Ibopamine: A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use in Congestive Heart Failure

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Abstract

Synopsis

Ibopamine is an orally administered dopamine agonist which is rapidly converted to its active metabolite epinine by esterase hydrolysis. Ibopamine acts predominantly as a vasodilator and inhibitor of neuroendocrine activation in congestive heart failure, but also has mild positive inotropic effects at higher doses. The beneficial effects on cardiac and systemic haemodynamic parameters seen in short term studies have been maintained in predominantly noncomparative trials for up to 1 year, and improvements in New York Heart Association (NYHA) functional class and clinical symptoms have been observed in patients with congestive heart failure of varying severity. In double-blind studies conducted in small numbers of patients, the efficacy of ibopamine was comparable to that of digoxin, captopril, enalapril and hydrochlorothiazide. Ibopamine can successfully replace treatment with intravenous dopamine in patients with severe heart failure, and is effective and well tolerated when administered in combination with digoxin, diuretics and/or angiotensin converting enzyme (ACE) inhibitors.

Synopsis

Ibopamine has shown no detrimental effects on renal function, few adverse effects on neurohormonal parameters and has demonstrated no significant proarrhythmic properties at therapeutic doses in patients with congestive heart failure. No adverse metabolic effects were observed during ibopamine therapy in patients with diabetes mellitus, nor did ibopamine have detrimental effects in patients with chronic obstructive pulmonary disease.

Synopsis

While reliable evidence is required concerning effects on mortality before the role of ibopamine can be clearly defined, the drug appears to be a useful agent for combination with conventional therapies in treating patients with mild to severe congestive heart failure.

Pharmacological Properties

Oral ibopamine 100 to 200mg has haemodynamic effects comparable to those of intravenous dopamine 2 to 6 μg/kg/min. Ibopamine exhibits vasodilatory properties in animal models, healthy volunteers and patients with congestive heart failure, and this vasodilatory action appears to affect resistance rather than capacitance vessels. Ibopamine also has mild positive inotropic activity, although this is thought to be negligible at therapeutic doses of the drug. At rest, cardiac and stroke volume indices are increased by 11 to 38%, and systemic vascular resistance is generally reduced by 14 to 40% in patients with congestive heart failure. Ibopamine also improves systolic function, ejection fraction and myocardial relaxation, and reduces left ventricular end-systolic volume and associated wall stress in these patients. Similar changes are observed during exercise. Blood pressure and heart rate are not usually affected by administration of ibopamine. Although pulmonary capillary pressure, right atrial pressure and pulmonary vascular resistance decreased significantly in most studies, transient increases in right atrial pressure and pulmonary capillary wedge pressure have occasionally been reported 15 to 30 minutes after administration of ibopamine. These increased levels then returned to, or decreased below, baseline within about 60 minutes. The haemodynamic effects of ibopamine are evident 30 minutes after oral administration and are maintained for 4 to 8 hours, although maximal effects are seen after 1 to 2 hours.

Pharmacological Properties

During 24- and 48-hour Holter monitoring, ibopamine had no proarrhythmic activity, although potential arrhythmogenicity has been reported in some patients. Ibopamine has variable effects on renal function. It significantly increased diuresis in most studies in healthy volunteers and patients with congestive heart failure, although other studies showed no significant changes in this parameter. Plasma renin activity and plasma aldosterone levels decreased significantly when elevated at baseline, and tended to remain unaltered if normal at baseline, after administration of ibopamine as a single dose of 50 to 200mg, or as 100mg 3 times daily. Comparable doses of ibopamine also decreased plasma noradrenaline (norepinephrine) levels by 9 to 40%, and in some instances these changes were accompanied by reductions in plasma adrenaline (epinephrine) and dopamine levels.

Pharmacological Properties

Ibopamine is extensively absorbed following oral administration. It is completely hydrolysed to its active metabolite epinine by intestinal, hepatic and plasma esterases, with a reported hydrolysis half-life in plasma of less than 60 seconds. Epinine is excreted predominantly through the kidneys after sulphate conjugation or oxidation. Repeated oral administration does not alter the bioavailability or plasma pharmacokinetics of ibopamine, and saturation of the enzymes involved in ibopamine metabolism does not occur. The pharmacokinetics of ibopamine appear to be independent of New York Heart Association (NYHA) class, but the apparent plasma half-life, maximum plasma concentration and area under the plasma concentration-time curve of total (free plus sulpho-conjugated) epinine are directly correlated with serum creatinine levels and patient age. These pharmacokinetic parameters are therefore increased in the elderly, in patients with renal impairment and, in addition, in patients with hepatic cirrhosis compared with healthy individuals. However, in patients with chronic renal impairment, the pharmacokinetic profile of free epinine does not vary with the severity of impairment.

Therapeutic Efficacy

Although ibopamine has not generally been exclusively studied in the elderly, most trials assessing ibopamine in the treatment of congestive heart failure have included a large proportion of elderly patients. In noncomparative and comparative studies of 10 days' to 12 months' duration, ibopamine maintained the haemodynamic, renal and neurohormonal improvements established in single-dose studies without significantly affecting heart rate or blood pressure, with improvements noted in NYHA functional class, symptom scores and exercise duration. In addition, diuretic requirements were lower in patients who received ibopamine than in those treated with placebo. In general, ibopamine did not display proarrhythmic effects.

Therapeutic Efficacy

Double-blind comparative trials conducted in predominantly small numbers of patients with heart failure (NYHA classes I to IV) indicate that the efficacy of ibopamine is comparable to that of digoxin, captopril, enalapril and hydrochlorothiazide. However, combination therapy with ibopamine and captopril, enalapril or hydrochlorothiazide in patients with moderate to severe disease is more efficacious than monotherapy with any of these agents. Oral ibopamine has successfully replaced intravenous dopamine in the treatment of patients with severe heart failure, and is also useful in combination with conventional digitalis, diuretic and vasodilator therapy in patients with varying degrees of congestive heart failure.

Therapeutic Efficacy

No trials specifically evaluating the effects of ibopamine on survival have been completed. However, mortality tended to be lower, while the risk of developing symptoms of worsening heart failure was significantly reduced, in patients who received ibopamine compared with digoxin for up to 1 year in a nonblinded postmarketing study including 3330 predominantly elderly patients.

Tolerability

Serious adverse effects have rarely been reported in clinical trials during short and long term administration of ibopamine in patients with congestive heart failure, including the elderly. Gastrointestinal and cardiovascular effects accounted for the majority of events reported, most of which were mild in nature. The tolerability of ibopamine was similar to that of placebo, and that of other drugs commonly used in congestive heart failure when used at doses of comparable efficacy. Although most studies have shown ibopamine to have no significant proarrhythmic effect, caution should be exercised in patients with pre-existing severe ventricular arrhythmias since exacerbation may occur.

Tolerability

Ibopamine did not adversely affect metabolic control in patients with diabetes mellitus and had no detrimental effects in patients with chronic obstructive pulmonary disease and concomitant congestive heart failure. Significant attenuation of symptom severity and improvement in NYHA class was observed in patients with congestive heart failure and chronic cor pulmonale. In patients with impaired renal function, ibopamine increased diuresis and renal blood flow.

Dosage and Administration

Oral ibopamine 100mg 3 times daily is the recommended starting dosage for the treatment of congestive heart failure. This is then titrated for maximal beneficial effect. The lowest recommended dosage should be used initially in the elderly.

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