Carvedilol (carvedilol)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Carvedilol is a nonselective beta-adrenergic blocking agent (beta-blocker) with selective alpha1-adrenergic blocking activity.
Carvedilol is a nonselective beta-adrenergic blocking agent (beta-blocker) with selective alpha1-adrenergic blocking activity. The principal physiologic action of carvedilol is to competitively block adrenergic stimulation of beta-receptors within the myocardium (beta1-receptors) and within bronchial and vascular smooth muscle (beta2-receptors), and to a lesser extent alpha1-receptors within vascular smooth muscle. The beta1-antagonist activity of carvedilol is similar to that of propranolol and greater than that of labetalol, and the duration of carvedilol's effect is longer than those of labetalol and propranolol.
Studies in animals indicate that the drug may exert an antioxidant effect on the myocardium and an antiproliferative effect on intimal tissue. The commercially available drug is a racemic mixture of the 2 enantiomers, (R)(+) and (S)(-), and both enantiomers have equal alpha1-adrenergic blocking activity; however, only the S(-)-enantiomer of carvedilol has beta-adrenergic blocking activity. Carvedilol does not exhibit intrinsic sympathomimetic (beta1-agonist) activity and possesses only weak membrane-stabilizing (local anesthetic) activity.
Vasodilation resulting in reduced total peripheral resistance mediated through carvedilol's alpha1-adrenergic blockade and reduced sympathetic tone appear to play a major role in the drug's hypotensive effect. Carvedilol causes reductions in cardiac output, exercise-induced tachycardia, isoproterenol-induced tachycardia, and reflex orthostatic tachycardia. Clinically important beta-adrenergic blocking activity of carvedilol usually is evident within 1 hour of oral administration, and the drug's hypotensive effect is similar to that of metoprolol.
Carvedilol's alpha1-adrenergic blocking effects, which contribute to the drug's hypotensive effects, generally are evident within 30 minutes of oral administration and include reductions in phenylephrine-induced pressor effects, vasodilation, and decreased peripheral vascular resistance. The dose-dependent hypotensive effect of carvedilol results in blood pressure (systolic and diastolic) reductions of 5-46% with little, if any, reflex tachycardia. This hypotensive effect occurs approximately 30 minutes after oral administration and has a maximum effect 1.5-7 hours after oral administration.
Carvedilol reduces peripheral vascular resistance and blood pressure as a result of its vasodilating effects; the drug produces both arterial and venous dilation. Carvedilol reduces blood pressure in both supine and standing patients; as a result of alpha1-blockade, the effect is most pronounced on standing blood pressure, and orthostatic hypotension can occur. The manufacturer states that the frequency and severity of orthostatic hypotension may be decreased by administering the drug with food and by strictly adhering to the usual starting dose and titration recommendations. (See Dosage and Administration.)
The precise mechanism of the beneficial effects of carvedilol in the treatment of heart failure has not been fully elucidated. beta-Adrenergic blockade and vasodilation generally are associated with reflex tachycardia and peripheral vasoconstriction in therapeutic agents in which one of these pharmacologic effects predominates, but the combined effects of carvedilol appear to attenuate these two major untoward responses by balancing the potential adverse effects associated with adrenergic blockade and vasodilation. The drug's vasodilatory action appears to enable the patient to tolerate the negative inotropic effect of carvedilol during the initiation and titration of therapy in the treatment of compensated heart failure. Chronic adrenergic stimulation and resultant activation of the renin-angiotensin system associated with compensated chronic heart failure result in sodium retention and vasoconstriction that, in turn, can induce further increases in preload and afterload that decrease cardiac output and stimulate additional sympathetic output.
Some evidence suggests that the combined adrenergic effects of carvedilol, especially vasodilation, may ameliorate the negative inotropic effects that could otherwise lead to myocardial dysfunction in the compensating heart failure patient.
