Isosorbide dinitrate

Last updated
Isosorbide dinitrate
Isosorbide dinitrate structure.svg
Isosorbide-dinitrate-from-xtal-3D-bs-17.png
Clinical data
Trade names Isordil, others [1]
Other namesISDN; (3R,3aS,6S,6aS)-hexahydrofuro[3,2-b]furan-3,6-diyl dinitrate
AHFS/Drugs.com Monograph
MedlinePlus a682348
License data
Pregnancy
category
  • AU:B1
Routes of
administration
By mouth
ATC code
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
  • 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 InfoCard 100.001.583 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C6H8N2O8
Molar mass 236.136 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 Yes check.svgY
  • Key:MOYKHGMNXAOIAT-JGWLITMVSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (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]

Contents

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 2020, it was the 299th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [6] [7]

Medical uses

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.

Side effects

Tolerance

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]

Other side effects

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.

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. [11]

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. It is sold under the trade name Isoket in the United Kingdom, Argentina, and Hong Kong. It is also a component of BiDil.

Related Research Articles

An antianginal is a drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease.

<span class="mw-page-title-main">Angina</span> Chest discomfort due to not enough blood flow to heart muscle

Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, which is the narrowing of blood vessels.

<span class="mw-page-title-main">Isosorbide mononitrate</span> Chemical compound

Isosorbide mononitrate, sold under many brand names, is a medication used for heart-related chest pain (angina), heart failure and esophageal spasms. It can be used both to treat and to prevent heart-related chest pain; however, it is generally less preferred than beta blockers or calcium channel blockers. It is taken by mouth.

Vasospasm refers to a condition in which an arterial spasm leads to vasoconstriction. This can lead to tissue ischemia and tissue death (necrosis). Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or delayed cerebral ischemia is a major contributor to post-operative stroke and death especially after aneurysmal subarachnoid hemorrhage. Vasospasm typically appears 4 to 10 days after subarachnoid hemorrhage.

<span class="mw-page-title-main">PDE5 inhibitor</span> Vasodilating drug

A phosphodiesterase type 5 inhibitor is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated.

<span class="mw-page-title-main">Methocarbamol</span> Medication for musculoskeletal pain

Methocarbamol, sold under the brand name Robaxin among others, is a medication used for short-term musculoskeletal pain. It may be used together with rest, physical therapy, and pain medication. It is less preferred in low back pain. It has limited use for rheumatoid arthritis and cerebral palsy. Effects generally begin within half an hour. It is taken by mouth or injection into a vein.

<span class="mw-page-title-main">Hydralazine</span> Anti-hypertension medication

Hydralazine, sold under the brand name Apresoline among others, is a medication used to treat high blood pressure and heart failure. This includes high blood pressure in pregnancy and very high blood pressure resulting in symptoms. It has been found to be particularly useful in heart failure, together with isosorbide dinitrate, for treatment of people of African descent. It is given by mouth or by injection into a vein. Effects usually begin around 15 minutes and last up to six hours.

<span class="mw-page-title-main">Variant angina</span> Medical condition

Variant angina, also known as Prinzmetal angina,vasospastic angina, angina inversa, coronary vessel spasm, or coronary artery vasospasm, is a syndrome typically consisting of angina. Variant angina differs from stable angina in that it commonly occurs in individuals who are at rest or even asleep, whereas stable angina is generally triggered by exertion or intense exercise. Variant angina is caused by vasospasm, a narrowing of the coronary arteries due to contraction of the heart's smooth muscle tissue in the vessel walls. In comparison, stable angina is caused by the permanent occlusion of these vessels by atherosclerosis, which is the buildup of fatty plaque and hardening of the arteries.

<span class="mw-page-title-main">Iloprost</span> Pharmaceutical drug

Iloprost is a medication used to treat pulmonary arterial hypertension (PAH), scleroderma, Raynaud's phenomenon and other diseases in which the blood vessels are constricted and blood cannot flow to the tissues. This damages the tissues and causes high blood pressure. There is ongoing research into using it as a frostbite treatment. Iloprost works by opening (dilating) the blood vessels to allow the blood to flow through again. It was developed by the pharmaceutical company Schering AG and is marketed by Bayer Schering Pharma AG in Europe and Actelion Pharmaceuticals in the USA. Iloprost is given via inhalation, and a therapeautic benefit of the drug is that a very low dose is required because of the deposition in the lung. Iloprost has few systemic side effects for that reason.

