Nitrates
High-yield Verified · Oct 2026Release nitric oxide, which activates soluble guanylate cyclase → cGMP → protein kinase G → myosin light-chain dephosphorylation → smooth-muscle relaxation — most of all in the veins.
Nursing view → administration, monitoring and patient teaching
Drugs
Mechanism
Metabolized to nitric oxide, which activates guanylate cyclase and raises cGMP in vascular smooth muscle, causing relaxation. Predominant venodilation reduces preload (and cardiac oxygen demand); higher doses add arterial and coronary vasodilation.
From prodrug to relaxed smooth muscle: NO → sGC → cGMP → PKG
Organic nitrates are bioactivated by mitochondrial or cytosolic aldehyde dehydrogenase (ALDH2) to nitric oxide (NO) — the same molecule as endothelium-derived relaxing factor, which the endothelium normally makes but which diseases such as atherosclerosis can deplete.
NO binds the ferrous (Fe²⁺) heme of the β1 subunit of soluble guanylate cyclase (sGC), changing its shape and switching on the catalytic domain, which converts GTP to cGMP. cGMP activates cGMP-dependent protein kinase I (PKG, cGK-I), which inhibits IP3-dependent calcium release, enhances calcium reuptake into the sarcoplasmic reticulum and opens calcium-activated potassium channels. Falling intracellular calcium inhibits myosin light-chain kinase; dephosphorylated myosin light chains let myosin heads detach from actin, and the smooth muscle relaxes.
The signal is ended by phosphodiesterases, which hydrolyze cGMP to inactive GMP. The NO–cGMP–PKG pathway also causes platelet disaggregation and prevents platelet adhesion.
Veins first: preload, afterload and the coronaries
Although nitroglycerin dilates both beds in a dose-related way, venous effects predominate. Dilating postcapillary vessels and large veins pools blood peripherally, cuts venous return and lowers left-ventricular end-diastolic pressure (preload). Arteriolar relaxation lowers systemic vascular resistance and arterial pressure (afterload), and the large epicardial coronary arteries dilate — although how much that coronary effect contributes to relief of exertional angina is unclear.
Myocardial oxygen demand falls (as measured by the pressure–rate product), so the supply–demand balance improves. Heart rate usually rises slightly as a compensatory response to the fall in pressure, and coronary perfusion pressure can be compromised if blood pressure falls too far or tachycardia shortens diastolic filling.
The effect on cardiac output depends on the starting point. With elevated filling pressures and high systemic vascular resistance, as in heart failure, cardiac index tends to rise; when filling pressures and cardiac index are normal, it may fall slightly.
Tolerance and rebound
Organic nitrates break the usual rule of keeping drug levels continuously above an effective concentration. In most exercise-testing trials, continuously delivered nitrates were no better than placebo after 24 hours or less; escalating the dose, even far above acute doses, consistently failed, and efficacy returned only after nitrates had been absent for several hours. Continuous IV nitroglycerin lost almost all of its hemodynamic effect by 48 hours, whereas 12-hour-a-day infusions did not.
Daily drug-free intervals of 10–12 hours are usually enough for nitroglycerin; immediate-release isosorbide dinitrate has needed at least 14 hours, consistent with its and its metabolites’ longer half-lives. Without rest periods, accumulating free radicals cause endothelial dysfunction; in a high-oxidant setting NO donors may form reactive nitrogen species. Animal data suggest hydralazine may mitigate nitrate tolerance.
The drug-free interval has a cost: in one trial, patients on nitroglycerin had less exercise tolerance at the end of the interval than those on placebo (rebound), and re-exposure after withdrawal can cause Monday disease — tachycardia, headache and dizziness.
Partners on the same pathway
Anything else that raises cGMP stacks with a nitrate. PDE5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil) block cGMP breakdown, and sGC stimulators such as riociguat increase cGMP synthesis independently of NO; with nitrates, both can cause hypotension, severe in the case of PDE5 inhibitors. Hydralazine, an arteriolar dilator, enhances vasodilation partly through cGMP-dependent mechanisms and pairs with isosorbide dinitrate in heart failure.