In patients with chronic heart failure and left ventricular dysfunction, carvedilol is associated with improvements in myocardial function through reduction in afterload as evidenced by improved left ventricular ejection fraction, reduced left ventricular volumes, and prevention of progression of left ventricular dilatation. Reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate were observed in patients with heart failure (New York Heart Association (NYHA) functional class II-IV) receiving angiotensin-converting enzyme (ACE) inhibitors, cardiac glycosides, and/or diuretics after initiating concurrent carvedilol therapy. During initial therapy with carvedilol, small and variable responses in cardiac output, stroke volume index, and systemic vascular resistance occur.
Chronic carvedilol therapy (12 -14 weeks) is associated with reductions in systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, and heart rate, and increased stroke volume index. Increases (7%) in left ventricular ejection fraction (LVEF) were observed in patients with heart failure (NYHA class II-III) receiving carvedilol at a target dosage of 25-50 mg twice daily for 26-52 weeks. The effect of carvedilol on LVEF was dose-related, with increases of 5, 6, and 8% reported with twice-daily doses of 6.25 mg, 12.5 mg, and 25 mg, respectively.
The precise mechanism of the beneficial effects of carvedilol in the treatment of left ventricular dysfunction following myocardial infarction (MI) has not been fully elucidated.
Carvedilol is rapidly and extensively absorbed following oral administration. Food decreases the rate of the drug's absorption (i.e., increases time to peak plasma concentration), but not the extent (i.e., no effect on bioavailability) of absorption. Administration with food may decrease the risk of orthostatic hypotension.
Carvedilol is substantially distributed into extravascular tissues. The half-life of carvedilol is 7-10 hours; 5-9 hours for R(+)-carvedilol, and 7-11 hours for S(-)-carvedilol. The drug is more than 98% bound to plasma proteins.
Carvedilol is extensively metabolized; phenol ring demethylation and hydroxylation produce 3 metabolites with beta-adrenergic blocking activity and (weak) vasodilating activity. Plasma concentrations of active metabolites are about 10% those of carvedilol. The 4'-hydroxyphenyl metabolite is 13 times more potent than carvedilol in beta-adrenergic blocking activity.
Carvedilol is excreted principally in feces as metabolites; less than 2% is excreted in urine unchanged.
Carvedilol is used for the management of hypertension and heart failure. Carvedilol also is used to reduce the risk of cardiovascular mortality in clinically stable patients with left ventricular dysfunction (manifested as a left ventricular ejection fraction (LVEF) of 40% or less) with or without symptomatic heart failure following an acute myocardial infarction (MI).
Generic name: carvedilol
Pronunciation: (KAR-ve-DIL-ol)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Carvedilol
Indications
The following indications are listed for Carvedilol:
- Heart Failure With Reduced Ejection Fraction Due To Dilated Cardiomyopathy
- Hypertension
- Left Ventricular Dysfunction Following Myocardial Infarction
Also known as: Elevated Blood Pressure, Essential Hypertension, Hfref Due To Dilated Cardiomyopathy, Hyperpiesia, Hyperpiesis, Hypertensive Disorder, Left Ventricular Dysfunction Following Acute Mi, Left Ventricular Dysfunction Following Acute Myocardial Infarction, Left Ventricular Dysfunction Following Ami, Left Ventricular Dysfunction Following Cardiac Infarct, Left Ventricular Dysfunction Following Cardiac Infarction, Left Ventricular Dysfunction Following Myocardial Infarct, Lv Dysfunction Following Mi, Systemic Arterial Hypertension, Systolic Heart Failure Due To Dilated Cardiomyopathy.
Dosing
Patients whose conditions are controlled with immediate-release carvedilol tablets alone or in combination with other drugs may be switched to carvedilol phosphate extended-release capsules. Patients who are receiving a daily carvedilol dosage of 6.25 (3.125 mg twice daily), 12.5 (6.25 mg twice daily), 25 (12.5 mg twice daily), or 50 mg (25 mg twice daily) as immediate-release tablets may be switched to a dosage of 10, 20, 40, or 80 mg once daily, respectively, as carvedilol phosphate extended-release capsules. Subsequent titration to higher or lower dosages may be necessary and should be guided by the patient's clinical response.
