Carvedilol

Oral
Left ventricular dysfunction post myocardial infarction

Oral
Hypertension

Oral
Heart failure

Oral
Chronic stable angina

Pharmacogenomics:

Carvedilol is clinically used as a racemic mixture of R- and S-enantiomers. Clinical pharmacokinetic studies have shown that CYP2D6 plays a major role in the metabolism of R- and S-carvedilol. Carvedilol is subject to the effects of genetic polymorphism with CYP2D6 poor metabolisers exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolisers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolisers.

Both inhibitors and inducers of the CYP2D6 isoenzymes may alter the metabolism of carvedilol in a stereoselective manner and this may lead to either an increased or decreased plasma concentration of R- and S-carvedilol. Analysis of side effects in clinical trials showed that CYP2D6 poor metabolisers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the α-blocking R(+)-enantiomer.

Severe: Contraindicated.

Should be taken with food. Take w/ food to reduce orthostatic effects.

Patient with decompensated heart failure requiring IV inotropic treatment, bronchial asthma or related bronchospastic conditions, 2nd- or 3rd-degree AV block without permanent pacemaker, severe bradycardia (<50 bpm), sick sinus syndrome, cardiogenic shock, untreated phaeochromocytoma, Severe hepatic impairment.

Patient with salt and volume depletion, hypotension; ischaemic heart disease, Prinzmetal’s variant angina, diabetes mellitus, thyrotoxicosis, peripheral vascular disease, psoriasis. Avoid abrupt withdrawal. Renal and mild to moderate hepatic impairment. Elderly. Pregnancy and lactation.

Significant: Hypotension with or without syncope, bradycardia.
Blood and lymphatic system disorders: Anaemia.
Cardiac disorders: Dyspnoea, pulmonary oedema.
Eye disorders: Visual impairment, eye irritation, dry eye.
Gastrointestinal disorders: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain.
General disorders and admin site conditions: Asthenia, fatigue.
Infections and infestations: Bronchitis.
Metabolism and nutrition disorders: Oedema, hypervolaemia, weight gain, hypercholesterolaemia, hyperglycaemia, hypoglycaemia.
Musculoskeletal and connective tissue disorders: Pain in extremities, arthralgia.
Nervous system disorders: Dizziness, headache.
Psychiatric disorders: Depression.
Renal and urinary disorders: Micturition disorders, abnormal renal function, renal failure.
Vascular disorders: Orthostatic hypotension, peripheral vascular disease.

PO: C

This drug may cause syncope during initial therapy, if affected, do not drive or operate machinery.

Monitor blood pressure, heart rate, BUN, blood glucose (diabetics), renal and liver function.

Symptoms: Severe hypotension, bradycardia, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, vomiting, disturbed consciousness and generalised seizures. Management: Initiate supportive treatment. Monitor vital parameters. Administer atropine IV for excessive bradycardia. In the case of drug resistant bradycardia, initiate pacemaker therapy. To support ventricular function, administer glucagon IV or sympathomimetics (e.g. dobutamine, isoprenaline). For peripheral vasodilation, administer norepinephrine with continuous monitoring of the circulation. For bronchospasm, administer β-sympathomimetics (aerosol or IV) or aminophylline via slow IV inj or infusion. Slow IV inj of diazepam or clonazepam may be given for seizures.

Additive effect with Ca channel blockers (e.g. diltiazem, verapamil), amiodarone, MAO inhibitors, reserpine, guanfacine, methyldopa. May increase atrioventricular conduction time and decrease heart rate with digitalis glycosides. Increased serum concentrations of ciclosporin. Increased hypoglycaemic effect of insulin and oral antidiabetics. May cause synergistic, negative inotropic and hypotensive effect with anaesthetics. Serum concentration may be reduced by CYP450 inducers (e.g. rifampicin, barbiturates) or increased by CYP450 inhibitors (e.g. ketoconazole, cimetidine, fluoxetine, haloperidol, erythromycin). Increased vasoconstriction effect with ergotamine.

Decreased rate of absorption and risk of orthostatic hypotension with food.

Description:
Mechanism of Action: Carvedilol is a non-selective β-blocker. It reduces peripheral vascular resistance by selective α₁ receptor blockade and suppresses renin-angiotensin system through non-selective β-blockade. Carvedilol has weak membrane stabilising properties and has no intrinsic sympathomimetic activity.
Onset: Antihypertensive: Within 30 minutes (α-blockade); within 1 hour (β-blockade).
Pharmacokinetics:
Absorption: Rapidly and extensively absorbed from the gastrointestinal tract, undergoes first pass effect. Rate of absorption is delayed with food. Absolute bioavailability: Approx 25-35% (immediate release). Time to peak plasma concentration: Approx 1 hour (immediate release); approx 5 hours (extended release).
Distribution: Distributed into extravascular tissues and is highly lipophilic. Plasma protein binding: >98% primarily to albumin. Volume of distribution: 115 L.
Metabolism: Extensively metabolised in the liver via CYPD2D6 and CYP2C9 enzymes by glucuronidation and aromatic ring oxidation, oxidative metabolites are further metabolised by conjugation via glucuronidation and sulfation.
Excretion: Primarily via faeces; urine (<2%, unchanged). Elimination half-life: 7-10 hours.

Source: National Center for Biotechnology Information. PubChem Database. Carvedilol, CID=2585, https://pubchem.ncbi.nlm.nih.gov/compound/Carvedilol (accessed on Jan. 21, 2020)

Store below 30°C. Protect from moisture.

Beta-Blockers

C07AG02 - carvedilol ; Belongs to the class of alpha and beta blocking agents. Used in the treatment of cardiovascular diseases.

Luzum J, Sweet K, Binkley P et al. CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure. Pharm Res. 34:1615-1625. doi: 10.1007/s11095-017-2104-8. Accessed 15/11/2019. PMID: 28181117

Takekuma Y, Takenaka T, Kiyokawa M et al. Evaluation of Effects of Polymorphism for Metabolic Enzymes on Pharmacokinetics of Carvedilol by Population Pharmacokinetic Analysis. Biol. Pharm Bull. 30(3):537-542. doi: 10.1248/bpb.30.537. Accessed 15/11/2019. PMID: 17329852

Annotation of FDA Label for Carvedilol and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 15/11/2019.

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Clinical Annotation for CYP2D6*1, CYP2D6*10, CYP2D6*2, CYP2D6*4, CYP2D6*5; Carvedilol Heart Diseases. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 15/11/2019.

Clinical Annotation for CYP2D6*1, CYP2D6*4; Carvedilol, Heart Failure. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 15/11/2019.

Coreg (GlaxoSmithKline). U.S. FDA. https://www.fda.gov/. Accessed 15/11/2019.

Coreg Tablets and Coreg CR Extended Release Capsules. U.S. FDA. https://www.fda.gov/. Accessed 26/11/2013.

Joint Formulary Committee. Carvedilol. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 26/11/2013.