chapter  10
54 Pages

Adverse Effects of Drugs on Electrophysiological Properties of the Heart

ByCynthia A. Carnes, Gary Gintant, Robert Hamlin

The heart possesses at least (i) three electrophysiological properties (chronotropy

or automaticity, dromotropy or conductivity, bathmotropy or irritability) (1,2);

(ii) 9 tissues or electrophysiological phenotypes (atrial myocardium, ventricular

myocardium [epicardial, midmyocardial (“M”), and endocardial tissues]),

His-Purkinje fibers, sinoatrial (SA) node, atrioventricular (AV) node, atrio-AV

nodal junctional fibers, and internodal pathways]; (iii) 15 or more voltage-or

ligand-gated ion channels, pumps, and exchangers (3); and (iv) 6 or more relatively

large signaling molecules [ryanodine, sarco/endoplasmic reticulum Caþþ ATPase

(SERCA), phospholambam, protein kinase A and C, calcineurin, sarcoplasmic

calcium buffers] that may be potential targets for therapeutic or toxic effects of

drugs. Because of the potential subtlety of toxic effects [e.g., small changes in heart

rate, minor lengthening of corrected QT (QTc)], and because they may not be

manifested for years (e.g., doxorubicin,mercury, arsenic), ormay require high doses

or concomitant provocateurs (e.g., hypertrophy, diabetes, heart failure, metabolites,

electrolyte disturbances), it is sometimes difficult to ascertain the potential for

toxicity. Acute toxic cardiovascular effects (as with strychnine or supratherapeutic

concentrations of dofetilide) may be easily identified, but subtle effects [as with

rofecoxib (4)] of arsenic, mercury, lead, phentermine-fenfluramine (5), 5-hydroxy-

tryptamine 2B (5-HT2B) agonists may be difficult to identify, yet result in far greater

morbidity and mortality. Notably, a leading cause of recent removals of drugs from

the market is toxicity due to electrophysiological effects on the heart, specifically

delayed repolarization, and the ventricular arrhythmia, torsades de pointes (TdP)

(6). This chapter will review proarrhythmic electrophysiological actions, provide

examples of how such effects are manifest, and discuss methods of identifying

potential toxic signals (7-14).