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carvedilol (Coreg)

Tradename: Coreg. Indications: 1) heart failure* NYHA class II or III 2) use in conjunction with digoxin, diuretic & ACE inhibitor 3) angina pectoris in patients with idiopathic cardiomyopathy 4) decreased left ventricular function after myocardial infarction [6] 5) may protect against microabuminuria in patients with diabetes mellitus type 2 [8] 6) hypertension [10] * may be useful in patients with NYHA class IV heart failure [4] Contraindications: 1) asthma or bronchospastic disease 2) uncompensated congestive heart failure (NYHA class IV) 3) cardiogenic shock 4) severe bradycardia 5) 2nd or 3rd degree heart block 6) symptomatic hepatic disease 7) pregnancy* * contraception indicated during therapy Dosage: 1) all dosages should be taken with food 2) start 3.125 mg PO BID for 2 weeks 3) if tolerated, increase to 6.25 mg PO BID 4) double dose every 2 weeks until maximum tolerated dose is reached 5) max dose 25 mg PO BID if < 85 kg, 50 mg BID if > 85 kg Extended release: Coreg CR (QD dosing) - do NOT crush or chew the caps - CAN open them & sprinkle the beads on applesauce - diminished bioavailability relative to Coreg: conversion Coreg 6.25 mg BID -> Coreg CR 20 mg QD Coreg 12.5 mg BID -> Coreg CR 40 mg QD Pharmacokinetics: 1) oral bioavailability is 25-30% secondary to 1st pass effect 2) protein-binding > 98% 3) metabolized by cyt P450 2D6 & cyt P450 2C9 4) metabolites excreted primarily in feces & bile 5) poorly dialyzable [11] Adverse effects: 1) common (> 10%) - dizziness - diarrhea - hyperglycemia* 2) less common (1-10%) - bradycardia, postural hypotension, edema, somnolence, insomnia, fatigue, abdominal pain, back pain, rhinitis, pharyngitis, dyspnea 3) uncommon (< 1%) - AV block, palpitations, peripheral ischemia, syncope, ataxia, vertigo, depression, nervousness, malaise, pruritus, rash, decreased libido (male), constipation, hypercholesterolemia*, hyperuricemia, flatulence, xerostomia, impotence, anemia, leukopenia, increased LFTs, hyperbilirubinemia, paresthesias, myalgias, weakness, abnormal vision, tinnitus, asthma, cough * less tendency to cause hyperglycemia & dyslipidemia than metoprolol because of alpha-blocking [7] Drug interactions: 1) dizziness with coadministration of cyt P450 2D6 inhibitors a) fluoxetine b) quinidine c) paroxetine 2) decreased levels with coadministration of cyt P450 2D6 inducers - rifampin (70% reduction of carvedilol levels) 3) carvedilol may enhance the effects of hypoglycemic agents 4) conduction disturbance with concurrent administration of calcium channel blockers 5) clonidine may potentiate hypotensive & bradycardic effects 6) carvedilol increases digoxin levels 15% 7) cimetidine increases carvedilol levels by 30% 8) paroxetine, fluoxetine & amiodarone may increase carvedilol levels 9) any drug which inhibits cyt P450 2C9 or 2D6 can increase carvedilol levels 10) any drug which induces cyt P450 2C9 or cyt P450b 2D6 can diminish carvedilol levels Mechanism of action: 1) racemic mixture of a) non-selective beta-adrenergic receptor antagonist activity in S(-) enantiomer & b) alpha-1-adrenergic receptor antagonist activity in both enantiomers 2) diminished cardiac output 3) diminished exercise-induced tachycardia 4) diminished reflex-induced tachycardia 5) induces vasodilation 6) reduces peripheral vascular resistance 7) has anti-oxidant effects on ischemic tissue 8) reduces mortality (23%) after MI

Interactions

drug interactions drug adverse effects (more general classes)

Related

cytochrome P450 2C9; cytochrome P450 BP-1; cytochrome P450 MP-4; S-mephenytoin-4-hydroxylase; limonene 6-monooxygenase; limonene 7-monooxygenase (CYP2C9, CYP2C10) cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6)

General

antiarrhythmic agent, Group II non-specific beta-adrenergic receptor antagonist (non-specific beta-blocker)

Properties

MISC-INFO: elimination route LIVER protein-binding >98% safety in lactation ?

Database Correlations

PUBCHEM cid=2585

References

  1. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998 Department of Veterans Affairs, VA National Formulary - restricted to patients with CHF
  3. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  4. Journal Watch 23(6):46, 2003 Krum H, Roecker EB, Mohacsi P et al, Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS Study. JAMA. 2003 Feb 12;289(6):712-8. PMID: 12585949
  5. Galaxo
  6. Prescriber's Letter 10(7):37 2003
  7. Prescriber's Letter 12(1): 2005 Carvedilol: is it a Better Choice in Patients with Diabetes? Detail-Document#: 210102 (subscription needed) http://www.prescribersletter.com
  8. Internal Medicine News, April 15, 2005
  9. Prescriber's Letter 14(3): 2007 New Formulation: Coreg CR (Carvedilol Extended-release) Detail-Document#: 230305 (subscription needed) http://www.prescribersletter.com
  10. Deprecated Reference
  11. Zhou H et al beta-blocker use and risk of mortality in heart failure patients initiating maintenance dialysis. Am J Kidney Dis 2021 May; 77:704 PMID: 33010357 https://www.ajkd.org/article/S0272-6386(20)31001-5/fulltext