Isosorbide Dinitrate

Isosorbide dinitrate is an organic nitrate used to prevent and treat angina, to treat acute and chronic heart failure, and, combined with hydralazine, to treat heart failure with reduced ejection fraction in patients of African ancestry. It is converted in the liver to isosorbide mononitrate and other active metabolites. It acts faster than the mononitrate when given sublingually, but tolerance develops with unbroken dosing. It is widely available in East Africa as tablets and in some hospitals as an infusion.

Classification. Organic nitrate; nitric oxide donor; venodilator.

Mechanism. Releases nitric oxide, raising cyclic GMP and relaxing vascular smooth muscle. Venodilation lowers preload; arteriolar and coronary dilation lower afterload and improve supply. In heart failure, combined with hydralazine it reduces oxidative stress and nitric oxide loss.

Pharmacodynamics. Sublingual onset in 2 to 5 minutes, duration 1 to 2 hours. Oral onset in 15 to 40 minutes, duration 4 to 6 hours (immediate release) and 8 to 12 hours (modified release). IV onset within minutes.

Pharmacokinetics. Extensive first pass metabolism; oral bioavailability 10 to 90% (varies between patients). Half life 1 hour for the parent; the active mononitrate metabolite has a half life of 4 to 5 hours. Excreted in urine.

Angina prevention, adult.

• Immediate release: 10 to 40 mg two or three times daily; give at 8 am, noon and 4 pm, or twice daily 7 hours apart, to leave a nitrate free interval of at least 14 hours.

• Modified release: 40 to 80 mg once or twice daily (second dose at noon or early afternoon).

• Maximum 240 mg daily.

Acute attack of angina, adult (sublingual). 5 mg under the tongue; repeat after 5 minutes if needed; maximum 3 doses.

Acute left ventricular failure or pulmonary oedema, adult. IV infusion 2 to 12 mg/hour (start 1 to 2 mg/hour and increase every 10 to 15 minutes); maximum 20 mg/hour; or sublingual 5 to 10 mg.

Heart failure with reduced ejection fraction in patients of African ancestry (with hydralazine), adult. Isosorbide dinitrate 20 mg with hydralazine 37.5 mg three times daily; increase to isosorbide dinitrate 40 mg with hydralazine 75 mg three times daily as tolerated (target daily doses 120 mg and 225 mg). Add to a beta blocker, renin angiotensin agent and mineralocorticoid antagonist.

Oesophageal spasm (specialist), adult. 10 to 20 mg before meals.

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; closed angle glaucoma; hypersensitivity.

Warnings. Headache, flushing, dizziness and postural hypotension. Tolerance with unbroken dosing. Rebound angina if stopped suddenly. Methaemoglobinaemia with very high doses. Hypotension is more common when combined with hydralazine.

Adverse effects. Headache, flushing, dizziness, hypotension, tachycardia, nausea, vomiting, weakness, syncope.

Interactions. Phosphodiesterase type 5 inhibitors and riociguat: profound hypotension (contraindicated). Other antihypertensives, alcohol, tricyclic antidepressants: additive hypotension. Heparin: reduced anticoagulant effect (rare). Aspirin: raises nitrate levels.

Special groups.

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

• Breastfeeding: no data; use with caution.

• Patients of African ancestry: first choice nitrate partner with hydralazine in heart failure with reduced ejection fraction.

• Older adults: start 10 mg two to three times daily.

• Kidney impairment: no adjustment.

• Liver impairment: use with caution in severe disease (reduced conversion to active metabolites).

Formulations. Tablets 5, 10, 20, 30, 40 mg; modified release tablets 20, 40, 60, 80 mg; sublingual tablets 5 mg; injection 1 mg/mL.

Administration. Oral before meals with water; sublingual tablets under the tongue. IV: use glass or polyethylene containers and sets; dilute in 5% glucose or 0.9% sodium chloride; infuse by pump with blood pressure monitoring.

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

Monitoring. Angina frequency, blood pressure and heart rate; signs of heart failure; headache and dizziness. For IV use, blood pressure every 5 to 10 minutes during titration.

Stopping. Reduce the dose over several days after long term use to avoid rebound angina.

Common prescribing errors. Three times daily dosing with no nitrate free interval; giving with sildenafil or tadalafil; confusing it with the mononitrate (different doses and half life); omitting hydralazine in African ancestry heart failure; using plain polyvinyl chloride sets for IV infusion.