K+ channel structure-activity relationships and mechanisms of drug-induced QT prolongation

Pharmacological intervention, often for the purpose of treating syndromes unrelated to cardiac disease, can increase the vulnerability of some patients to life-threatening rhythm disturbances. This may be due to an underlying propensity sternming from genetic defects or polymorphisms, or structural abnormalities that provide a substrate allowing for the initiation of arrhythmic triggers. A number of pharmacological agents that have proven useful in the treatment of allergic reactions, gastrointestinal disorders, and psychotic disorders, among others, have been shown to reduce repolarizing K+ currents and prolong the QT interval on the electrocardiogram. Understanding the structural determinants of K+ channel blockade may provide new insights into the mechanism and rate-dependent effects of drugs on cellular physiology. Drug-induced disruption of cellular repolarization underlies electrocardiographic abnormalities that are diagnostic indicators of arrhythmia susceptibility.