NITROLINGUAL
Clinical safety rating: caution
Comprehensive 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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NITROLINGUAL (NITROLINGUAL).
| Breastfeeding | Nitroglycerin is excreted in human milk in small amounts. M/P ratio unknown. No adverse effects reported in breastfeeding infants. Caution when administered to nursing women. |
| 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. |
■ 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 component of the formulation","Concurrent use of PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) or sGC stimulators (riociguat)","Severe anemia","Increased intracranial pressure (e.g., head trauma, cerebral hemorrhage)","Constrictive pericarditis, cardiac tamponade, restrictive cardiomyopathy","Acute myocardial infarction with low filling pressure (e.g., right ventricular infarction)"]
| 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)."] |
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| 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. |