title: Mexiletine's antifibrillatory actions are limited by the occurrence of convulsions in conscious animals.
abstract: The antiarrhythmic actions of the racemate and enantiomers of mexiletine were studied in conscious and anaesthetised rats. Racemate or enantiomers, at 20 mg/kg i.v., had little effect on ischaemia-induced ventricular fibrillation in conscious or anaesthetised rats. In conscious rats 20 mg/kg caused convulsions in 78-89% of rats when the plasma concentration of racemate was 20 +/- 2 microM. In anaesthetized animals a higher dose (40 mg/kg) of racemate could be given; this completely prevented ischaemia-induced fibrillation when the plasma concentration was 26 +/- 2 microM. Racemate and enantiomers accumulated in the heart and brain of conscious animals to give tissue: plasma ratios of 7.5 and 23, respectively. With electrical stimulation, both racemate and enantiomers dose dependently (4-32 mg/kg) increased threshold currents for induction of ventricular fibrillation, increased refractory period and minimally changed the ECG; findings expected with a Class Ib antiarrhythmic. The above studies failed to show major differences between racemate or enantiomers except for consistently lower (20-30%) plasma concentrations of R(-) at all dose levels. In conclusion, mexiletine prevented ischaemia-induced ventricular fibrillation in anaesthetised animals but only when given at doses producing convulsions in conscious animals.
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: L N
authors.initials: LN
authors.lastname: Igwemezie
authors.forename: G N
authors.initials: GN
authors.lastname: Beatch
authors.forename: K M
authors.initials: KM
authors.lastname: McErlane
authors.forename: M J
authors.initials: MJ
authors.lastname: Walker
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008801:Mexiletine / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced*; D013237:Stereoisomerism; D014693:Ventricular Fibrillation / Q000517:prevention & control*
chemical_list: D008801:Mexiletine