Pirmenol, a novel pyridinemethanol derivative, is active in a variety of experimental arrhythmic models of diverse etiology. Animal pharmacology studies showed that
pirmenol is highly efficacious whether the arrhythmias were atrial or ventricular in origin; chemically, mechanically, or electrically induced; or of the automaticity or reentrant types. The conscious coronary artery-ligated (Harris) dog model best allowed simulation of a variety of clinical situations in which
pirmenol could be used either alone or in combination.
Pirmenol was highly effective by both the intravenous and oral routes, causing immediate suppression, prevention, or termination of
cardiac arrhythmias. Preclinical studies in the dog showed an excellent correlation between the dose of
pirmenol, plasma levels, and antiarrhythmic efficacy. Administration of
pirmenol in the dog at intentionally accelerated infusion rates suggested a relatively wide margin of safety for
pirmenol compared with other class I agents. In vitro electrophysiologic studies in dog Purkinje fibers revealed possibly unique differences of
pirmenol from other antiarrhythmic agents. It depresses fast and slow response automaticity and its electrophysiologic effects were less variable than other class I drugs over a spectrum of
potassium levels. To test the relevance of the in vitro electrophysiologic results,
pirmenol's antiarrhythmic efficacy was assessed in several in vivo dog models in which serum
potassium was either increased or decreased. Studies comparing
pirmenol and
disopyramide clearly showed a relative lack of serum
potassium dependence for
pirmenol, suggesting a potential clinical advantage over
disopyramide and other antiarrhythmics in variable
potassium settings. The clinical relevance of these observations will have to be established in patients with variable
potassium levels. Overall,
pirmenol compared favorably with other reference agents in efficacy and safety in extensive preclinical investigations.