Dilatrend Mechanism of Action

Pharmacotherapeutic Group: Alpha (α) and beta (β) adrenergic receptor blocking agents. ATC Code: C07AG02.
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 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. Some of the limitations of traditional β-blockers do not appear to be shared by some of the vasodilating β-blockers, such as carvedilol. 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.
Renal Impairment: 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.
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.
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 over-activity. 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.
Renal Impairment: Carvedilol reduces morbidity and mortality in dialysis patients with dilated cardiomyopathy. A meta-analysis of placebo-controlled clinical trials including a large number of patients (>4000) with mild to moderate chronic kidney disease supports carvedilol treatment of patients with left ventricular dysfunction with or without symptomatic heart failure to reduce rates of all cause of mortality as well as heart failure related events.
Left Ventricular Dysfunction following Acute Myocardial Infarction: In a double-blind placebo-controlled study in 1959 patients with a recent myocardial infarction and left ventricular ejection fraction ≤ 40%or wall motion index ≤ 1.3 (with or without symptomatic heart failure), carvedilol did not show a statistically significant reduction of the co-primary endpoint; all-cause mortality or cardiovascular hospitalisation (8% reduction vs placebo, p=0.297), but significantly reduced all-cause mortality by 23% (p=0.031), all-cause mortality or non-fatal myocardial infarction by 29% (p=0.002), mortality due to cardiovascular causes by 25% (p=0.024) and hospitalisation for non-fatal myocardial infarction by 41% (p=0.014). Additionally, a post-hoc analysis showed that carvedilol significantly reduced death or major cardiovascular hospitalisation by 17% (p= 0.019).
Pharmacokinetics: Absorption: Following oral administration of a 25 mg capsule to healthy subjects, carvedilol is rapidly absorbed with a peak plasma concentration C_max of 21 mg/L reached after approximately 1.5 hour (t_max). The C_max values are linearly related to the dose. Following oral administration, carvedilol undergoes extensive first pass metabolism that results in an absolute bioavailability of about 25% in healthy male subjects. Carvedilol is a racemate and the S-(-)- enantiomer appears to be metabolized more rapidly than the R-(+)- enantiomer, showing an absolute oral bioavailability of 15% compared to 31% for the R-(+)- enantiomer. The maximal plasma concentration of R-carvedilol is approximately 2 fold higher than that of S-carvedilol.
In vitro studies have shown that carvedilol is a substrate of the efflux transporter P-glycoprotein. The role of P-glycoprotein in the disposition of carvedilol was also confirmed in vivo in healthy subjects.
Distribution: Carvedilol is a highly lipophilic compound, showing a plasma protein binding of around 95%. The distribution volume ranges between 1.5 and 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. Enterohepatic circulation of the parent substance has been shown in animals.
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.
Pharmacokinetic studies in human have shown that the oxidative metabolism of carvedilol is stereoselective. The results of an in vitro study suggested that different cytochrome P450 isoenzymes may be involved in the oxidation and hydroxylation processes including CYP2D6, CYP3A4, CYP2E1, CYP2C9, as well as CYP1A2.
Studies in healthy volunteers and in patients have shown that the R-enantiomer is predominantly metabolized by CYP2D6. The S-enantiomer is mainly metabolized by CYP2D6 and CYP2C9.
Genetic Polymorphism: The results of clinical pharmacokinetic studies in human subjects have shown that CYP2D6 plays a major role in the metabolism of R and of S-carvedilol. As a consequence plasma concentrations of R and S-carvedilol are increased in CYP2D6 slow metabolisers. The importance of CYP2D6 genotype in the pharmacokinetics of R and S-carvedilol was confirmed in population pharmacokinetics studies, whereas other studies did not confirm this observation. It was concluded that CYP2D6 genetic polymorphism may be of limited clinical significance.
Elimination: Following a single oral administration of 50 mg carvedilol, around 60%are secreted into the bile and eliminated with the faeces in the form of metabolites within 11 days. Following a single oral dose, only about 16% are excreted into the urine in form of carvedilol or its metabolites. The urinary excretion of unaltered drug represents less than 2%. After intravenous infusion of 12.5 mg to healthy volunteers, the plasma clearance of carvedilol reaches around 600 mL/min and the elimination half-life around 2.5 hours. The elimination half-life of a 50 mg capsule observed in the same individuals was 6.5 hours corresponding indeed to the absorption half-life from the capsule. Following oral administration, the total body clearance of the S-carvedilol is approximately two times larger than that of the R-carvedilol.
Special Populations: Children: Investigation in paediatrics has shown that the weight-adjusted clearance is significantly larger in paediatrics as compared to adults.
Elderly: Age has no statistically significant effect on the pharmacokinetics of carvedilol in hypertensive patients.
Renal Impairment: 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 is not eliminated during dialysis because it does not cross the dialysis membrane, probably due to its high plasma protein binding.
Hepatic Impairment: See Contraindications and Use in Special Population/Hepatic Impairment.
Heart Failure: In a study in 24 Japanese 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.
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 embryo toxicity (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).