Nitrates

Quick revision

Nitrates are converted to nitric oxide, which switches on guanylyl cyclase and raises cyclic GMP inside vascular smooth muscle so the vessel relaxes; the effect is greatest in the veins, so preload falls, cardiac work falls and angina eases — and the two things that ruin nitrate therapy are tolerance, which needs a daily nitrate-free interval, and combination with a PDE5 inhibitor, which can drop the blood pressure catastrophically.

• Nitrates release nitric oxide, the endothelium-derived relaxing factor, which activates guanylyl cyclase and converts guanosine triphosphate into cyclic GMP. (1) (2)
• Rising cyclic GMP activates cGMP-dependent protein kinases, which reduce calcium availability and switch off myosin light chain kinase, so vascular smooth muscle relaxes. (2)
• Nitrates dilate venous capacitance vessels, arterioles and coronary arteries, but the maximal effect is on the venous capacitance vessels. (2)
• Venodilation pools blood in the venous system and reduces preload — the volume of blood returning to and filling the heart — which lowers cardiac work and relieves anginal symptoms. (1)
• Reduced preload lowers myocardial oxygen demand, while coronary dilation improves perfusion, so supply and demand move in the helpful direction together. (2)
• Sublingual glyceryl trinitrate starts working in one to three minutes with a maximum effect at about five minutes, and its half-life is only two to three minutes. (1)
• Isosorbide dinitrate undergoes extensive first-pass metabolism in the liver, so its oral bioavailability is around 20% and its elimination half-life is about one hour. (2)
• Isosorbide mononitrate escapes the first-pass effect, so oral bioavailability is 100% and the elimination half-life is five to six hours — which is what makes it the once-daily prophylactic option. (2)
• Tolerance can develop within as little as 12 to 24 hours of continuous exposure, after which the clinical effect fades. (2) (3)
• Preventing tolerance requires a daily nitrate-free interval, described as at least 10 to 12 hours; continuous intravenous infusion is a recognised way to induce tolerance. (2) (1)
• Headache affects more than 10% of patients and can be severe, throbbing and persistent; hypotension, orthostatic symptoms, flushing, reflex tachycardia and syncope follow from the vasodilation. (2) (1)
• Concurrent use with a phosphodiesterase-5 inhibitor such as sildenafil, vardenafil or tadalafil is absolutely contraindicated because the combination can cause life-threatening hypotension. (1) (2)
• Riociguat, a soluble guanylate cyclase stimulator, is contraindicated with nitrates for the same reason — both raise cyclic GMP and the effects stack. (2)
• Right ventricular infarction is a contraindication, because a preload-dependent right ventricle can be tipped into profound hypotension and cardiogenic shock. (1) (2)
• Hypertrophic cardiomyopathy is also listed as an absolute contraindication to nitrate therapy. (2) (3)
• Methaemoglobinaemia is a rare complication, arising when nitrate ions released during metabolism oxidise haemoglobin; methylene blue can act as an antidote. (2)

Overview

Nitrates are among the oldest cardiovascular drugs still in daily use, and their pharmacology is unusually clean. Each of them is a source of nitric oxide, the molecule the endothelium itself releases to relax the vessels it lines. Once released, nitric oxide activates guanylyl cyclase, which converts guanosine triphosphate into cyclic GMP. Cyclic GMP then activates protein kinases that reduce the calcium available to the contractile machinery and inactivate myosin light chain kinase, and the smooth muscle relaxes. (1) (2)

Where that relaxation happens is what makes nitrates antianginal drugs rather than simply antihypertensive ones. They dilate venous capacitance vessels, arterioles and coronary arteries, but the effect is maximal on the veins. Blood pools in the venous system, so less returns to the heart; that fall in preload reduces the work the heart must do and with it the oxygen the myocardium needs. Coronary dilation improves the supply side at the same time, which is why the anginal symptom settles. (2) (1)

The clinical division within the class is about time course rather than mechanism. Glyceryl trinitrate given under the tongue acts within one to three minutes and disappears within minutes, which suits the acute attack. Isosorbide dinitrate is heavily metabolised by the liver on first pass, and isosorbide mononitrate avoids that step altogether, giving it a longer half-life and a prophylactic role. Transdermal glyceryl trinitrate patches are reserved for prophylaxis rather than for rescue. (1) (2)

Two problems dominate the safe use of the class. The first is tolerance: effect can be lost within 12 to 24 hours of continuous exposure, so a daily nitrate-free interval is built into treatment rather than being optional. The second is the interaction with drugs that act on the same cyclic GMP pathway. Phosphodiesterase-5 inhibitors prevent cyclic GMP being broken down and riociguat stimulates the enzyme that makes it, so either combination can produce hypotension described as life-threatening. (2) (1) (3)

Classification and drug examples

All therapeutic nitrates share one mechanism, so the class is divided by how fast a preparation acts and how long it lasts. That, in turn, is decided by the molecule and by the route — specifically, by whether the preparation has to survive a pass through the liver before reaching the circulation.

