| Summary: | Sudden cardiac death due to ischaemia-induced ventricular arrhythmias is
the leading cause of death worldwide. Today, we have not yet developed a drug
that is ideal in suppressing ischaemia-induced arrhythmias. The best drug used
clinically is amiodarone. This is an antiarrhythmic with class I, II, III, and IV
activities. This multi-antiarrhythmic activity of amiodarone makes this drug
pharmacologically complex. However, it also suggests that drug combinations
could produce a better antiarrhythmic than single drugs. Researchers have used
this hypothesis to study different drug mixtures such as quinidine plus mexiletine.
Duff et al. (1986 and 1990), have suggested possible synergistic interaction
between quinidine (a class la) and mexiletine (a class lb) drug. However, other
researchers, including Nortran Pharmaceuticals (in Vancouver) are trying to
develop new antiarrhythmics which have both class lb and class III activity. Their
proposal is based on the prediction of the modulated receptor hypothesis which
states that combinations of class lb and class III drugs could act synergistically to
produce a better antiarrhythmic protection than either drug alone. This is based
on the possibility that a greater prolongation of the effective refractory period can
be produced when an action potential prolonging drug (ie, class III) and an
inactive-state sodium channel blocker (ie, class lb) are mixed. Mixture of class lb
plus class III could provide a better antiarrhythmic than class la plus class lb
because a class III drug can produce a greater prolongation of the action
potential duration, thus allowing for a greater block of inactive-state sodium
channels by class lb drug.
In the present study, we chose tedisamil (a class III agent) and lidocaine
(a class lb agent) to study the mechanistic interaction between a class III and lb
drug which have been shown by Nortran Pharmaceuticals to have superior
antiarrhythmic protection compared to each drug alone.
Rat models were used to induce ischaemia-induced arrhythmias by
occlusion of their left main coronary artery. Tedisamil alone, lidocaine alone, and
various combinations of tedisamil and lidocaine were studied for their
electrophysiological and antiarrhythmic effects.
The results support a possible synergistic interaction between tedisamil
and lidocaine. This is because tedisamil produced a leftward shift in the
antiarrhythmic dose-response curve of lidocaine alone, and vice-versa. As well,
the isobologram showed that the combination of tedisamil and lidocaine
produced an ED₅₀ antiarrhythmic isobologram which lay below the line of
additivity. Although this was not statistically significant, it still suggests that
tedisamil and lidocaine have at least an additive interaction, and possibly a
synergistic interaction. Interestingly, 2 μmole/kg/min tedisamil plus 2
μmole/kg/min lidocaine produced the best antiarrhythmic protection because the
antiarrhythmic ED5 0 was furthest below the line of additivity in the isobologram.
This combination synergistically reduced the arrhythmia score and ventricular
tachycardia, as well as completely abolishing ventricular fibrillation.
In summary, this thesis supports the prediction of modulated receptor
hypothesis that class lb plus class III combination can produce a better
antiarrhythmic protection than either drug alone. === Medicine, Faculty of === Anesthesiology, Pharmacology and Therapeutics, Department of === Graduate
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