Dipyridamole

(BAN, USAN, rINN)
Dipyridamole Chemical formula
Synonyms: Dipiridamol; Dipiridamolis; Dipirydamol; Dipyridamol; Dipyridamoli; Dipyridamolum; NSC-515776; RA-8. 2,2′,2″,2′″-[(4,8-Dipiperidinopyrimido[5,4d]pyrimidine-2,6-diyl)dinitrilo]tetraethanol.
Cyrillic synonym: Дипиридамол.

💊 Chemical information

Chemical formula: C24H40N8O4 = 504.6.
CAS — 58-32-2.
ATC — B01AC07.
ATC Vet — QB01AC07.

Pharmacopoeias.

In Chin., Eur., Jpn, and US.

Ph. Eur. 6.2

(Dipyridamole). A bright yellow crystalline powder. Practically insoluble in water; soluble in dehydrated alcohol; freely soluble in acetone. It dissolves in dilute solutions of mineral acids. Protect from light.

USP 31

(Dipyridamole). An intensely yellow, crystalline powder or needles. Slightly soluble in water; very soluble in chloroform, in alcohol, and in methyl alcohol; very slightly soluble in acetone and in ethyl acetate. Store in airtight containers. Protect from light.

💊 Adverse Effects, Treatment, and Precautions

Gastrointestinal disturbances, including nausea, vomiting, and diarrhoea, headache, dizziness, faintness, hypotension, facial flushing, and skin rash and other hypersensitivity reactions may occur after use of dipyridamole. Dipyridamole can also induce chest pain or lead to a worsening of the symptoms of angina. Cardiac arrhythmias have been reported in patients given dipyridamole during thallium-201 imaging. Aminophylline may reverse some of the adverse effects. Dipyridamole should be used with caution in patients with hypotension, unstable angina, aortic stenosis, recent myocardial infarction, heart failure, or coagulation disorders. Intravenous dipyridamole should not be given to patients with these conditions or to those with arrhythmias, conduction disorders, asthma, or a history of bronchospasm (but see Myocardial Imaging, below). Oral dipyridamole should be stopped 24 hours before intravenous use for stress testing.

Effects on the biliary tract.

Gallstones containing unconjugated dipyridamole were removed from 2 patients who had been taking dipyridamole for 15 and 10 years, respectively.1 A gallstone containing unconjugated dipyridamole recurred in a patient who continued to take the drug after endoscopic removal of a similar stone 18 months earlier.2
1. Moesch C, et al. Biliary drug lithiasis: dipyridamole gallstones. Lancet 1992; 340: 1352–3
2. Sautereau D, et al. Recurrence of biliary drug lithiasis due to dipyridamole. Endoscopy 1997; 29: 421–3.

Effects on the heart.

Transient myocardial ischaemia occurred in 4 patients with unstable angina and multivessel coronary artery disease during oral treatment with dipyridamole.1 See Myocardial Imaging, below, for additional reports.
1. Keltz TN, et al. Dipyridamole-induced myocardial ischemia. JAMA 1987; 257: 1515–16.

Effects on the muscles.

Symptoms resembling acute pseudopolymyalgia rheumatica developed in a patient taking dipyridamole.1
1. Chassagne P, et al. Pseudopolymyalgia rheumatica with dipyridamole. BMJ 1990; 301: 875.

Effects on taste.

A disagreeable taste associated with other gastrointestinal symptoms occurred in a patient taking dipyridamole.1 Two similar cases had been reported to the UK CSM.
1. Willoughby JMT. Drug-induced abnormalities of taste sensation. Adverse Drug React Bull 1983; 100: 368–71.

Myocardial imaging.

Dipyridamole may be used in association with thallium-201 in myocardial stress imaging. Safety data from over 3900 patients has been summarised.1 Adverse effects which occurred within 24 hours of dipyridamole intravenously (mean dose 560 micrograms/kg) were recorded. Ten patients had major adverse effects and 1820 patients experienced minor adverse effects. Myocardial infarction occurred in 4 patients, 3 of whom had unstable angina before scanning. Six patients developed acute bronchospasm, 4 of whom had a history of asthma or had wheezing before using dipyridamole. Adverse effects considered to be minor included chest pain in 19.7% of patients, STT-segment depression in 7.5%, ventricular extrasystoles in 5.2%, headache in 12.2%, dizziness in 11.8%, nausea in 4.6%, and hypotension in 4.6%. Aminophylline was effective in relieving symptoms of adverse effects in 97% of 454 patients. Hypersensitivity reactions including anaphylaxis and angioedema have been reported.2,3 UK licensed product information contra-indicates intravenous dipyridamole in patients with hypotension, unstable angina, aortic stenosis, recent myocardial infarction, heart failure, coagulation disorders, arrhythmias, conduction disorders, asthma, or a history of bronchospasm. However, a review4 of pharmacological stress testing suggested that with appropriate patient selection and adequate monitoring, the incidence of life-threatening adverse reactions is negligible. It was also considered that dipyridamole-thallium-201 imaging could be safely performed in the early post-myocardial infarction period.
1. Ranhosky A, et al. The safety of intravenous dipyridamole thallium myocardial perfusion imaging. Circulation 1990; 81: 1205–9
2. Weinmann P, et al. Anaphylaxis-like reaction induced by dipyridamole during myocardial scintigraphy. Am J Med 1994; 97: 488
3. Angelides S, et al. Acute reaction to dipyridamole during myocardial scintigraphy. N Engl J Med 1999; 340: 394
4. Beller GA. Pharmacologic stress imaging. JAMA 1991; 265: 633–8.