Mechanism of action

A nitrate is a nitric oxide delivery vehicle. Nitric oxide activates guanylyl cyclase in vascular smooth muscle, cyclic GMP accumulates, cGMP-dependent protein kinases lower intracellular calcium and inactivate myosin light chain kinase, and the vessel relaxes — most of all on the venous side, which is what makes the preload fall.

Molecular target

Soluble guanylyl cyclase in vascular smooth muscle, reached by nitric oxide released from the drug

1. The drug releases nitric oxide

   Organic nitrates are metabolised in the vessel wall to nitric oxide, the same endothelium-derived relaxing factor the body uses to regulate vascular tone. The drug is effectively substituting for an endogenous signal. (2) (1)

2. Nitric oxide switches on guanylyl cyclase

   The enzyme converts guanosine triphosphate into cyclic guanosine monophosphate, so cyclic GMP concentrations inside the smooth muscle cell rise. (1) (2)

3. Cyclic GMP relaxes the muscle

   Cyclic GMP activates cGMP-dependent protein kinases, which inhibit calcium release and deactivate myosin light chain kinase. Without calcium-driven myosin activation the contractile apparatus cannot maintain tone, so the vessel dilates. (2)

4. Veins respond more than arteries

   Venous capacitance vessels, arterioles and coronary arteries all dilate, but the maximal effect is venous. Blood is held in the venous compartment instead of returning to the heart. (2)

5. Preload falls and cardiac work falls with it

   Less blood returning to the heart means less stretch on the ventricle before contraction. Cardiac work drops, myocardial oxygen demand drops, and the mismatch between oxygen supply and demand that causes anginal pain narrows. (1) (2)

6. Coronary dilation adds to the supply side

   Dilation of the coronary arteries increases coronary perfusion, so nitrates improve supply as well as reducing demand. This is also the basis of their off-label use in coronary artery spasm. (2) (1)

7. Continuous exposure blunts the response

   Effect can be lost within 12 to 24 hours of uninterrupted exposure. This is tolerance, and the counter-measure is a daily interval without the drug rather than a larger amount of it. (2) (3)

8. The same pathway explains the dangerous interactions

   Phosphodiesterase-5 inhibitors prevent the breakdown of cyclic GMP and riociguat stimulates soluble guanylate cyclase. Either one, added to a nitrate, amplifies the same signal and can cause life-threatening hypotension. (2) (1)

Major clinical uses

Pharmacokinetics

• The route chosen is really a decision about the liver. Preparations that bypass first-pass metabolism act fast and suit rescue treatment; oral preparations that survive it or avoid it altogether suit prevention. (2) (1)
• Tolerance is the defining pharmacokinetic-pharmacodynamic problem of the class: uninterrupted exposure over 12 to 24 hours costs the drug its clinical effect, and a daily nitrate-free interval described as at least 10 to 12 hours is what restores it. (2) (3)
• Continuous intravenous nitrate infusion is a recognised way to generate tolerance, which is why transition to an intermittent oral schedule with long nitrate-free intervals is described. (1)
• Because glyceryl trinitrate is metabolised so quickly, there is no serum level to follow; monitoring is clinical, using blood pressure and symptom response. (1)
• Closer observation is described for patients with low blood pressure or heart rate, those on long-term diuretics, older patients with autonomic dysfunction, those taking other vasodilators and those who are volume-depleted. (2)
• This page gives no dose regimens by design. Amounts, intervals and formulations depend on the indication, the preparation and the individual patient, and belong in a prescribing reference used by the treating clinician.

