Dipyridamole

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Structural formula
Structural formula of dipyridamole
General
Non-proprietary name Dipyridamole
other names
  • 2,6-bis [bis (2-hydroxyethyl) amino] -4,8-dipiperidinopyrimido [5,4- d ] pyrimidine
  • Dipyridamolum ( Latin )
  • 2,2 ', 2' ', 2' '' - (4,8-Di (piperidin-1-yl) pyrimido [5,4- d ] pyrimidin-2,6-diyl) bis (azanetriyl) tetraethanol ( IUPAC )
Molecular formula C 24 H 40 N 8 O 4
Brief description

bright yellow, crystalline powder

External identifiers / databases
CAS number 58-32-2
EC number 200-374-7
ECHA InfoCard 100,000,340
PubChem 3108
DrugBank DB00975
Wikidata Q419374
Drug information
ATC code

B01 AC07

Drug class

Antiplatelet drugs

properties
Molar mass 504.63 g · mol -1
Physical state

firmly

Melting point

163 ° C

pK s value

6.4

solubility

practically insoluble in water (8.17 mg · l −1 at 25 ° C), slightly soluble in acetone , soluble in ethanol

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 315-319-335
P: 261-305 + 351 + 338
Toxicological data

8400 mg kg −1 ( LD 50 ,  rat ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Dipyridamole is a drug with a platelet aggregation-inhibiting effect, which was first launched on the market by Boehringer Ingelheim under the trade name Persantin for thrombosis and embolism prophylaxis . Today the drug is sold in combination with acetylsalicylic acid (ASA) under the trade name Aggrenox (in Austria: Asasantin ). This combination is prescribed to prevent recurrence of cerebral ischemia (TIA or stroke) if an increased risk of recurrence is assumed in individual cases. However, the increased benefit of this combination therapy compared to ASA alone is currently debatable.

Pharmacodynamics

A distinction is made between two mechanisms of action. On the one hand, dipyridamole acts as a specific blocker of adenosine transporters and thus inhibits the reuptake of adenosine into the presynapse . There is more adenosine available which, via a G s- coupled receptor on the coronary vascular muscle cell, triggers relaxation via cAMP . This explanatory model is used to explain the application as a coronary dilator as well as in diagnostics (see below). The use in therapy is obsolete due to the steal effect (see below).

Another mechanism of action is the inhibition of phosphodiesterase , in platelets there is an increase in cAMP, which in turn lowers the concentration of free Ca 2+ in the cytosol of the platelets. This effect leads to reduced platelet aggregation. This explains the effectiveness in stroke prophylaxis.

Restrictions on use and side effects

In the case of regional anesthesia procedures close to the spinal cord ( spinal anesthesia or epidural anesthesia ), the combination of dipyridamole and ASA should be discontinued 48 hours in advance, but can be given again immediately after the procedure.

Diagnosis

Another field of application of dipyridamole is myocardial scintigraphy and stress echocardiography . By administering the substance under controlled conditions (ECG monitoring, blood pressure measurement, emergency readiness), a drug-induced cardiac load can be achieved and the perfusion of the myocardium can be assessed using single-photon emission computer tomography (SPECT) or the wall movement can be assessed using ultrasound .

Dipyridamole acts as a vasodilator , so it expands healthy blood vessels, which then have increased blood flow. Stenosed vessels remain narrowed, so that there - in relation to the now enlarged healthy vessels - there is a further decrease in blood flow. This effect is called the steal effect (see above). The myocardial cells are no longer adequately supplied, which leads to ischemia (antidote: theophylline ).

Combination with acetylsalicylic acid

Today the drug is sold in combination with acetylsalicylic acid ( Aggrenox , formerly Asasantin ). However, the greater benefit of this combination therapy compared to the administration of ASA alone is currently controversial.

