Dilatrend Mechanism of Action





Full Prescribing Info
Pharmacology: 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. It is racemic, and both R(+) and S(-) enantiomers have the same α-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-stabilizing properties. Carvedilol suppresses the renin-angiotensin-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. It 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 β-blockade and α1-mediated vasodilation. A reduction in blood pressure is not associated with a concomitant increase in total peripheral resistance, as observed with pure β-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 long-term effect of carvedilol on hypertension is documented in several double-blind controlled studies.
Coronary Heart Disease: In patients with coronary heart disease, carvedilol has demonstrated 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 causes of 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.
Pharmacokinetics: Absorption: Following oral administration, carvedilol is rapidly absorbed. In healthy volunteers, the maximum serum concentration is reached after approximately 1 hr. The absolute bioavailability of carvedilol in humans is approximately 25%.
Distribution: Carvedilol is a highly lipophilic compound, approximately 98-99% bound to plasma proteins. The distribution volume is approximately 2 L/kg.
Metabolism: In humans, carvedilol is extensively metabolized into a variety of metabolites that are eliminated mainly in the bile. The first-pass effect after oral administration amounts to about 60-75%. Enterohepatic circulation of the parent substance has been shown in animals.
Carvedilol is metabolized extensively by the liver and glucuronidation is one of the major reactions. Demethylation and hydroxylation at the phenol ring produce 3 metabolites with β-adrenergic receptor-blocking activity. Based on preclinical studies, the 4'-hydroxyphenol metabolite is approximately 13 times more potent than carvedilol for β-blockade. Compared to carvedilol, the 3 active metabolites exhibit weak vasodilating activity. In humans, the concentrations of the 3 active metabolites are about 10 times lower than that of the parent substance. Two (2) of the hydroxycarbazole metabolites of carvedilol are extremely potent antioxidants, demonstrating a 30- to 80-fold greater potency than carvedilol.
Elimination: The average elimination half-life of carvedilol is approximately 6 hrs. Plasma clearance is approximately 500-700 mL/min. The primary route of excretion is via the feces. Elimination is mainly biliary. A minor part is eliminated via the kidneys in the form of various metabolites.
Pharmacokinetics in Special Populations: Patients with Renal Impairment: The autoregulatory blood supply is preserved and the glomerular filtration is unchanged during chronic treatment with carvedilol.
In patients with hypertension and renal insufficiency, the area under plasma level-time curve, elimination half-life and maximum plasma concentration does not change significantly. Renal excretion of the unchanged drug decreases in the patients with renal insufficiency; however, changes in pharmacokinetic parameters are modest.
Several open studies have shown that carvedilol is an effective agent in patients with renal hypertension. The same is true in patients with chronic renal failure, or those on hemodialysis or after renal transplantation. Carvedilol causes a gradual reduction in blood pressure both on dialysis and nondialysis days, and the blood pressure-lowering effects are comparable with those seen in patients with normal renal function. Carvedilol is not eliminated during dialysis because it does not cross the dialysis membrane, probably due to its high plasma protein-binding.
On the basis of results obtained in comparative trials on hemodialyzed patients, it was concluded that carvedilol was more effective than calcium-channel blockers and was better tolerated.
Patients with Hepatic Impairment: In patients with cirrhosis of the liver, the systemic availability of the drug is increased by up to 80% because of a reduction in the first-pass effect. Therefore, carvedilol is contraindicated in patients with clinically manifest liver dysfunction (see Contraindications).
Geriatric Use: The pharmacokinetics of carvedilol in hypertensive patients was not affected by age. A study in elderly hypertensive patients showed that there was no difference in the adverse event profile. Another study which included elderly patients with coronary heart disease showed no difference in the adverse events reported:
Pediatric Use: There is limited data available on pharmacokinetics in people <18 years.
Diabetic Patients: In hypertensive patients with non-insulin-dependent diabetes, no influence of carvedilol on fasting or postprandial blood glucose concentration, glycolated hemoglobin A1 or need for change of the dose of antidiabetic agents was found.
In patients with non-insulin-dependent diabetes, carvedilol had no statistically significant influence on the glucose tolerance test. In hypertensive nondiabetic patients with impaired insulin sensitivity (syndrome X) carvedilol improved the insulin sensitivity. The same results were found in hypertensive patients with non-insulin-dependent diabetes.
Toxicology: Preclinical Safety Data: In carcinogenicity studies conducted in rats and mice employing dosages up to 75 mg/kg/day and 200 mg/kg/day, respectively [38-100 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 and 200 mg/kg, respectively (38-100 times MRHD).
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