<span class="mw-page-title-main">Nitroglycerin (medication)</span> Medication

Nitroglycerin, also known as glyceryl trinitrate (GTN), is a vasodilator used for heart failure, high blood pressure (hypertension), anal fissures, painful periods, and to treat and prevent chest pain caused by decreased blood flow to the heart (angina) or due to the recreational use of cocaine. This includes chest pain from a heart attack. It is taken by mouth, under the tongue, applied to the skin, or by injection into a vein.

Hydralazine/isosorbide dinitrate, sold under the brand name Bidil, is a fixed-dose combination medication used to treat self-identified Black people with congestive heart failure. It is a combination of hydralazine hydrochloride and isosorbide dinitrate.

<span class="mw-page-title-main">Nicorandil</span> Chemical compound

Nicorandil is a vasodilator drug used to treat angina.

Esophageal spasm is a disorder of motility of the esophagus.

Prostaglandin E<sub>1</sub> Erectile dysfunction medication

Prostaglandin E1 (PGE1) is a naturally occurring prostaglandin and is also used as a medication (alprostadil).

<span class="mw-page-title-main">Nutcracker esophagus</span> Medical condition

Nutcracker esophagus, jackhammer esophagus, or hypercontractile peristalsis, is a disorder of the movement of the esophagus characterized by contractions in the smooth muscle of the esophagus in a normal sequence but at an excessive amplitude or duration. Nutcracker esophagus is one of several motility disorders of the esophagus, including achalasia and diffuse esophageal spasm. It causes difficulty swallowing, or dysphagia, with both solid and liquid foods, and can cause significant chest pain; it may also be asymptomatic. Nutcracker esophagus can affect people of any age but is more common in the sixth and seventh decades of life.

<span class="mw-page-title-main">Diffuse esophageal spasm</span> Medical condition

Diffuse esophageal spasm (DES), also known as distal esophageal spasm, is a condition characterized by uncoordinated contractions of the esophagus, which may cause difficulty swallowing (dysphagia) or regurgitation. In some cases, it may cause symptoms such as chest pain, similar to heart disease. In many cases, the cause of DES remains unknown.

<span class="mw-page-title-main">Beta-adrenergic agonist</span> Medications that relax muscles of the airways

Beta adrenergic agonists or beta agonists are medications that relax muscles of the airways, causing widening of the airways and resulting in easier breathing. They are a class of sympathomimetic agents, each acting upon the beta adrenoceptors. In general, pure beta-adrenergic agonists have the opposite function of beta blockers: beta-adrenoreceptor agonist ligands mimic the actions of both epinephrine- and norepinephrine- signaling, in the heart and lungs, and in smooth muscle tissue; epinephrine expresses the higher affinity. The activation of β1, β2 and β3 activates the enzyme, adenylate cyclase. This, in turn, leads to the activation of the secondary messenger cyclic adenosine monophosphate (cAMP); cAMP then activates protein kinase A (PKA) which phosphorylates target proteins, ultimately inducing smooth muscle relaxation and contraction of the cardiac tissue.

<span class="mw-page-title-main">Nitrovasodilator</span> Drug that causes vasodilation by releasing nitric oxide

A nitrovasodilator is a pharmaceutical agent that causes vasodilation by donation of nitric oxide (NO), and is mostly used for the treatment and prevention of angina pectoris.

<span class="mw-page-title-main">Acute decompensated heart failure</span> Medical condition

Acute decompensated heart failure (ADHF) is a sudden worsening of the signs and symptoms of heart failure, which typically includes difficulty breathing (dyspnea), leg or feet swelling, and fatigue. ADHF is a common and potentially serious cause of acute respiratory distress. The condition is caused by severe congestion of multiple organs by fluid that is inadequately circulated by the failing heart. An attack of decompensation can be caused by underlying medical illness, such as myocardial infarction, an abnormal heart rhythm, infection, or thyroid disease.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 "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 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. "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 2020". ClinCalc. Retrieved 7 October 2022.
  7. "Isosorbide Dinitrate - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  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.