Description
Carvedilol is a vasodilating beta-blocker useful in the treatment of hypertension and
angina pectoris. In addition to lowering blood pressure, carvedilol decreases total
vascular resistance without the reflex tachycardia usually occurring with vasodilators.
It is reported to be well tolerated with renal sparing effects.
Chemical Properties
Colourless Crystalline Solid
Originator
Boehringer Mannheim (Germany)
Uses
A nonselective -adrenergic blocker with a1-blocking activity. An antihypertensive used in the treatment of congestive heart failure.
Uses
An α1- and β-adrenergic receptor antagonist.
Uses
Carvedilol is a nonselective β-adrenergic blocker with α1-blocking activity. Carvedilol is an antihypertensive used in the treatment of congestive heart failure.
Uses
For the treatment of mild or moderate (NYHA class II or III) heart failure of ischemic or cardiomyopathic origin.
Definition
ChEBI: A member of the class of carbazoles that is an adrenergic antagonist with non-selective beta- and alpha-1 receptor blocking properties which helps in the management of congestive heart failure.
Manufacturing Process
1-(9H-Carbazol-4-yloxy)-3-((2-(2-methoxyphenoxy)ethyl)amino)-2-propanol
may be synthesized by the method of preparation of S-(-)-(1-carbazol-4-
yloxy)-3-[2-(2-methoxyphenoxy)]ethylaminopropan-2-ol (Patent US
4,697,022 and 4,824,963).
27.5 g 4-hydroxycarbazole are dissolved in a mixture of 150 ml 1 N aqueous
sodium hydroxide solution and 70 ml dimethylsulfoxide. To this is added at
ambient temperature 13.9 g epichlorohydrin, followed by stirring for 18 hours
at ambient temperature. 280 ml water are then added thereto, followed by
stirring for 15 min and filtering off with suction. The filter residue is washed
with 0.1 N aqueous sodium hydroxide solution and water and subsequently
dissolved in methylene chloride. The methylene chloride solution is dried over
anhydrous sodium sulfate, treated with active charcoal and floridin and
evaporated. 4-(2,3-Epoxypropoxy)-carbazole is purified by recrystallising twice
from ethyl acetate. From the mother liquors there are isolated a further 4-
(2,3-epoxypropoxy)-carbazole.
10 g 4-(2,3-epoxypropoxy)-carbazole are, together with 13.97 g o-methoxyphenoxyethylamine, heated under reflux in 70 ml isopropanol for 2
hours. The solvent is evaporated off and the residue is stirred for 2 hours with
a mixture of 115 ml toluene, 35 ml cyclohexane and 40 ml ethyl acetate.
After filtering off with suction, the (1-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)]-ethylaminopropan-2-ol is recrystallised from 150 ml ethyl
acetate.
Brand name
Coreg (GlaxoSmithKline);Dilatrend.
Therapeutic Function
Beta-adrenergic blocker
General Description
Carvedilol (Coreg) is a β-blocker that hasa unique pharmacological profile. Like labetalol, it is aβ-blocker that possesses α1-blocking activity. Only the(S) enantiomer possesses the β-blocking activity, althoughboth enantiomers are blockers of the α1-receptor. Overall,its β-blocking activity is 10- to 100-fold of its α-blocking activity.
Biological Activity
Potent β -adrenoceptor and α 1 -adrenoceptor antagonist (K i values are 0.81, 0.96 and 2.2 nM for β 1 -, β 2 - and α 1 -adrenoceptors respectively) that displays antihypertensive and peripheral vasodilatory activity. Blocks cardiac inward-rectifier K + (K IR ) channels, voltage-dependent Ca 2+ channels and exhibits antioxidant properties at higher concentrations.
Biochem/physiol Actions
Cavedilol is a non-selective β-adrenergic blocker with α1 blocking activity. Carvedilol is used specifically for the treatment of heart failure and high blood pressure. It has been shown to improve left ventricular ejection fraction and may reduce mortality.
Clinical Use
Carvedilol is also unique in that it possesses antioxidantactivity and an antiproliferative effect on vascular smoothmuscle cells. It thus has a neuroprotective effect and the abilityto provide major cardiovascular organ protection. It isused in treating hypertension and congestive heart failure.
Veterinary Drugs and Treatments
Carvedilol may be useful as adjunctive therapy in the treatment
of heart failure (dilated cardiomyopathy) in dogs. There is a fair
amount of controversy at present among veterinary cardiologists as
to whether this drug will find a therapeutic niche.
in vitro
carvedilol potently inhibited fe2+-initiated lipid peroxidation in rat brain homogenate with an ic50 of 8.1 μm. in rat brain homogenate, carvedilol protected against fe2+-induced α-tocopherol depletion with an ic50 of 17.6 μm. carvedilol dose-dependently decreased the intensity of the dmpo-oh signal, with an ic50 of 25 μm [1]. carvedilol prevented vascular smooth muscle cell migration, proliferation, and neointimal formation following vascular injury. in human cultured pulmonary artery vascular smooth muscle cells, carvedilol (0.1-10 μm) concentration-dependently inhibited the mitogenesis stimulated by platelet-derived growth factor, epidermal growth factor, thrombin, and serum, with ic50 values ranging from 0.3 to 2.0 μm. carvedilol concentration-dependently inhibited vascular smooth muscle cell migration induced by platelet-derived growth factor with an ic50 value of 3 μm [3].
Drug interactions
Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: NSAIDs antagonise hypotensive effect.
Anti-arrhythmics: increased risk of myocardial
depression and bradycardia; increased risk of
bradycardia, myocardial depression and AV block
with amiodarone; increased risk of myocardial
depression and bradycardia with flecainide.
Antibacterials: concentration reduced by rifampicin.
Antidepressants: enhanced hypotensive effect with
MAOIs.
Antihypertensives; enhanced hypotensive effect;
increased risk of withdrawal hypertension with
clonidine; increased risk of first dose hypotensive
effect with post-synaptic alpha-blockers such as
prazosin.
Antimalarials: increased risk of bradycardia with
mefloquine.
Antipsychotics enhanced hypotensive effect with
phenothiazines.
Calcium-channel blockers: increased risk of
bradycardia and AV block with diltiazem;
hypotension and heart failure possible with
nifedipine and nisoldipine; asystole, severe
hypotension and heart failure with verapamil.
Ciclosporin: increased trough concentration, reduce
dose by 20% in affected patients.
Cytotoxics: possible increased risk of bradycardia
with crizotinib.
Diuretics: enhanced hypotensive effect.
Fingolimod: possibly increased risk of bradycardia.
Moxisylyte: possible severe postural hypotension.
Sympathomimetics: severe hypertension with
adrenaline and noradrenaline and possibly with
dobutamine.
Metabolism
Carvedilol is subject to considerable first-pass metabolism
in the liver; the absolute bioavailability is about 25%. It
is extensively metabolised in the liver, primarily by the
cytochrome P450 isoenzymes CYP2D6 and CYP2C9,
and the metabolites are excreted mainly in the bile.
References
[1] M.D. M R B, PH.D. The role of third-generation beta-blocking agents in chronic heart failure[J]. Clinical Cardiology, 2009, 21 S1: I3-I13. DOI:
10.1002/clc.4960211303
