Carvedilol

Abstract

Carvedilol competitively blocks β¹, β² and α₁ receptors. The drug lacks sympathomimetic activity and has vasodilating properties that are exerted primarily through α₁-blockade. Animal models indicate that carvedilol confers protection against myocardial necrosis, arrhythmia and cell damage caused by oxidising free radicals, and the drug has no adverse effects on plasma lipid profiles. Recent data have confirmed the antihypertensive efficacy of carvedilol in patients with mild to moderate essential hypertension. Carvedilol has similar efficacy to other β-blocking agents, calcium antagonists, ACE inhibitors and hydrochlorothiazide. Carvedilol also improves exercise tolerance and ischaemic symptoms in patients with stable angina pectoris. Significant reductions in serious cardiac events after acute myocardial infarction and in frequency and severity of ischaemic events in patients with unstable angina have also been demonstrated. Interest in the use of carvedilol in patients with congestive heart failure (CHF) has culminated in the publication of a cumulative analysis of data from 1094 patients with mild to severe CHF who participated in the US Carvedilol Heart Failure Study Program (4 trials). After a median follow-up of 6.5 months, a significant overall reduction in mortality relative to placebo (3.2 vs 7.8%) was revealed in patients who had received carvedilol 6.25 to 50 mg twice daily (plus diuretics and ACE inhibitors). All-cause mortality, risk of hospitalisation for cardiovascular reasons and hospitalisation costs were also reduced significantly (by 65, 28% and 62%, respectively) in these trials. In addition, the Australia and New Zealand Heart Failure Research Collaborative Group showed a 26% reduction in the combined risk of death or hospitalisation with carvedilol 12.5 to 50 mg/day relative to placebo after a mean 19-month follow-up period in 415 patients with CHF (relative risk 0.74). Adverse events with carvedilol appear to be less frequent than with other β-blocking agents, are dosage-related and are usually seen early in therapy. Events most commonly reported are related to the vasodilating (postural hypotension, dizziness and headaches) and the β-blocking (dyspnoea, bronchospasm, bradycardia, malaise and asthenia) properties of the drug. Carvedilol appears to date to have little effect on the incidence of worsening heart failure. Concomitant administration of carvedilol with some medications requires monitoring. Carvedilol is therefore likely to have a beneficial role in the management of controlled CHF, but further clinical studies are required to show the place of β-adrenoceptor blocking therapy in general in this indication, and the position of carvedilol relative to other similar agents. Carvedilol is also confirmed as effective in the management of mild to moderate hypertension and ischaemic heart disease. Carvedilol competitively blocks β₁, β₂ and α₁ adrenoceptors, lacks sympathomimetic activity and has vasodilating properties exerted mainly through α₁-blockade. Single oral doses of carvedilol 12.5 to 200mg reduce SBP and DBP with no reflex tachycardia. Significant reductions in blood pressure have been reported, starting 30 minutes after administration, with maximal decreases at 1.5 to 7 hours. Exercise-induced increases in SBP and heart rate are attenuated by the drug, and stroke index and cardiac index are preserved after single doses of 20 to 60mg in healthy volunteers. Cardiac index was reduced after carvedilol 25 mg/day for 6 to 9 months in patients with hypertension. Carvedilol has been associated with improved myocardial function, particularly improvements in afterload (left ventricular ejection fraction) and decreased left ventricular volumes in patients with left ventricular dysfunction, and regression of left ventricular hypertrophy in patients with mild to moderate essential hypertension. Carvedilol has demonstrated protective effects against myocardial necrosis and arrhythmia and against cell damage caused by oxidising free radicals in several animal models. The drug also does not adversely affect renal function at dosages of up to 50 mg/day, has antiproliferative effects on intimai tissue and does not affect plasma lipid profiles. Increased insulin sensitivity has been reported with carvedilol 25 to 50 mg/day in a 12-week study in patients with mild to moderate essential hypertension. Oral carvedilol shows predominantly linear pharmacokinetics. Absolute oral bioavailability is 20 to 25% and peak plasma concentrations (C_max) are seen 1 to 2 hours after administration. The terminal elimination half-life has ranged from 2 to 8 hours in clinical studies. There are no significant age-related variations in the pharmacokinetic properties of the drug. Carvedilol is highly lipophilic and protein bound. No dosage alterations are required in patients with renal failure. However, patients with liver dysfunction show stereoselective alterations in metabolism of the drug; this may affect the balance between β- and α-adrenergic effects. The antihypertensive efficacy of carvedilol 25 to 50 mg/day in patients with mild to moderate essential hypertension is well established. Recent comparative trials have confirmed earlier findings and show carvedilol to be of equivalent efficacy to other antihypertensive agents (notably atenolol, labetalol, pindolol, metoprolol, nitrendipine, hydrochlorothiazide and captopril). A 29-week comparison of carvedilol 12.5 to 50 mg/day with enalapril 10 to 40 mg/day showed similar antihypertensive response rates and quality-of-life effects for both drugs. Enalapril reduced SBP by 5 to 10mm Hg more than carvedilol in this study. Confirmation of the ability of carvedilol to improve ischaemic and exercise parameters in patients with stable angina pectoris has also been...