Isosorbide Dinitrate: Organic Nitrate in Angina Pectoris and Heart Failure
Isosorbide dinitrate (ISDN) is a classical organic nitrate used to treat coronary artery disease. Well-known brand names include Isoket, Sorbit, Iso Mack, and numerous generics. ISDN has been established in cardiology for decades and is one of three major nitrate preparations alongside isosorbide mononitrate (ISMN) and glyceryl trinitrate.
The antianginal effect is based on reduction of preload and afterload of the heart, thereby reducing myocardial oxygen demand. ISDN is used for attack prophylaxis and in sustained-release formulations for long-term therapy of stable angina pectoris as well as chronic heart failure. A special feature is the specific drug combination ISDN plus hydralazine (Bidil), which in studies in African American patients with heart failure reduced mortality (V HeFT, A HeFT trial).
Mechanism of Action
Isosorbide dinitrate is a prodrug that is converted in vascular smooth muscle through enzymatic reduction (mainly aldehyde dehydrogenase 2) to nitric oxide (NO). NO activates soluble guanylate cyclase and increases intracellular cGMP levels. cGMP leads through activation of protein kinase G and reduction of intracellular calcium to relaxation of vascular smooth muscle.
Vasodilation is dose-dependent and affects venous vessels at low doses. The result is a reduction in venous return to the heart (preload reduction), which reduces left ventricular end-diastolic pressure and thus myocardial oxygen demand. At higher doses, additional arterial dilation with reduction of peripheral resistance (afterload reduction) and widening of coronary arteries (improved oxygen supply) occur.
Pharmacokinetically, sublingual ISDN has rapid onset after 2 to 5 minutes and duration of action of 1 to 2 hours. Oral administration works after 30 minutes and lasts 4 to 6 hours. Extended-release formulations work up to 12 hours. Half-life of ISDN itself approximately 1 hour, the active metabolite isosorbide 5 mononitrate 4 to 5 hours. Tolerance develops with continuous therapy, which is why nitrate-free intervals are important.
Indications
- Acute treatment of angina pectoris: sublingual or as spray for acute attack
- Attack prophylaxis of stable angina pectoris: oral extended-release form for long-term therapy
- Chronic heart failure with reduced LVEF: in combination with hydralazine as alternative or supplement to RAS inhibitor therapy
- Acute pulmonary edema and acute left ventricular failure: intravenously in emergency medicine
- Hypertensive crisis: intravenously, occasionally
- Periinterventional in coronary spasms: intracoronary or intravenous
Dosage and Administration
Acute sublingual treatment: 5 mg under the tongue or 1.25 mg as spray, if necessary repeat after 5 to 10 minutes. If symptoms persist for more than 15 minutes, call emergency number 112.
Attack prophylaxis oral: 20 to 40 mg twice daily (standard form) or 60 to 80 mg once daily (extended-release form). Important is a nitrate-free interval of at least 8 to 10 hours daily to avoid tolerance development, usually at night.
Heart failure: 20 mg to 40 mg three times daily in combination with hydralazine 75 mg three times daily.
Intravenous: 1 to 10 mg/hour under blood pressure monitoring, titration according to clinical effect and tolerability.
Adverse Effects
Very common: Headaches (especially at start of therapy, often improving after 1 to 2 weeks), hot flushes, orthostatic hypotension, reflex tachycardia.
Common: Dizziness, nausea, fatigue, vomiting.
Occasional to rare: Marked hypotension with syncope, paradoxical worsening of angina pectoris (due to coronary ischemia from steal phenomenon), allergic skin reaction, methemoglobinemia at very high doses, tolerance development with loss of effect.
Important: Tolerance development is an important phenomenon with continuous use. Daily nitrate-free intervals of at least 8 to 10 hours prevent tolerance and maintain effectiveness.
Drug Interactions
- Phosphodiesterase 5 inhibitors (sildenafil, tadalafil, vardenafil) for erectile dysfunction or pulmonary hypertension: Life-threatening hypotension, combination strictly contraindicated; washout period 24 hours for sildenafil, 48 hours for tadalafil
- Other vasodilators (ACE inhibitors, calcium antagonists, alpha blockers): Additive hypotension
- Tricyclic antidepressants and antipsychotics: Additive orthostasis
- Alcohol: Enhances vasodilation and hypotension
- Riociguat (sGC stimulator for pulmonary hypertension): Contraindicated due to severe hypotension
Special Precautions
Pregnancy and lactation: Data limited. In emergency situations such as pulmonary edema or hypertensive crisis, therapy is not withheld. Otherwise, restrictive use.
Aortic stenosis and hypertrophic obstructive cardiomyopathy: Caution or contraindication, because preload reduction can worsen the pressure gradient and critically impair hemodynamics.
Patient information: Patients should learn that persistent chest pain for more than 15 to 20 minutes despite repeated nitrate use is an emergency and emergency number 112 should be called (acute myocardial infarction). Sublingual nitrate does not replace continuous therapy.
Administration while sitting or lying down: Due to hypotension risk, ISDN should not be taken sublingually while standing to avoid syncope.
You Might Also Be Interested In
- Isosorbide Mononitrate, active metabolite as monotherapy
- Glyceryl Trinitrate, another organic nitrate (Nitrolingual spray)
- Molsidomin, nitrate-related mechanism of action
- Ranolazin, further antianginal therapy
- Bisoprolol, beta blocker in CAD
Frequently Asked Questions
When do I take ISDN sublingually?
Sublingual ISDN or spray is used for acute angina pectoris attack or threatening symptoms (e.g., before physical exertion). If chest pain persists for more than 15 to 20 minutes or is accompanied by shortness of breath, dizziness, and profuse sweating, emergency number 112 should be called immediately, as a heart attack may be present.
Why do I get headaches after ISDN?
Nitrates also dilate cerebral vessels, which at the start of therapy typically triggers nitrate headaches. These usually improve after 1 to 2 weeks of use. Paracetamol can help in the initial phase. If headaches remain unbearable, dose reduction or switching preparations may be appropriate.
What is nitrate tolerance and how do I avoid it?
With continuous nitrate use, the effect is lost after days to weeks because NO production in blood vessels decreases. A daily nitrate-free interval of at least 8 to 10 hours, usually at night, maintains effectiveness. Extended-release preparations are usually taken in the morning and midday, with a nitrate-free night.
Why is combination with Viagra dangerous?
Phosphodiesterase 5 inhibitors such as sildenafil enhance the NO effect of nitrates, which can lead to life-threateningly severe blood pressure drop. The combination is strictly contraindicated. Patients on nitrates must not take sildenafil, tadalafil, and vardenafil, and must observe a washout period of at least 24 to 48 hours.
Sources
- ESC Guideline Chronic Coronary Syndrome and Heart Failure
- Gelbe Liste, Isosorbide Dinitrate Drug Profile
- BfArM, Federal Institute for Drugs and Medical Devices
- EMA Product Information Isosorbide Dinitrate Preparations
Legal Notes and Disclaimer
The information provided on this page is for general information purposes only and does not constitute medical advice, diagnosis, or treatment recommendation. It does not replace the advice of a licensed physician or pharmacist. Medicines should only be taken on medical prescription or pharmacy-only release. All statements are based on product information published at the time of creation and recognized scientific sources; the current product information of the manufacturer is always authoritative. Sanoliste assumes no liability for completeness, currency, or correctness of the information presented. In case of medical emergency, call emergency number 112.