Alpha (α) and beta (β) adrenergic receptor blocking agents
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.
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.
Clinical studies showed the following results for carvedilol:
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).