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A pharmacological comparison of methanesulfonamide class III antiarrhythmic agents in various species

University of British Columbia

In the search for new and more effective antiarrhythmic agents a great deal of effort has been expended on the development of new Class III drugs. This class of antiarrhythmics act by prolonging action potential duration and thereby increasing refractoriness. For most of these new Class III drugs the mechanism by which they produce their effects on action potential duration is blockade of one or more cardiac potassium channels. A large number of potassium channels have been described with at least six different types occurring in cardiac tissue. The full pharmacological profile of new class III drugs has not been investigated since they have only recently been developed. We therefore considered it appropriate to compare the pharmacological actions of three sotalol derivatives (sematilide, ibutilide, and E4031) and a structurally dissimilar compound (almokalant), in a number of species, using a variety of cardiovascular models. Each of the chosen drugs was administered over a wide range of doses (except almokalant) in order to fully explore their pharmacological actions. The species used included primates, guinea pigs and rats. Most of the studies were performed in intact animals in which blood pressure, heart rate, and E C G responses were recorded together with electrical stimulation of the left ventricle and, in some cases, recording of monophasic action potentials. In addition an in vitro preparation of guinea pig vas deferens was studied as being representative of nerve/smooth muscle preparations. At low doses the responses expected of blockers of the cardiac delayed rectifier potassium current were observed in all species excluding rats. There was a selective dose-dependent widening of the Q-Tc interval of the E CG and increased refractoriness in species with delayed rectifier currents in their ventricles (primates & guinea pigs). In the rat, a species which lacks a delayed rectifier current, no such effects were observed. The profile of action of low doses of such drugs was best exemplified by sematilide and almokalant in baboons. Sematilide and almokalant produced a dose-related widening of the monophasic action potential (MAP), as recorded from the right ventricle, and this correlated with widening of the Q-Tc interval and increased refractoriness. Furthermore, such effects were dependent upon heart rate such that at higher heart rates effects on action potential duration were less ("negative frequency dependence"). Ibutilide and E4031 had similar cardiovascular profiles. Results in primates were then compared with those obtained in guinea pigs using a wide range of doses, from low to very high. Similar studies were also performed in the rat. In the guinea pig, at low doses, the pattern of E CG and cardiovascular changes were similar to those seen in primates. However, at higher doses signs of possible sodium channel blockade were seen in terms of ECG changes and responses to electrical stimulation. Signs of sodium channel blockade were seen in rats and these occurred only after very high doses. In none of the tests was ibutilide different from E 4031. This was somewhat unexpected in view of the fact that the actions of ibutilide may not be due to blockade of the delayed rectifier, but to activation of an inward sodium current. Thus, in terms of cardiovascular actions in intact animals, the class III drugs tested were very similar to each other. In addition to in vivo studies, the effects of the drugs on a field stimulated vas deferens preparation from guinea pigs were studied. The pattern of response of the vas deferens was similar in the presence of ibutilide and E4031. Both ibutilide and E4031 produced bell shaped concentration response curves, enhancing the field stimulation induced contractions at low concentrations but inhibiting them at higher concentrations. In conclusion, the above studies helped establish the pharmacological profile of a group of new Class III antiarrhythmics. The drugs were remarkably similar to each other, even in terms of the possible sodium channel blocking actions at high doses and were very potent in producing QTc widening in species other than the rat. In terms of in vitro effects ibutilide and E4031 had very similar actions.

Thesis/Dissertation

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2009-01-14

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http://hdl.handle.net/2429/3650

Pharmaceutical Sciences

University of British Columbia

UBCV

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