Pimobendan

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Abstract
Pimobendan is a novel cardiotonic vasodilator (inodilator) which derives its inotropic activity from a combination of phosphodiesterase III inhibition and sensitisation of myocardial contractile proteins to calcium. The acute haemodynamic benefits of pimobendan (2.5 to 10mg orally; 5 to 10mg intravenously) seen in patients maintained on conventional diuretic, digitalis and vasodilator therapy for chronic heart failure (increases in cardiac output and stroke volume, and reductions in left ventricular preload and afterload) persisted on short term (1 month) therapy, and showed only limited evidence of attenuation on longer term (6 months) oral therapy with pimobendan 2.5 or 5mg twice daily. Adjunctive therapy with pimobendan 1.25 to 5mg twice daily for periods of 3 to 6 months improved exercise tolerance on symptom-limited exercise testing, New York Heart Association (NYHA) functional class, and quality of life, and additionally reduced the need for hospitalisation in patients with moderate to severe chronic heart failure. Pimobendan appears to be well tolerated at therapeutic doses (1.25 to 5mg twice daily) in patients with chronic heart failure, and preliminary indications suggest that it is largely devoid of the proarrhythmic effects of classical phosphodiesterase III inhibitors. Although information regarding the long term effects of pimobendan on mortality is currently lacking, the drug nevertheless shows potential benefit as an adjunctive therapy in patients with chronic heart failure. Pimobendan exhibits combined inotropic and peripheral vasodilator (inodilator) properties, which are attributable to selective inhibition of phosphodiesterase III (inotropic and vasodilator effects) and sensitisation of cardiac myofilaments to intracellular calcium (inotropic effect). Despite similar degrees of phosphodiesterase III inhibition with pimobendan in ventricular myocardium from failing and nonfailing human heart [concentration reducing basal activity to 50% (IC50) ≈ 0.7 μmol/L], the in vitro inotropic response to the drug was less pronounced in tissue from failing heart. In contrast, papillary muscle fibres from failing human myocardium were more sensitive to the calcium-sensitising effect of pimobendan (100 to 300 μmol/L) than those from normal myocardium. The blunted inotropic action of pimobendan in the failing heart has been linked with attenuated adenylate cyclase activity and reduced cyclic adenosine monophosphate (cAMP) formation. Although the metabolite UD-CG 212 is more potent than pimobendan as a phosphodiesterase III inhibitor and as an inotrope in vitro, results from one animal model suggest that UD-CG 212 makes only a minor contribution to the cardiovascular effects of pimobendan in vivo. In various intact animal models, pimobendan and UD-CG 212 dilated the arterial and venous vasculature and produced positive inotropic and chronotropic effects. Venodilation appeared to be the predominant vascular effect of low dose intravenous pimobendan (≤ 0.3 mg/kg) and UD-CG 212 (≤0.03 mg/kg), with arterial vasodilatation and positive inotropy more prominent at higher doses. Regional vasodilatation was most pronounced in the splanchnic circulation, myocardium and brain following intravenous administration of pimobendan (0.1 to 1.0 mg/kg) and UD-CG 212 (0.03 to 0.24 mg/kg) to the anaesthetised pig. Pimobendan, in contrast to UD-CG 212, directly increased total coronary, epicardial and endocardial blood flow. While pimobendan prolonged action potential duration in vitro, it shortened ventricular refractoriness in vivo, and lacked antiarrhythmic activity in a canine postmyocardial infarction model of sudden cardiac death. Instead, pimobendan (0.3 mg/kg intravenously) increased the incidence of ischaemic ventricular fibrillation in this model and tended to increase 24-hour mortality after recent myocardial ischaemia. Oral administration of pimobendan 2.5 to 10mg produced sustained (≈ 9 hours) increases in cardiac output and stroke volume, and reductions in left ventricular preload and afterload on acute administration in patients maintained on conventional digitalis, diuretic and vasodilator therapy for moderate to severe congestive heart failure. The drug additionally showed direct inotropic and lusitropic properties. Pimobendan 5mg orally did not significantly affect myocardial oxygen consumption in patients with ischaemic cardiomyopathy, but on intravenous infusion (1.25 mg/hour) improved the myocardial oxygen supply/demand ratio in patients with moderate heart failure and idiopathic cardiomyopathy. Haemodynamic responses correlated more closely with plasma concentrations of UD-CG 212 than pimobendan following single dose administration; at steady-state, haemodynamic changes showed no obvious correlation with plasma pimobendan or UD-CG 212 concentrations. The haemodynamic benefits of pimobendan 2.5 or 5mg twice daily were largely maintained on short term (4 weeks) and longer term (6 months) therapy in patients with moderate to severe chronic congestive heart failure. Long term (6 months) therapy with pimobendan 5mg twice daily did not significantly affect plasma noradrenaline (norepinephrine) levels or