Carvedilol

Structural formula
	Structural formula without stereochemistry
General
Non-proprietary name	Carvedilol
other names	( RS ) -1- (4-carbazolyloxy) -3- [2- (2-methoxyphenoxy) ethylamino] -2-propanol; (±) -1- (4-Carbazolyloxy) -3- [2- (2-methoxyphenoxy) ethylamino] -2-propanol; rac -1- (4-carbazolyloxy) -3- [2- (2-methoxyphenoxy) ethylamino] -2-propanol;
Molecular formula	C 24 H 26 N 2 O 4
Brief description	white to almost white, crystalline and polymorphic powder
External identifiers / databases
EC number	615-871-8
ECHA InfoCard	100.117.236
PubChem	2585
ChemSpider	2487
DrugBank	DB01136
Wikidata	Q412534
Drug information
ATC code	C07 AG02
Drug class	Alpha blockers , beta blockers
Mechanism of action	Competitive antagonist at α 1 , β 1 and β 2 adrenoceptors
properties
Molar mass	406.47 g · mol -1
Physical state	firmly
Melting point	114.5 ° C
pK s value	7.6
solubility	practically insoluble in water (0.583 mg l −1 at 25 ° C), sparingly soluble in ethanol , practically insoluble in dilute acids
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
H and P phrases	H: 411
	P: 273
Toxicological data	25 mg kg −1 ( LD 50 , rat , iv )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Carvedilol is a chiral drug from the group of beta blockers , which is used as a racemate for the treatment of high blood pressure ( arterial hypertension ), angina pectoris and chronic heart failure . It differs from other beta blockers in that it has additional effects as an alpha blocker and vasodilator . Carvedilol is subject to medical prescription .

Clinical information

Application areas (indications)

Carvedilol is used to treat essential hypertension and coronary artery disease with angina pectoris . Carvedilol is also approved in combination with diuretics and ACE inhibitors for the treatment of chronic heart failure.

Contraindications (contraindications)

Absolute contraindications are decompensated heart failure, heart failure with a resting heart rate <50 min ⁻¹ , acute pulmonary embolism , Prinzmetal's angina , cor pulmonale , bronchial asthma , untreated pheochromocytoma , clinically relevant liver dysfunction, intravenous therapy with antiarrhythmic drugs, complete right thighs Heart disease, hemodynamically effective heart valve defects, people under 18 years of age.

Relative contraindications are unstable angina pectoris, 1st degree AV block, peripheral vascular diseases and hypothyroidism.

Adverse effects (side effects)

An undesirable drug effect can be an aggravation of Prinzmetal's angina (a form of angina pectoris ), shortness of breath due to bronchospasm , nasal congestion, body aches, abdominal pain, headache, aggravation of intermittent claudication and Raynaud's syndrome . In patients with heart failure or impaired kidney function, deterioration in kidney function may occur, and rarely also kidney failure. Other possible side effects are bradycardia , AV blocks , orthostatic hypotension with dizziness, syncope , nausea and diarrhea. Visual disturbances and eye irritation, confusion, sleep disturbances, psychosis (depression), edema, changes in liver values, allergic reactions, exacerbation of heart failure, thrombopenia and leukopenia can occur rarely .

Pharmacological properties

Mechanism of action (pharmacodynamics)

Carvedilol is a competitive receptor antagonist for β- and α ₁ -adrenoceptors . The observed vasodilation occurs mainly through a blockade of α ₁ -adrenoceptors. Carvedilol has no intrinsic sympathomimetic activity. Because of its vasodilating properties, carvedilol lowers the peripheral vascular resistance and because of the β-blockade the plasma renin activity is decreased. Carvedilol also acts as a FIASMA (functional inhibitor of acid sphingomyelinase ).

Absorption and distribution in the body (pharmacokinetics)

Carvedilol is quickly absorbed, the maximum effective level is reached after about an hour. The absolute bioavailability in humans is around 25%. The plasma half-life after oral administration (tablets of 6.25 to 25 mg, given in a dose of 3.125 to 25 mg once or twice per day) is about six to ten hours. Excretion takes place predominantly in the biliary via the liver; a small proportion is excreted in the form of metabolites via the kidneys.

Clinical studies

Proof of heart failure

COPERNIKUS ( Carvedilol Prospective Randomized Survival Trail ), was a study in which Carvedilol was used versus placebo . Patients with NYHA IV heart failure were included . Carvedilol reduced all-cause mortality by 35% over placebo. Included were patients with drinking volume restrictions and taking additional medication with ACE inhibitors , diuretics and digitalis glycosides . This study first demonstrated the benefits of beta-blockers in this stage of heart failure. There is also a contraindication of beta blockers in acute decompensated heart failure.

