Isosorbide dinitrate (original) (raw)

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Chemical compound

Pharmaceutical compound

Isosorbide dinitrate
Clinical data
Trade names Isordil, others[1]
Other names ISDN; (3_R_,3a_S_,6_S_,6a_S_)-hexahydrofuro[3,2-_b_]furan-3,6-diyl dinitrate
AHFS/Drugs.com Monograph
MedlinePlus a682348
License data US DailyMed: Isosorbide dinitrate
Pregnancy category AU: B1
Routes of administration By mouth
ATC code C01DA08 (WHO) C05AE02 (WHO)
Legal status
Legal status In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 10–90%, average 25%
Metabolism Liver
Elimination half-life 1 hour
Excretion Kidney
Identifiers
IUPAC name 1,4:3,6-dianhydro-2,5-di-_O_-nitro-D-glucitol
CAS Number 87-33-2 checkY
PubChem CID 6883
DrugBank DB00883 checkY
ChemSpider 6619 checkY
UNII IA7306519N
KEGG D00516 checkY
ChEBI CHEBI:6061 checkY
ChEMBL ChEMBL2171310 ☒N
CompTox Dashboard (EPA) DTXSID0045832 Edit this at Wikidata
ECHA InfoCard 100.001.583 Edit this at Wikidata
Chemical and physical data
Formula C6H8N2O8
Molar mass 236.136 g·mol−1
3D model (JSmol) Interactive image
SMILES [O-][N+](=O)O[C@H]1[C@H]2OC[C@H](O[N+]([O-])=O)[C@H]2OC1
InChI InChI=1S/C6H8N2O8/c9-7(10)15-3-1-13-6-4(16-8(11)12)2-14-5(3)6/h3-6H,1-2H2/t3-,4+,5-,6-/m1/s1 checkYKey:MOYKHGMNXAOIAT-JGWLITMVSA-N checkY
☒NcheckY (what is this?) (verify)

Isosorbide dinitrate is a medication used for heart failure, esophageal spasms, and to treat and prevent chest pain from not enough blood flow to the heart.[1] It has been found to be particularly useful in heart failure due to systolic dysfunction together with hydralazine.[2][1] It is taken by mouth or under the tongue.[1]

Common side effects include headache, lightheadedness with standing, and blurred vision.[1] Severe side effects include low blood pressure.[1] It is unclear if use in pregnancy is safe for the baby.[1] It should not be used together with PDE5 Inhibitors.[1] Isosorbide dinitrate is in the nitrate family of medications and works by dilating blood vessels.[1]

Isosorbide dinitrate was first written about in 1939.[3] It is on the World Health Organization's List of Essential Medicines.[4] Isosorbide dinitrate is available as a generic medication.[1][5] A long-acting form exists.[1] In 2022, isosorbide was the 119th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[6][7]

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:

  1. Impaired biotransformation of isosorbide dinitrate to its active principle NO (or a NO-related species)
  2. Neurohormonal activation, causing sympathetic activation and release of vasoconstrictors such as endothelin and angiotensin II which counteract the vasodilation induced by isosorbide dinitrate
  3. Plasma volume expansion
  4. The oxidative stress hypothesis[8]

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]

Mechanism of action

[edit]

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]

Society and culture

[edit]

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.

  1. ^ a b c d e f g h i j k l "Isosorbide Dinitrate/Mononitrate". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  2. ^ 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. PMID 18441861.
  3. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 454. ISBN 9783527607495. Archived from the original on 20 December 2016.
  4. ^ 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.
  5. ^ "Competitive Generic Therapy Approvals". U.S. Food and Drug Administration (FDA). 29 June 2023. Archived from the original on 29 June 2023. Retrieved 29 June 2023.
  6. ^ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  7. ^ "Isosorbide Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  8. ^ Münzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG (January 1995). "Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance". The Journal of Clinical Investigation. 95 (1): 187–94. doi:10.1172/JCI117637. PMC 295403. PMID 7814613.
  9. ^ 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. PMID 10467211.
  10. ^ 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. PMID 18634978.
  11. ^ Rang HP, Ritter J, Flower RJ, Henderson G (2016). Pharmacology (8th ed.). Elsevier. p. 261. ISBN 978-0-7020-5362-7.