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DIPYRIDAMOLE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dipyridamole is a coronary vasodilator. It is an antithrombotic agent most often used to modify platelet function. It is also used intravenously as a non-nitrate coronary vasodilator for noninvasive stress thallium cardiac imaging. Dipyridamole is also available in combination with aspirin. Refer to "SALICYLATES" management for information on aspirin overdose.

Specific Substances

    1) RA 8
    2) CAS 58-32-2
    1.2.1) MOLECULAR FORMULA
    1) C24H40N8O4

Available Forms Sources

    A) FORMS
    1) Dipyridamole is available as 5 mg/mL intravenous solution and 25 mg, 50 mg, and 75 mg oral tablets(Prod Info dipyridamole oral tablets, 2013; Prod Info dipyridamole intravenous injection, 2011).
    2) Dipyridamole is also available in combination with aspirin as oral extended-release capsules (dipyridamole 200 mg and aspirin 25 mg) (Prod Info AGGRENOX(R) oral extended release capsules, 2015).
    B) USES
    1) Dipyridamole is used to prevent thrombosis after cardiac valve replacement in adults. It is also used as an alternative to exercise with thallium myocardial perfusion imaging to detect coronary artery disease (Prod Info dipyridamole oral tablets, 2013; Prod Info dipyridamole intravenous injection, 2011).
    2) Extended-release dipyridamole in combination with aspirin is used to reduce the risk of stroke in patients who have had an ischemic stroke due to thrombosis or who have had transient ischemia of the brain (Prod Info AGGRENOX(R) oral extended release capsules, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Dipyridamole is used to prevent thrombosis after cardiac valve replacement in adults. It is also used as an alternative to exercise with thallium myocardial perfusion imaging to detect coronary artery disease. Dipyridamole is also available in combination with aspirin. Refer to "SALICYLATES" management for information on aspirin overdose.
    B) PHARMACOLOGY: Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes, resulting in an increase in local concentrations of adenosine. By acting on the platelet A(2)-receptor, the increase in concentration of adenosine stimulates platelet adenylate cyclase and in turn increases the levels of cyclic-3',5'-adenosine monophosphate (cAMP), which inhibits platelet aggregation.
    C) TOXICOLOGY: Inhibition of adenosine uptake in arterial endothelial cells causes vasodilation and hypotension.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) MOST COMMON (greater than 11%): Angina pectoris, ECG changes (mostly ST-T changes), headache, and dizziness. OTHER EFFECTS: Hypotension, nausea, vomiting, abdominal distress, diarrhea, flushing, tachycardia, hypersensitivity reactions, and dyspnea. RARE: Thrombocytopenia, seizures, cardiac arrest, myocardial infarction, ventricular fibrillation, stroke, and transient cerebral ischemia may occur.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Dizziness, warm feeling, flushing, sweating, restlessness, weakness, dizziness, hypotension, and tachycardia may occur with overdose.
    2) SEVERE TOXICITY: A woman with long-standing angina developed myocardial infarction after ingesting approximately 5 g of dipyridamole tablets. Loss of consciousness, hypotension, deep ST depression and T wave inversion, elevated PT and PTT, and respiratory arrest developed in another woman after dipyridamole overdose.
    0.2.20) REPRODUCTIVE
    A) Dipyridamole is classified as US Food and Drug Administration (FDA) pregnancy category B; dipyridamole/aspirin combination is FDA pregnancy category D. Limited human data indicated a congenital anomaly occurred in one infant whose mother used the drug during the first trimester. Teratogenicity has not been reported in mice, rabbit, and rat reproduction studies. No reports describing the use of dipyridamole during human lactation are available and the effects on a nursing infant from exposure are unknown. The manufacturer states that dipyridamole is excreted in human milk. In rats, high doses of dipyridamole caused a reduction in implantations and live fetuses.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturers do not report any carcinogenic potential for dipyridamole or dipyridamole/aspirin in humans.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea or hypotension.
    E) Monitor coagulation studies after in patients with severe overdose.
    F) Monitor serial troponin and ECG in patients with chest pain.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Dipyridamole is also available in combination with aspirin. Refer to "SALICYLATES" management for information on aspirin overdose.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Consider using a xanthine derivative (eg, aminophylline 50 to 240 mg) to reverse the hemodynamic effects of dipyridamole overdose. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, CNS depression, hemodynamic instability, or severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Dipyridamole is highly protein-bound. Hemodialysis is not expected to be of value in overdose.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be referred to a healthcare facility for evaluation and treatment. Patients should be observed for 6 hours with frequent monitoring of vital signs and cardiac function. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted. Patients with unstable vital signs and/or life-threatening cardiac dysrhythmias should be admitted to an intensive care unit.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings.
    H) PITFALLS
    1) Prolonged observation may be needed after overdose with extended-release formulations. When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Tmax: Oral: immediate-release tablets: 75 minutes. Extended-release capsules: 2 hours (range, 1 to 6 hours). Absorption: 30% to 70% of the dose ingested. Protein binding: 99%. Vd: 1 to 2.5 L/kg. Metabolism: Metabolized in the liver and conjugated as a glucuronide and excreted with the bile. Elimination half-life: 10 to 16 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hypotension and ventricular dysrhythmias.