renin activity in patients with moderate congestive heart failure. Pimobendan is well absorbed following oral administration, with a bioavailability of ≈ 70% in healthy young volunteers. The pharmacokinetic properties of the drug are linear over intravenous and oral dose ranges of 2.5 to 5mg and 1.25 to 10mg, respectively. Mean peak plasma concentrations of pimobendan and UD-CG 212 of 16 and 13 μg/L, respectively, occurred at 1.6 and 2.8 hours, respectively, following a single oral dose of pimobendan 2.5mg in patients with chronic heart failure. No evidence of pimobendan or UD-CG 212 accumulation was seen in patients with heart failure receiving maintenance therapy with pimobendan 5mg twice daily. Pimobendan undergoes hepatic metabolism to the active O-demethyl metabolite UD-CG 212. Following oral administration of radiolabelled pimobendan, 74% of total radioactivity was excreted in the faeces and 17% in the urine over an unspecified period, predominantly as glucuronides of pimobendan and UD-CG 212. The mean plasma elimination half-life of pimobendan ranged from 0.7 to 1.9 hours in healthy volunteers and patients with heart failure, while that of UD-CG 212 was 3.1 to 3.8 hours. Pimobendan absorption and elimination following a single oral dose (2.5mg) were comparable in healthy young (19 to 30 years) and elderly (67 to 84 years) volunteers. Similarly, plasma concentration-time profiles of pimobendan and UD-CG 212 after single intravenous doses of pimobendan 2.5 and 5mg were comparable in healthy young volunteers and patients with severe renal impairment. In patients receiving conventional diuretic, inotropic and vasodilator therapy for moderate to severe chronic heart failure, adjunctive therapy with pimobendan 1.25 to 5mg twice daily for ≤ 6 months significantly increased exercise duration (14 to 35%) during symptom-limited exercise testing. Pimobendan has shown limited effect on New York Heart Association (NYHA) functional status when the latter has been employed as a therapeutic end-point in heart failure. In patients receiving diuretics for moderate congestive heart failure, adjunctive therapy with pimobendan 5mg twice daily (titrated to 2.5 to 10mg twice daily after 1 month) for 6 months produced an improvement in mean NYHA class (from 2.51 to 2.13) comparable to that seen with enalapril 10 mg/day. Similarly, improvement in NYHA functional class occurred in a significantly higher proportion of patients with chronic heart failure receiving adjunctive treatment with pimobendan 2.5mg twice daily for 2 months than with placebo (64 vs 35%). A reduction in hospitalisation rate and an improvement in quality of life, indicated by significant increases (vs placebo) in Minnesota Living with Heart Failure Questionnaire total score and physical dimension (dyspnoea and fatigue) subscore, as well as Specific Activity Scale score, occurred after 3 to 6 months’ adjunctive therapy with pimobendan 1.25 to 5mg twice daily in patients with moderate to severe chronic congestive heart failure. Pimobendan-associated improvements in exercise tolerance duration and peak oxygen consumption were only weakly correlated with the improvement in quality of life. Preliminary indications suggest a possible role for adjunctive pimobendan therapy (≤ 5mg twice daily) in improving the quality of life in severely symptomatic patients with intractable congestive heart failure. At therapeutic oral dosages of 1.25 to 5mg twice daily, administered for periods of up to 6 months, pimobendan has been well tolerated in small groups of patients with chronic heart failure. Treatment withdrawal due to adverse events was not significantly more frequent with pimobendan 2.5 to 10 mg/day (9%) than with placebo (4%) over a 3-month treatment period. Headache (occurring in 8 to 33% of patients) was the only dose-related adverse effect of pimobedan 1.25 to 5mg twice daily in patients with moderate to severe heart failure. Anginal symptoms or evidence of myocardial ischaemia were absent after oral administration of pimobendan 5mg to patients with ischaemic cardiomyopathy. Ventricular tachycardia and/or ventricular fibrillation occurred with equal frequency (≈ 2%) in pimobendan- and placebo-treated patients with chronic heart failure, while ventricular ectopy was variously unaltered or increased by pimobendan. In contrast to the adverse findings with classical phosphodiesterase inhibitors, preliminary data do not indicate any obvious detrimental effect of pimobendan on patient survival: the incidence of sudden cardiac death over a 6-month period in patients receiving oral pimobendan 2.5 or 5mg twice daily for moderate to severe heart failure (7%) was comparable to that in placebo recipients (9%). Dose-finding studies suggest that an oral dosage of pimobendan 2.5mg twice daily is well tolerated and confers maximal therapeutic efficacy in adjunctive treatment of chronic heart failure. Caution is advised in the use of the drug in elderly patients at risk of hypotension. Dosage adjustment for renal impairment appears unwarranted. However, in view of the large intersubject variation in the bioavailability of the drug, pimobendan dosage may need to be titrated to individual response.
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