The nitrate ion released during metabolism can also oxidize hemoglobin from Fe²⁺ to Fe³⁺. Ferric hemoglobin cannot bind oxygen, so large exposures cause methemoglobinemia — a rare effect at ordinary doses.
Comparing the drugs
The three nitrates
| Drug | Main routes and onset | Bioavailability | Half-life | Active metabolites |
|---|---|---|---|---|
| Nitroglycerin | Sublingual: onset 1–3 min, maximum by 5 min; also spray, patch, ointment, IV | About 40% sublingual (variable); avoids first-pass metabolism | About 2–3 min | 1,2- and 1,3-dinitroglycerin (about 2% and 10% of the activity; about 10-fold longer half-lives) |
| Isosorbide dinitrate | Oral: antianginal effect from about 1 h | About 25% on average (10–90%); extensive first-pass metabolism | About 1 h | Isosorbide 5-mononitrate (75–85%) and 2-mononitrate (15–25%), both active |
| Isosorbide mononitrate | Oral: peak plasma level in 30–60 min (immediate-release) | About 100%; no first-pass metabolism | About 5 h | Is itself the major active metabolite of isosorbide dinitrate |
Daily drug-free interval needed to avoid tolerance: 10–12 h for nitroglycerin; at least 14 h for immediate-release isosorbide dinitrate.
Effect by vascular bed
| Drug | Effect | Consequence |
|---|---|---|
| Veins (predominant) | Dilation of postcapillary vessels and large veins | Peripheral pooling, ↓ venous return, ↓ LV end-diastolic pressure (preload) |
| Arterioles | Relaxation, dose-related | ↓ Systemic vascular resistance and arterial pressure (afterload); reflex tachycardia |
| Epicardial coronaries | Dilation | Contribution to exertional angina relief unclear; improves flow in vasospastic angina |
| Platelets | NO–cGMP–PKG signalling | Platelet disaggregation; less platelet adhesion |
Pharmacokinetics
- Sublingual route and first pass — nitroglycerin
- Sublingual nitroglycerin avoids first-pass metabolism, giving immediate, short relief: bioavailability about 40% (varying with sublingual hydration and mucosal metabolism), peak plasma level at 6–7 minutes, onset 1–3 minutes, maximum by 5 minutes and effect lasting at least 25 minutes. Oral nitrates need relatively larger doses because of hepatic metabolism.
- Ultra-rapid clearance — nitroglycerin
- Volume of distribution about 3 L/kg, cleared at close to 1 L/kg/min — far more than hepatic blood flow — with extrahepatic metabolism in red blood cells and vessel walls; the serum half-life is about 3 minutes. A liver reductase converts it to dinitroglycerins and, ultimately, glycerol.
- Transdermal delivery — nitroglycerin
- A patch reaches steady-state plasma levels by about 2 hours and holds them while worn; after removal, levels fall with a half-life of about an hour.
- Dinitrate metabolism — isosorbide dinitrate
- Absorption is nearly complete but bioavailability varies widely (10–90%, about 25% on average) because of extensive first-pass metabolism, and rises during chronic therapy. Clearance (2–4 L/min) exceeds hepatic blood flow, so extrahepatic metabolism must also occur; denitration yields the active 5-mononitrate (half-life about 5 hours) and 2-mononitrate (about 2 hours).
- Mononitrate — isosorbide mononitrate
- Absolute bioavailability about 100% because there is no first-pass metabolism; about 5% protein-bound. It is denitrated and glucuronidated, with 96% of a dose in urine within 5 days (about 2% unchanged). Its half-life is not prolonged in renal failure, cirrhosis or cardiac dysfunction.
