Coronary Vasodilator – Inhibitor of Platelet Adhesion and Aggregation
Action And Clinical Pharmacology: Dipyridamole normalizes increased platelet adhesiveness and tendency to aggregate (Hellem’s method). Dipyridamole has been found to lengthen abnormally shortened platelet survival time in a dose-dependent manner; 400 mg/day or 100 mg/day plus 1 g ASA.
It is believed that platelet reactivity and interaction with prosthetic cardiac valve surfaces, resulting in abnormal shortened platelet survival time is a significant factor in connection with prosthetic heart valve replacement.
In a controlled clinical trial involving patients who had undergone surgical placement of prosthetic heart valves (mitral and/or aortic valve replacement), Persantine, in combination with anticoagulants, significantly decreased the incidence of post-operative thromboembolic events, without increasing hemorrhagic complications. The incidence of thromboembolic events in patients receiving dipyridamole in a dose of 400 mg/day in combination with anticoagulants was 1.3% compared to 14.3% to the control group treated with anticoagulant alone.
In vitro dipyridamole potentiates the aggregation-inhibiting effects of adenosine and prostaglandin E1, inhibits platelet uptake of adenosine, serotonin and glucose and increases platelet cyclic AMP levels. At higher concentrations dipyridamole inhibits platelet aggregation induced by ADP or collagen.
Myocardial blood flow increases in a dose-dependent fashion after i.v. or oral dipyridamole, with flows 170% or more above normal. Maximal increases are achieved at about 2 Âµg/mL with 0.8 Âµg/mL being the threshold serum level. Single oral doses of 150 mg dipyridamole produce the maximal response. At normal therapeutic doses, no significant alterations of peripheral blood flow, systemic blood pressure, or heart rate have been observed.
Dipyridamole is a coronary vasodilator in man. The mechanism of vasodilation has not been fully elucidated, but may result from inhibition of uptake of adenosine, an important mediator of coronary vasodilation. The vasodilatory effects of dipyridamole are abolished by administration of the adenosine receptor antagonist theophylline.
How dipyridamole-induced vasodilation leads to abnormalities in thallium distribution (when administered i.v. for myocardial perfusion imaging) and ventricular function is also uncertain, but presumably represents a “steal” phenomenon. In this situation, relatively intact vessels dilate, and sustain enhanced flow, leaving reduced pressure and flow across areas of hemodynamically important coronary vascular constriction.
Pharmacokinetics: Dipyridamole is readily absorbed from the gastrointestinal tract, reaching peak plasma levels in man 1 to 3 hours following oral administration. Peak plasma levels are dose dependent and range from about 0.5 Âµg/mL after a 25 mg dose to 1.6 Âµg/mL after a 75 mg dose. Blood levels are quite variable, possibly depending on food intake and gastrointestinal peristalsis. Ingestion on an empty stomach may result in higher blood levels. Following i.v. administration, the distribution half-life in man is about 25 minutes and after oral administration about 3 hours. When plasma levels of drug are followed for up to 60 hours after i.v. or oral administration of 20 to 50 mg, plasma levels decline tri-exponentially with half-lives of 5 minutes (i.v. only), 53 minutes and about 10 to 12 hours. The volume of distribution is about 140 L with about 92 to 99% binding to plasma proteins, primarily alpha1-acid glycoprotein.
Indications And Clinical Uses: Oral: Thromboembolic Disease: The prevention of post-operative thromboembolic complications associated with prosthetic heart valves.
Parenteral: Myocardial Perfusion Imaging: I.V. dipyridamole can be used to induce pharmacologic vasodilation for myocardial perfusion imaging.
Contra-Indications: Hypersensitivity to dipyridamole. I.V. administration of dipyridamole is not recommended in states of shock or collapse. tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: Rare serious adverse reactions associated with the administration of i.v. dipyridamole for myocardial imaging have been reported. These have included fatal and non-fatal myocardial infarction, ventricular fibrillation, symptomatic ventricular tachycardia, stroke and transient cerebral ischemia.
Since excessive doses of dipyridamole (i.v. or oral) or i.v. doses given too rapidly can produce peripheral vasodilation, dipyridamole should be used with caution in patients with hypotension, rapidly worsening angina, subvalvular aortic stenosis or hemodynamic instability. In rare cases, such patients may be at risk for developing myocardial ischemia and infarction.
An i.v. bolus of dipyridamole (40 to 50 mg over 4 minutes) can result in chest pain in patients with coronary artery disease. Rarely, hypotension or ventricular arrhythmias occur with a rapid, i.v. bolus. The infusion rate should be monitored to minimize this risk. The symptoms can generally be reversed with an i.v. injection of 50 to 250 mg of aminophylline over several minutes.