Adverse effects

Common

• Headache: Occurs in more than 10% of patients and is the single most characteristic nitrate effect. With glyceryl trinitrate it can be severe, throbbing and persistent. (2) (1)
• Hypotension and orthostatic symptoms: A direct extension of the vasodilator action; dizziness, light-headedness and syncope belong to the same picture. (2) (1)
• Reflex tachycardia: The baroreflex response to a falling blood pressure, reported among the common nitrate effects. (2)
• Cutaneous flushing: Dilation of skin vessels, reported alongside the other vasodilator effects. (2)
• Nausea and vomiting: Described with both glyceryl trinitrate and isosorbide, along with weakness, palpitations, vertigo and sweating. (1) (2)

Serious adverse effects

• Life-threatening hypotension with a PDE5 inhibitor or riociguat: Combining a nitrate with sildenafil, vardenafil, tadalafil or riociguat raises cyclic GMP far beyond the intended level, accentuating the hypotensive effect and precipitating syncope. The combination is listed as an absolute contraindication rather than a caution, and the medication history has to be established before a nitrate is given. (1) (2)
• Profound hypotension and cardiogenic shock in right ventricular infarction: A right ventricle damaged by infarction depends on filling pressure to sustain output, so the preload reduction that normally helps becomes harmful. Right ventricular infarction is an explicit contraindication; recognising it before giving a nitrate is the safeguard. (1)
• Methaemoglobinaemia: A rare complication in which nitrate ions released during metabolism oxidise haemoglobin into methaemoglobin, which cannot carry oxygen normally. Diagnosis requires an arterial or venous blood gas with co-oximetry, and methylene blue can work as an antidote. (2)
• Loss of effect through tolerance: Not a toxicity but a safety issue in its own right, because a patient may believe they are protected when the drug has stopped working; it can appear within 12 to 24 hours of continuous exposure. A daily nitrate-free interval is built into treatment, and unexplained loss of symptom control prompts review by the treating clinician. (2) (3)
• Overdose picture: Excess nitrate produces profound systemic hypotension, heart block with bradycardia, syncope, nausea, vomiting and raised intracranial pressure. Management described includes stopping the drug, passive leg elevation and intravenous fluid, given cautiously where renal failure or heart failure is present. (2)

Drug-specific effects

• Glyceryl trinitrate: The severe throbbing headache and the rapid, marked blood pressure fall that follow its speed of onset; phlebitic and haemodynamic effects make real-time blood pressure monitoring standard during intravenous use. (1)
• Isosorbide dinitrate: Monday disease — tachycardia, dizziness and headache on re-exposure after a drug-free interval, arising from tolerance built up during continuous therapy. (2)
• Isosorbide mononitrate: Its complete bioavailability and longer half-life make sustained exposure easy to achieve, which is precisely why a daily drug-free part of the day matters with it. (2)

Contraindications, precautions and interactions

Contraindications

• Concurrent use of a phosphodiesterase-5 inhibitor such as sildenafil, vardenafil or tadalafil. (1) (2)
• Concurrent use of riociguat, a soluble guanylate cyclase stimulator. (2)
• Right ventricular infarction. (1) (2)
• Hypertrophic cardiomyopathy. (2) (3)
• Known allergy to nitrates, although a genuine allergic reaction is described as extremely rare. (2) (1)
• Raised intracranial pressure and severe anaemia, both listed as contraindications to glyceryl trinitrate. (1)

Precautions

• Low baseline blood pressure or heart rate, where the vasodilator effect has less margin. (2)
• Long-term diuretic therapy and volume depletion, both of which magnify the preload reduction. (2) (3)
• Older patients with autonomic dysfunction, in whom the reflex compensation for a falling blood pressure is impaired. (2)
• Concurrent treatment with other vasodilators, where hypotensive effects add together. (2)
• Pregnancy, listed among the situations warranting caution with nitrate therapy. (3)
• Uninterrupted dosing schedules, which are the setting in which tolerance develops and effect is silently lost. (2)

Drug interactions

• Phosphodiesterase-5 inhibitors (sildenafil, vardenafil, tadalafil): Accentuate the hypotensive effect of nitrates and can precipitate syncope; the combined rise in cyclic GMP is described as producing life-threatening hypotension. (1) (2)
• Riociguat: Stimulates soluble guanylate cyclase, so cyclic GMP rises from both directions at once and life-threatening hypotension can result. (2)
• Other vasodilators and antihypertensive drugs: Additive lowering of blood pressure, which is why closer observation is described when they are combined with a nitrate. (2)
• Diuretics: Long-term diuretic use is listed among the situations calling for closer monitoring, because volume depletion deepens the fall in preload. (2)
• Beta blockers: A deliberate pairing rather than a hazard in one setting: isosorbide mononitrate is licensed with a beta blocker for prevention of variceal haemorrhage. (2)
• Hydralazine: Also a deliberate combination — a fixed-dose product of isosorbide dinitrate with hydralazine hydrochloride is approved for heart failure in African American patients. (2)

