It is used for angina, in addition to other medications for congestive heart failure, and for esophageal spasms.[1] It is available as an oral tablet both in extended release and slow release. The onset of action for Isosorbide Dinitrate is thirty minutes and the onset of action for oral extended release is 12–24 hours.
Long-acting nitrates can be more useful as they are generally more effective and stable in the short term.
After long-term use for treating chronic conditions, tolerance may develop in patients, reducing its effectiveness. The mechanisms of nitrate tolerance have been thoroughly investigated in the last 30 years and several hypotheses have been proposed. These include:
Impaired biotransformation of isosorbide dinitrate to its active principle NO (or a NO-related species)
Neurohormonal activation, causing sympathetic activation and release of vasoconstrictors such as endothelin and angiotensin II which counteract the vasodilation induced by isosorbide dinitrate
The last hypothesis might represent a unifying hypothesis, and an isosorbide dinitrate-induced inappropriate production of oxygen free radicals might induce a number of abnormalities which include the ones described above.
Furthermore, nitrate tolerance is shown to be associated with vascular abnormalities which have the potential to worsen patients prognosis:[9] these include endothelial and autonomic dysfunction.[10]
In the short run, isosorbide dinitrate can cause severe headaches, necessitating analgesic administration for relief of pain, as well as severe hypotension, and, in certain cases, bradycardia.
Rarely occurring are allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); fainting; fast or slow heartbeat; nausea; new or worsening chest pain; vomiting.
Similar to other nitrites and organic nitrates, isosorbide dinitrate is converted to nitric oxide (NO), an active intermediate compound which activates the enzyme guanylate cyclase (atrial natriuretic peptide receptor A). This stimulates the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP) which then activates a series of protein kinase-dependent phosphorylations in the smooth muscle cells, eventually resulting in the dephosphorylation of the myosin light chain of the smooth muscle fiber. The subsequent sequestration of calcium ions results in the relaxation of the smooth muscle cells and vasodilation.[11]
Isosorbide dinitrate is sold in the US under the brand names Dilatrate-SR by Schwarz and Isordil by Valeant, according to FDA Orange Book. It is sold under the trade name Isoket in the United Kingdom, Argentina, and Hong Kong. It is also a component of BiDil.
^Chavey WE, Bleske BE, Van Harrison R, Hogikyan RV, Kesterson SK, Nicklas JM (April 2008). "Pharmacologic management of heart failure caused by systolic dysfunction". American Family Physician. 77 (7): 957–964. PMID18441861.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Nakamura Y, Moss AJ, Brown MW, Kinoshita M, Kawai C (September 1999). "Long-term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large-scale postinfarction studies. Multicenter Myocardial Ischemia Research Group". American Heart Journal. 138 (3 Pt 1): 577–85. doi:10.1016/s0002-8703(99)70163-8. PMID10467211.
^Gori T, Parker JD (July 2008). "Nitrate-induced toxicity and preconditioning: a rationale for reconsidering the use of these drugs". Journal of the American College of Cardiology. 52 (4): 251–4. doi:10.1016/j.jacc.2008.04.019. PMID18634978.
^Rang HP, Ritter J, Flower RJ, Henderson G (2016). Pharmacology (8th ed.). Elsevier. p. 261. ISBN978-0-7020-5362-7.
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