Dopexamine Hydrochloride

Summary

Synopsis

Dopexamine hydrochloride is a novel synthetic catecholamine, structurally related to dopamine, with marked intrinsic agonist activity at β₂- adrenoceptors, lesser agonist activity at dopamine DA₁-and DA₂- receptors and β₁- adrenoceptors, and an inhibitory action on the neuronal catecholamine uptake mechanism. The drug is administered by intravenous infusion, and is characterised by a rapid onset and short duration of action. Short term haemodynamic studies in volunteers and patients with severe chronic heart failure have indicated that dopexamine hydrochloride reduces afterload through pronounced arterial vasodilatation, increases renal perfusion by selective renal vasodilatation and evokes mild cardiac stimulation through direct and indirect positive inotropism. Preliminary smallscale noncomparative studies indicate that dopexamine hydrochloride displays beneficial haemodynamic effects in patients with acute heart failure and those requiring haemodynamic support following cardiac surgery, and that these effects are substantially maintained during longer term administration (≤24 hours). Dopexamine hydrochloride appears to be generally well tolerated. Nausea and vomiting are the most frequently reported adverse effects, and respond to dosage reduction. Occasional reports of chest pain/angina pectoris precipitated by tachycardia indicates the need for caution in the use of dopexamine hydrochloride in patients with ischaemic heart disease. Thus, dopexamine hydrochloride may prove to be a useful alternative to dopamine and dobutamine in the treatment of acute heart failure and the postoperative management of low cardiac output states, although controlled studies are required to establish its efficacy and tolerability with respect to that of established therapies.

Pharmacodynamic Studies

Dopexamine hydrochloride displays dopaminergic and β₂-adrenergic agonist activity in isolated cardiac and vascular preparations, and produces a marked inhibition of neuronal catecholamine uptake. In dogs, dopexamine hydrochloride reduced blood pressure and afterload, increased heart rate and improved indices of myocardial contractility. The positive chronotropic and inotropic actions of the drug resulted from indirect β₁-adrenoceptor stimulation, arising from baroreflex activation and inhibition of norepinephrine (noradrenaline) reuptake, and from direct cardiac β₂-adrenoceptor stimulation. Dopexamine hydrochloride increased renal, myocardial and skeletal muscle blood flow. The drug displayed activity against ischaemic arrhythmias in the rat.

In healthy volunteers, short term (≤ 3 hours) intravenous infusion of dopexamine hydrochloride resulted in dose-related increases in cardiac output and heart rate, reductions in renal vascular resistance and minimal changes in blood pressure. In patients with chronic congestive heart failure, dopexamine hydrochloride augmented left ventricular performance, producing a pronounced systemic vasodilatation, positive chronotropy and mild positive inotropy, and minimal changes in cardiac filling pressures and arterial blood pressure. Dopexamine hydrochloride-mediated improvements in isovolumic phase indices of left ventricular contractility were indicative of a direct positive inotropism. Blood flow to the hepatic-splanchnic and renal vascular beds was selectively increased, and accompanied by marginal increases in natriuresis and diuresis. Myocardial oxygen consumption and metabolic function were unaltered by dopexamine hydrochloride, while myocardial efficiency was slightly improved. Plasma norepinephrine levels were either unaffected or increased. Longer term (≤ 72 hours) intravenous infusion of high dose dopexamine hydrochloride was frequently characterised by a rapid and progressive attenuation of the haemodynamic response in patients with chronic congestive heart failure. Direct drug comparisons, performed in patients with chronic congestive heart failure, indicated that the acute haemodynamic effects of dopexamine hydrochloride were similar to those of dobutamine, with both drugs reducing preload and increasing cardiac output through enhanced inotropy and reduced afterload. Dopexamine hydrochloride had a comparable effect to sodium nitroprusside on loading conditions in chronic congestive heart failure, but displayed a more marked inotropic effect coupled with a less pronounced tachycardic action. In patients with left ventricular dysfunction, dopexamine hydrochloride showed greater chronotropism and preload-reducing properties than dopamine.

