Effects of congestive heart failure on the pharmacokinetics and pharmacodynamics of antiarrhythmic agents.

Changes in the pharmacokinetics of antiarrhythmic agents should be expected in patients with congestive heart failure (CHF). The direction of the changes, however, is not always predictable. The volume of distribution is often decreased by as much as 40%, and loading doses should, therefore, be appropriately reduced. Drug clearance may also be diminished due to decreased blood flow to the liver and kidneys, as well as decreased hepatic drug-metabolizing activity. Infusion rates should similarly be lowered to avoid toxicity. However, decreases in both volume of distribution and clearance may result in little, if any, change in elimination half-life, despite higher plasma concentrations. On the other hand, the elimination half-life of antiarrhythmic agents that have a large volume of distribution and are highly cleared by the liver may be twice as long in patients with CHF compared with normal subjects. Thus, the total daily dose of drug should also be lower in these patients. In addition, the time necessary to reach steady state is longer, so that premature dose escalation may lead to excessive drug accumulation. In terms of their pharmacodynamic effects, all antiarrhythmic agents have the potential to manifest a degree of negative inotropy, which must be anticipated as a possible side effect in patients with CHF. Some of the newer agents, such as tocainide and encainide, appear to cause only minimal myocardial depression. Other potential complications of all antiarrhythmic therapy include proarrhythmia and possible drug interactions with digitalis and diuretics.