Clinical features and basic mechanisms of quinidine-induced arrhythmias.
Quinidine therapy is one of the most common causes of the acquired long QT syndrome and the morphologically distinctive tachyarrhythmia torsade de pointes. Clinical data from our institution and others have revealed a number of characteristic features: quinidine plasma concentrations are generally low, marked QRS prolongation is absent, hypokalemia is frequent and abrupt heart rate slowing just before the initiation of a paroxysm is almost invariable. The lack of correlation between plasma quinidine concentrations and this adverse drug effect raises the possibility either that external factors (for example, hypokalemia) modulate the response to quinidine in vivo or that one or more unmeasured active metabolites play a role. Therefore, the effect of alterations in extracellular potassium and stimulation rate on the electrophysiologic effects of quinidine were examined in canine Purkinje fibers. It was found that a form of triggered automaticity, early afterdepolarizations, is reliably produced in the presence of quinidine when extracellular potassium is lowered and the stimulation rate is slowed. More recently, the effects of a number of quinidine metabolites, as well as the commonly found impurity dihydroquinidine, were characterized in canine Purkinje fibers in a similar fashion. Although quinidine was the most potent of the substances tested, both dihydroquinidine and 3-hydroxyquinidine prolonged action potential and produced early afterdepolarizations as did quinidine at long cycle lengths. Quinidine-induced torsade de pointes is a potentially lethal adverse drug effect, occurring in 1 to 3% of patients. Hypokalemia and slow heart rates are commonly observed in a clinical setting and, in the tissue bath, quinidine and several of its metabolites induce abnormal automatic behavior when extracellular potassium is lowered and stimulation rate is slowed.(ABSTRACT TRUNCATED AT 250 WORDS)
D M
DM
Roden
K A
KA
Thompson
B F
BF
Hoffman
R L
RL
Woosley
D000120:Acecainide / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D011690:Purkinje Fibers / Q000187:drug effects; D011802:Quinidine / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D011817:Rabbits; D013610:Tachycardia / Q000139:chemically induced*; D013997:Time Factors
D000120:Acecainide; D011802:Quinidine