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Combined Alpha and Beta-Adrenoceptor Blocker.
Pharmacology: Pharmacodynamics: Carvedilol is a vasodilatory non-selective beta-blocker, which reduces the peripheral vascular resistance by selective alpha 1-receptor blockade and suppresses the renin-angiotensin system through non-selective beta-blockade. Plasma renin activity is reduced and fluid retention is rare.
Carvedilol has no intrinsic sympathomimetic activity (ISA). Like propranolol, it has membrane stabilising properties.
Carvedilol is a racemate of two stereoisomers. Both enantiomers were found to have alpha-adrenergic blocking activity in animal models. Non-selective beta1- and beta2-adrenoceptor blockade is attributed mainly to the S(-) enantiomer.
The antioxidant properties of carvedilol and its metabolites have been demonstrated in in vitro and in vivo animal studies and in vitro in a number of human cell types.
In hypertensive patients, a reduction in blood pressure is not associated with a concomitant increase in peripheral resistance, as observed with pure beta-blocking agents. Heart rate is slightly decreased. Stroke volume remains unchanged. Renal blood flow and renal function remain normal, as does peripheral blood flow, therefore, cold extremities, often observed with beta-blockers, are rarely seen. In hypertensive patients, carvedilol increases the plasma norepinephrine concentration.
In prolonged treatment of patients with angina, carvedilol has been seen to have an anti-ischaemic effect and to alleviate pain. Haemodynamic studies demonstrated that carvedilol reduces ventricular pre- and after-load. In patients with left ventricular dysfunction or congestive heart failure, carvedilol has a favourable effect on haemodynamics and left ventricular ejection fraction and dimensions.
Carvedilol has no negative effect on the serum lipid profile or electrolytes. The ratio of HDL (high-density lipoproteins) and LDL (low-density lipoproteins) remains normal.
Pharmacokinetics: Carvedilol is well absorbed from the gastrointestinal tract but is subject to considerable first-pass metabolism in the liver; the absolute bioavailability is about 25%. Peak plasma concentrations occur 1 to 2 hours after an oral dose. It has high lipid solubility. Carvedilol is more than 98% bound to plasma proteins. It is extensively metabolized in the liver, primarily by the cytochrome P450 isoenzymes CYP2D6 and CYP2C9, and the metabolites are excreted mainly in the bile. The elimination half-life is about 6 to 10 hours. Carvedilol has been shown to accumulate in breast milk in animals.