- Interval length tracks half-life
- The tolerance-sparing drug-free interval is 10–12 hours for short-lived nitroglycerin but at least 14 hours for immediate-release isosorbide dinitrate, consistent with the longer half-lives of the dinitrate and its active metabolites.
Pharmacogenomics
Uses & drug choice
- Acute angina attack (sublingual nitroglycerin — rescue)
- Chronic angina prevention (long-acting isosorbide, transdermal patch)
- Acute coronary syndromes, acute heart failure, hypertensive emergency (IV nitroglycerin)
Adverse effects
- Throbbing headache
- Vasodilation and venous pooling increase the volume of blood in the cranial space. Headache is dose-related, worst at the start of therapy, and usually subsides with continued use.
- Flushing
- Cutaneous vasodilation — one of the side effects that come from the drug’s vasodilating action.
- Dizziness and orthostatic hypotension
- Venous pooling lowers venous return; severe hypotension is most likely with upright posture, volume depletion or preload-dependent states.
- Reflex tachycardia
- A compensatory sympathetic response to the fall in blood pressure; it also shortens diastolic filling time, which can compromise coronary perfusion.
- Severe hypotension and syncope (worse with PDE5 inhibitors)
- The nitrate drives cGMP synthesis while the PDE5 inhibitor blocks cGMP breakdown, so vasodilation is potentiated; sGC stimulators add cGMP synthesis independently of NO.
- Paradoxical bradycardia with increased angina
- When blood pressure falls too far, effective coronary perfusion pressure is lost; nitroglycerin-induced hypotension may be accompanied by paradoxical bradycardia and worsening angina.
Toxicity & antidote
Overdose is exaggerated vasodilation: hypotension, venous pooling and low cardiac output with compensatory tachycardia. Extra blood in the cranial space can raise intracranial pressure — persistent throbbing headache, confusion, vomiting and visual disturbance, progressing in severe cases to heart block, bradycardia, seizures and coma. There is no antagonist; increasing central volume (IV saline, leg elevation) is the approach, and epinephrine or other arterial vasoconstrictors are not recommended.
Methemoglobinemia is rare: nitrate ions oxidize hemoglobin iron from Fe²⁺ to Fe³⁺, which cannot carry oxygen. Suspect it with hypoxemia despite a normal arterial PO₂ and adequate cardiac output; the blood is chocolate-brown and does not redden in air. Methylene blue is the antidote, with NADH-methemoglobin reductase deficiency or G6PD deficiency as relative contraindications.
Interactions
Contraindications
- Recent PDE5-inhibitor use (sildenafil, vardenafil, tadalafil) — tadalafil’s label requires ≥ 48 h before a nitrate; the sildenafil and vardenafil labels say a safe interval is unknown — Both raise cGMP; together they cause profound, potentially fatal hypotension.
- Soluble guanylate cyclase (sGC) stimulators such as riociguat — Labeled contraindication — taking them together can cause hypotension.
- Acute circulatory failure or shock (caution with low SBP or volume depletion) — A labeled contraindication; in volume-depleted or already hypotensive patients even small doses can cause severe hypotension.
- IV nitroglycerin with pericardial tamponade, restrictive cardiomyopathy, or constrictive pericarditis — Labeled contraindication — in these conditions cardiac output depends on venous return, which nitroglycerin reduces.
- Right ventricular infarction — These hearts are preload-dependent; dropping preload can cause severe hypotension and collapse.
- Hypertrophic obstructive cardiomyopathy (caution in aortic stenosis) — Less preload shrinks the left ventricle and worsens the outflow obstruction; in aortic stenosis even small doses can cause severe hypotension.
- Increased intracranial pressure — Cerebral vasodilation can raise intracranial pressure further.
- Severe anemia — Labeled contraindication — large doses can turn hemoglobin into methemoglobin and worsen the anemia.
- Allergy to nitroglycerin, other nitrates or nitrites, or an ingredient — Labeled contraindication (hypersensitivity).
