Dipyridamole

Dipyridamole

Systematic (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
Trade names	Persantine
AHFS/Drugs.com	monograph
MedlinePlus	a682830
Pregnancy cat.	B
Legal status	?
Routes	PO, IV
Pharmacokinetic data
Protein binding	99%
Metabolism	Hepatic
Half-life	Alpha (40 mins), Beta (10 Hours)
Identifiers
CAS number	58-32-2 Y
ATC code	B01AC07
PubChem	CID 3108
DrugBank	APRD00360
ChemSpider	2997 Y
UNII	64ALC7F90C Y
KEGG	D00302 Y
ChEBI	CHEBI:4653 Y
ChEMBL	CHEMBL932 Y
Chemical data
Formula	C24H40N8O4
Mol. mass	504.626 g/mol
SMILES	eMolecules & PubChem
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 Y Key:IZEKFCXSFNUWAM-UHFFFAOYSA-N Y
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Dipyridamole (trade name Persantine) is a drug that inhibits thrombus formation^[1] when given chronically and causes vasodilation when given at high doses over a short time.

Mechanism and effects

• It acts as a thromboxane synthase inhibitor, therefore lowering the levels of TXA2 and thus stops the effects of TXA2 (platelet aggregation, bronchioconstriction and vasoconstriction).
• It inhibits the cellular reuptake of adenosine into platelets, red blood cells and endothelial cells leading to increased extracellular concentrations of adenosine.
• It also inhibits the enzyme adenosine deaminase, which normally breaks down adenosine into inosine. This inhibition leads to further increased levels of extracellular adenosine.
• Dipyridamole also inhibits the phosphodiesterase enzymes that normally break down cAMP (increasing cellular cAMP levels and blocking the platelet response to ADP) and/or cGMP (resulting in added benefit when given together with NO or statins).

Medical uses

• 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 has shown to prevent AV-shunt failure in dialysis patients.
• It increases the release of t-PA from brain microvascular endothelial cells
• It results in an increase of 13 - HODE and decrease of 12 - HETE in the subendothelial matrix (SEM) and reduced thrombogenicity of the SEM.
• Pretreatment it reduced reperfusion injury in volunteers.
• It has been shown to increase myocardial perfusion and left ventricular function in patients with ischemic cardiomyopathy.
• It results in a reduction of the number of thrombin and PECAM-1 receptors on platelets in stroke patients.
• cAMP impairs platelet aggregation and also causes arteriolar smooth muscle relaxation. Chronic therapy did not show significant drop of systemic blood pressure.
• It inhibits the replication of mengovirus RNA.^[2]
• It can be used for myocardial stress testing as an alternative to exercise-induced stress methods such as treadmills.

Use in individuals with a history of stroke

Modified release dipyridamole is used in conjunction with aspirin (under the trade names Aggrenox in the USA or Asasantin Retard in the UK) in the secondary prevention of stroke and transient ischaemic attack. This practice has been confirmed by the ESPRIT trial.^[3] Dipyridamole absorption is pH-dependent and concomitant treatment with gastric acid suppressors (such as a proton pump inhibitor) will inhibit the absorption of liquid & plain tablets.^[4][5] Modified release preparations are buffered and absorption is not affected.^[6][7]

It is not, however, licensed as monotherapy for stroke prophylaxis, although a Cochrane Review has suggested that dipyridamole may reduce the risk of further vascular events in patients presenting after cerebral ischaemia.^[8]

A triple therapy of aspirin, clopidogrel and dipyridamole has been investigated, but this combination led to an increase in adverse bleeding events.^[9]

• Via the mechanisms mentioned above, when given as 3 to 5 min infusion it rapidly increases the local concentration of adenosine in the coronary circulation which causes vasodilation.
• 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 and Tc99m-Sestamibi. However relative differences in perfusion not necessarily imply absolute decrease in blood supply in the tissue supplied by a stenosed artery.

Other uses

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

Overdose

Dipyridamole
Classification and external resources
ICD-10	T46.3
ICD-9	972.4

Dipyridamole overdose can be treated with aminophylline^[10] and reverses its hemodynamic effects (vasodilation). Symptomatic treatment is recommended, possibly including a vasopressor drug. Gastric lavage should be considered. Administration of xanthine derivatives (e.g., aminophylline) may reverse the hemodynamic effects of dipyridamole overdose. Since dipyridamole is highly protein bound, dialysis is not likely to be of benefit.

See also

Cilostazol

References

1. ^ "Dipyridamole" at Dorland's Medical Dictionary
2. ^ Dipyridamole in the laboratory: Fata-Hartley, Cori L.; Ann C. Palmenberg. "Dipyridamole reversibly inhibits mengovirus RNA replication". doi:10.1128/JVI.79.17.11062-11070.2005. http://jvi.asm.org/cgi/content/full/79/17/11062?view=long&pmid=16103157. Retrieved 2007-02-13. 
3. ^ Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A (May 2006). "Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial". Lancet 367 (9523): 1665–73. doi:10.1016/S0140-6736(06)68734-5. PMID 16714187. http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(06)68734-5. 
4. ^ 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.
5. ^ 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.
6. ^ http://emc.medicines.org.uk/medicine/304/SPC/Persantin+Retard+200mg/#EXCIPIENTS
7. ^ Stockley, Ivan (2009). Stockley’s Drug Interactions. The Pharmaceutical Press. ISBN 0853694249. 
8. ^ De Schryver ELLM, Algra A, van Gijn J. (2007). Algra, Ale. ed. "Dipyridamole for preventing stroke and other vascular events in patients with vascular disease.". Cochrane Database of Systematic Reviews 2007 (2): CD001820. doi:10.1002/14651858.CD001820.pub3. PMID 17636684. http://www.cochrane.org/reviews/en/ab001820.html. 
9. ^ Sprigg N, Gray LJ, England T, et al. (2008). Berger, Jeffrey S.. 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. doi:10.1371/journal.pone.0002852. PMC 2481397. PMID 18682741. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002852. 
10. ^ Aggrenox. RxList.com. URL: http://www.rxlist.com/cgi/generic/aggrenox_od.htm. Accessed on: May 1, 2007.