Range Of Toxicity

    A) TOXICITY: CHILDREN: Ingestion of 625 mg in a 19-month-old produced toxicity, while ingestion of 400 mg in a child weighing 30 pounds (29 mg/kg) produced no signs of toxicity. ADULTS: Doses of up to 2000 mg/day have been used therapeutically. Acute ingestions of 200 to 1250 mg have produced toxicity. A woman with long-standing angina developed non-ST elevation myocardial infarction after ingesting approximately 5 g of dipyridamole tablets. Loss of consciousness, hypotension, deep ST depression and T wave inversion, elevated PT and PTT, respiratory arrest developed in a woman after ingesting 1.75 g of dipyridamole.
    B) THERAPEUTIC DOSES: ADULTS: Thallium myocardial perfusion: 0.142 mg/kg/min (0.57 mg/kg total) as an IV infusion over 4 minutes prior to thallium; a total dose in excess of 60 mg will most likely not be necessary. Thrombosis prophylaxis, heart valve replacement: 75 to 100 mg orally 4 times daily as an adjunct to warfarin therapy. Stroke prevention: One capsule of extended-release dipyridamole 200 mg/aspirin 25 mg orally twice daily. CHILDREN: Safety and effectiveness of dipyridamole have not been established in pediatric patients. Oral doses of 1 to 4.2 mg/kg/day have been used in children with platelet dysfunction and cardiac valve replacement. Oral doses of 4 to 10 mg/kg/day have been used investigationally to treat proteinuria in pediatric renal disease.

