Carvedilol

Abstract

Synopsis

Carvedilol is a β-adrenoceptor antagonist which also causes peripheral vasodilation primarily via α₁-adrenergic blockade. Carvedilol produces its antihypertensive effect partly by reducing total peripheral resistance by blocking α₁-adrenoceptors and by preventing β-adrenoceptor-mediated compensatory mechanisms. This combined action avoids many of the unwanted effects associated with traditional β-blocker or vasodilator therapy.

In clinical trials published to date, most of which enrolled small numbers of patients, the antihypertensive efficacy of carvedilol administered once daily was similar to that of atenolol, labetalol, pindolol, propranolol, metoprolol, nitrendipine (in elderly patients), slow release nifedipine or captopril in patients with mild-to-moderate essential hypertension. Combined therapy with carvedilol 25mg and hydrochlorothiazide 25mg, nicardipine 60mg or slow release nifedipine 20mg has an additive antihypertensive effect. Carvedilol and atenolol at similar doses were equally effective at reducing blood pressure in patients who had previously not responded adequately to hydrochlorothiazide monotherapy.

As a result of its multiple mechanisms of action, carvedilol is suited for the management of specific groups of hypertensive patients, such as those with renal impairment. In patients with non-insulin-dependent or insulin-dependent diabetes mellitus carvedilol does not appear to affect glucose tolerance or carbohydrate metabolism.

Initial studies have demonstrated that carvedilol and slow release nifedipine have similar efficacy in patients with stable angina pectoris and there is evidence that carvedilol has a beneficial haemodynamic effect in patients with congestive heart failure (NYHA class II or III) secondary to ischaemic heart disease.

A postmarketing surveillance study has shown that carvedilol is generally well tolerated with only 7% (164/2226) of patients (83% of the total number received 25mg daily for 12 weeks) withdrawing from treatment because of adverse events. Vertigo, headache, bronchospasm, fatigue and skin reactions were the most common events causing withdrawal.

Thus, clinical experience to date suggests that carvedilol is likely to be a valuable addition to the options currently available for treating patients with mild-to-moderate essential hypertension, and may offer particular benefit in specific populations of hypertensive patients.

Pharmacodynamic Properties

Racemic carvedilol is an arylethanolamine β-adrenoceptor antagonist with vasodilating properties. Antagonism of β₁-adrenoceptor-mediated responses with carvedilol (demonstrated in various animal models and in healthy volunteers) is similar in potency, but longer lasting (15 to 16 hours) than that of propranolol (12 hours), and much greater in both potency and duration of effect than that of labetalol (1.5 hours). Some studies have shown that at a dose producing β₁-blocking activity, carvedilol also antagonises β₂-adrenoceptors but to a lesser extent, thus indicating weak selectivity for β₁-adrenoceptors. However, other studies have failed to show any β₂-adrenoceptor selectivity.

Antagonism of α₁-adrenoceptors accounts for most of the vasodilatory activity of carvedilol, although at high concentrations (>1 μmol/L) antagonism of calcium channels has been observed consistently in various animal models. Although this does not appear to contribute to the antihypertensive effects of carvedilol, it may be of significance in specific vascular beds. Carvedilol exhibits no intrinsic sympathomimetic/partial agonist activity and only weak membrane-stabilising (local anaesthetic) activity.

Carvedilol has cardioprotective effects in animal models of acute myocardial infarction and is more effective in this regard than propranolol at comparable β-blocking doses. Carvedilol also protects against neuronal damage in in vitro and in vivo models of brain ischaemia and has antiproliferative effects in vascular smooth muscle in vitro.

Single oral doses of carvedilol as low as 12.5mg reduce resting and exercise blood pressure in healthy volunteers. In hypertensive patients carvedilol dose-dependently reduced mean diastolic blood pressure. Elderly hypertensive patients (aged > 65 years, baseline supine blood pressure 185/103mm Hg) respond equally well to carvedilol; a single 12.5mg dose adequately reduced mean peak supine blood pressure in many patients. Single doses of carvedilol 25mg and nitrendipine 20mg were equally effective.

Carvedilol generally has little or no effect on heart rate or cardiac index in healthy volunteers; however, cardiac output was reduced in exercising hypertensive patients treated with carvedilol, and the drug had less effect than propranolol or metoprolol on heart rate in resting or exercising hypertensive patients.

In patients with coronary artery disease, initial results show that carvedilol improved exercise capacity and left ventricular function and increased ejection fraction. There is also some evidence that left ventricular hypertrophy regresses in patients with hypertension treated with carvedilol and that the drug improves cardiac function in patients with idiopathic dilated cardiomyopathy.