High-yield
- NO — nitrate bioactivated (ALDH2) to nitric oxide
- G — guanylate cyclase (soluble) makes cGMP
- K — kinase G lowers intracellular calcium; myosin light-chain kinase is inhibited
- Calm — myosin light chains dephosphorylated, smooth muscle relaxes (veins most)
- Need — continuous nitrates lose effect within 24 hours; higher doses do not fix it
- Night off — 10–12 hours drug-free for nitroglycerin (at least 14 hours for immediate-release dinitrate)
- Off has a price — rebound angina at the end of the interval, and Monday disease on re-exposure
Practice questions
Q1A 61-year-old man with stable angina took sildenafil the evening before he developed exertional chest pain. After one sublingual nitroglycerin tablet he becomes lightheaded and faints; blood pressure is 70/40 mm Hg.
Which mechanism explains the severity of his hypotension?
- A.Nitroglycerin directly inhibits phosphodiesterase-5
- B.Nitroglycerin raises cGMP synthesis while sildenafil blocks its breakdown
- C.Sildenafil blocks the ALDH2 bioactivation of nitroglycerin
- D.Nitroglycerin is a selective arterial dilator
- E.Methemoglobinemia from the nitroglycerin tablet
Show answer
B. Nitroglycerin raises cGMP synthesis while sildenafil blocks its breakdown — Nitrates release NO, which activates soluble guanylate cyclase to make cGMP; phosphodiesterases end the signal by hydrolyzing cGMP to GMP. A PDE5 inhibitor blocks that breakdown, so vasodilation is potentiated, and the labels warn that the combination can cause severe hypotension, syncope or myocardial ischemia. Nitroglycerin’s part is the nitric oxide — ALDH2 bioactivates it — while sildenafil is the PDE-5 inhibitor, so blocking ALDH2 would weaken nitroglycerin rather than deepen its effect. Nitroglycerin’s venous effects predominate (hydralazine is the selective arterial dilator), and ordinary doses of organic nitrates cause methemoglobinemia only extremely rarely.
Q2A 70-year-old woman with chronic angina was switched to a nitroglycerin patch worn continuously, 24 hours a day. Two weeks later her angina is as frequent as before; doubling the patch strength does not help.
What is the best explanation and remedy?
- A.Poor skin absorption — move the patch to a hairier site
- B.Progression of coronary disease — add a second nitrate
- C.Allergy to the adhesive — switch to ointment
- D.Methemoglobinemia — give methylene blue
- E.Nitrate tolerance — remove the patch for a daily 10–12-hour drug-free interval
Show answer
E. Nitrate tolerance — remove the patch for a daily 10–12-hour drug-free interval — Continuously delivered nitrates are no better than placebo after 24 hours or less, and dose escalation consistently fails; efficacy returns only after nitrates have been absent for several hours. For nitroglycerin, a daily drug-free interval of 10–12 hours is usually sufficient.
Q3A 34-year-old woman has recurrent chest pain at rest between midnight and early morning. During an episode the ECG shows transient ST elevation that resolves within minutes of a sublingual nitrate. Coronary angiography shows no fixed obstruction.
Which drug class is first-line for preventing her attacks?
- A.Long-acting nitrate alone
- B.Aspirin
- C.Nonselective β-blocker
- D.Calcium-channel blocker
- E.PDE5 inhibitor
Show answer
D. Calcium-channel blocker — This is coronary vasospasm (Prinzmetal angina): rest pain at night or early morning with ECG changes that resolve on a fast-acting nitrate. Calcium antagonists are first-line because of their coronary vasodilatory effect; sublingual nitrates relieve attacks and long-acting nitrates are added when the response is incomplete. β-blockers, particularly nonselective ones, are avoided because they can worsen the symptoms.
Q4A 55-year-old man is brought in after a large intentional ingestion of isosorbide dinitrate. He is cyanotic with an SpO₂ of 85% on oxygen, but arterial PO₂ is normal and his blood looks chocolate-brown.
What explains his cyanosis, and what is the treatment?
