Isosorbide dinitrate

Isosorbide Dinitrate (ISDN) is a nitrate-class medication primarily used for the prevention and treatment of angina pectoris, management of congestive heart failure (CHF), and as adjunctive therapy in acute and chronic heart failure, especially in combination with hydralazine in patients intolerant to ACE inhibitors. As a vasodilator, it exerts its therapeutic effect via nitric oxide donation, relaxing both venous and arterial smooth muscle. Unlike its mononitrate counterpart, ISDN undergoes extensive first-pass metabolism and has a shorter half-life, often requiring multiple daily doses.

 

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Brand Names

• Isordil®

• Sorbitrate®

• Dilatrate®

• Isochron®

• Cedocard®

• Isoket®

• Isodinit®

(Brand names vary depending on country and formulation.)

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Pharmacological Classification

• Therapeutic class: Antianginal, Vasodilator

• Pharmacological class: Organic nitrate

• ATC code: C01DA08

• Regulatory classification: Prescription-only (Rx)

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Mechanism of Action

Isosorbide dinitrate works by donating nitric oxide (NO), a potent endogenous vasodilator. This activates soluble guanylate cyclase (sGC) in vascular smooth muscle, resulting in:

• ↑ cGMP levels, leading to smooth muscle relaxation

• Predominant venous dilation → ↓ preload → ↓ myocardial oxygen demand

• At higher doses, arteriolar dilation occurs → ↓ afterload

• Improved coronary blood flow

• Relief of anginal symptoms through improved oxygen delivery and reduced myocardial workload

Additionally, in chronic heart failure, especially in Black patients, ISDN combined with hydralazine improves survival and symptom control.

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Therapeutic Uses

Approved Indications

• Treatment and prevention of angina pectoris (chronic stable angina)

• Adjunctive therapy in congestive heart failure

• Management of acute decompensated heart failure (parenteral form)

• Hypertensive emergencies (off-label)

Off-Label / Guideline-Supported Indications

• Chronic heart failure (NYHA Class III–IV) in combination with hydralazine, particularly in African-American patients (per A-HeFT trial)

• Post-myocardial infarction vasodilation

• Esophageal spasm-related chest pain

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Dosage and Administration

Oral Immediate-Release Tablets

• Initial: 5–20 mg 2 to 3 times daily

• Maintenance: 10–40 mg 2 to 3 times daily

• Dose frequency should include a nitrate-free interval of at least 12–14 hours/day (often overnight) to prevent tolerance

Sublingual Tablets

• 2.5–5 mg sublingually as needed for acute anginal episodes

• May repeat every 5–10 minutes, up to 3 doses in 15–30 minutes

• Not for daily prophylaxis

Extended-Release Tablets

• 40–80 mg once or twice daily, with asymmetric dosing (e.g., 40 mg at 8 AM and 20 mg at 2 PM)

Intravenous Form (Isoket® IV)

• Used in acute heart failure or severe angina

• Starting dose: 2–20 mcg/min; titrate upward based on response

• Requires continuous cardiac monitoring

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Contraindications

• Hypersensitivity to nitrates or any excipient

• Concurrent use of PDE5 inhibitors (e.g., sildenafil, tadalafil) → risk of severe hypotension

• Severe hypotension or shock (SBP < 90 mmHg)

• Acute myocardial infarction with low filling pressures

• Severe anemia

• Constrictive pericarditis, tamponade

• Increased intracranial pressure

• Closed-angle glaucoma (relative contraindication)

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Adverse Effects

Very Common

• Headache (frequent and dose-limiting)

• Flushing

• Dizziness, postural hypotension

Common

• Reflex tachycardia

• Palpitations

• Weakness

• Nausea

• Fainting

Less Common/Rare

• Paradoxical bradycardia

• Cyanosis (in overdose or high-dose settings)

• Methemoglobinemia (especially in IV form)

