Arrhythmogenic actions of antiarrhythmic drugs.
Cardiac arrhythmias may result from abnormalities of impulse propagation or abnormalities of impulse initiation. When arrhythmias are initiated by antiarrhythmic drugs, the most common mechanisms appear to be conduction block or reentry, and abnormal impulse initiation, which may be triggered by afterdepolarizations. The effects of drugs on conduction may result from their actions on the fast sodium channel, the slow calcium channel or their ability to prolong repolarization. The extent to which a drug that depresses fast sodium or slow calcium entry will exert its toxic effects depends in large part on its binding characteristics to its channel receptor site. Such toxicity represents a continuum for the therapeutic effects of these drugs. The factors that control drug access to binding sites, including lipid solubility, molecular size and extent of ionization, are reviewed, as are the contributions to conduction abnormalities of drug-induced changes in repolarization. The mechanisms whereby drugs induce abnormalities of impulse initiation are still a matter of conjecture. Apparently, drugs that increase inward plateau currents or decrease repolarizing potassium ion currents carry increased risk. Moreover, there is evidence for the role of early after depolarizations occurring secondary to prolonged repolarization as a possible cause of arrhythmias, including torsades de pointes. The mechanisms whereby antiarrhythmic drugs may contribute to this type of tachyarrhythmia are reviewed.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects; D011955:Receptors, Drug / Q000187:drug effects; D012964:Sodium / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D007473:Ion Channels; D011955:Receptors, Drug; D012964:Sodium