CORGARD 40MG TABLET

Indications

• Hypertension
• Angina pectoris
• Arrhythmias
• Migraine prophylaxis
• Thyrotoxicosis (adjunctive therapy)

Dosage

Adults: Initially 40 mg once daily, increased in steps of up to 80 mg weekly if required, with a maximum dose of 240 mg per day.

Mechanism of action

Nadolol antagonizes beta-1 and beta-2 adrenoceptors, inhibiting cyclic AMP signaling in the heart which results in decreased strength and speed of myocardial contractions, as well as reduced heart rate and conduction velocity. In vascular smooth muscle, beta-2 blockade prevents relaxation, increasing peripheral vascular resistance. It also reduces renin release from the juxtaglomerular apparatus, limiting angiotensin II-mediated vasoconstriction and aldosterone-mediated fluid retention. Additionally, nadolol inhibits glycogenolysis in the liver and skeletal muscle and reduces insulin release from the pancreas.

Pharmacodynamics

Nadolol effectively lowers blood pressure through its action as a non-selective beta blocker, which allows for a long duration of action suitable for once-daily dosing. Its therapeutic index is wide, with starting doses often at 40 mg daily and the potential for escalation to 240 mg daily. Patients should be cautioned against abrupt discontinuation, as this may trigger exacerbation of ischemic heart disease.

Pharmacokinetics

Nadolol is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 2-4 hours after oral administration. It exhibits a prolonged elimination half-life, allowing for once-daily dosing. The drug is not extensively metabolized in the liver and is primarily excreted unchanged in the urine. Caution is advised in patients with renal impairment, as dosage adjustments may be necessary.

Contra-indications

• Severe bradycardia
• Sick sinus syndrome
• Second or third-degree AV block
• Cardiogenic shock
• Severe asthma or bronchospastic disease

Adverse effects

• Bradycardia
• Fatigue
• Dizziness
• Hypotension
• Cold extremities
• Depression
• Sexual dysfunction
• Gastrointestinal disturbances
• Insomnia
• Worsening of asthma

Interactions

• Propafenone (increases risk of cardiovascular adverse effects)
• Ciclosporin (increases exposure)
• Lapatinib (increases exposure)
• Macrolides (increases exposure)
• Ranolazine (increases exposure)
• Vemurafenib (increases exposure)

Precautions

• Caution in patients with renal impairment
• Caution in patients with hepatic impairment
• Monitor heart rate and blood pressure regularly
• Gradual withdrawal is advised to avoid exacerbation of ischemic heart disease

Pregnancy

Nadolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is classified as category C.

Breast-feeding

Nadolol is excreted in breast milk; caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Nadolol 40 mg tablets
• Nadolol 80 mg tablets
• Nadolol 120 mg tablets
• Nadolol 240 mg tablets

Mechanism of action

Although nadolol is described as a non selective beta blocker, it does not interact with beta 3 adrenal receptors. Antagonism of beta-1 and beta-2 adrenoceptors in the heart inhibits cyclic AMP and its signalling pathway, decreasing the strength and speed of contractions as well as the speed of relaxation and conduction. Antagonism of beta-2 adrenoceptors in the smooth muscle cells of the vasculature inhibits their relaxation, leading to an increase in peripheral vascular resistance and reducing the risk of severe hypotension. The increase in peripheral vascular resistance may contribute to the decrease in insulin sensitivity associated with nadolol use. Antagonism of beta-1 adrenoceptors in the juxtaglomerular apparatus of the kidney inhibits the release of renin, and therefore angiotensin II mediated vasoconstriction, aldosterone mediated water retention, and the release of epinephrine. Antagonism of beta-2 adrenoceptors in the liver and skeletal muscle inhibits glycogenolysis, in the lungs prevents bronchodilation, and in the pancrease inhibits insulin release. Nadolol inhibits response to adrenergic stimuli by competitively blocking beta1-adrenergic receptors within the myocardium and beta2-adrenergic receptors within bronchial and vascular smooth muscle. In the management of angina pectoris, the mechanism of action of nadolol is thought to be blockade of catecholamine induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure which result in a net decrease in myocardial oxygen consumption. However, nadolol may increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure, particularly in patients with heart failure. Through its beta-adrenergic blocking action, nadolol increases airway resistance (especially in asthmatic patients) and inhibits the release of free fatty acids and insulin by adrenergic stimulation. It has been postulated that beta-adrenergic blocking agents reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release. Nadolol decreases blood pressure in both supine and standing positions.

Pharmacodynamics

Nadolol is a nonselective beta adrenal receptor blocker that is used to lower blood pressure. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as patients start at doses of 40mg daily but may be increased to doses as high as 240mg daily. Patients taking nadolol should not aburptly stop taking it as this may lead to exacerbation of ischemic heart disease.