Pharmacokinetic Studies

There is little published information on the pharmacokinetic properties of dopexamine hydrochloride in animals or humans. Dose titration of dopexamine hydrochloride 1 to 4 μg/kg/min resulted in proportional increases in plasma drug concentrations in volunteers, with a peak of 124 mg/L after 1 hour. On termination of infusion, plasma drug concentrations declined rapidly and monoexponentially with an elimination half-life of 7 minutes (vs 11 minutes in patients with low cardiac output) and a plasma clearance of 36 ml/min/kg (vs 17 ml/min/kg in patients following cardiac surgery). Tissue distribution of dopexamine hydrochloride was extensive, with the drug acting as a substrate for the extraneuronal catecholamine uptake mechanism (Uptake₂). Dopexamine hydrochloride was extensively metabolised by O-methylation and subsequent sulphate conjugation to yield 2 major products which were excreted with the parent drug in the urine and faeces. Urinary excretion was biphasic with a terminal half-life of 4 days; the 2-methoxy, 1-sulphate metabolite accounted for more than 90% of the excreted drug recovered from the urine. Over 12 days after administration, the urinary and faecal routes accounted for the elimination of more than 50% and 20%, respectively, of the original dose.

Therapeutic Trials

Noncomparative dose-titration studies indicated that intravenous infusions of dopexamine hydrochloride 0.5 to 6.0 μg/kg/min produced a beneficial systemic and renal vasodilatation, in conjunction with enhanced diuresis and improvements in indices of myocardial function, in patients with acute heart failure. In contrast to its action in patients with chronic heart failure, dopexamine hydrochloride lacked significant preloadreducing properties in those with acute heart failure. Long term (24 hours) intravenous infusion of dopexamine hydrochloride in patients with acute heart failure following myocardial infarction was associated with sustained haemodynamic improvements, with no evidence of appreciable tolerance to the haemodynamic effects.

Noncomparative dose-titration studies in patients with compromised left ventricular function subsequent to cardiac surgery reported that intravenous infusions of dopexamine hydrochloride 1.0 to 10.0 μg/kg/min produced dose-related increases in cardiac output and heart rate, reductions in afterload, but no changes in preload. These haemodynamic effects were associated with a tendency towards increased diuresis.

Adverse Effects

Dopexamine hydrochloride was well tolerated during short and extended term (≤ 72 hours) intravenous infusion at doses of 0.5 to 10.0 μg/kg/min. Nausea, vomiting, tachycardia, chest pain/angina pectoris, ventricular ectopy and tremor (which occurred in 2% to 5% of patients) accounted for the majority of reported adverse effects and responded rapidly to dose reduction or infusion termination. However, chest pain/angina pectoris precipitated by tachycardia have been chiefly encountered in patients with pre-existing ischaemic heart disease. In most patients, the dopexamine hydrochloride-induced tachycardia is within limits of clinical acceptability and there is no evidence of significant arrhythmogenic potential. Reversible reductions in neutrophil and platelet counts have been recorded in healthy subjects receiving short term intravenous infusions of dopexamine hydrochloride 1 to 4 μg/kg/min. There have been no reports of biochemical abnormalities following administration of the drug to normoglycaemic patients.

Dosage and Administration

For the treatment of acute heart failure and haemodynamic support in patients following cardiac surgery, dopexamine hydrochloride should be infused intravenously at an initial dose of 0.5 μg/kg/min and then titrated upwards in dosage increments of 1.0 μg/ kg/min, in accordance with haemodynamic response, to a maximum of 6.0 μg/kg/min. The use of dopexamine hydrochloride is contraindicated in patients with thrombocytopenia. Caution is advised in the case of patients with hyperglycaemia and hypokalaemia in view of the drug’s β-adrenergic action.