Isosorbide Mononitrate
Isosorbide mononitrate (IMN)
Generic Name
Isosorbide mononitrate (IMN)
Mechanism
- NO Release: Intracellular enzymes convert IMN to nitric oxide (NO), the physiologic vasodilator.
- cGMP Pathway: NO activates guanylate cyclase → increased cyclic GMP (cGMP).
- Smooth‑muscle Relaxation: cGMP activates protein kinase G → phosphorylation of myosin light‑chain phosphatase → decreased intracellular Ca²⁺ → vasodilation.
- Hemodynamic Effect: Decreased venous return (pre‑load) and arterial resistance (after‑load) reduce myocardial oxygen demand, preventing angina.
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Pharmacokinetics
| Parameter | Detail |
| Absorption | Oral bioavailability ~45 %; steady states reached 1–2 days. |
| Distribution | Widely distributed; plasma protein binding 35–45 %. |
| Metabolism | Primarily hydrolyzed in the liver and gut; metabolites inactive. |
| Elimination | Renal excretion (~30 % unchanged). Clearance ∼0.7 L h⁻¹. |
| Half‑life | 4–6 h for plasma levels; sustained vasodilatory effect for 12–24 h. |
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Indications
- Stable Angina Pectoris (pre‑vention; not acute attacks)
- Chronic Heart Failure (NYHA II–III) as adjunct therapy
- Short‑term Management of acute coronary syndrome when not contraindicated
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Contraindications
- Contraindications
- Severe systemic hypotension or recent major hemorrhage
- Acute, uncontrolled hypertension with nitrate‑sensitive migraines
- Concurrent use of phosphodiesterase‑5 inhibitors (e.g., sildenafil)
- Known hypersensitivity to any nitrate
- Warnings
- Tolerance: may develop after 7–10 days of continuous use; utilize nitrate‑free “holiday”
- Rebound Angina: abrupt discontinuation can precipitate severe angina or ischemia
- Hyponatremia: can occur in heart‑failure patients due to fluid shifts
- Pregnancy: classified as category C; use only if benefits outweigh risks
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Dosing
| Form | Typical Starting Dose | Titration | Max Daily Dose |
| Oral Tablets (20 mg, 40 mg, 80 mg) | 20 mg BID | Increase by 20 mg every 5–7 days to ≤40 mg BID; titrate to OH at 60 mg BID | 60 mg BID (max 120 mg/day total) |
| Oral Tablets (40 mg) | As above (40 mg BID) | Titrate to tolerability | 120 mg/day |
| Oral Dissolve‑Shield/Extended‑Release (80 mg) | 40 mg BID | Incrementally (20 mg) | 120 mg/day |
| As Needed for Angina | ≤80 mg/24 h | Same limits | 120 mg/day |
• Administration Tips
• Take tablets with water, with or without food.
• Split tablets in emergencies (e.g., 40 mg tablet → two 20 mg doses).
• Reintroduce after a nitrate‑free period to avoid tolerance.
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Adverse Effects
- Common
- ⎜Headache (≈30 %)⎜ – usually dose‑related, improves with titration
- ⎜Flushing, dizziness, light‑headedness⎜ – transient
- Less Common (≤5 %)
- ⎜Hypotension, syncope, nausea, vomiting⎜
- ⎜Tachycardia, palpitations⎜
- ⎜Blurred vision or visual disturbances (if rapidly dissolved forms used)⎜
- Serious (≤1 %)
- ⎜Rebound angina, acute myocardial infarction (rapid taper/discontinuation)⎜
- ⎜Severe hypotension (especially in volume‑depleted patients)⎜
- ⎜Hyponatremia in heart‑failure populations⎜
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Monitoring
- Vital Signs – BP, HR (baseline; 2 h post‑dose; weekly during titration)
- Blood Pressure – target ≥125/75 mmHg when tolerating ≥40 mg BID
- Serum Electrolytes – sodium (baseline; periodically in HF patients)
- Renal Function – creatinine clearance (baseline; annually or if clinical change)
- Echocardiogram – at baseline and 6–12 months in HF cohort
- Tolerance Development – patient report of worsening headaches or decreased benefit; evaluate for “holiday” necessity.
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Clinical Pearls
- Nitrate Holiday: A 24‑hour nitrate‑free interval every week (or 48 h every 2 weeks) is essential to maintain sensitivity and reduce headache incidence.
- Rapid Dissolve Form: Use only for breakthrough angina; never exceed 80 mg within 24 h.
- Combination with Beta‑Blockers: Simultaneous use reduces heart rate and enhances ischemic protection; monitor for bradycardia.
- Pregnancy Package: In the event of pregnancy, discontinue IMN promptly and consider low‑dose aspirin if indicated; counseling on pregnancy risks is mandatory.
- Drug Interactions: Avoid simultaneous use with PDE‑5 inhibitors; clear “black‑box" warning.
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• Key Takeaway: *Isosorbide mononitrate* offers sustainable angina relief and heart‑failure support through sustained NO release, but requires vigilant dosing schedules, tolerance monitoring, and awareness of serious interaction risks.