Generic Name

Isosorbide dinitrate

Mechanism

Isosorbide dinitrate is a *organic nitrate* that undergoes endothelial‑mediated conversion to nitric oxide (NO). NO activates soluble guanylate cyclase (sGC) in vascular smooth muscle, increasing cyclic guanosine monophosphate (cGMP). Elevated cGMP leads to dephosphorylation of myosin light chains and relaxation of arterial and venous tone, which:
• Reduces preload (↓ venous return)
• Decreases pulmonary capillary wedge pressure
• Diminishes myocardial oxygen demand by lowering afterload and improving coronary perfusion

The vasodilatory effect is preferential for veins (<30 mmHg) and arterioles, contributing to its antianginal efficacy.

Pharmacokinetics

• Absorption: Rapid oral absorption; peak plasma levels 30–60 min after a 20 mg dose.
• Bioavailability: ~50 % due to first‑pass metabolism; dose‐dependent ~30–60 % for ≥40 mg.
• Metabolism: Extensive hepatic metabolism via aldehyde oxidase and β‑oxidation → 5,6‑dihydro‑isosorbide‑5‑carboxylate (active metabolite).
• Half‑life: 3–5 h for the drug; active metabolite ~11 h.
• Excretion: 60–70 % renal (glucuronide conjugates); 15–20 % biliary.
• Drug interactions: CYP3A4 inhibitors (ketoconazole, clarithromycin) modestly ↑ plasma exposure; phosphodiesterase‑5 inhibitors (sildenafil) ↑ hypotensive risk.

Indications

• Stable angina pectoris: as chronic antianginal therapy.
• Heart failure with preserved or reduced ejection fraction: to improve exercise tolerance and reduce hospitalizations.
• Acute coronary syndromes (in combination with other agents) for transient relief of anginal chest pain.

Contraindications

• Contraindicated: Hypotension (SBP <90 mmHg), severe aortic stenosis, intracranial bleed, chronic hemolytic anemia (e.g., G6PD deficiency) due to methemoglobinemia risk.
• Warnings:
• Hypertension & Hypotension: Monitor blood pressure; titrate slowly.
• Headache/Vasodilation: Common; consider dose adjustment or add a nonsteroidal anti‑inflammatory for severe cases.
• Drug interactions: Avoid concomitant use with PDE‑5 inhibitors (risperidone, sildenafil) due to additive vasodilatory effect.
• Tolerance: Rapid tolerance develops (≈48 h); use a 10‑day drug‑free interval (e.g., nightly break) to mitigate.

Dosing

Oral tablets (20 mg)
• Maintenance: 20 mg PO BID (every 12 h) → 40 mg BID if tolerated.
• Dosing schedule:
• 08:00 h – 20 mg
• 20:00 h – 20 mg
• 24 h drug‑free interval (skip 20:00 h dose) → minimizes tolerance.
• Adjustments:
• Reduce dose in hepatic or renal impairment (avoid if CrCl <30 mL/min).
• Initiate at 10 mg BID for first 3 days in patients ≥80 yrs or with hypotension.

Sublingual tablets (0.25 mg–4 mg)
• For acute anginal episodes: 1–2 sublingual tablets as needed, spaced 5 min apart.

Adverse Effects

Common (≥10 %)
• Headache (≈30 %)
• Flushing
• Dizziness
• Nausea

Serious (≤1 %)
• Reversible methemoglobinemia (rare) – monitor in G6PD deficiency.
• Severe hypotension ≥40 mmHg decrease from baseline.
• Syncope – especially in patients on beta‑blocker or calcium channel blocker dual therapy.
• Drug tolerance – loss of efficacy.

Monitoring

• Blood pressure: twice weekly for first 2 weeks, then monthly.
• Heart rate: baseline, then 1–2 weeks after dose escalation.
• Renal function: CrCl at baseline, then every 3 months.
• Methemoglobin: baseline and if symptomatic (cyanosis, dyspnea).
• Patient diary: note headaches, flushing, or syncope for tolerance assessment.

Clinical Pearls

• Titrate on the “drug‑free” principle: A 10‑day daily break (usually overnight) every 2–4 weeks prevents tolerance without compromising efficacy.
• Combine with beta‑blockers: If started on isosorbide dinitrate‑hydrochlorothiazide combination, the diuretic portion can offset nitrate‑induced headache via improved cerebral perfusion.
• Avoid high‑dose nitrate “spray” abuse: Sublingual or transdermal sprays produce intense flushing; reserve for acute episodes only.
• Methemoglobin threshold: >5 % signals the need to stop and reassess; consider ascorbic acid (500 mg PO) as a prophylactic for patients on chronic nitrates.
• G6PD patients: use isosorbide mononitrate instead; it has a lower methemoglobin risk spectrum.
• Drug‑interaction vigilance: In patients on sildenafil or other PDE‑5 inhibitors, discontinue the nitrate ≥24 h before the PDE‑5 agent to avoid severe hypotension.
• Use caution in left ventricular dysfunction with hypotension**: monitor for increased pulmonary capillary wedge pressure; consider adding a β‑blocker or ACE‑I.

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• Key takeaways
• *Isosorbide dinitrate* provides sustained anti‑anginal coverage with minimal daily dosing and low systemic side effects when titrated appropriately.
• The 10‑day drug‑free interval mitigates tolerance, a primary limitation of nitrate therapy.
• Monitoring for hypotension and methemoglobinemia ensures safe use, especially in patients with renal or hepatic compromise.