According to the JASAP study, which was carried out in Japan, the combination of dipyridamole with ASA 1.47 times more strokes than with ASA alone; the headache rate was also increased. The JASAP study initiated by the manufacturing company Boehringer Ingelheim itself could not prove the superiority of dipyridamole / ASA over ASA. In 2011, despite the cost difference between the combination therapy and ASA (daily dose: € 1.60 vs. € 0.03), the guidelines of the German Society for Neurology recommended combination therapy with ASA / dipyridamole for secondary prophylaxis of stroke in patients with a high risk of recurrence .

According to a statistical evaluation by IQWiG , the combination of ASA and dipyridamole is no more effective than the administration of ASA or clopidogrel alone in preventing repeated strokes after the first stroke . The benefit assessment of the IQWiG report is based on the statistical analysis of the results of six studies, including a. ESPS-2, ProFESS and JASAP. The results of the ESPRIT study were not taken into account in the benefit assessment by IQWiG. The Federal Joint Committee took the IQWiG report as the basis for its resolution of May 16, 2013 to exclude the drug from the prescription. The Federal Ministry of Health , however, asked on the basis of information from the Federal Institute for Drugs and Medical Devices (BfArM), which sees a contradiction between the risk-benefit assessment of the regulatory authority and the assessment of the advisability by IQWiG, prior to the implementation of the decision to B -GA for a supplementary opinion. A final decision is pending (as of December 12, 2013).

Trade names

Monopreparations

Persantin (A)

Combination preparations

Aggrenox (D), Asasantin (A, CH)