Patients with a history or presence of bronchial hyperreactivity may be at risk of developing bronchospasm during the use of i.v. dipyridamole as an adjunct to myocardial perfusion imaging. Although the actual overall incidence of this occurrence is small (Ãsl0.2%), the clinical information to be gained through the use of i.v. dipyridamole should be weighed against the potential risk to the patient.
Precautions: I.V. dipyridamole as an adjunct to myocardial perfusion imaging should be used with caution in patients with unstable angina, as such patients may be at risk for severe myocardial infarction.
As with exercise induced stress, the use of i.v. dipyridamole as an adjunct to myocardial perfusion imaging may occasionally precipitate cardiac arrhythmias in patients with severe heart disease. Scanning should therefore be performed with constant monitoring of the patient’s ECG. Parenteral aminophylline should be readily available and should be administered as a slow i.v. injection of 50 to 250 mg in the event of occurrences such as chest pain, bronchospasm, severe nausea/vomiting, hypotension, severe headache.
In the case of severe hypotension, the patient should be placed in a supine position with the head tilted down if necessary, before administration of parenteral aminophylline. If 250 mg of aminophylline does not relieve chest pain symptoms within a few minutes, sublingual nitroglycerin may be administered. If chest pain continues despite use of aminophylline and nitroglycerin, the possibility of myocardial infarction should be considered. If the clinical condition of a patient with an adverse event permits a 1-minute delay in the administration of parenteral aminophylline, thallium-201 may be injected and allowed to circulate for 1 minute before the injection of aminophylline. This will allow initial thallium perfusion imaging to be performed before reversal of the pharmacologic effects of dipyridamole on the coronary circulation.
Pregnancy: Reproductive studies have been performed in mice, rats, and rabbits at doses of up to 125 mg/kg and have not revealed evidence of impaired embryonic development attributable to dipyridamole. However, there have not been adequate, well-controlled studies in pregnant women and the drug should be used during pregnancy only if the expected benefits outweigh the potential risks.
Lactation: Dipyridamole is excreted in human milk. Caution should therefore be used when this drug is administered to nursing mothers.
Children: The safety and effectiveness of dipyridamole have not been established in the pediatric population.
Drug Interactions: The use of oral maintenance xanthines (e.g., theophylline, aminophylline) may abolish the coronary vasodilation produced by i.v. dipyridamole administration. This could lead to false-negative imaging results. Xanthine derivatives (e.g., found in coffee, tea) may weaken the effect of dipyridamole.
Caution is necessary when dipyridamole is used concurrently with anticoagulants or thrombolytics as the combined use of such agents may result in an increased risk of hemorrhage.
Dipyridamole may increase the hypotensive effect of blood pressure lowering drugs.
Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors. In patients with myasthenia gravis, readjustment of therapy may be necessary during treatment with dipyridamole.
Adverse Reactions: Serious adverse events (fatal and non-fatal myocardial infarction, severe ventricular arrhythmias, and serious CNS abnormalities) associated with the i.v. administration of dipyridamole for myocardial imaging are described in Warnings.
Adverse reactions at therapeutic doses are usually minimal and transient. Occasionally, headache, dizziness, nausea, flushing, syncope or weakness and skin rash have occurred during initiation of therapy. Mild occasional gastric distress can be avoided by administration of tablets with a glass of milk. Gastric irritation, emesis and abdominal cramping may occur at high dosage levels. Rare cases of what appears to be an aggravation of angina pectoris have been reported, usually at the initiation of therapy.
On those uncommon occasions when adverse reactions have been persistent or intolerable to the patient, withdrawal of the medication has been followed promptly by cessation of the undesirable symptoms.
When dipyridamole is used in combination with ASA, the only side effect clearly attributable to dipyridamole is headache. This symptom shows an increase of 5.5% in the combination treated group over that occurring in a group of patients treated with ASA alone. Other adverse reactions which occur during combination therapy are similar to those mentioned above, together with the well documented side effects of ASA therapy, notably gastric distress and gastrointestinal bleeding.
At the higher doses of dipyridamole there may be an increase in the incidence of adverse reactions.
In very rare cases, increased bleeding during or after surgery has been reported.
When i.v. dipyridamole was used as an adjunct to myocardial perfusion imaging in a study of 3 911 patients, the following events occurred in greater than 1% of the patients (see Table I). Less common events (i.e., occurred in 1% or less of the patients in the study) included, in decreasing order of frequency:
Cardiovascular: electrocardiographic abnormalities unspecified, arrhythmia unspecified, palpitation, ventricular tachycardia, bradycardia, myocardial infarction, AV block, syncope, orthostatic hypotension, atrial fibrillation, supraventricular tachycardia, ventricular arrhythmia unspecified, heart block unspecified, cardiomyopathy, edema.
