Dilatrend Mechanism of Action

Therapeutic / Pharmacologic Class of Drug: Alpha (α) and beta (β) adrenergic receptor blocking agents.
Pharmacology: Pharmacodynamics: 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 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 non-selective for the β₁ and β₂-adrenoceptors and are associated with the laevorotatory S(-) enantiomer.
Carvedilol has no intrinsic sympathomimetic activity and (like propranolol) it has membrane stabilising properties. Carvedilol suppresses the renin-angiotensin-aldosterone system through β-blockade, which reduces the release of renin, thus making fluid retention rare.
Carvedilol reduces 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 / Efficacy Studies: 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-ischaemic (improved total exercise time, time to 1mm ST segment depression and time to angina) and anti-anginal properties that were maintained during long-term treatment. Acute haemodynamic 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 mortality and hospitalisations and improves symptoms and left ventricular function in patients with ischaemic or non-ischaemic chronic heart failure. The effect of carvedilol is dose dependent.
Pharmacokinetics: Absorption: Following oral administration, carvedilol is rapidly absorbed. Carvedilol is a substrate of the intestinal efflux transporter P-glycoprotein which plays a major role in the bioavailability of certain drugs. In healthy volunteers the maximum serum concentration is reached after approximately one hour. The absolute bioavailability of carvedilol in humans isapproximately 25%.
Distribution: Carvedilol is a highly lipophilic compound, approximately 98% to 99% bound to plasma proteins. The distribution volume is approximately 2 L/kg.
Metabolism: In humans, carvedilol is extensively metabolized in the liver via oxidation and conjugation 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.
The oxidative metabolism of carvedilol is stereoselective. The R-enantiomer is predominantly metabolized by CYP2D6 and CYP1A2, while the S-enantiomer is mainly metabolised by CYP2C9 and to a lesser extend by CYP2D6. Other CYP450 isoenzymes involved in the metabolism of carvedilol include CYP3A4, CYP2E1 and CYP2C19. The maximal plasma concentration of R-carvedilol are approximately 2 fold higher than that S-carvedilol.
The R-enantiomer is predominantly metabolised through hydroxylation.
In slow metabolisers of CYP2D6 an increase of the plasma concentration of carvedilol, mainly the R-enantiomer may occur, leading to an increase in the α-blocking activity.
Demethylation and hydroxylation at the phenol ring produce 3 metabolites with β-adrenergic receptor blocking activity. Based on pre-clinical studies, the 4'-hydroxyphenol metabolite is approximately 13 times more potent than carvedilol for β-blockade. Compared to carvedilol, the three active metabolites exhibit weak vasodilating activity. In humans, the concentrations of the three active metabolites are about 10 times lower than that of the parent substance. Two of the hydroxy-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 faeces. 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 haemodialysis or after renal transplantation. 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 basis of results obtained in comparative trials on haemodialysed 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).
Patients with heart failure: In a study in 24 patients with heart failure, the clearance of R-and S-carvedilol was significantly lower than previously estimated in healthy volunteers. These results suggested that the pharmacokinetics of R-and S-carvedilol is significantly altered by heart failure.
Geriatric use: Age has no statistically significant effect on the pharmacokinetics of carvedilol in hypertensive patients. A study in elderly hypertensive patients showed that there was no difference in the adverse event profile compared to younger patients. Another study which included elderly patients with coronary heart disease showed no difference in the adverse events reported vs those reported by younger patients.
Paediatric 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 haemoglobin 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.
Toxicology: Preclinical Safety: Carcinogenicity: 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.
Mutagenicity: Carvedilol was not mutagenic in in vitro or in vivo mammalian tests and non-mammalian tests.
Impairment of Fertility: Administration of carvedilol to adult female rats at toxic doses (≥200 mg/kg, ≥100 times MRHD) resulted in impairment of fertility (poor mating, fewer corpora lutea and fewer implants).
Teratogenicity: There is no evidence from animal studies that carvedilol has any teratogenic effects. 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 rats and rabbits at doses of 200 mg/kg and 75 mg/kg, respectively (38 to 100 times MRHD).