Pharmacokinetics and pharmacodynamics of antiarrhythmic agents in patients with congestive heart failure.

Changes in the pharmacokinetics of antiarrhythmic agents may be anticipated in patients with congestive heart failure (CHF), although the magnitude or direction of change is not always predictable. Factors complicating antiarrhythmic therapy in patients with CHF include both physiologic changes resulting from the disease state and unwanted effects of drug therapy for CHF. The volume of distribution is often significantly decreased (by as much as 50%) and loading doses should be reduced proportionately. Decreased blood flow to the liver and kidneys and decreased hepatic drug-metabolizing activity serve to diminish drug clearance. In some cases, simultaneous decreases in volume of distribution and clearance may result in little, if any, change in elimination half-life, despite higher plasma concentrations. Conversely, the elimination half-life of antiarrhythmic agents may be doubled in patients with CHF, necessitating a reduction in dosage. In the latter case, the time needed to reach steady state is lengthened, so that premature escalation of dosage may lead to excessive drug accumulation. In terms of their pharmacodynamics, most antiarrhythmic agents have a degree of negative inotropic effect at some concentration, and patients with reduced myocardial reserve are especially vulnerable to these effects. Some of the newer agents (such as tocainide, mexiletine, and encainide) appear to cause only minimal myocardial depression. Potential complications during therapy with all antiarrhythmic agents that are of special concern in patients with CHF include diuretic-induced hypokalemia, proarrhythmia, and possible interactions with cardiac glycosides and other drugs. Therapy for patients with CHF should be initiated with low doses of the agent selected, and the dosage carefully titrated while the patient is monitored, to confirm both efficacy and the absence of adverse effects. During subsequent outpatient therapy the patient should be carefully observed for sign of unexpected reactions, toxicity, or electrolyte imbalance.