Dipyridamole

Dipyridamole
Names
Trade namesPersantine, others
IUPAC name
  • 2,2',2'',2'''-(4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine-2,6-diyl)bis(azanetriyl)tetraethanol
Clinical data
Main usesPrevent blood clots, as part of myocardial perfusion imaging[1]
Side effectsHeadache, dizziness, flushing, chest pain, gastrointestinal upset, nausea, diarrhea, rash, itchiness[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • B
Routes of
use		By mouth, IV
External links
AHFS/Drugs.comMonograph
MedlinePlusa682830
Legal
Legal status
Pharmacokinetics
Bioavailability37–66%[3]
Protein binding~99%
MetabolismLiver (glucuronidation)[4]
Elimination half-lifeα phase: 40 min,
β phase: 10 hours
ExcretionBiliary (95%), urine (negligible)
Chemical and physical data
FormulaC24H40N8O4
Molar mass504.636 g·mol−1
3D model (JSmol)
SMILES
  • OCCN(CCO)C(N=C1N2CCCCC2)=NC3=C1N=C(N(CCO)CCO)N=C3N4CCCCC4
InChI
  • InChI=1S/C24H40N8O4/c33-15-11-31(12-16-34)23-26-20-19(21(27-23)29-7-3-1-4-8-29)25-24(32(13-17-35)14-18-36)28-22(20)30-9-5-2-6-10-30/h33-36H,1-18H2 checkY
  • Key:IZEKFCXSFNUWAM-UHFFFAOYSA-N checkY

Dipyridamole, sold under the brand name Persantine and others, is a medication used to prevent blood clots and as part of thallium myocardial perfusion imaging.[1] For blood clots prevention it is used together with either aspirin or warfarin.[2] It is taken by mouth or by injected into a vein.[1]

Side effects may include headache, dizziness, flushing, chest pain, gastrointestinal upset, nausea, diarrhea, rash, and itchiness.[2] Other side effects may include liver problems and anaphylaxis.[1] While there is no clear harm with use in pregnancy, such use has not been well studied.[5] It works by dilating blood vessels and decreasing platelet aggregation.[2]

Dipyridamole was approved for medical use in the United States in 1961.[1] It is available as a generic medication.[2] In the United Kingdom 60 pills of 200 mg costs the NHS about £13 as of 2021.[6] This amount in the United States costs about 88 USD.[7]

Medical uses

  • Dipyridamole is used to dilate blood vessels in people with peripheral arterial disease and coronary artery disease[8]
  • Dipyridamole has been shown to lower pulmonary hypertension without significant drop of systemic blood pressure
  • It inhibits formation of pro-inflammatory cytokines (MCP-1, MMP-9) in vitro and results in reduction of hsCRP in patients.
  • It inhibits proliferation of smooth muscle cells in vivo and modestly increases unassisted patency of synthetic arteriovenous hemodialysis grafts.[9]
  • It has been shown to increase myocardial perfusion and left ventricular function in patients with ischemic cardiomyopathy.
  • It can be used for myocardial stress testing as an alternative to exercise-induced stress methods such as treadmills.

Stroke

A combination of dipyridamole and aspirin (acetylsalicylic acid/dipyridamole) is FDA-approved for the secondary prevention of stroke and has a bleeding risk equal to that of aspirin use alone.[8] Dipyridamole absorption is pH-dependent and concomitant treatment with gastric acid suppressors (such as a proton pump inhibitor) will inhibit the absorption of liquid and plain tablets.[10][11] Modified release preparations are buffered and absorption is not affected.[12][13]

However, it is not licensed as monotherapy for stroke prophylaxis, although a Cochrane review suggested that dipyridamole may reduce the risk of further vascular events in patients presenting after cerebral ischemia.[14]

A triple therapy of aspirin, clopidogrel, and dipyridamole has been investigated, but this combination led to an increase in adverse bleeding events.[15]

  • Vasodilation occurs in healthy arteries, whereas stenosed arteries remain narrowed. This creates a "steal" phenomenon where the coronary blood supply will increase to the dilated healthy vessels compared to the stenosed arteries which can then be detected by clinical symptoms of chest pain, electrocardiogram and echocardiography when it causes ischemia.
  • Flow heterogeneity (a necessary precursor to ischemia) can be detected with gamma cameras and SPECT using nuclear imaging agents such as Thallium-201, Tc99m-Tetrofosmin and Tc99m-Sestamibi. However, relative differences in perfusion do not necessarily imply any absolute decrease in blood supply in the tissue supplied by a stenosed artery.

Interactions

Due to its action as a phosphodiesterase inhibitor, dipyridamole is likely to potentiate the effects of adenosine. This occurs by blocking the nucleoside transporter through which adenosine enters erythrocyte and endothelial cells.[16]

According to Association of Anaesthetists of Great Britain and Ireland 2016 guidelines, dipyridamole is considered to not cause risk of bleeding when receiving neuroaxial anaesthesia and deep nerve blocks. It does not therefore require cessation prior to anaesthesia with these techniques, and can continue to be taken with nerve block catheters in place.[17]

Overdose

Dipyridamole overdose can be treated with aminophylline[4]: 6  or caffeine which reverses its dilating effect on the blood vessels. Symptomatic treatment is recommended, possibly including a vasopressor drug. Gastric lavage should be considered. Since dipyridamole is highly protein bound, dialysis is not likely to be of benefit.

