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Isosorbide dinitrate

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Isosorbide dinitrate
Clinical data
Trade namesIsordil, others[1]
Other names(3R,3aS,6S,6aS)-hexahydrofuro[3,2-b]furan-3,6-diyl dinitrate
AHFS/Drugs.comMonograph
MedlinePlusa682348
License data
Pregnancy
category
  • AU: B1
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability10–90%, average 25%
MetabolismLiver
Elimination half-life1 hour
ExcretionKidney
Identifiers
  • 1,4:3,6-dianhydro-2,5-di-O-nitro-D-glucitol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.001.583 Edit this at Wikidata
Chemical and physical data
FormulaC6H8N2O8
Molar mass236.136 g·mol−1
3D model (JSmol)
  • [O-][N+](=O)O[C@H]1[C@H]2OC[C@H](O[N+]([O-])=O)[C@H]2OC1
  • 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 checkY
  • Key:MOYKHGMNXAOIAT-JGWLITMVSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Isosorbide dinitrate (ISDN) 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 in black people.[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 medications within the sildenafil family.[1] ISDN 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, the safest and most effective medicines needed in a health system.[4] ISDN is available as a generic medication.[1] A long-acting form exists.[1]

Medical uses

It is used for angina, in addition to other medications for congestive heart failure, and for esophageal spasms.[1]

Long-acting nitrates can be more useful as they are generally more effective and stable in the short term.

Side effects

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. Severe 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.
  2. Impaired biotransformation of ISDN to its active principle NO (or a NO-related species)
  3. Neurohormonal activation, causing sympathetic activation and release of vasoconstrictors such as endothelin and angiotensin II which counteract the vasodilation induced by ISDN
  4. Plasma volume expansion
  5. The oxidative stress hypothesis (proposed by Munzel et al. in 1995)

The last hypothesis might represent a unifying hypothesis, and an ISDN-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:[5] these include endothelial and autonomic dysfunction.[6] In the short run, ISDN can cause severe headaches, necessitating analgesic (very rarely up to morphine) administration for relief of pain, as well as severe hypotension, and, in certain cases, bradycardia. This makes some physicians nervous and should prompt caution when starting nitrate administration.

Mechanism of action

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.[7]

Society and culture

Isosorbide dinitrate is sold in the US under the brand names Dilatrate-SR by Schwarz and Isordil by Valeant, according to FDA Orange Book. In the United Kingdom, Argentina, and Hong Kong, a trade name of it is Isoket. It is also a component of BiDil.

References

  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, William E.; Bleske, Barry E.; Van Harrison, R.; Hogikyan, Robert V.; Kesterson, Sean K.; Nicklas, John M. (1 April 2008). "Pharmacologic management of heart failure caused by systolic dysfunction". American Family Physician. 77 (7): 957–964. ISSN 0002-838X. PMID 18441861.
  3. ^ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 454. ISBN 9783527607495. Archived from the original on 2016-12-20.
  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. ^ (Nakamura et al.)
  6. ^ (Gori et al.).
  7. ^ Rang; et al. Pharmacology (8th ed.). Elsevier. p. 261. ISBN 978-0-7020-5362-7.
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