Dipyridamole

Mechanism of Action

Dipyridamole functions predominantly by inhibiting the function of phosphodiesterase and adenosine deaminase.[11] Phosphodiesterase is useful for the conversion of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP) to their non-cyclic equivalent.[11][12] The inhibition of this enzyme increases the intracellular concentration of secondary messenger molecules cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP).[12] The increased cAMP and cGMP inhibit platelet aggregation and platelet-related thrombosis reversibly.[13][14] This anti-platelet action allows for its indication for thromboembolism prophylaxis in mechanical valve replacement as an adjunct to anticoagulant and its use in secondary stroke prophylaxis.[14] Further, the accumulation of these secondary messengers, along with the downstream release of prostacyclin/PGD2, promotes vasodilatory effects on the coronary artery vasculature.[12] This vasodilatory effect induces coronary steal in a pharmacologic stress test to induce myocardial ischemia in vessels affected by coronary artery disease.

Administration

Dipyridamole is available in tablet forms of 25 mg, 50 mg, 75 mg strengths. The generic version is also available. In addition to its tablet formulation, there is also an intravenous solution of the strength of 5 mg/mL. The intravenous solution is applicable for its adjunctive use during pharmacologic stress testing, typically administered over four minutes.

Indication Specific Dosing

Thromboembolism prophylaxis in post-cardiac valve replacement: 75 to 100 mg PO 4 times daily as an adjunct to warfarin.

Myocardial perfusion scan: injectable solution of 5mg/mL is administered at a dose of 0.142 mg/kg/min IV infusion over 4 minutes. The maximal allowed dose for this use is 70 mg.

Dosing Adjustments

The dosing recommendations for patients with significant obesity have not undergone thorough evaluation, although a general guideline of a maximum dose of 70 mg has been recommended. There is no need to dose adjust this medication for those patients with renal or hepatic impairment. Caution is advised in geriatric patients using this medication as its oral formulation is a Beers List medication, although the extended-release form combined with aspirin is not on the Beers List.[15]

Pediatric Dosing

Pediatric use of this medication has limited data, but guidelines suggest 2.0 to 6.0mg/kg/daily for its antiplatelet effect. Given the limited data, dipyridamole is not a first-line agent for the use of antiplatelet therapy for pediatric and adolescent patients.

Adverse Effects

Most Commonly Reported Adverse Effects [16]

1. Chest pain (20%)
2. Angina exacerbation, IV (19.7%)
3. Abnormal ECG (15.9%)
4. Headache, IV (12.2%)
5. Dizziness (12%)

Other Reported Adverse Effects

Generalized System Effects

• Diaphoresis, fatigue, increased appetite, increased thirst, malaise, and weakness

Cardiopulmonary Effects

• Arrhythmia, bronchospasm, cough, chest pain, cardiomyopathy, flushing, heart attack, ischemic electrocardiogram changes, lowered blood pressure, orthostatic hypotension, palpitations, and shortness of breath.

Central Nervous System Effects

• Ataxia, changes in vision, dizziness, general weakness, headache, hypertonia, numbness/tingling, tinnitus, tremor, and vertigo

Dermatologic System Effects

• Hypersensitivity reaction, injection site reaction, pruritis, skin rash, and urticaria

Gastrointestinal System Effects

• Abdominal pain, dyspepsia, dysphagia, nausea, eructation, flatulence, tenesmus, and vomiting

Psychiatric System Effects

• Depersonalization

Lymphatic System Effects

• Edema

Musculoskeletal System Effects

• Arthralgia, back pain, claudication, generalized weakness, myalgia, and rigidity

Contraindications

The main contraindications for the application of dipyridamole are previous hypersensitivity reactions and thrombocytopenia.

Disease-related Concerns

• Cardiovascular disease: Use requires caution in patients with hypotension, unstable angina, and/or recent MI; may enhance exercise-induced myocardial ischemia in patients with chronic stable angina.
• Hepatic impairment: Use requires caution in patients with hepatic impairment.

Concurrent Drug Therapy Issues

• Antiplatelet agents/anticoagulants: Use requires caution in patients on other antiplatelet agents or anticoagulation.

Dosage Form Specific Issues

• Injection: Severe adverse reactions have infrequently occurred with IV administration. Use the IV dosage form with caution in patients with bronchospastic disease or unstable angina. Testers should have aminophylline ready in case of urgency or emergency with IV use.

Monitoring

Current guidelines do not suggest routine laboratory testing for therapeutic monitoring of dipyridamole. There are no required scheduled laboratory evaluations for associated toxicities. The American Society of Nuclear Cardiology does suggest monitoring the patients for toxicity while undergoing perfusion testing with particular attention for signs of hypoperfusion, including extremity cyanosis, pallor, or decreased temperature.[17] In addition to the physical manifestations, vigilance for the changes in heart rate, blood pressure, or respiration should occur while using dipyridamole for pharmacologic stress testing.[16][18]

Pharmacokinetic Parameters

• Half-life elimination: 10 to 12 hours
• Peak time: 2 to 2.5 hours
• Onset: 24 minutes
• Duration: 3 hours
• Protein-bound: 91 to 99%
• Vd: 2 to 3 L/kg
• Clearance: 2.3 to 3.5 mL/min/kg
• Excretion: Fecal excretion
• Metabolism: Liver
• Dialyzable: not-dialyzable

Toxicity

To reverse any complications and side effects of dipyridamole, aminophylline (50 to 250 mg IV push over 30 to 60 seconds given no sooner than 1 minute after the radiotracer injection) should be on hand for urgent/emergent use.[18] This use is particularly used in the setting of adverse effects while undergoing pharmacologic stress testing.

Enhancing Healthcare Team Outcomes

When using dipyridamole in the setting of pharmacologic stress testing, it is essential to actively look out for the clinical findings associated with an adverse pharmacologic stress test. As outlined above, monitoring for hypoperfusion while undergoing diagnostic testing is imperative to assist in preventing adverse events. It is essential that the entire interprofessional stress-testing team is aware of and actively evaluate the signs of hypoperfusion. The entire team, including the ultrasound technician, nursing team, cardiologist, and any other assistants involved in administering the stress test, understand the signs and symptoms of toxicity. A pharmacist should also review the patient's medication profile to ensure no drug-drug interactions and alert the team of any findings that may raise concerns. In addition to the importance of active monitoring, having the appropriate resources to reverse induced hypoperfusion is also essential to deter sequela. Maintaining an adequate stock solution of aminophylline with suitable syringes is important to allow for time-sensitive reversal when appropriate and necessary.[18] Interprofessional coordination will drive better patient results with minimal adverse events. [Level 5]