Mechanisms of action

Dipyridamole has two known effects, acting via different mechanisms of action:

Research

Dipyridamole is currently undergoing repurposing for treatment of ocular surface disorders. These include pterygium and dry eye disease. The first report of topical dipyridamole's benefit in treating pterygium was published in 2014.[18] A subsequent report of outcomes in 25 patients using topical dipyridamole was presented in 2016.[19]

Dipyridamole also has non-medicinal uses in a laboratory context, such as the inhibition of cardiovirus growth in cell culture.

It inhibits the replication of mengovirus RNA.[20]

See also

References

  1. 1 2 3 4 5 "Dipyridamole Monograph for Professionals". Drugs.com. Archived from the original on 12 May 2021. Retrieved 26 December 2021.
  2. 1 2 3 4 5 "Dipyridamole". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. Archived from the original on 16 May 2021. Retrieved 26 December 2021.
  3. ↑ Nielsen-Kudsk, F; Pedersen, AK (May 1979). "Pharmacokinetics of Dipyridamole". Acta Pharmacologica et Toxicologica. 44 (5): 391–9. doi:10.1111/j.1600-0773.1979.tb02350.x. PMID 474151.
  4. 1 2 "Aggrenox (aspirin/extended-release dipyridamole) Capsules. Full Prescribing Information" (PDF). Boehringer Ingelheim Pharmaceuticals, Inc. Archived (PDF) from the original on 29 September 2016. Retrieved 1 December 2016.
  5. ↑ "Dipyridamole Use During Pregnancy". Drugs.com. Archived from the original on 5 December 2020. Retrieved 26 December 2021.
  6. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 135. ISBN 978-0857114105.
  7. ↑ "Dipyridamole Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 26 December 2021.
  8. 1 2 3 Brown DG, Wilkerson EC, Love WE (March 2015). "A review of traditional and novel oral anticoagulant and antiplatelet therapy for dermatologists and dermatologic surgeons". Journal of the American Academy of Dermatology. 72 (3): 524–34. doi:10.1016/j.jaad.2014.10.027. PMID 25486915.
  9. ↑ Dixon BS, Beck GJ, Vazquez MA, et al. (2009). "Effect of dipyridamole plus aspirin on hemodialysis graft patency". N Engl J Med. 360 (21): 2191–2201. doi:10.1056/nejmoa0805840. PMC 3929400. PMID 19458364.
  10. ↑ Russell TL, Berardi RR, Barnett JL, O’Sullivan TL, Wagner JG, Dressman JB. pH-related changes in the absorption of "dipyridamole" in the elderly. Pharm Res (1994) 11 136–43.
  11. ↑ Derendorf H, VanderMaelen CP, Brickl R-S, MacGregor TR, Eisert W. "Dipyridamole" bioavailability in subjects with reduced gastric acidity. J Clin Pharmacol (2005) 45, 845–50.
  12. ↑ "Archived copy". Archived from the original on 2009-07-05. Retrieved 2010-02-06.{{cite web}}: CS1 maint: archived copy as title (link)
  13. ↑ Stockley, Ivan (2009). Stockley's Drug Interactions. The Pharmaceutical Press. ISBN 978-0-85369-424-3.
  14. ↑ De Schryver EL, Algra A, van Gijn J (2007). Algra A (ed.). "Dipyridamole for preventing stroke and other vascular events in patients with vascular disease". Cochrane Database of Systematic Reviews (2): CD001820. doi:10.1002/14651858.CD001820.pub3. PMID 17636684. Archived from the original on 2011-07-22. Retrieved 2021-08-11.
  15. ↑ Sprigg N, Gray LJ, England T, et al. (2008). Berger JS (ed.). "A randomised controlled trial of triple antiplatelet therapy (aspirin, clopidogrel and dipyridamole) in the secondary prevention of stroke: safety, tolerability and feasibility". PLoS ONE. 3 (8): e2852. Bibcode:2008PLoSO...3.2852S. doi:10.1371/journal.pone.0002852. PMC 2481397. PMID 18682741.
  16. ↑ Gamboa A, Abraham R, Diedrich A, Shibao C, Paranjape SY, Farley G, et al. Role of adenosine and nitric oxide on the mechanisms of action of dipyridamole. Stroke. 2005;36(10):2170-2175.
  17. ↑ AAGBI Guidelines Neuraxial and Coagulation June 2016
  18. ↑ Carlock, Beth H.; Bienstock, Carol A.; Rogosnitzky, Moshe (2014-03-25). "Pterygium: Nonsurgical Treatment Using Topical Dipyridamole – A Case Report". Case Reports in Ophthalmology. 5 (1): 98–103. doi:10.1159/000362113. ISSN 1663-2699. PMC 3995373. PMID 24761148.
  19. ↑ "Topical Dipyridamole for Treatment of Pterygium and Associated Dry Eye Symptoms: Analysis of User-Reported Outcomes". ResearchGate. Archived from the original on 2021-08-28. Retrieved 2019-05-19.
  20. ↑ Dipyridamole in the laboratory: Fata-Hartley, Cori L.; Ann C. Palmenberg (2005). "Dipyridamole reversibly inhibits mengovirus RNA replication". Journal of Virology. 79 (17): 11062–11070. doi:10.1128/JVI.79.17.11062-11070.2005. PMC 1193570. PMID 16103157.
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