Clinical pharmacokinetics in heart failure. An updated review

Abstract

Pharmacokinetics is the study of the effect that the body has on drug absorption, distribution, metabolism and excretion. The pharmacokinetics of a specific drug are assessed by the volume of distribution, bioavailability, clearance and elimination half-life. Elimination half-life is directly related to the volume of distribution and inversely related to clearance. Any 1 or more of these parameters may be altered by physiological changes such as ageing, or disease states such as congestive heart failure. Congestive heart failure is associated with hypoperfusion to various organs including the sites of drug clearance, i.e. the liver and kidneys. It also leads to organ congestion as seen in the liver and gut. The main changes in drug pharmacokinetics seen in congestive heart failure are a reduction in the volume of distribution and impairment of clearance. The change in elimination half-life consequently depends on whether both clearance and the apparent volume of distribution change, and the extent of that change. Pharmacokinetic changes are not always predictable in congestive heart failure, but it seems that the net effect of reduction in the volume of distribution and impairment of clearance is that plasma concentrations of drugs are usually higher in patients with congestive heart failure than in healthy subjects. The changes in pharmacokinetics assume importance only in the case of drugs with a narrow therapeutic ratio (e.g. digoxin) and some of the antiarrhythmics such as lignocaine (lidocaine), procainamide and disopyramide. This necessitates reduction in both the loading and maintenance doses. Prolongation of the elimination half-life leads to delay in reaching steady-state, and therefore dose increments must be made more gradually. Plasma concentration measurements of the drugs concerned are a good guide to therapy and help to avoid toxicity. Pharmacokinetic changes are of less importance in the case of drugs with immediate clinical response, e.g. diuretics and intravenous vasodilators such as nitrates and phosphodiesterase inhibitors. The dose in the latter group can be titrated to the desired effect. Not all adverse reactions to drugs that may occur in heart failure are the result of alterations in pharmacokinetics; rather, some may be due to important drug interactions. An interaction may occur directly e.g. reduction of renal clearance of digoxin by captopril and quinidine; or indirectly, e.g. through diuretic-induced hypokalaemia, which exacerbate arrhythmias associated with digoxin and antiarrhythmics such as quinidine and procainamide.