ISOSORBIDE DINITRATE

Clinical safety rating: safe

Animal studies have demonstrated safety

How it works

Isosorbide dinitrate is a nitrate vasodilator that relaxes vascular smooth muscle via release of nitric oxide (NO), which activates guanylate cyclase, increasing cGMP, leading to venous and arterial dilation. Venodilation reduces preload; arterial dilation reduces afterload, decreasing myocardial oxygen demand.

What the body does with it

Metabolism	Extensively metabolized in the liver by glutathione-organic nitrate reductase to isosorbide mononitrates (active metabolites) and inorganic nitrate.
Excretion	Renal excretion of metabolites (approximately 80-100% of absorbed dose as inactive metabolites, primarily isosorbide-2-mononitrate and isosorbide-5-mononitrate); less than 2% excreted unchanged in urine. Biliary/fecal excretion is minimal.
Half-life	Terminal elimination half-life is approximately 1-4 hours (mean ~1.5 hours) for isosorbide dinitrate; active metabolites (isosorbide-5-mononitrate) have longer half-life (~4-6 hours). Clinical context: Short half-life necessitates frequent dosing or use of extended-release formulations for sustained antianginal effect.
Protein binding	Approximately 30% bound to plasma proteins (primarily albumin).
Volume of Distribution	Apparent volume of distribution is 1-4 L/kg (mean ~2-3 L/kg), indicating extensive tissue distribution.
Bioavailability	Sublingual: 40-60% (avoids first-pass metabolism); Oral (immediate-release): 10-30% (extensive first-pass hepatic metabolism by glutathione-organic nitrate reductase); Oral (extended-release): 20-40% (reduced first-pass due to slower release).
Onset of Action	Sublingual: 2-5 minutes; Oral (immediate-release): 15-30 minutes; Oral (extended-release): 30-60 minutes; Intravenous: 1-2 minutes.
Duration of Action	Sublingual: 1-2 hours; Oral (immediate-release): 4-6 hours; Oral (extended-release): 8-12 hours. Note: Tolerance develops with continuous exposure, requiring nitrate-free intervals (typically 10-14 hours) to maintain efficacy.

Classification & Brands

Dosing & administration

Oral: 5-40 mg every 6 hours; sublingual: 2.5-5 mg every 2-3 hours for acute angina or prophylaxis; chewable: 5-10 mg every 2-3 hours; intravenous: initial 1-2 mg/hour, increase by 1-2 mg/hour every 3-5 minutes until response, usual range 2-10 mg/hour (titrate to effect).

Dosage form	TABLET
Renal impairment	No specific dose adjustment defined; caution in severe renal impairment (eGFR <30 mL/min) due to potential metabolite accumulation; monitor hemodynamics.
Liver impairment	Child-Pugh A: No dose adjustment; Child-Pugh B: Reduce dose by 25-50% due to impaired metabolism; Child-Pugh C: Avoid use or reduce dose by 75% with close monitoring.
Pediatric use	Limited data; oral: 5-10 mg/m² every 8 hours; intravenous: 0.5-1 mcg/kg/min, titrate to effect (max 10 mcg/kg/min).
Geriatric use	Start at low end of dosing range (oral: 5 mg every 8 hours; sublingual: 2.5 mg as needed); consider reduced hepatic clearance; monitor for hypotension and dizziness.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Phosphodiesterase inhibitors (eg sildenafil) can cause severe hypotension Can cause tolerance with continuous use and severe headaches.

Breastfeeding	Excreted into breast milk in small amounts (M/P ratio not established). Limited human data; unlikely to harm nursing infant. Caution with higher doses due to potential for infant hypotension.
Teratogenic Risk	No adequate studies in pregnant women. Animal reproduction studies have not been conducted. Use only if clearly needed. First trimester: limited data, no known teratogenicity. Second/third trimester: may cause fetal tachycardia, hypotension; avoid near term due to risk of uterine relaxation and postpartum hemorrhage.

Warnings & precautions

■ FDA Black Box Warning

None. (No FDA black box warning for isosorbide dinitrate.)

Side Effect Profile

Common Effects	Headache
Serious Effects

Absolute Contraindications

["Hypersensitivity to nitrates","Concomitant use of phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)","Severe anemia","Increased intracranial pressure (e.g., head trauma, cerebral hemorrhage)","Severe hypotension or hypovolemia","Acute myocardial infarction with inadequate ventricular filling pressure"]

Clinical Precautions

Precautions

["Hypotension, especially with volume depletion or concomitant phosphodiesterase-5 inhibitors","Tolerance and cross-tolerance to other nitrates","Abrupt discontinuation may cause withdrawal symptoms","Use caution in hypertrophic cardiomyopathy, acute myocardial infarction, or increased intracranial pressure"]

Clinical Tips & Counseling

Drug interactions

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