation of preclinical results to humans requires great cautio n, since malignant QT prolongations by terfenadine and astemizole are extre mely rare clinical events. However, since prolongation of the QT interval o ften precedes the development of torsade de pointes, any significant delay in cardiac repolarisation produced by noncardiovascular drugs in preclinica l, and particularly in clinical, studies should, in general, be considered to indicate a potential cardiac risk in humans. Its significance should sub sequently be evaluated in appropriate studies in patients with conditions k nown to predispose to arrhythmias.