Pharmacokinetic Properties

Carvedilol is rapidly absorbed when administered orally with maximum plasma concentrations (C_max) reached 1 to 2 hours after single 25 or 50mg doses in healthy volunteers and hypertensive patients. Carvedilol undergoes extensive first-pass hepatic metabolism resulting in a low and variable absolute bioavailability of about 25%. The rate of absorption (as indicated by a slight increase in the time to reach maximum plasma concentrations), but not the extent of absorption, is decreased by food. Carvedilol is highly lipophilic and is widely distributed into extravascular tissues with a volume of distribution of 1.5 to 2 L/kg in healthy volunteers. Metabolism is primarily hepatic with less than 2% of a dose excreted unchanged in urine. Some metabolites appear to be active but whether this is of any clinical relevance is uncertain. Elimination is primarily biliary with 60% of a dose excreted in faeces. Thus, dosage adjustment in renally impaired patients is not required. However, peak plasma carvedilol concentrations and bioavailability are significantly increased in patients with severe hepatic impairment (e.g. cirrhosis) and the use of carvedilol in these patients is not recommended.

Therapeutic Efficacy

Data from clinical studies, analysed individually and combined in a meta-analysis, have conclusively demonstrated that carvedilol administered as a once daily 25mg dose has a significant antihypertensive effect in patients with mild-to-moderate essential hypertension. Indeed, a meta-analysis of 36 studies reported a decrease of 16/11mm Hg in mean systolic/diastolic blood pressures after 2 to 4 weeks of once daily (25mg) treatment in patients with a baseline blood pressure of 166/103mm Hg. No significant difference in antihypertensive effect was seen when carvedilol 50mg was administered daily as a single dose or as two 25mg doses. A 24-hour antihypertensive effect has been observed after once daily carvedilol administration in patients treated for 24 months.

Published studies to date comparing the antihypertensive effect of carvedilol with that of other agents have generally enrolled small numbers of patients and may not have had sufficient statistical power to detect potential differences between treatments. Nonetheless, these studies have shown that in hypertensive patients (generally treated for 4 to 12 weeks) once daily carvedilol 25 or 50mg had a similar effect to that of once daily pindolol 15mg, atenolol 50 to 100mg, hydrochlorothiazide 25mg, or nitrendipine 20mg (in elderly patients), or twice daily labetalol 200mg, propranolol 80mg, metoprolol 100mg, slow release nifedipine 20 to 40mg or captopril 25 to 50mg. In patients who had failed to respond sufficiently to hydrochlorothiazide therapy, the addition of carvedilol or atenolol produced a similar reduction in blood pressure after 6 weeks, with 67% of the carvedilol group and 71% of the atenolol group achieving a diastolic blood pressure ⩽ 90mm Hg. Other studies have demonstrated an additive antihypertensive effect when carvedilol 25mg and either hydrochlorothiazide 25mg, slow release nifedipine 20mg, or nicardipine 60 mg/day were given in combination. In small groups of hypertensive patients with concomitant disorders, carvedilol reduced blood pressure in those with renal failure and in patients with non-insulin-dependent diabetes, carvedilol 25mg once daily was as effective as nifedipine 10mg 3 times daily.

Compared with placebo, carvedilol increases exercise capacity and reduces myocardial oxygen consumption in patients with chronic stable angina pectoris and a 25mg dose administered twice daily has similar effects on total exercise time and time to 1mm ST-segment depression as slow release nifedipine 20mg administered twice daily. In addition, initial studies show that carvedilol 12.5 to 50mg twice daily has a beneficial effect (improved exercise time and resting left ventricular ejection fraction) in patients with chronic congestive heart failure (NYHA class II or III) secondary to ischaemic heart disease, although lower doses may be needed for safe initiation of therapy.

Tolerability

Results of a postmarketing surveillance study in 2226 patients treated with carvedilol for 12 weeks show that a daily 25mg dose administered as monotherapy is well tolerated by most patients. Treatment was withdrawn because of adverse events in 7% of patients; the most common adverse events responsible for withdrawal were vertigo (1.7%), headache (1.4%), bronchospasm (0.5%), fatigue (0.5%) and skin reactions (0.5%). Orthostatic hypotension has been reported in less than 1% of patients receiving carvedilol and has necessitated withdrawal of therapy in a few patients treated with a ⩾50mg daily dose.

Dosage and Administration

Most patients with mild-to-moderate hypertension respond to an oral carvedilol dose of 25mg administered once daily but if necessary this can be increased to 50 mg/day. All patients should initially receive 12.5mg daily for the first 2 days of therapy, and the maximum total daily dosage should not exceed 50mg. The recommended dosage for elderly hypertensive patients is 12.5mg once daily; this can be titrated (at intervals of 2 weeks) up to a maximum of 50 mg/day. In clinical studies, most patients with stable angina pectoris or congestive heart failure received 12.5 to 50 mg twice daily.

Carvedilol is not recommended for use in patients with hepatic dysfunction due to its increased bioavailability. Dosage adjustment is not necessary in patients with renal impairment.