Organic Nitrates

Organic nitrates release nitric oxide, which activates guanylate cyclase and raises cyclic GMP in vascular smooth muscle, causing relaxation. Venodilation lowers preload and ventricular wall tension, arterial and coronary dilation lowers afterload and relieves spasm, and the result is lower myocardial oxygen demand and better subendocardial flow. They relieve angina and pulmonary congestion but do not improve survival.

Members. Glyceryl trinitrate (nitroglycerin), isosorbide dinitrate and isosorbide mononitrate.

Pharmacokinetics. Glyceryl trinitrate has high first pass metabolism, so it is given sublingually, as spray, buccally, transdermally or intravenously, with onset in 1 to 3 minutes by sublingual route and half-life of about 3 minutes. Isosorbide dinitrate undergoes first pass metabolism to active mononitrate metabolites. Isosorbide mononitrate has near-complete oral bioavailability and a half-life of about 5 hours.

Tolerance. Continuous exposure leads to loss of effect within 24 to 48 hours through depleted sulphydryl groups and oxidative stress. A nitrate-free period of 8 to 12 hours each day restores effect.

• Glyceryl trinitrate: short-acting; acute relief, prophylaxis before exertion, intravenous infusion in acute coronary syndrome and acute pulmonary oedema, and topical use for anal fissure.
• Isosorbide dinitrate: oral, longer acting; angina and heart failure (with hydralazine).
• Isosorbide mononitrate: oral; maintenance prophylaxis, once or twice daily.

• Acute angina: glyceryl trinitrate sublingual tablet 300 to 600 micrograms or spray 400 micrograms (1 to 2 puffs), sitting down, repeated after 5 minutes up to 3 doses.
• Prophylaxis: isosorbide mononitrate 20 mg twice daily (8 am and 2 pm) or modified-release 30 to 120 mg once daily in the morning; isosorbide dinitrate 10 to 40 mg two or three times daily with asymmetric timing; glyceryl trinitrate patch 5 to 10 mg over 12 hours, removed for the rest of the day.
• Acute coronary syndrome and acute pulmonary oedema: glyceryl trinitrate intravenous infusion starting at 10 to 20 micrograms/minute, increased every 5 to 10 minutes to 200 micrograms/minute, guided by pain, blood pressure and congestion. In severe pulmonary oedema with high blood pressure, higher doses and sublingual boluses are used with close monitoring.
• Heart failure in patients of African ancestry: isosorbide dinitrate 20 to 40 mg with hydralazine 25 to 75 mg three times daily.
• Anal fissure: topical glyceryl trinitrate 0.4% ointment applied twice daily.
• Oesophageal spasm: sublingual nitrate before meals.
• Selection: use the shortest-acting form for acute relief and a nitrate-free interval for prophylaxis. Glyceryl trinitrate tablets lose potency, so keep them in the original glass container and replace as the label instructs.

Contraindications. Use of sildenafil or vardenafil within 24 hours, tadalafil within 48 hours, or riociguat. Severe aortic stenosis, hypertrophic obstructive cardiomyopathy, systolic blood pressure under 90 mmHg, right ventricular infarction, severe anaemia, raised intracranial pressure, pericardial tamponade and constrictive pericarditis.

Adverse effects. Headache (often limiting), flushing, dizziness, postural hypotension, syncope, reflex tachycardia, and methaemoglobinaemia with high doses. Tolerance reduces effect without a nitrate-free period.

Interactions. Phosphodiesterase 5 inhibitors cause profound hypotension. Antihypertensives, alcohol and other vasodilators add hypotension. Heparin infusion may reduce intravenous glyceryl trinitrate effect.

Monitoring. Blood pressure and heart rate (continuous with infusion), symptom response, and methaemoglobin where high doses are used.

Referral and escalation. Chest pain not relieved by two doses 5 minutes apart needs emergency care. Severe hypotension from nitrates is treated by lying the patient flat, raising the legs and giving fluids.

Special groups. Older adults: sit before dosing to avoid falls. Pregnancy: used cautiously. Children: rarely used. Region: counsel on cost-related reuse of expired tablets.