Central and Peripheral Nervous System: hypoesthesia, hypertonia, nervousness/anxiety, tremor, abnormal coordination, somnolence, dysphonia, migraine, vertigo.
Gastrointestinal: dyspepsia, dry mouth, abdominal pain, flatulence, vomiting, eructation, dysphagia, tenesmus, increased appetite.
Respiratory: pharyngitis, bronchospasm, hyperventilation, rhinitis, coughing, pleural pain.
Other: myalgia, back pain, injection site reaction unspecified, diaphoresis, asthenia, malaise, arthralgia, injection site pain, rigor, earache, tinnitus, vision abnormalities unspecified, dysgeusia, thirst, depersonalization, eye pain, renal pain, perineal pain, breast pain, intermittent claudication, leg cramping.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Hypotension, if it occurs, is likely to be of short duration but vasopressor substances may be used if necessary. Symptoms such as feeling warm, flushes, sweating, accelerated pulse, restlessness, feeling of weakness and dizziness, and anginal complaints may occur. tag_DosageDosage
Dosage And Administration: Oral: Thromboembolic Disease: The recommended oral dose is 100 mg q.i.d., 1 hour before meals. A lower dose of 100 mg of dipyridamole daily together with 1 g ASA daily, prolongs platelet survival to the same extent.
Parenteral: Myocardial Perfusion Imaging: The dose of i.v. dipyridamole used as an adjunct to myocardial perfusion imaging should be adjusted according to the weight of the patient. Prior to use, dipyridamole i.v. should be diluted 1:1 with Dextrose Injection, USP 5%. The recommended dose is 0.142 mg/kg/minute, infused over 4 minutes. A total dose of greater than 60 mg is not recommended for use in any patient. The imaging agent should be injected within 5 minutes following the 4 minute infusion of dipyridamole. Do not mix i.v. dipyridamole with other drugs in the same syringe or infusion container.
Availability And Storage: Tablets: 25 mg: Each orange, round, sugar-coated tablet, imprinted with the Ingelheim tower on one side contains: dipyridamole 25 mg. Nonmedicinal ingredients: acacia, carnauba wax, colloidal silica, FD&C Yellow No. 6, lactose, magnesium stearate, maize starch, polyethylene glycol, sucrose, talc, titanium dioxide and white wax. Energy: 1.01 kJ (0.24 kcal). Bottles of 100 and 500. Store at room temperature (15 to 30Â°C).
50 mg: Each coral-red, round, sugar-coated tablet, imprinted with the Ingelheim tower on one side contains: dipyridamole 50 mg. Nonmedicinal ingredients: acacia, calcium hydrogen phosphate, carnauba wax, colloidal silica, FD&C Yellow No. 6, magnesium stearate, maize starch, polyethylene glycol, red iron oxide, sucrose, talc, titanium dioxide and white wax. Energy: 1.01 kJ (0.24 kcal). Bottles of 100 and 500. Store at room temperature (15 to 30Â°C).
75 mg: Each reddish-orange, round, sugar-coated tablet, imprinted with the Ingelheim tower on one side contains: dipyridamole 75 mg. Nonmedicinal ingredients: acacia, calcium hydrogen phosphate, carnauba wax, colloidal silica, FD&C Yellow No. 6, magnesium stearate, maize starch, polyethylene glycol, sucrose, talc, titanium dioxide and white wax. Energy: 1.01 kJ (0.24 kcal). Bottles of 100 and 500. Store at room temperature (15 to 30Â°C).
100 mg: Each white, round, sugar-coated tablet, imprinted with the Ingelheim tower on one side contains: dipyridamole 100 mg. Nonmedicinal ingredients: acacia, calcium hydrogen phosphate, carnauba wax, colloidal silica, FD&C Yellow No. 6, magnesium stearate, maize starch, polyethylene glycol, sucrose, talc, titanium dioxide and white wax. Energy: 1.01 kJ (0.24 kcal). Bottles of 100. Store at room temperature (15 to 30Â°C).
Parenteral: Each mL contains: dipyridamole 5 mg. Nonmedicinal ingredients: hydrochloric acid, polyethylene glycol, tartaric acid and water for injection. Ampuls of 10 mL, packages of 5. Protect from direct light, and avoid freezing. Store at room temperature (less than 30Â°C).
PERSANTINEÂ® Boehringer Ingelheim Dipyridamole Coronary Vasodilator – Inhibitor of Platelet Adhesion and Aggregation