Organic Nitrates
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Direct answer
Organic nitrates (glyceryl trinitrate, isosorbide dinitrate and mononitrate, nitroprusside) are prodrugs converted to nitric oxide, which activates guanylyl cyclase, raises cGMP and relaxes vascular smooth muscle — predominantly veins — reducing preload and myocardial oxygen demand. They relieve angina within minutes, treat acute coronary syndromes, acute left ventricular failure and oesophageal spasm; their signature problems are throbbing headache, reflex tachycardia, tolerance with continuous use (prevented by a nitrate-free interval of 8–12 hours), and dangerous hypotension when combined with PDE-5 inhibitors like sildenafil.
What you must remember
- Glyceryl trinitrate 0.5 mg sublingual: acts within 1–2 minutes, lasts up to 30 minutes; the tablet may be repeated every 5 minutes up to three doses, after which medical help is mandatory.
- Venodilatation dominates (preload), so nitrates shine in left ventricular failure and fail in preload-dependent states — aortic stenosis, right ventricular infarction — where they cause collapse.
- Headache is the commonest adverse effect and is dose-related; it usually responds to simple analgesia and tolerance develops.
- Tolerance develops within 24–72 hours of continuous exposure: use eccentric dosing, remove transdermal patches overnight, or switch to isosorbide mononitrate once daily.
- Sildenafil within 24 hours (tadalafil 48 hours) of a nitrate can cause profound hypotension — an absolute contraindication and a favourite single-best-answer stem.
- Isosorbide dinitrate is a prodrug largely converted to the active mononitrate, which has near-complete oral bioavailability and a long half-life.
- Sodium nitroprusside is a venous and arterial dilator for hypertensive emergencies; prolonged high-dose infusion causes cyanide toxicity (treated with thiosulfate and hydroxocobalamin).
- Intravenous nitrates in acute coronary syndrome are contraindicated with right ventricular infarction, marked hypotension, and recent PDE-5 inhibitor use.
Worked example — chest pain at the outpatient desk
A 60-year-old with effort angina asks how to use the small brown bottle he was prescribed, and the counselling session doubles as pharmacology revision. Tell him the tablet goes under the tongue and must sting or fizz slightly — if it does not dissolve with that sensation, the supply has lost potency, since sublingual glyceryl trinitrate degrades within months of the bottle being opened. Instruct him to sit down first: preload reduction in a standing patient produces syncope. Ask about sildenafil or tadalafil by name, because the combination is the single most dangerous drug interaction in this chapter. For prevention, convert him to isosorbide mononitrate 30 mg once daily in the morning so that the overnight nitrate-free interval prevents tolerance — the same logic that removes a transdermal patch at night. Then explain the headache he may feel in the first week, and that it fades. Finally, screen his other tablets: if he is on a beta-blocker, the reflex tachycardia from nitrates is already blunted, which is precisely why the two drugs combine so well in angina, whereas adding verapamil to a beta-blocker would not be.
Where students slip
Two examination answers go wrong repeatedly. The first: "nitrates dilate coronary arteries and increase flow" — the main antianginal effect in stable disease is demand reduction through preload fall; coronary dilatation matters chiefly in vasospastic angina, and nitrates with calcium channel blockers are the drugs of choice there while beta-blockers can worsen spasm. The second: tolerance management — students write "increase the dose", which is the one strategy that guarantees deeper tolerance; the correct answer is scheduling, a nitrate-free interval of 8–12 hours. A quieter point worth a mark: methaemoglobinaemia is a recognised complication of high-dose or prolonged nitrate/nitrite exposure (amyl nitrite famously) and is treated with methylene blue — and amyl nitrite itself survives in toxicology as part of the cyanide antidote kit.
Frequently asked questions
Why is sublingual the preferred route for acute anginal relief?
Sublingual absorption bypasses first-pass hepatic metabolism, giving therapeutic levels within 1–2 minutes — oral glyceryl trinitrate is almost useless because the liver destroys most of the first pass.
How is nitrate tolerance prevented?
By allowing a nitrate-free interval of 8–12 hours daily — eccentric twice-daily dosing of dinitrate, morning dosing of mononitrate, or overnight removal of transdermal patches.
Why are nitrates dangerous in right ventricular infarction?
The right ventricle is preload-dependent; venodilatation collapses right-sided filling and produces abrupt hypotension, so nitrates are withheld until volume is given.
Which class of drugs is absolutely contraindicated with nitrates?
Phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil); both pathways raise cGMP, and the combined effect can produce life-threatening hypotension.
What is the toxicity of sodium nitroprusside and its antidote?
Prolonged infusion releases cyanide, causing lactic acidosis, arrhythmia and tachyphylaxis; treatment is sodium thiosulfate (with or without hydroxocobalamin or nitrites) to detoxify cyanide to thiocyanate.