The Pharmacokinetics and Pharmacodynamics of Newer Inotropic Agents

Summary

In the past few years an intense effort has been directed toward the development of new inotropic agents for the treatment of chronic cardiac failure. Traditionally, therapy of this disease has included treatment with digitalis glycosides, diuretics, sodium restriction and vasodilators. While digitalis has proven to be an effective inotropic agent, it possesses a low therapeutic index and many patients remain symptomatic or ‘refractory’ despite its inotropic effects. This review focuses on the pharmacokinetics and pharmacodynamics of newer inotropic agents that have been developed or which are currently undergoing investigation.

Amrinone and milrinone are two bipyridine derivatives which have been shown to be effective in the short term treatment of cardiac failure. Milrinone is currently being evaluated for its long term efficacy. The mechanism of action of amrinone and milrinone appears to be unrelated to the cardiac glycosides and sympathomimetic agents, and they are rapidly and well absorbed following oral administration. The bioavailability of milrinone appears to be somewhat reduced in patients with chronic cardiac failure. The distribution of these drugs to extravascular tissues is very rapid; the volume of distribution suggests that they are not extensively bound to tissues. While the volume of distribution of amrinone appears to be unaffected by the presence of heart failure, that of milrinone appears to be somewhat enhanced. The major route of elimination of both drugs appears to be excretion into urine as unchanged drug. A substantial fraction of the amrinone dose, however, undergoes hepatic metabolism to many metabolites, including an N-acetyl derivative. Clearance of amrinone and milrinone is dramatically reduced in patients with chronic cardiac failure compared with normal volunteers, resulting in proportionate increases in the serum half-lives of these drugs. Studies examining the acute and chronic disposition of these agents in cardiac failure patients have not demonstrated changes in their pharmacokinetics secondary to improvements in cardiocirculatory function. Both drugs show strong correlations between mean improvements in haemodynamics and drug serum concentrations, although considerable intrapatient variability may exist. It is currently unclear as to whether the site for the pharmacological action of amrinone is pharmacokinetically distinguishable from plasma.

Enoximone and its sulphoxide metabolite, piroximone, are two compounds currently undergoing investigation for the treatment of chronic cardiac failure. Like the bipyridine derivatives, the mechanism of action of these compounds appears to be unrelated to sodium-potassium ATPase inhibition or sympathomimetic activity. Following oral administration of enoximone a substantial fraction of the dose is converted to piroximone on the first pass through the liver. The volumes of distribution of enoximone and piroximone do not suggest extensive tissue distribution of these drugs. The major pathway for elimination of enoximone is conversion to piroximone with subsequent renal excretion. Discrepancies exist in the literature concerning the half-life of these drugs. This discrepancy may be explained by the existence of terminal phases of disposition which have only recently been recognised. Any relationships between the haemodynamic effects of these drugs and their serum concentrations remain to be determined.

Dobutamine, a synthetic catecholamine, was the first inotropic agent to become available for therapeutic use after the advent of digoxin. The limited data examining dobutamine pharmacokinetics suggest that it possesses an extremely high clearance, a limited volume of distribution, and a very short half-life. Strong relationships exist between changes in mean haemodynamic parameters and mean plasma dobutamine concentrations.

Ibopamine, the 3,4- di-isobutyryl ester derivative of deoxyadrenaline (deoxyepinephrine; epinine) is an orally active, positive inotropic drug with dopaminergic vasodilatory activity. Upon oral administration, deoxyadrenaline exists primarily in the conjugated state in plasma. Elimination of this drug is primarily through metabolism; homovanillic acid is the primary urinary metabolite. The time course of haemodynamic effects of ibopamine greatly exceed the plasma persistence of free deoxyadrenaline. The site of action of ibopamine may be in a physiological compartment which is pharmacokinetically distinguishable from plasma.

The development and investigation of newer inotropic agents in the treatment of chronic cardiac failure is evolving. Many more studies are needed to fully elucidate the pharmacokinetics of these and future compounds, as well as the relationships between the pharmacokinetics of these drugs and their effects in patients.