Comparison tables

High-yield exam pearls

• Nitrates are venodilators first and everything else second. (2) (1) They dilate venous capacitance vessels, arterioles and coronary arteries, but the maximal effect is venous. That is why preload reduction, rather than afterload reduction or coronary dilation, is the principal way they relieve angina.
• The mechanism is a signalling cascade, and every important interaction sits on it. (2) (1) Nitric oxide raises cyclic GMP; PDE5 inhibitors stop cyclic GMP being broken down; riociguat stimulates the same guanylate cyclase that makes it. Combining any of them stacks the same signal and produces life-threatening hypotension.
• First-pass metabolism explains the whole mononitrate versus dinitrate distinction. (2) Isosorbide dinitrate is heavily extracted by the liver on first pass, leaving about 20% oral bioavailability and a one-hour half-life; isosorbide mononitrate bypasses that step entirely with 100% bioavailability and a five- to six-hour half-life.
• Sublingual dosing exists to dodge the liver. (2) (1) The sublingual route avoids the first-pass effect, which is why it is preferred when a rapid effect is needed, and why sublingual glyceryl trinitrate works within one to three minutes.
• Tolerance is a dosing-schedule problem, not a dose problem. (2) (1) (3) Effect can be lost within 12 to 24 hours of uninterrupted exposure, so the answer is a daily interval without drug rather than more drug. Continuous intravenous infusion is the classic way tolerance is generated.
• Monday disease is the tolerance story told backwards. (2) It describes tachycardia, dizziness and headache appearing on re-exposure after a drug-free interval, and it is attributed to the tolerance that develops during continuous therapy.
• Right ventricular infarction turns a helpful drug into a dangerous one. (1) An infarcted right ventricle depends on filling pressure to maintain output, so removing preload with a nitrate can cause profound hypotension progressing to cardiogenic shock.
• A blue patient on a nitrate who does not respond to oxygen suggests methaemoglobinaemia. (2) Nitrate ions released during metabolism can oxidise haemoglobin to methaemoglobin. The diagnosis is made on an arterial or venous blood gas with co-oximetry, and methylene blue is described as an antidote.

Common exam traps

• Trap: "Nitrates work mainly by dilating the coronary arteries." Actually: Coronary dilation contributes, but the dominant action is venodilation. Blood pools in the venous system, preload falls, cardiac work falls and the anginal symptom eases; arterial and coronary effects are secondary. (1) (2)
• Trap: "Isosorbide dinitrate is the right choice for an attack that is happening now." Actually: Its licensed role is prevention or treatment of angina pectoris but not the acute episode. Rapid relief is the job of a short-acting sublingual preparation, because the sublingual route avoids first-pass metabolism. (2)
• Trap: "A nitrate patch can simply be left on all the time for continuous protection." Actually: Uninterrupted exposure is exactly what produces tolerance, within as little as 12 to 24 hours. Maintaining effect requires a daily nitrate-free interval described as at least 10 to 12 hours, and transdermal patches are reserved for prophylaxis rather than acute relief. (2) (1)
• Trap: "A patient can take a nitrate as long as they took their erectile dysfunction tablet yesterday." Actually: Concurrent phosphodiesterase-5 inhibitor use is listed as an absolute contraindication, and the timing question is not one a page like this can settle. The interaction produces life-threatening hypotension and the decision belongs to the treating clinician with a current prescribing reference. (1) (2)
• Trap: "Nitrates are safe in every kind of myocardial infarction because they treat ischaemia." Actually: Right ventricular infarction is a specific contraindication. Preload reduction in that setting can cause profound hypotension and cardiogenic shock. (1)
• Trap: "Headache with a nitrate means an allergy." Actually: Headache is the expected pharmacological consequence of vasodilation and affects more than one in ten patients. True allergy to nitrates is listed separately and is described as extremely rare. (2) (1)

Self-test questions

Answers are hidden until you open them. These questions are written from this page's cited content and are for study only — they are not clinical guidance.

