IMDUR 60 MG TABLETS

Indications

• Angina pectoris
• Stable angina
• Variant angina

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing guidelines.

Adults: The usual starting dose for adults is 20 mg once daily, which may be increased based on response, typically up to 120 mg daily in divided doses.

Mechanism of action

Isosorbide mononitrate acts as a prodrug for nitric oxide (NO), which is a potent vasodilator gas released upon drug metabolism. NO activates soluble guanylyl cyclase in vascular endothelial cells, increasing intracellular cyclic GMP (cGMP) concentrations. cGMP activates cGMP-dependent protein kinases, leading to reduced intracellular calcium concentrations through several mechanisms, resulting in relaxation of smooth muscle cells.

Pharmacodynamics

Isosorbide mononitrate is an anti-anginal agent and vasodilator that relaxes vascular smooth muscle to prevent and manage angina pectoris. The pharmacological action is mediated by nitric oxide, which predominantly relaxes the veins, reducing central venous pressure and cardiac preload. This can lead to decreased stroke volume and potential postural hypotension in healthy individuals. At therapeutic doses, it mainly affects larger muscular arteries, reducing systemic vascular resistance and cardiac afterload, while also opposing coronary artery spasms.

Pharmacokinetics

Isosorbide mononitrate is well absorbed from the gastrointestinal tract, with a bioavailability of approximately 100% due to its first-pass metabolism being avoided. The drug has a half-life of about 5 hours, allowing for twice-daily dosing in most cases. It is primarily excreted in the urine as its metabolites, with minimal excretion of unchanged drug.

Adverse effects

• Headache
• Dizziness
• Hypotension
• Nausea
• Flushing
• Palpitations

Interactions

• Concurrent use with phosphodiesterase-5 inhibitors (e.g., sildenafil) may lead to severe hypotension
• Antihypertensive agents may enhance the hypotensive effect
• Alcohol may increase the vasodilatory effects

Precautions

• Use with caution in patients with hypotension
• Caution in patients with aortic stenosis or hypertrophic obstructive cardiomyopathy
• Monitor for signs of tolerance with long-term use

Pregnancy

Isosorbide mononitrate should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether isosorbide mononitrate is excreted in human milk. Caution should be exercised when administering to a nursing mother.

Storage

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

Formulations

• Tablets
• Extended-release tablets

Mechanism of action

Isosorbide mononitrate acts as a prodrug for nitric oxide (NO), which is a potent vasodilator gas that is released when the drug is metabolized. NO activates soluble guanylyl cyclase in vascular endothelial cells, which increases the intracellular concentrations of cyclic GMP (cGMP). cGMP activates cGMP-dependent protein kinases, such as protein kinase G and I, which activates the downstream intracellular cascades. The downstream cascade results in reduced intracellular concentrations of calcium, caused by processes including inhibition of IP₃-mediated pathway, phosphorylation of big calcium-activated potassium channel leading to cell hyperpolarization and reduced calcium influx, and increased calcium efflux via the Ca2+-ATPase-pump. Reduced intracellular calcium concentrations lead to the dephosphorylation of myosin light chains and the relaxation of smooth muscle cells.

Pharmacodynamics

Isosorbide mononitrate is an anti-anginal agent and vasodilator that relaxes vascular smooth muscle to prevent and manage angina pectoris. The pharmacological action is mediated by the active metabolite, [nitric oxide], which is released when isosorbide mononitrate is metabolized. Nitric oxide works on both arteries and veins, but predominantly veins: by relaxing veins and reducing the central venous pressure, nitric oxide causes venous pooling and a decrease in the venous return to the heart, thus decreasing cardiac preload. In healthy subjects, the stroke volume is decreased and venous pooling can occur in the standing posture, leading to postural hypotension and dizziness. At therapeutic doses of isosorbide mononitrate, nitric oxide has a bigger effect on larger muscular arteries over small resistance arteries. Arterial relaxation leads to reduced systemic vascular resistance and systolic blood (aortic) pressure, decreasing to decreased cardiac afterload. The direct dilator effect on coronary arteries opposes the coronary artery spasm in variant angina or angina pectoris. At larger doses, nitric oxide causes the resistance arteries and arterioles to dilate, reducing arterial pressure via coronary vasodilatation. This leads to increased coronary blood flow. Reduced cardiac preload and afterload caused by nitric oxide causes a reduction in myocardial oxygen consumption; decreased myocardial oxygen demand, along with increased coronary blood flow, leads to an increased in the oxygen content of coronary sinus blood and the relief from ischemia. The end effect of isosorbide mononitrate include decreased cardiac oxygen consumption, redistribution coronary flow toward ischemic areas via collaterals, and the relief of coronary spasms. Nitric oxide can also increase the rate of relaxation of cardiac muscles, which is an effect outside of vascular smooth muscles. Organic nitrates can also relax other types of smooth muscles, including esophageal and biliary smooth muscle. The anti-anginal activity of isosorbide mononitrate was observed about 1 hour after dosing, and the peak effect was achieved from 1-4 hours after dosing. The duration of anti-anginal action of at least 12 hours was observed with an asymmetrical dosing regimen.