💊 Interactions

Dipyridamole may enhance the actions of oral anticoagulants due to its antiplatelet effect. It inhibits the reuptake of adenosine and may enhance its effects; the dose of adenosine must be reduced if both drugs are given. Dipyridamole may also inhibit the uptake of fludarabine and may reduce its efficacy. The absorption of dipyridamole may be reduced by drugs such as antacids that increase gastric pH.

Anticoagulants.

Dipyridamole may induce bleeding in patients receiving oral anticoagulants without altering prothrombin times.

Xanthines.

Xanthines may antagonise some of the effects of dipyridamole due to their action as adenosine antagonists. Aminophylline may be used to reverse some of the adverse effects of dipyridamole. Intravenous caffeine has been reported1 to attenuate the haemodynamic response to dipyridamole and it has been suggested that caffeine should be avoided for at least 24 hours before the test in patients receiving dipyridamole for myocardial imaging.
1. Smits P, et al. Dose-dependent inhibition of the hemodynamic response to dipyridamole by caffeine. Clin Pharmacol Ther 1991; 50: 529–37.

💊 Pharmacokinetics

Dipyridamole is incompletely absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 75 minutes after an oral dose. Dipyridamole is more than 90% bound to plasma proteins. A terminal half-life of 10 to 12 hours has been reported. Dipyridamole is metabolised in the liver and is mainly excreted as glucuronides in the bile. Excretion may be delayed by enterohepatic recirculation. A small amount is excreted in the urine. Dipyridamole is distributed into breast milk.
1. Mahony C, et al. Dipyridamole kinetics. Clin Pharmacol Ther 1982; 31: 330–8
2. Mahony C, et al. Plasma dipyridamole concentrations after two different dosage regimens in patients. J Clin Pharmacol 1983; 23: 123–6.

💊 Uses and Administration

Dipyridamole is an adenosine reuptake inhibitor and phosphodiesterase inhibitor with antiplatelet and vasodilating activity and is used in thromboembolic disorders. Oral dipyridamole is used for the prophylaxis of thromboembolism after cardiac valve replacement and in the management of stroke (below); it has also been used in the management of myocardial infarction. Dipyridamole given intravenously results in marked coronary vasodilatation and is used in stress testing in patients with ischaemic heart disease (see Myocardial Imaging, below). For the prophylaxis of thromboembolism after cardiac valve replacement, dipyridamole is given with an oral anticoagulant. The usual adult dose is 300 to 600 mg daily by mouth in divided doses before meals. Children have been given 5 mg/kg by mouth daily in divided doses. For the secondary prevention of stroke or transient ischaemic attack dipyridamole is given as a modifiedrelease preparation, alone or with aspirin, in a dose of 200 mg twice daily.
1. FitzGerald GA. Dipyridamole. N Engl J Med 1987; 316: 1247–57
2. Gibbs CR, Lip GYH. Do we still need dipyridamole? Br J Clin Pharmacol 1998; 45: 323–8.

Myocardial imaging.

Perfusion abnormalities due to coronary artery disease are usually absent at rest but are present during stress, and stress imaging may therefore be used in the assessment of myocardial function. The stress is usually supplied by exercise, but when exercise is inappropriate pharmacological methods such as dipyridamole may be used. Dipyridamole has been used with thallium-201 scintigraphy in adults and children and is usually given intravenously in a dose of 567 micrograms/kg over 4 minutes. Thallium-201 is given within 3 to 5 minutes after completion of the infusion of dipyridamole. Initial images are obtained after 5 minutes and delayed images are obtained 2.5 to 4 hours later. Dipyridamole (300 to 400 mg) has also been given as an oral suspension; thallium-201 is given about 45 minutes later to coincide with peak dipyridamole-serum concentrations. Dipyridamole has also been used in echocardiography.1,2 The intravenous dipyridamole dose used to obtain maximum sensitivity is often higher (750 to 840 micrograms/kg) than the dose used in scintigraphy.1
1. Beller GA. Pharmacologic stress imaging. JAMA 1991; 265: 633–8
2. Buchalter MB, et al. Dipyridamole echocardiography: the bedside stress test for coronary artery disease. Postgrad Med J 1990; 66: 531–5.