• Syncope

• Rash or allergic reactions

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Precautions and Warnings

• Avoid abrupt withdrawal: May precipitate angina or myocardial ischemia

• Tolerance develops rapidly with continuous exposure

• A nitrate-free interval of 12–14 hours is essential

• Use with caution in:

  • Hypovolemia

  • Severe liver dysfunction (due to impaired metabolism)

  • Hypothyroidism

  • Malnutrition or hypothermia

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Nitrate Tolerance

Mechanism

• Decreased bioactivation of nitrates

• Depletion of intracellular sulfhydryl groups

• Increased oxidative stress and neurohormonal activation

Prevention

• Include a daily nitrate-free interval (often overnight)

• Avoid around-the-clock nitrate therapy

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Drug Interactions

Major

• Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil): Severe hypotension, syncope, death

• Riociguat: Potentiates hypotensive effects

Moderate

• Calcium channel blockers: Additive hypotension

• Beta-blockers: May enhance bradycardia or hypotension

• Antihypertensives and diuretics: Potentiate blood pressure-lowering

• Tricyclic antidepressants and antipsychotics: May exacerbate orthostatic hypotension

• Alcohol: Additive hypotensive effects

Pharmacokinetic Interactions

• Probenecid may reduce renal excretion of some nitrates

• Ergot alkaloids: Reduced coronary perfusion may worsen ischemia

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Pharmacokinetics

• Absorption: Rapid after oral or sublingual administration

• Bioavailability: ~25% due to extensive first-pass metabolism

• Metabolism: Hepatic metabolism to isosorbide mononitrate (active metabolite)

• Onset:

  • Oral: ~30 minutes

  • Sublingual: ~2–5 minutes

• Duration:

  • Oral: 4–6 hours

  • Sublingual: 1–2 hours

• Half-life: 1–2 hours (parent); ~4–6 hours (mononitrate metabolite)

• Excretion: Renal (primarily as metabolites)

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Monitoring Parameters

• Blood pressure and heart rate (especially post-initiation or dose changes)

• Signs of orthostatic hypotension

• Frequency and severity of anginal episodes

• Nitrate tolerance (assess therapeutic effectiveness over time)

• Signs of volume depletion or hypoperfusion

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Use in Special Populations

Pregnancy

• Category C (FDA): Use only if clearly needed

• No adequate human studies; animal data are limited

Lactation

• Unknown if excreted in breast milk; use with caution

Elderly

• More susceptible to hypotension; start at lower doses

Renal or Hepatic Impairment

• Use caution; dosage adjustment may be necessary due to altered metabolism or excretion

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Comparison: ISDN vs. ISMN

Feature	Isosorbide Dinitrate (ISDN)	Isosorbide Mononitrate (ISMN)
Bioavailability	Low (~25%)	High (~90–100%)
First-pass metabolism	Extensive	Minimal
Dosing frequency	2–3 times daily	Once or twice daily
Metabolite	Converted to ISMN	Parent drug
Tolerance development	Common	Common (requires nitrate-free interval)
Onset of action	Fast (especially sublingual)	Slower
Indicated for acute angina?	Yes (sublingual)	No

Clinical Use Summary

• Preferred agent for short-term angina relief and prophylaxis.

• Can be combined with hydralazine in heart failure, especially in African-American populations.

• Tolerance is a major limitation—always incorporate nitrate-free interval.

• Not ideal for around-the-clock therapy without interval planning.

• Sublingual ISDN is used for immediate angina relief, unlike ISMN.

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Storage and Stability

• Store below 25°C (77°F)

• Protect from light and moisture

• Keep in original packaging to maintain stability (especially sublingual tablets)

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Overdose and Toxicity

Symptoms

• Severe hypotension

• Reflex tachycardia

• Nausea, vomiting

• Methemoglobinemia

• Cyanosis

• Syncope

Management

• Positioning (supine with legs elevated)

• IV fluids

• Vasopressors (if unresponsive to fluids)

• Methylene blue for methemoglobinemia

• Supplemental oxygen and cardiac monitoring