Glyceryl Trinitrate

Glyceryl trinitrate is a short acting organic nitrate that relaxes veins and, at higher doses, arteries. It relieves the pain of angina within minutes, treats acute heart failure with pulmonary oedema, and controls blood pressure in perioperative and obstetric emergencies when given intravenously. Tolerance develops quickly with continuous use. It is cheap, and sublingual tablets and sprays are widely available in East Africa, but the tablets lose strength once the bottle is opened.

Classification. Organic nitrate; nitric oxide donor; venodilator.

Mechanism. Converted to nitric oxide in vascular smooth muscle, raising cyclic GMP and causing relaxation. Veins dilate at low doses (lowering preload and ventricular wall tension); arteries and coronary vessels dilate at higher doses. Relieves ischaemia by lowering oxygen demand and, to a lesser extent, by improving supply.

Pharmacodynamics. Sublingual onset in 1 to 3 minutes, duration 20 to 30 minutes. IV onset within 1 to 2 minutes; duration only minutes after stopping. Transdermal patch onset in 30 to 60 minutes. Tolerance occurs within 24 to 48 hours of continuous exposure.

Pharmacokinetics. Extensive first pass metabolism, so oral bioavailability is under 1%; sublingual and transdermal routes avoid it. Half life 1 to 4 minutes. Metabolised in the liver and blood vessels by glutathione dependent enzymes to dinitrates; excreted in urine.

Acute angina (relief or before exertion), adult.

• Sublingual tablet 300 to 600 micrograms under the tongue, or oral spray 400 micrograms (1 to 2 sprays) under the tongue.

• Sit down; if pain persists after 5 minutes, repeat once; if pain persists 5 minutes after the second dose, call emergency help; maximum 3 doses within 15 minutes.

• Use 5 minutes before activity known to cause angina to prevent it.

Acute heart failure with pulmonary oedema, adult. Sublingual 400 to 800 micrograms every 5 to 10 minutes while setting up the IV infusion; IV infusion starting at 10 to 20 micrograms/minute, increased by 5 to 10 micrograms/minute every 5 to 10 minutes; usual 20 to 100 micrograms/minute; maximum 200 micrograms/minute (some units to 400). Keep systolic pressure above 100 mmHg.

Unstable angina and myocardial infarction with ongoing ischaemia, adult. Start the IV infusion at 10 micrograms/minute and titrate to pain relief and blood pressure.

Hypertensive emergency (perioperative or with acute coronary syndrome), adult. IV infusion 5 to 100 micrograms/minute.

Prevention of angina (specialist), adult. Transdermal patch 5 mg or 10 mg applied for 12 to 16 hours daily with a nitrate free interval of 8 to 12 hours; or buccal tablet 1 to 5 mg three times daily.

Chronic anal fissure (off label, specialist), adult. Rectal ointment 0.4% 2.5 cm (about 1.5 mg) twice daily for up to 8 weeks.

Children. IV 0.25 to 0.5 micrograms/kg/minute, titrated to effect (maximum 5 micrograms/kg/minute); specialist units only.

Contraindications. Concurrent phosphodiesterase type 5 inhibitor (sildenafil within 24 hours, tadalafil within 48 hours); severe hypotension or hypovolaemia; obstructive hypertrophic cardiomyopathy; severe aortic stenosis; severe anaemia; raised intracranial pressure (head injury, cerebral bleed); constrictive pericarditis and cardiac tamponade; right ventricular infarction (caution); closed angle glaucoma; hypersensitivity.

Warnings. Headache (common, usually settles), flushing, dizziness, and fainting (sit before use). Tolerance with continuous patches (leave a nitrate free interval). Methaemoglobinaemia with very high IV doses. Rebound angina on stopping long term patches suddenly. Do not use in hypotension. Tablets lose potency after 8 weeks of opening; keep in the original glass container, tightly closed.

Adverse effects. Headache, flushing, dizziness, hypotension, tachycardia, nausea, syncope, skin irritation (patch), methaemoglobinaemia.

Interactions. Sildenafil, tadalafil, vardenafil: profound, potentially fatal hypotension. Riociguat: contraindicated. Other antihypertensives, alcohol, tricyclic antidepressants: additive hypotension. Heparin: higher doses may be needed for effect. Aspirin: raises nitrate levels. Ergot alkaloids: reduced effect.

Special groups.

• Pregnancy: acceptable when needed (for example pre-eclampsia with pulmonary oedema); monitor maternal blood pressure.

• Breastfeeding: no data; use with caution.

• Patients of African ancestry: no dose change.

• Older adults: sit before use; risk of falls from hypotension.

• Kidney impairment: no adjustment.

• Liver impairment: no adjustment for single doses.

Formulations. Sublingual tablets 300, 500, 600 micrograms; spray 400 micrograms a dose; infusion 1 mg/mL (50 mg in 50 mL) and 5 mg/mL; transdermal patches 5 and 10 mg over 24 hours; buccal tablets 1, 2, 3 mg; rectal ointment 0.4%.

Administration. Sublingual: sit down, place under the tongue, do not swallow, spit out after pain relief. IV: use non polyvinyl chloride (glass or polyethylene) containers and sets as the drug sticks to polyvinyl chloride; dilute in 5% glucose or 0.9% sodium chloride; use by pump. Patches: apply to clean, hairless skin, rotate sites, remove at night.

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

Monitoring. Blood pressure and heart rate every 5 to 10 minutes during IV titration; continuous ECG in acute settings; chest pain relief. Review need for continued nitrate within 48 hours of an acute event.

Stopping. Taper IV infusions over hours when stopping after prolonged use; remove patches overnight (nitrate free interval).

Common prescribing errors. Giving to a patient who took sildenafil or tadalafil; leaving patches on 24 hours a day; using plain polyvinyl chloride tubing for infusions; prescribing in right ventricular infarction without volume; keeping tablets in a pill box or past 8 weeks of opening; failing to tell patients to sit and to call for help if pain lasts 5 minutes after the second dose.