- A.Pulmonary edema — give a loop diuretic
- B.Cyanide toxicity — give hydroxocobalamin
- C.Nitrate ions oxidized hemoglobin to the ferric (Fe³⁺) state — give methylene blue
- D.Carbon monoxide — give hyperbaric oxygen
- E.Right-to-left shunt — give a pulmonary vasodilator
Show answer
C. Nitrate ions oxidized hemoglobin to the ferric (Fe³⁺) state — give methylene blue — Nitrate ions released during metabolism oxidize hemoglobin iron from Fe²⁺ to Fe³⁺, and ferric hemoglobin cannot bind oxygen. Hypoxemia despite a normal arterial PO₂ and chocolate-brown blood that does not redden in air point to methemoglobinemia; methylene blue is the antidote.
Q5A pharmacology student compares two oral nitrates. One has an average bioavailability of about 25% that varies widely between patients; the other, its metabolite, is almost completely bioavailable.
Why is the second drug almost completely bioavailable?
- A.It is not subject to first-pass hepatic metabolism
- B.It is given sublingually
- C.It is highly protein-bound
- D.It is excreted unchanged in the urine
- E.It is metabolized only by red blood cells
Show answer
A. It is not subject to first-pass hepatic metabolism — Isosorbide dinitrate undergoes extensive first-pass hepatic metabolism, so its bioavailability ranges from 10% to 90% (about 25% on average). Isosorbide mononitrate, its major active metabolite, is not subject to first-pass metabolism and has an absolute bioavailability of about 100%; it is only about 5% protein-bound, and only about 2% of a dose is excreted unchanged.
Sources
- Nitroglycerin — formulations, mechanism, sublingual use — StatPearls (NCBI)
- Nitrates — vasodilation, tolerance, nitrate-free interval — StatPearls (NCBI)
- CIALIS (tadalafil) — nitrate contraindication and 48-hour interval (FDA label) — FDA / DailyMed
- NITROSTAT (nitroglycerin sublingual) — prescribing information — DailyMed (NLM)
- Antianginal – nitrates (Ch. 6.8) and sildenafil (6.13) — Open RN — Nursing Pharmacology
- NITRO-DUR (nitroglycerin transdermal) — prescribing information — DailyMed (NLM)
- NITRO-BID (nitroglycerin ointment) — prescribing information — DailyMed (NLM)
- NITROLINGUAL Pumpspray — prescribing information — DailyMed (NLM)
- Isosorbide dinitrate tablets — prescribing information — DailyMed (NLM)
- Isosorbide mononitrate extended-release tablets — prescribing information — DailyMed (NLM)
- Nitroglycerin in 5% Dextrose Injection — prescribing information (IV) — DailyMed (NLM)
- VIAGRA (sildenafil) — nitrate contraindication — DailyMed (NLM)
- Vardenafil tablets — nitrate contraindication — DailyMed (NLM)
- REVATIO (sildenafil, pulmonary hypertension) — nitrate contraindication — DailyMed (NLM)
- Drugs@FDA — IMDUR (NDA 020225) marketing status — U.S. FDA
- Drugs@FDA — ISORDIL (NDA 012093) marketing status — U.S. FDA
- Biochemistry, Cyclic GMP — PDE5 inhibitors and nitrates — StatPearls (NCBI)
- Administration of Medications Via Other Routes — transdermal patches — Open RN — Nursing Skills
- Methemoglobinemia — ferric hemoglobin and nitrate exposure — StatPearls (NCBI)
- Coronary Artery Vasospasm and Prinzmetal Angina — nitrate response, calcium antagonists first-line — StatPearls (NCBI)
- BiDil (isosorbide dinitrate/hydralazine) — heart failure in self-identified Black patients (FDA label) — FDA / DailyMed
- Table of Pharmacogenomic Biomarkers in Drug Labeling (CYB5R: isosorbide dinitrate, mononitrate) — U.S. Food and Drug Administration
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.