Carvedilol and carvedilol phosphate are administered orally. Food has little, if any, effect on the oral bioavailability of carvedilol immediate-release tablets but may decrease the rate of absorption, resulting in reduced and delayed peak plasma concentrations. Therefore, to potentially decrease the risk of orthostatic hypotension, it is recommended that carvedilol be administered with food. In addition, the manufacturer suggests that manifestations of vasodilation in patients receiving concomitant therapy with an angiotensin-converting enzyme (ACE) inhibitor may be reduced by administering carvedilol 2 hours prior to the latter drug.
Food increases the bioavailability of carvedilol phosphate extended-release capsules and the manufacturer states that the extended-release capsules should be taken with food. Carvedilol extended-release capsules should be taken once daily in the morning and should be swallowed whole; the capsule and/or its contents should not be crushed, chewed, or taken in divided doses. However, carvedilol extended-release capsules may be opened carefully and the entire contents sprinkled over a spoonful of applesauce, immediately prior to administration. The applesauce should not be warm, and the drug and applesauce mixture should be consumed in entirety. The drug and applesauce mixture should not be stored for future use. The absorption of the beads sprinkled on foods other than applesauce has not been studied.
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No dosing information is available for this tab.
Drug interactions
Metabolized by cytochrome P-450 (CYP) isoenzymes, principally CYP2D6 and CYP2C9; also metabolized to a lesser extent by CYP3A4, CYP2C19, CYP1A2, CYP2E1.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
Bronchial asthma or related bronchospastic conditions.
Second or third degree AV block.
Sick sinus syndrome or severe bradycardia (unless permanent pacemaker is in place).
Cardiogenic shock or decompensated heart failure requiring IV inotropic therapy; initiate carvedilol only after the patient is weaned from IV therapy.
Clinically apparent or otherwise severe hepatic impairment.
History of serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any ingredient in the formulation.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in 5% or more of patients with heart failure receiving immediate-release carvedilol tablets include dizziness, headache, fatigue, asthenia, arthralgia, hypotension, bradycardia, generalized edema, diarrhea, nausea, vomiting, hyperglycemia, weight gain, increased BUN, increased nonprotein nitrogen (NPN), increased cough, and abnormal vision.
Adverse effects reported in patients with left ventricular dysfunction following MI receiving immediate-release carvedilol tablets generally were similar to those in patients receiving the drug for the treatment of heart failure. Additional adverse effects reported in 3% or more of such patients include anemia, dyspnea, and pulmonary edema.
Adverse effects reported in 2% or more of patients receiving immediate-release carvedilol tablets for the treatment of hypertension include dizziness, bradycardia, diarrhea, insomnia, and postural hypotension.
Adverse effects reported in 2% or more of patients receiving extended-release carvedilol phosphate capsules for the treatment of hypertension include nasopharyngitis, dizziness, nausea, and peripheral edema.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
Safety and efficacy not established in children younger than 18 years of age.
In a clinical trial in pediatric patients (mean age 6 years, range 2 months to 17 years) with chronic heart failure (NYHA class II-IV), carvedilol resulted in beta-blockade activity as demonstrated by a placebo-corrected heart rate reduction of 4-6 beats/minute; however, no clinically important effect on treatment outcome was observed after 8 months of follow-up. Common adverse effects included chest pain, dizziness, and dyspnea.
Category C. (See Users Guide.)
Crosses the placenta in rats. Perinatal and neonatal distress have been reported with other alpha- and beta-blockers.
Distributed into milk in rats; not known whether distributed into human milk. Because of the risk of adverse effects in the infant, discontinue nursing or the drug, taking into account the importance of the drug to the woman.
No substantial differences in safety or efficacy relative to younger adults, but possibility exists of increased sensitivity to carvedilol in some individuals. Some clinicians suggest using a reduced initial carvedilol dosage in geriatric patients, since such patients are at increased risk of developing orthostatic hypotension and experience is limited regarding the use of the drug in patients 75 years of age or older. Plasma concentrations of carvedilol are about 50% higher in geriatric individuals than in younger individuals.
ICD codes
No ICD codes are available for this drug.
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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