Individual evidence

  1. ↑ a b European Pharmacopoeia Commission (ed.): EUROPEAN PHARMACOPOE 5TH EDITION . tape 5.0-5.8 , 2006.
  2. ↑ a b c Entry on dipyridamole. In: Römpp Online . Georg Thieme Verlag, accessed on December 28, 2014.
  3. ↑ a b Datasheet Dipyridamole from Sigma-Aldrich , accessed on March 28, 2011 ( PDF ).
  4. ↑ Karow / Lang, Pharmakologie und Toxikologie, 17th edition.
  5. ↑ B. Deuticke, E. Gerlach: Competitive inhibition of adenosine deaminase as a possible cause of the coronary dilating effect of a pyrimidopyrimidine compound , Naunyn-Schmiedeberg's Archives of Pharmacology , Volume 255, 1966, pp. 107-119. doi : 10.1007 / BF00544874 .
  6. ↑ Wiebke Gogarten, Hugo Van Aken: Perioperative thrombosis prophylaxis - platelet aggregation inhibitors - importance for anesthesia In: AINS - anesthesiology · intensive care medicine · emergency medicine · pain therapy. 47, 2012, pp. 242-252, doi : 10.1055 / s-0032-1310414 .
  7. ↑ SA Kozek-Langenecker, D. Fries, M. Gütl, N. Hofmann, P. Innerhofer, W. Kneifl, L. Neuner, P. Perger, T. Pernerstorfer, G. Pfanner, et al .: Locoregional anesthesia under anticoagulant medication. Recommendations of the Perioperative Coagulation Working Group (AGPG) of the Austrian Society for Anaesthesiology and Intensive Care Medicine (ÖGARI). DER ANAESTHESIST Volume 54, Number 5 (2005), pp. 476-484, doi : 10.1007 / s00101-005-0827-0 .
  8. ↑ R. Sicari, P. Nihoyannopoulos u. a .: Stress echocardiography expert consensus statement: European Association of Echocardiography (EAE) (a registered branch of the ESC). In: European journal of echocardiography. Volume 9, Number 4, July 2008, pp. 415-437, doi : 10.1093 / ejechocard / jen175 . PMID 18579481 .
  9. ↑ G. Herold (Ed.): Internal medicine. 2010, p. 231.
  10. ↑ a b Shinichiro Uchiyama, Yasuo Ikeda u. a .: The Japanese Aggrenox (Extended-Release Dipyridamole plus Aspirin) Stroke Prevention versus Aspirin Program (JASAP) Study: A Randomized, Double-Blind, Controlled Trial. In: Cerebrovascular Diseases. 31, 2011, pp. 601-613, doi : 10.1159 / 000327035 .
  11. ↑ a b Thomas Lempert, Enrico Völzke: Medicinal studies: New transparency through study registers. In: Deutsches Ärzteblatt 108 (23). June 10, 2011, accessed March 13, 2013 .
  12. ↑ Japanese study with Aggrenox unpublished for a year ... No indication of an advantage over ASA alone, but a risk signal. arznei-telegram , May 3, 2010, accessed on March 13, 2013 .
  13. ↑ Final report A09-01 (PDF; 103 kB) "Dipyridamole + ASS after a stroke or TIA", IQWiG, February 14, 2011.
  14. ↑ HC Diener, L. Cunha et al. a .: European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. In: Journal of the Neurological Sciences. 143, 1996, pp. 1-13, doi : 10.1016 / S0022-510X (96) 00308-5 .
  15. ↑ Ralph L. Sacco, Hans-Christoph Diener a. a .: Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke. In: New England Journal of Medicine. 359, 2008, pp. 1238-1251, doi : 10.1056 / NEJMoa0805002 .
  16. ↑ ESPRIT Study Group: Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomized controlled trial. In: The Lancet. 367, 2006, pp. 1665-1673, doi : 10.1016 / S0140-6736 (06) 68734-5 .
  17. ^ ESPRIT Study Group; PH Halkes, J. van Gijn, L J. Kappelle, PJ Koudstaal, A. Algra: Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a randomized controlled trial . In: The Lancet Neurology . Vol. 6, No. 2, 2007, pp. 115-124.
  18. ↑ IQWiG: Stroke treatment: Dipyridamole plus ASA offers no advantages. Additional benefit compared to ASA and clopidogrel has not been proven / severe bleeding occurs more frequently with combination treatment. April 11, 2011, accessed December 11, 2013 .
  19. ↑ B-GA: Resolution of the Federal Joint Committee on an amendment to the Drugs Directive (AM-RL): Appendix III - Overview of the prescription restrictions and exclusions Dipyridamole in combination with acetylsalicylic acid. May 16, 2013, accessed December 11, 2013 .
  20. ↑ B-GA: Basic reasons for the decision of the Federal Joint Committee on an amendment to the Drugs Directive: Appendix III - Overview of the prescription restrictions and exclusions Dipyridamole in combination with acetylsalicylic acid. May 16, 2013, accessed December 11, 2013 .
  21. ↑ The resolutions and statements on the Drugs Directive / Annex III: Dipyridamole in combination with acetylsalicylic acid are documented in the information archive of the G-BA.
  22. ↑ Orlowski, Ulrich: Decision of the Federal Joint Committee according to § 91 SGB V of 16 May 2013 on an amendment to the Drugs Directive (AM-RL): Appendix III - Overview of the prescription restrictions and exclusions: Dipyridamole in combination with acetylsalicylic acid; here: Request for a supplementary statement in accordance with Section 94 (1) sentence 3 SGB V. 16 July 2013, accessed on 11 December 2013 .
  23. ↑ Hecken, Josef: Supplementary statement according to Section 94 (1) 3 SGB V on the resolution of the G-BA dated May 16, 2013 on a prescription exclusion of dipyridamole in combination with acetylsalicylic acid. September 23, 2013, accessed December 12, 2013 .
  24. ↑ Orlowski, Ulrich: Decision of the Federal Joint Committee pursuant to Section 91 SGB V of May 16, 2013; here: Amendment of the Medicines Directive (AM-RL): Appendix III - Overview of the prescription restrictions and exclusions: Dipyridamole in combination with acetylsalicylic acid. Request for a further supplementary statement in accordance with Section 94 (1) sentence 3 SGB V. October 7, 2013, accessed on December 12, 2013 .
  25. ↑ B-GA: Information archive - Resolution: Drugs Directive / Annex III: Dipyridamole in combination with acetylsalicylic acid. October 7, 2013, accessed December 12, 2013 .
  26. ↑ Red List Online, as of September 2009.
  27. ↑ AM comp. d. Switzerland, as of September 2009.
  28. ↑ AGES-PharmMed, as of September 2009.