Pharmacology: Pharmacodynamics: Mechanism of action: Carvedilol is a multiple action adrenergic receptor blocker with alpha1, beta1 and beta2 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 beta-adrenergic receptor blocking properties are non-selective for the beta1 and beta2-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 beta-blockade, which reduces the release of renin, thus making fluid retention rate. Carvedilol reduces the peripheral vascular resistance via selective blockade of alpha1-adrenoceptors. Carvedilol attenuates the increase in blood pressure induced by phenylephrine, an alpha1-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 beta-blockade and alpha1 mediated vasodilation.
A reduction in blood pressure is not associated with a concomitant increase in total peripheral resistance, as observed with pure beta-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 over activity. It also decreases the myocardial preload (pulmonary artery pressure and pulmonary capillary wedge pressure) and after load (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.
Pharmacokinetics: Absorption: Following oral administration, carvedilol is rapidly absorbed. In healthy volunteers the maximum serum concentration is reached after approximately one hour. The absolute bioavailability of carvedilol in humans is approximately 25%.
Distribution: Carvedilol is a highly lipophilic compound, approximately 98% to 99% bound to plasma proteins. The distribution volume approximately 2L/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 beta-adrenergic receptor blocking activity. Compared to carvedilol, the three active metabolites are about 10 times lower than that of the parent substance. Two of the hydroxyl-carbazole 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 hours. 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.
Carvedilol causes a gradual reduction in blood pressure both on dialysis and non-dialysis 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 other basis of results obtained in comparative trials on hemodialysed 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 is hypertensive patients were not affected by age.
Pediatric use: There is limited data available on pharmacokinetics in people younger than 18 years of age.
Diabetic patients: In hypertensive patients with non-insulin-dependent diabetes no influence of carvedilol on fasting or post-prandial 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 non-diabetic 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.