1. Through which second messenger do nitrates relax vascular smooth muscle?

   • Cyclic AMP, via adenylyl cyclase
   • Cyclic GMP, via guanylyl cyclase
   • Inositol trisphosphate, via phospholipase C
   • Diacylglycerol, via protein kinase C
   Show answer

   Answer: Cyclic GMP, via guanylyl cyclase

   Nitrates release nitric oxide, which activates guanylyl cyclase. That enzyme converts guanosine triphosphate into cyclic GMP, and the rise in cyclic GMP activates protein kinases that lower calcium availability and inactivate myosin light chain kinase, relaxing the muscle. (1) (2)

2. Which vascular bed shows the maximal nitrate effect?

   • Venous capacitance vessels
   • Renal afferent arterioles
   • Pulmonary capillaries
   • Cerebral arteries
   Show answer

   Answer: Venous capacitance vessels

   Nitrates dilate venous capacitance vessels, arterioles and coronary arteries, but the maximal effect is seen in the venous capacitance vessels. Pooling blood there reduces preload and therefore myocardial oxygen demand. (2)

3. Why does isosorbide mononitrate have much higher oral bioavailability than isosorbide dinitrate?

   • It is more water-soluble
   • It is given at a higher strength
   • It does not undergo the hepatic first-pass effect
   • It is absorbed through the buccal mucosa only
   Show answer

   Answer: It does not undergo the hepatic first-pass effect

   Isosorbide dinitrate undergoes an extensive first-pass effect in the liver, which cuts oral bioavailability to around 20% and leaves an elimination half-life of about one hour. Isosorbide mononitrate does not undergo that first-pass step, so bioavailability after oral administration is 100% and the half-life is five to six hours. (2)

4. How quickly can nitrate tolerance develop, and what prevents it?

   • Over several months; prevented by increasing the dose
   • Within 12 to 24 hours; prevented by a daily nitrate-free interval
   • Only after years of therapy; prevented by adding a diuretic
   • It does not develop with oral formulations
   Show answer

   Answer: Within 12 to 24 hours; prevented by a daily nitrate-free interval

   Tolerance may develop within as little as 12 to 24 hours, with a subsequent loss of clinical effect. A drug-free interval of at least 10 to 12 hours a day is what maintains responsiveness, and continuous intravenous infusion is a recognised route to tolerance. (2) (3)

5. Why is a phosphodiesterase-5 inhibitor absolutely contraindicated with a nitrate?

   • Because the PDE5 inhibitor blocks nitric oxide production
   • Because both drugs raise cyclic GMP, and the combination can cause life-threatening hypotension
   • Because the combination causes severe hypertension
   • Because the PDE5 inhibitor prevents nitrate absorption
   Show answer

   Answer: Because both drugs raise cyclic GMP, and the combination can cause life-threatening hypotension

   Phosphodiesterase-5 inhibitors such as sildenafil, vardenafil and tadalafil accentuate the hypotensive effect of nitrates and can precipitate syncope. The combined rise in cyclic GMP produces hypotension described as life-threatening, which is why the combination is listed as absolutely contraindicated. (1) (2)

6. Which infarct pattern makes nitrate use particularly hazardous?

   • Anterior left ventricular infarction
   • Lateral wall infarction
   • Right ventricular infarction
   • Old, healed inferior infarction
   Show answer

   Answer: Right ventricular infarction

   In right ventricular infarction, the reduction in preload produced by a nitrate can cause profound hypotension leading to cardiogenic shock. It is listed among the contraindications for that reason. (1)

7. What is Monday disease?

   • A withdrawal syndrome from beta blockers
   • Tachycardia, dizziness and headache on re-exposure to nitrate after a drug-free interval
   • A form of methaemoglobinaemia unique to mononitrates
   • An allergic reaction to nitrate patches
   Show answer

   Answer: Tachycardia, dizziness and headache on re-exposure to nitrate after a drug-free interval

   Monday disease arises from the tolerance that develops during continuous nitrate exposure. After a drug-free interval, re-exposure produces tachycardia, dizziness and headache as the vasodilator response returns. (2)

8. Which rare adverse effect of nitrates is diagnosed with co-oximetry and treated with methylene blue?

   • Methaemoglobinaemia
   • Haemolytic anaemia
   • Agranulocytosis
   • Carbon monoxide poisoning
   Show answer

   Answer: Methaemoglobinaemia

   Nitrate ions released during metabolism can oxidise haemoglobin into methaemoglobin, which cannot carry oxygen in the normal way. Blood gas analysis with co-oximetry is what confirms it, and methylene blue is the described antidote. (2)

Frequently asked questions

References

1. Nitroglycerin (StatPearls) StatPearls Publishing / NCBI Bookshelf, 2023
2. Isosorbide (StatPearls) StatPearls Publishing / NCBI Bookshelf, 2023
3. Nitrates (StatPearls) StatPearls Publishing / NCBI Bookshelf, 2023

Related drug classes

• Cardiac glycosides
• Sinus node and metabolic cardiac agents
• Beta blockers
• Dihydropyridine calcium channel blockers

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