Stroke.

The value of long-term antiplatelet therapy with aspirin in patients who have suffered an ischaemic stroke or transient ischaemic attack is well-established, with a reduction in the risk of both stroke and other vascular events.1 The use of dipyridamole has been more controversial. Early studies with dipyridamole, used alone or with aspirin, failed to show any benefit over aspirin alone. The European Stroke Prevention Study-2 (ESPS-2),2 which compared aspirin and dipyridamole, alone or together, with placebo, found that both drugs reduced the risk of stroke and that the effects appeared to be additive. The study used a low dose of aspirin and a modified-release formulation of dipyridamole, which may explain the discrepancy with earlier studies.3 Subsequent meta-analyses3-6 have confirmed that dipyridamole, alone or with aspirin, reduces the risk of recurrent stroke, but have been based mainly on the ESPS-2, which may be a limitation.3 However, a further large study7 comparing aspirin alone with aspirin and dipyridamole also found that the incidence of vascular events (including stroke) was lower in those receiving both drugs. Most guidelines8,9 therefore now recommend aspirin with dipyridamole as one of the preferred options for long-term management of ischaemic stroke.
1. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81–106. Correction. ibid.; 1540
2. Diener HC, et al. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1–13
3. Wilterdink JL, Easton JD. Dipyridamole plus aspirin in cerebrovascular disease. Arch Neurol 1999; 56: 1087–92
4. Antithrombotic Trialists’ Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86. Correction. ibid.; 141
5. Leonardi-Bee J, et al. Dipyridamole for preventing recurrent ischemic stroke and other vascular events: a meta-analysis of individual patient data from randomized controlled trials. Stroke 2005; 36: 162–8
6. De Schryver ELLM, et al. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2007 (accessed 19/03/08)
7. Halkes PH, et al. ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367: 1665–73. Correction. ibid. 2007; 369: 274
8. European Stroke Organisation (ESO) Executive Committee. ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25: 457–507. Also available at: http://www.eso-stroke.org/pdf/ESO08_Guidelines_English.pdf (accessed 11/07/08
9. Albers GW, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133 (suppl): 630S–669S.

💊 Preparations

BP 2008: Dipyridamole Tablets; USP 31: Dipyridamole Injection; Dipyridamole Oral Suspension; Dipyridamole Tablets.

Proprietary Preparations

Arg.: Maxicardil; Persantin; Sedangor; Austral.: Persantin; Austria: Persantin; Belg.: Coronair; Dipyridan†; Docdipyri; Persantine; Braz.: Persantin; Canad.: Novo-Dipiradol†; Persantine; Chile: Persantin; Cz.: Curantyl N†; Persantin†; Denm.: Persantin; Fin.: Atrombin; Dipyrin; Persantin; Fr.: Cleridium†; Persantine; Ger.: Curantyl N†; Gr.: Adezan; Persantin; Hong Kong: Persantin; Procardin; India: Persantin; Indon.: Cardial; Persantin; Vasokor; Vasotin; Irl.: Persantin; Israel: Cardoxin; Ital.: Corosan; Novodil; Persantin; Jpn: Persantin; Malaysia: Persantin†; Mex.: Digal; Dipres; Dirinol; Lodimol; Persantin; Pracem; Trepol; Trompersantin†; Vadinar; Neth.: Persantin; Norw.: Persantin; NZ: Persantin; Pytazen; Philipp.: Persantin; Port.: Persantin; Rus.: Curantyl (Курантил); Persantin (Персантин); S.Afr.: Persantin; Plato; Singapore: Persantin; Procardin; Spain: Persantin; Swed.: Persantin; Thai.: Agremol; Persantin; Posanin; Turk.: Drisentin; Kardisentin; Tromboliz; UK: Persantin; USA: Persantine; Venez.: Megalis†; Meranol†; Persantin; Precar†. Multi-ingredient: Arg.: Agrenox; Licuamon; Austral.: Asasantin; Austria: Asasantin; Thrombohexal; Belg.: Aggrenox; Canad.: Aggrenox; Cz.: Aggrenox; Denm.: Asasantin; Fin.: Asasantin; Fr.: Asasantine; Ger.: Aggrenox; Asasantin†; Gr.: Aggrenox; Hong Kong: Aggrenox; Hung.: Asasantin; India: Dynasprin; Indon.: Aggrenox; Irl.: Asasantin; Mex.: Asasantin†; Neth.: Asasantin; Norw.: Asasantin; Philipp.: Aggrenox; Port.: Aggrenox; S.Afr.: Asasantin; Swed.: Asasantin; Switz.: Asasantine; Thai.: Aggrenox; UK: Asasantin; USA: Aggrenox.
Published January 30, 2019.