NITROLINGUAL
Clinical safety rating
cautionComprehensive clinical and safety monograph for NITROLINGUAL (NITROLINGUAL).
Nitroglycerin is converted to nitric oxide (NO), which activates guanylyl cyclase, increasing cGMP levels in vascular smooth muscle. This leads to dephosphorylation of myosin light chains, causing vasodilation. It predominantly dilates venous capacitance vessels, reducing preload, and to a lesser extent dilates arterioles, reducing afterload.
| Metabolism | Nitroglycerin is extensively metabolized in the liver by glutathione-S-transferases and in vascular smooth muscle by mitochondrial aldehyde dehydrogenase (ALDH2), producing dinitrate metabolites (1,2- and 1,3-glyceryl dinitrate) and mononitrates. |
| Excretion | Renal (primarily as glucuronide conjugates and denitrated metabolites): ~60-80%; Fecal: ~20-40%; Biliary: negligible. Less than 1% excreted unchanged. |
| Half-life | 2-3 minutes for sublingual nitroglycerin; rapid decline due to extensive first-pass metabolism and high clearance (30-40 L/min). Clinical context: extremely short half-life necessitates continuous or frequent dosing for sustained effect. |
| Protein binding | ~60% bound, primarily to albumin; low affinity, allowing rapid equilibration with tissues. |
| Volume of Distribution | ~3 L/kg (0.1-0.2 L/kg for parent drug; larger due to extensive tissue distribution including vascular smooth muscle). High Vd reflects extensive uptake into vessel walls and other tissues. |
| Bioavailability | Sublingual: ~40-60% (avoiding first-pass hepatic metabolism); Oral: <1% (extensive presystemic clearance by hepatic glutathione-organic nitrate reductase). |
| Onset of Action | Sublingual: 1-3 minutes; Transmucosal absorption yields rapid therapeutic effect for acute angina. |
| Duration of Action | Sublingual: 30-60 minutes; hemodynamic effects resolve quickly, requiring frequent redosing for prolonged relief. Tolerance may develop with continuous exposure. |
| Molecular Weight | 227.09 |
1 to 2 sprays (0.4 mg/spray) sublingually at onset of angina, may repeat every 5 minutes up to 3 doses; prophylactic use: 1 spray 5-10 minutes before activity.
| Dosage form | AEROSOL |
| Renal impairment | No dose adjustment required for any GFR level. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: consider dose reduction (e.g., 1 spray); Child-Pugh C: avoid use or use extreme caution with reduced dose. |
| Pediatric use | Not established in pediatric patients for sublingual spray; avoid use in children. |
| Geriatric use | Start with lower dose (1 spray) due to increased sensitivity and risk of hypotension. |
| 1st trimester | Avoid use unless clearly needed. Limited data; potential risk of fetal hypoxia due to maternal hypotension. |
| 2nd trimester | Use only if clearly indicated. May cause fetal bradycardia and reduced uteroplacental perfusion. |
| 3rd trimester | Avoid near term due to risk of uterine relaxation and maternal hypotension compromising fetal oxygenation. |
Clinical note
Comprehensive clinical and safety monograph for NITROLINGUAL (NITROLINGUAL).
| Placental transfer | Nitroglycerin crosses the placenta with a fetal-to-maternal ratio of approximately 0.8. |
| Breastfeeding | Limited data; negligible amounts likely excreted into breast milk. Use with caution, monitor infant for hypotension. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | FDA Pregnancy Category C. No adequate studies in pregnant women. In animal studies, nitroglycerin caused decreased fetal weight and increased fetal resorptions at doses 50 times the human dose. Risk cannot be ruled out; use only if clearly needed. No known teratogenicity in first trimester, but caution in third trimester due to maternal hypotension risk. |
| Fetal Monitoring | Monitor maternal blood pressure and heart rate during administration. Fetal heart rate monitoring recommended if used near term. Assess for signs of maternal hypotension, which can reduce placental perfusion. |
| Fertility Effects | No known impairment of fertility in animal studies. Limited data in humans. Theoretical risk of transient hypotension affecting reproductive organ perfusion, but no evidence of adverse fertility effects. |
■ FDA Black Box Warning
Do not use NITROLINGUAL with phosphodiesterase-5 (PDE-5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) or soluble guanylyl cyclase (sGC) stimulators (e.g., riociguat), as severe hypotension, syncope, or myocardial ischemia can occur.
| Serious Effects |
Hypersensitivity to nitroglycerin or any componentSevere anemiaIncreased intracranial pressure (e.g., head trauma, cerebral hemorrhage)Acute circulatory failure (shock, vascular collapse)Concomitant use with phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)Right ventricular infarctionConstrictive pericarditisCardiac tamponade
| Precautions | Hypotension: May cause severe hypotension, especially in volume-depleted patients or those with low systolic blood pressure., Headache: Common and may be severe; tolerance may develop., Tolerance: Continuous or frequent use may lead to tolerance, requiring nitrate-free intervals., Abrupt withdrawal: May precipitate angina; taper if discontinuing long-term therapy., Hypertrophic cardiomyopathy: May worsen outflow obstruction., Increased intracranial pressure: Use cautiously in patients with elevated intracranial pressure (e.g., cerebral hemorrhage). |
| Food/Dietary | No specific food interactions. Avoid alcohol, which can exacerbate hypotension. Maintain adequate hydration. |
| Clinical Pearls | NITROLINGUAL (nitroglycerin sublingual spray) is first-line for acute angina. Administer 1-2 sprays at onset of chest pain; may repeat every 5 minutes up to 3 doses. Avoid in patients with severe hypotension (SBP <90 mmHg), right ventricular infarction, or concomitant use of phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) within 24-48 hours. Monitor for orthostatic hypotension; patient should sit or lie down during administration. The spray is absorbed via oral mucosa; do not inhale or swallow. Onset: 1-3 minutes; duration: 30-60 minutes. Do not shake canister; prime before first use or if not used for >6 weeks. |
| Patient Advice | Use 1-2 sprays under or on the tongue at first sign of chest pain. · Do not shake the canister; hold it upright and spray onto or under the tongue. · Avoid swallowing or inhaling the spray; let it absorb through the oral mucosa. · Wait 5 minutes after the first dose; if chest pain persists, repeat up to 3 doses total. · If pain is not relieved after 3 doses, seek emergency medical help immediately. · Do not take with erectile dysfunction medications (e.g., sildenafil, tadalafil) within 24-48 hours. · Sit or lie down when using the spray to prevent dizziness or fainting. · Store at room temperature away from heat; do not freeze. Check expiration date. · Prime the spray before first use (spray 5 times into air) or if not used for 6 weeks (spray once). · Common side effects: headache, dizziness, flushing, low blood pressure. |
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