Comparison with metoprolol

The started in 1996 and 2003 in The Lancet published COMET study with a total of 3029 patients showed a superiority of 2 x 25 mg carvedilol (the maximum daily dose), compared to 2 x 50 mg metoprolol in non-retarded form in patients with heart failure. With carvedilol, 88 fewer patients died than with metoprolol over an average of five study years, which corresponds to a statistically significant reduction in mortality of 17%. The relevance of these study results is controversial to this day, as the metoprolol was administered in a lower dose and with a different galenic than is the case with today's standard therapy for heart failure. Critics accuse the heads of the study, financed by the Carvedilol providers Hoffmann-La Roche and GlaxoSmithKline , that it should have been discontinued in 1999 at the latest because of these findings. In the current guidelines for the treatment of heart failure in Europe and the USA, the beta blockers bisoprolol , carvedilol and metoprolol are presumably considered to be equivalent in adequate doses.

Stereoisomerism

Carvedilol is chiral , so it contains a stereocenter. There are thus two enantiomers , the ( R ) form and the ( S ) form. The commercial preparations contain the drug as a racemate (1: 1 mixture of enantiomers). The active stereoisomer ( eutomer ) is the ( S ) form of carvedilol.

( R ) -enantiomer (above) and ( S ) -enantiomer of carvedilol.

Trade names

Monopreparations

CarLich (D), Carvedigamma (D), Dilatrend (D, A, CH), Dimetil (D), Querto (D), numerous generics (D, A, CH)

Combination preparations

Co-Dilatrend (A)

literature

Poole-Wilson PA, Swedberg K, Cleland JG et al .: Comparison of Carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomized controlled trial . Lancet 2003; 362: 7-13. PMID 12853193 .

Individual evidence

↑ ^a ^b European Pharmacopoeia Commission (ed.): EUROPEAN PHARMACOPOE 5TH EDITION . tape 5.0-5.8 , 2006.
↑ ^a ^b ^c Entry on carvedilol in the ChemIDplus database of the United States National Library of Medicine (NLM) .
↑ Entry on Carvedilol. In: Römpp Online . Georg Thieme Verlag, accessed on June 25, 2019.
↑ ^a ^b Carvedilol data sheet from Sigma-Aldrich , accessed on March 15, 2011 ( PDF ).

^ Anne Paschen: Heart. 2016, p. 262.

↑ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P: Identification of novel functional inhibitors of acid sphingomyelinase . In: PLoS ONE . 6, No. 8, 2011, p. E23852. doi : 10.1371 / journal.pone.0023852 .

^ Anne Paschen: Heart. In: Jörg Braun, Roland Preuss (Ed.): Clinic Guide Intensive Care Medicine. 9th edition. Elsevier, Munich 2016, ISBN 978-3-437-23763-8 , pp. 185–283, here: pp. 262 f. ( Carvedilol ).

↑ Joni Agustiana, Azlina Harun Kamaruddina, Subhash Bhatiaa: Single enantiomeric β-blockers — The existing technologies , Process Biochemistry 45 ( 2010 ) 1587-1604.

↑ Red List online, as of October 2009.

↑ AM comp. d. Switzerland, as of October 2009.

↑ AGES-PharmMed, as of October 2009.

[Ph._Eur._5-1] European Pharmacopoeia Commission (ed.): EUROPEAN PHARMACOPOE 5TH EDITION . tape 5.0-5.8 , 2006.

[ChemIDplus-2] Entry on carvedilol in the ChemIDplus database of the United States National Library of Medicine (NLM) .

[3] Entry on Carvedilol. In: Römpp Online . Georg Thieme Verlag, accessed on June 25, 2019.

[Sigma-4] Carvedilol data sheet from Sigma-Aldrich , accessed on March 15, 2011 ( PDF ).

[5] Anne Paschen: Heart. 2016, p. 262.

[pmid18504571-6] Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P: Identification of novel functional inhibitors of acid sphingomyelinase . In: PLoS ONE . 6, No. 8, 2011, p. E23852. doi : 10.1371 / journal.pone.0023852 .

[7] Anne Paschen: Heart. In: Jörg Braun, Roland Preuss (Ed.): Clinic Guide Intensive Care Medicine. 9th edition. Elsevier, Munich 2016, ISBN 978-3-437-23763-8 , pp. 185–283, here: pp. 262 f. ( Carvedilol ).

[8] Anne Paschen: Heart. In: Jörg Braun, Roland Preuss (Ed.): Clinic Guide Intensive Care Medicine. 9th edition. Elsevier, Munich 2016, ISBN 978-3-437-23763-8 , pp. 185–283, here: pp. 262 f. ( Carvedilol ).

[Agustiana-9] Joni Agustiana, Azlina Harun Kamaruddina, Subhash Bhatiaa: Single enantiomeric β-blockers — The existing technologies , Process Biochemistry 45 ( 2010 ) 1587-1604.

[10] Red List online, as of October 2009.

[11] AM comp. d. Switzerland, as of October 2009.

[12] AGES-PharmMed, as of October 2009.