Isosorbide
Isosorbide
Generic Name
Isosorbide
Mechanism
Isosorbide is a *vasodilator* that works by releasing nitric‑oxide (NO) from the endothelium.
• NO-mediated: NO activates guanylate cyclase → ↑cyclic‑GMP → smooth‑muscle relaxation.
• Results in decreased systemic vascular resistance and reduced preload/afterload.
• Does not inhibit cyclooxygenase, thereby sparing platelet function and reducing GI irritation.
Pharmacokinetics
| Parameter | Details |
| Absorption | Oral forms: ~ 90 % bioavailability; oral dissolution in acidic pH is well tolerated. |
| Distribution | Widely distributed; crosses the blood‑brain barrier (low‑dose effect). |
| Metabolism | Hydrolyzed by plasma esterases to isosorbide mononitrate or inactive metabolites. No major CYP involvement. |
| Excretion | Renal (major route). Elimination half‑life: 3 – 4 h for isosorbide dinitrate; ~10 h for controlled‑release isosorbide mononitrate. |
| Special Populations | Renal impairment: no significant accumulation; adjust dose if creatinine clearance < 30 mL/min for prolonged regimens. |
Indications
- Stable angina pectoris (short‑term and long‑term prevention).
- Pre‑operative prophylaxis in coronary artery disease patients.
- Chronic heart failure adjunct (usually in combination with nitrates).
- Pre‑operative prophylaxis for coronary artery bypass graft (CABG) surgery when NO donors are indicated.
Contraindications
- Contraindications
- Hypersensitivity to isosorbide, nitrate, or any excipient.
- Severe hypotension (SBP 24 h continuous exposure; recommended “nitrate‑free interval” (at least 10–14 h daily).
- Concurrent use with phosphodiesterase‑5 inhibitors (sildenafil, tadalafil) → risk of severe hypotension.
- Pregnancy – category B; use only if benefit outweighs risk.
- Concomitant antihypertensives – add‑on therapy may cause additive hypotension; start dose titration.
Dosing
| Form | Typical Dose | Frequency | Titration Notes |
| Isosorbide dinitrate (tablet) | 5 mg PO q6‑8 h → titrate ↑ every 1–2 days to pain control OR ≤ 50 mg/day | Taper as needed; avoid > 50 mg/day unless supervised | Start low; increase by 5–10 mg increments until response or side‑effects. |
| Isosorbide mononitrate (tablet, XR) | 5 mg PO q24 h → titrate ↑ 2.5–5 mg every 3–5 days to 20–30 mg q24 h | Day‑dose. | Use at bedtime; adjust for breakthrough angina. |
| Isosorbide dinitrate (IV) | 0.3 mg/kg over 5 min → repeat every 10 min if needed | Only in acute settings (e.g., hypertensive crisis) | Monitor BP closely; stop if < 90 mm Hg SBP. |
Adverse Effects
| Common (≥ 5 %) | Serious (rare) |
| Headache, flushed skin, dizziness, nausea, postural hypotension | Severe hypotension, syncope, myocardial infarction (unlikely but watch for ischemic changes), anaphylaxis (rare) |
| Methemoglobinemia (rare, after prolonged high doses) | Tolerance with continuous use; risk of organ ischemia if untreated |
| Hypotension (especially with oral dinitrate) | Severe GI bleed if combined with antithrombotics (monitor hemoglobin) |
Monitoring
- Blood pressure: baseline, daily during titration, at 2–4 h post‑dose.
- Heart rate: watch for reflex tachycardia.
- Serum creatinine / eGFR: baseline; every 1–3 months if CKD.
- Methemoglobin level: in patients with 5‑ASA, sulfa drugs, or prolonged therapy.
- Symptoms of nitrate tolerance: evaluate every 4–6 weeks during chronic use.
Clinical Pearls
- “Nitrate‑free interval” is key: ensure at least 10–14 h of no nitrate use to prevent tolerance—especially critical for oral dinitrate users.
- Isosorbide mononitrate is preferable for once‑daily dosing in stable angina and reduces the risk of hypotension compared to dinitrate.
- Avoid concurrent use with phosphodiesterase‑5 inhibitors or high‑dose antihypertensives; the NO‑mediated vasodilation can lead to precipitous drops in blood pressure.
- In patients with renal insufficiency, isosorbide is safe but monitor renal function; there is no dose adjustment for moderate CKD.
- Pre‑operative “Nitrate stress test”: administer 10–20 mg IV isosorbide dinitrate to detect silent ischemia; positive test predicts peri‑operative cardiac events.
- When prescribing in pregnancy, stay within maximum recommended daily doses and counsel on possible fetal effects; isotopic evidence is limited but considered relatively safe (category B).
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• References
1. Katzung BG. *Basic & Clinical Pharmacology*. 15th ed. McGraw‑Hill; 2022.
2. Mayo Clinic Proceedings. “Nitrate therapy in angina: dosing and monitoring.” 2023.
3. UpToDate. “Isosorbide dinitrate and mononitrate (drug, dosing, side effects, interactions).” 2025.