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Carvedilol

Alpha (α) and beta (β) adrenergic receptor blocking agents

Composition

Active ingredient: carvedilol.

1 tablet contains 3.125 mg, 6.25 mg, 12.5 mg or 25 mg carvedilol.

Tablets for oral administration. The tablets are uncoated, round, and biconvex with a bilateral scoreline, and either pale pink (3.125 mg), yellow (6.25 mg), light brown (12.5 mg) or white to pale yellowish-beige (25 mg).

Properties and effects

Mechanism of action Carvedilol is a multiple action adrenergic receptor blocker with α₁, β₁ and β₂ adrenergic receptor blockade properties. Carvedilol has been shown to have organ-protective effects. Carvedilol is a potent antioxidant and a scavenger of reactive oxygen radicals. Carvedilol is racemic, and both R(+) and S(-) enantiomers have the same alpha-adrenergic receptor blocking properties and antioxidant properties. Carvedilol has antiproliferative effects on human vascular smooth muscle cells. A decrease in oxidative stress has been shown in clinical studies by measuring various markers during chronic treatment of patients with carvedilol.

Carvedilol's β-adrenergic receptor blocking properties are nonselective for the β₁ and β₂-adrenoceptors and are associated with the levorotatory S(-) enantiomer.

Carvedilol has no intrinsic sympathomimetic activity and (like propranolol) it has membrane stabilising properties. Carvedilol suppresses the renin-angio-tensin-aldosterone system through β-blockade, which reduces the release of renin, thus making fluid retention rare.

Carvedilol reduces the peripheral vascular resistance via selective blockade of α₁-adrenoceptors. Carvedilol attenuates the increase in blood pressure induced by phenylephrine, an α₁-adrenoceptor agonist, but not that induced by angiotensin II. Carvedilol has no adverse effect on the lipid profile. A normal ratio of high-density lipoproteins to low density lipoproteins (HDL/LDL) is maintained.

Efficacy

Clinical studies showed the following results for carvedilol:

Hypertension

Carvedilol lowers blood pressure in hypertensive patients by a combination of P-blockade and al mediated vasodilation. A reduction in blood pressure is not associated with a concomitant increase in total peripheral resistance, as observed with pure P-blocking agents. Heart rate is slightly decreased. Renal blood flow and renal function are maintained in hypertensive patients. Carvedilol has been shown to maintain stroke volume and reduce total peripheral resistance. Blood supply to distinct organs and vascular beds including kidneys, skeletal muscles, forearms, legs, skin, brain or the carotid artery is not compromised by carvedilol. There is a reduced incidence of cold extremities and early fatigue during physical activity. The longterm effect of carvedilol on hypertension is documented in several double-blind controlled studies.

Coronary heart disease

In patients with coronary heart disease, carvedilol has demon strated anti-ischemic (improved total exercise time, time to 1 mm ST segment depression and time to angina) and anti anginal properties that were maintained during long-term treatment. Acute hemodynamic studies have demonstrated that carvedilol significantly decreases myocardial oxygen demand and sympathetic overactivity. It also decreases the myocardial preload (pulmonary artery pressure and pulmonary capillary wedge pressure) and afterload (total peripheral resistance).

Chronic heart failure

Carvedilol significantly reduces all cause mortality and the need for cardiovascular hospitalization. Carvedilol also increases ejection fraction and improves symptoms in patients with ischemic or non-ischemic chronic heart failure. The effect of carvedilol is dose dependent.

Pre-clinical safety data

In carcinogenicity studies conducted in rats and mice, employing dosages up to 75 mg/kg/day and 200 mg/kg/day respectively (38 to 100 times the maximum recommended human dose [MRHD] ), carvedilol had no carcinogenic effect.

Carvedilol was not mutagenic in in vitro or in vivo mammalian tests and non-mammalian tests.

Administration of carvedilol to pregnant rats at maternally toxic doses (≥ 200 mg/kg, ≥ 100 times MRHD) resulted in impairment of fertility (poor mating, fewer corpora lutea, implants, and embryonic responses). Doses > 60 mg/kg (> 30 times MRHD) caused delays in physical growth/development of offspring. There was embryotoxicity (increased post-implantation deaths) but no malformations in rabbits and rats at doses of 75 mg/kg and 200 mg/kg, respectively (38 to 100 times MRHD).

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