Isosorbide Mononitrate

Isosorbide mononitrate is an oral organic nitrate that prevents angina by relaxing veins and, to a lesser degree, arteries. Unlike glyceryl trinitrate, it is the active metabolite itself, so it has almost complete oral bioavailability and a long duration. It does not relieve an attack once it has started. Continuous exposure causes tolerance, so dosing must leave a nitrate free interval each day. It is cheap and widely available in East Africa.

Classification. Organic nitrate; nitric oxide donor; venodilator.

Mechanism. Releases nitric oxide in vascular smooth muscle, raising cyclic GMP and causing relaxation. Venodilation lowers preload and wall tension; coronary dilation helps supply. Tolerance develops from depletion of sulphydryl groups and neurohormonal activation.

Pharmacodynamics. Oral onset in 30 to 60 minutes; peak at 1 to 2 hours (immediate release) or 3 to 4 hours (modified release); duration 6 to 8 hours (immediate release) and 12 to 14 hours (modified release). Lowers exercise induced ischaemia and increases exercise time.

Pharmacokinetics. Bioavailability almost 100% with no first pass loss. Half life 4 to 5 hours. Not bound to protein; metabolised in the liver to inactive compounds and excreted in urine.

Prevention of angina, adult.

• Immediate release: 20 mg twice daily, taken at 8 am and 2 pm (or 7 hours apart) to give a nitrate free interval of at least 14 hours overnight.

• Modified release: 30 to 60 mg once daily in the morning, increased to 120 mg if needed; maximum 240 mg daily in some labels.

• Start at the low end (10 mg twice daily, or 30 mg modified release) in older adults, if headache is a problem, or in low body weight.

Chronic heart failure (adjunct in selected patients), adult. Not a first line vasodilator; use isosorbide dinitrate with hydralazine instead in patients of African ancestry.

Children. Not established.

Contraindications. Concurrent phosphodiesterase type 5 inhibitor (sildenafil within 24 hours, tadalafil within 48 hours) or riociguat; severe hypotension or hypovolaemia; obstructive hypertrophic cardiomyopathy; severe aortic stenosis; constrictive pericarditis; cardiac tamponade; raised intracranial pressure; severe anaemia; acute circulatory failure; hypersensitivity.

Warnings. Headache, flushing and dizziness, especially in the first week. Tolerance with unbroken dosing. Rebound angina if stopped suddenly after long use (taper over days). Do not use to treat an acute attack. Methaemoglobinaemia is rare. Syncope on standing.

Adverse effects. Headache, flushing, dizziness, postural hypotension, tachycardia, nausea, weakness, palpitations.

Interactions. Phosphodiesterase type 5 inhibitors: profound hypotension (contraindicated). Other vasodilators, antihypertensives, alcohol: additive hypotension. Aspirin: may raise nitrate levels. Dihydroergotamine: raised ergot levels.

Special groups.

• Pregnancy: use only if clearly needed; limited data.

• Breastfeeding: no data; use with caution.

• Patients of African ancestry: no dose change.

• Older adults: start 10 mg twice daily or 30 mg modified release.

• Kidney impairment: no adjustment.

• Liver impairment: no adjustment in mild to moderate disease; use with caution in severe disease.

Formulations. Tablets 10, 20, 40 mg; modified release tablets 25, 30, 40, 50, 60, 120 mg.

Administration. Oral. Swallow modified release tablets whole in the morning. For immediate release, give the second dose about 7 hours after the first. Do not crush.

Baseline. Blood pressure (lying and standing), heart rate, haemoglobin, drug history for phosphodiesterase type 5 inhibitors.

Monitoring. Angina frequency and nitrate headache; blood pressure; tolerance (loss of effect). Review need after a stable period if revascularised.

Stopping. Reduce the dose gradually over several days to avoid rebound angina.

Common prescribing errors. Twice daily dosing at 12 hour intervals (no nitrate free interval, so tolerance); giving modified release more than once a day; giving with sildenafil or tadalafil; using it to treat an acute attack; starting at 60 mg in older adults.