CARVICARD-25

Indications

• Hypertension
• Angina
• Chronic heart failure
• Heart failure adjunct therapy

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: Initially 12.5 mg once daily for 2 days, then increased to 25 mg once daily; dosage can be increased if necessary up to 50 mg daily, with increases at intervals of at least 2 weeks.

Mechanism of action

Carvedilol inhibits exercise-induced tachycardia by blocking beta-adrenergic receptors, which reduces adrenergic stimulation in the myocardium. Its action on alpha-1 adrenergic receptors relaxes vascular smooth muscle, decreasing peripheral vascular resistance. At higher doses, it may exhibit calcium channel blocking and antioxidant activity, preventing the oxidation of low-density lipoprotein. The drug is a racemic mixture, with the S(-)-enantiomer responsible for beta-adrenergic blockade.

Pharmacodynamics

Carvedilol effectively reduces heart rate and blood pressure due to its dual action as a beta and alpha-1 antagonist. It has a long duration of action, generally requiring once-daily dosing, and demonstrates a broad therapeutic index. Abrupt discontinuation of carvedilol can exacerbate coronary artery disease, necessitating careful tapering when stopping treatment.

Pharmacokinetics

Carvedilol is well-absorbed after oral administration, with peak plasma concentrations typically occurring 1 to 2 hours post-dose. It undergoes extensive first-pass metabolism in the liver, leading to variable bioavailability. The drug is primarily eliminated by hepatic metabolism, with a half-life of approximately 7 to 10 hours. Renal function does not significantly impact its metabolism, making it suitable for patients with varying degrees of renal impairment.

Contra-indications

• Asthma
• Cardiogenic shock
• Hypotension
• Marked bradycardia
• Metabolic acidosis due to beta-blockade
• Phaeochromocytoma (except when used with alpha-blockers)
• Prinzmetal’s angina
• Second-degree AV block
• Third-degree AV block
• Uncontrolled heart failure

Adverse effects

• Abdominal discomfort
• Bradycardia
• Confusion
• Depression
• Diarrhoea
• Dizziness
• Dry eye (reversible on discontinuation)
• Dyspnoea
• Erectile dysfunction
• Fatigue
• Headache
• Heart failure
• Nausea
• Paraesthesia
• Peripheral coldness
• Peripheral vascular disease
• Rash (reversible on discontinuation)
• Sleep disorders
• Syncope
• Visual impairment
• Vomiting
• Atrioventricular block
• Bronchospasm
• Hallucination

Interactions

• Carvedilol may increase exposure to relugolix
• Carvedilol may decrease exposure to rifampicin

Precautions

• Monitor lung function in patients with a history of obstructive airway disease
• Use with caution in patients with diabetes mellitus due to risk of masking hypoglycaemic symptoms
• Gradual dose reduction is preferred when discontinuing to avoid rebound worsening of myocardial ischaemia
• Monitor patients for signs of toxicity, especially in infants if the mother is using carvedilol during breastfeeding

Pregnancy

Beta-blockers may cause intra-uterine growth restriction, neonatal hypoglycaemia, and systemic bradycardia; the risk is greater in severe hypertension.

Breast-feeding

With systemic use in the mother, infants should be monitored as there is a risk of possible toxicity; however, the amount in breast milk is generally too small to affect infants.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets: 12

Mechanism of action

Carvedilol inhibits exercise induced tachycardia through its inhibition of beta adrenoceptors. Carvedilol's action on alpha-1 adrenergic receptors relaxes smooth muscle in vasculature, leading to reduced peripheral vascular resistance and an overall reduction in blood pressure. At higher doses, calcium channel blocking and antioxidant activity can also be seen. The antioxidant activity of carvedilol prevents oxidation of low density lipoprotein and its uptake into coronary circulation. Carvedilol is a nonselective beta-adrenergic blocking agent 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. The precise mechanism of the beneficial effects of carvedilol in the treatment of congestive heart failure has not been fully elucidated. beta1-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. For more Mechanism of Action (Complete) data for CARVEDILOL (18 total), please visit the HSDB record page.

Pharmacodynamics

Carvedilol reduces tachycardia through beta adrenergic antagonism and lowers blood pressure through alpha-1 adrenergic antagonism. It has a long duration of action as it is generally taken once daily and has a broad therapeutic index as patients generally take 10-80mg daily. Patients taking carvedilol should not abruptly stop taking this medication as this may exacerbate coronary artery disease.