Clinical Effects

Summary Of Exposure

    A) USES: Dipyridamole is used to prevent thrombosis after cardiac valve replacement in adults. It is also used as an alternative to exercise with thallium myocardial perfusion imaging to detect coronary artery disease. Dipyridamole is also available in combination with aspirin. Refer to "SALICYLATES" management for information on aspirin overdose.
    B) PHARMACOLOGY: Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes, resulting in an increase in local concentrations of adenosine. By acting on the platelet A(2)-receptor, the increase in concentration of adenosine stimulates platelet adenylate cyclase and in turn increases the levels of cyclic-3',5'-adenosine monophosphate (cAMP), which inhibits platelet aggregation.
    C) TOXICOLOGY: Inhibition of adenosine uptake in arterial endothelial cells causes vasodilation and hypotension.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) MOST COMMON (greater than 11%): Angina pectoris, ECG changes (mostly ST-T changes), headache, and dizziness. OTHER EFFECTS: Hypotension, nausea, vomiting, abdominal distress, diarrhea, flushing, tachycardia, hypersensitivity reactions, and dyspnea. RARE: Thrombocytopenia, seizures, cardiac arrest, myocardial infarction, ventricular fibrillation, stroke, and transient cerebral ischemia may occur.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Dizziness, warm feeling, flushing, sweating, restlessness, weakness, dizziness, hypotension, and tachycardia may occur with overdose.
    2) SEVERE TOXICITY: A woman with long-standing angina developed myocardial infarction after ingesting approximately 5 g of dipyridamole tablets. Loss of consciousness, hypotension, deep ST depression and T wave inversion, elevated PT and PTT, and respiratory arrest developed in another woman after dipyridamole overdose.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension was reported in 4.6% of patients in a study of adjunct IV dipyridamole used with thallium myocardial perfusion imaging (n=3911) (Prod Info dipyridamole IV injection, 2007).
    b) In postmarketing surveillance with dipyridamole therapy, hypotension has rarely been reported (Prod Info dipyridamole oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) Hypotension may occur with overdose (Prod Info dipyridamole oral tablets, 2008).
    b) CASE REPORT: A 23-year-old woman developed weakness, dyspnea, and loss of consciousness after ingesting 70 dipyridamole 25 mg tablets (total: 1.75 g). On admission, she was hypotensive (BP 70/30 mmHg) and developed respiratory arrest shortly after arrival. Laboratory results revealed metabolic acidosis, prothrombin time (PT) of 16.4 s, (control value: 11.9 s), and a partial thromboplastin time (PTT) of 37.6 s (control value: 26.4 s). An ECG showed deep ST depression (2.5 mm) and T wave inversion over the precordial and the limb leads; however, cardiac enzyme values were normal. Following supportive care, including therapy with IV aminophylline 250 mg, and continuous infusion of dopamine, her ECG, blood pressure, and PT normalized (Chen et al, 1994).
    B) ANGINA
    1) WITH THERAPEUTIC USE
    a) Chest pain or angina pectoris was reported in 19.7% of patients in a study of adjunct IV dipyridamole used with thallium myocardial perfusion imaging (n=3911) (Prod Info dipyridamole IV injection, 2007).
    b) In uncontrolled trials with dipyridamole, angina pectoris has rarely been reported (Prod Info dipyridamole oral tablets, 2008).
    c) Angina developed in 16% to 41% of patients receiving dipyridamole in conjunction with thallium-201 imaging (Blumenthal & McCauley, 1988). In a study of 1,000 patients given dipyridamole before myocardial perfusion imaging, chest pain was the most common (30%) adverse effect reported (Johnston et al, 1995).
    d) CASE REPORT: Myocardial stunning (prolonged, reversible post-ischemic regional ventricular dysfunction) was seen in a 65-year-old undergoing dipyridamole-thallium imaging (Lette et al, 1989).
    e) CASE REPORT: Severe myocardial ischemia, persisting for 90 minutes and unrelieved by aminophylline and nitroglycerin, was reported in a 59-year-old woman following 0.56 mg/kg IV of dipyridamole. Emergency angioplasty was required (Lewen et al, 1987).
    C) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) Cardiac death has been associated with IV dipyridamole administration; there have also been reports of asystole and sinus node arrest, sinus node depression, and conduction block. Patients with cardiac conduction abnormalities or significant coronary artery disease are at greater risk for severe adverse reactions to IV dipyridamole (Prod Info dipyridamole IV injection, 2007).
    b) CASE REPORT: A 71-year-old woman who received 300 mg orally developed asystole within one hour. After resuscitation, acute transmural anterior infarction was noted (Blumenthal & McCauley, 1988).
    D) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Ventricular premature beats occur frequently after intravenous use of dipyridamole to enhance thallium-201 imaging (Homma et al, 1987). Ventricular fibrillation is rarely reported (Bayliss et al, 1983).
    b) Patients with myocardial ischemia may exhibit QTc interval prolongation on ECG during dipyridamole (an adenosine reuptake inhibitor) or adenosine infusion (Guideri et al, 1995).
    c) ECG abnormalities (ST-T segment changes, 7.5%; extrasystoles, 5.2%; unspecified, 0.8%) were among the most frequent adverse events in a study of adjunct IV dipyridamole used in patients who underwent thallium myocardial perfusion imaging (n=3911) (Prod Info dipyridamole IV injection, 2007).
    E) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance with dipyridamole therapy, tachycardia has rarely been reported (Prod Info dipyridamole oral tablets, 2008). ECG abnormalities, including tachycardia, were reported in 3.2% of patients in a study of adjunct IV dipyridamole used with thallium myocardial perfusion imaging (n=3911) (Prod Info dipyridamole IV injection, 2007).
    2) WITH POISONING/EXPOSURE
    a) Tachycardia may occur with overdose (Prod Info dipyridamole oral tablets, 2008).
    F) VENTRICULAR FIBRILLATION
    1) WITH THERAPEUTIC USE
    a) Ventricular fibrillation has been associated with IV dipyridamole administration; there have also been reports of asystole and sinus node arrest, sinus node depression, and conduction block. Patients with cardiac conduction abnormalities or significant coronary artery disease are at greater risk for severe adverse reactions to IV dipyridamole (Prod Info dipyridamole IV injection, 2007).
    G) MYOCARDIAL INFARCTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 62-year-old woman with a history of angina presented with severe chest pain 6 hours after ingesting approximately 50 dipyridamole 100 mg tablets. On presentation, she had a heart rate of 92 beats/min and blood pressure of 140/90 mmHg. An initial ECG revealed sinus rhythm with left bundle branch block. Laboratory results revealed elevated creatine kinase of 583 Units/L (normal range: less than 175 Units/L), MB isoenzyme greater than 8% (normal range: less than 6% to 8% CK). The creatine kinase increased to 924 Units/L 6 hours later. She remained hemodynamically stable and was discharged several hours later against medical advice (Jahangiri & Holdright, 1992).
    H) ST SEGMENT DEPRESSION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 23-year-old woman developed weakness, dyspnea, and loss of consciousness after ingesting 70 dipyridamole 25 mg tablets (total: 1.75 g). On admission, she was hypotensive (BP 70/30 mmHg) and developed respiratory arrest shortly after arrival. Laboratory results revealed metabolic acidosis, prothrombin time (PT) of 16.4 s, (control value: 11.9 s), and a partial thromboplastin time (PTT) of 37.6 s (control value: 26.4 s). An ECG showed deep ST depression (2.5 mm) and T wave inversion over the precordial and the limb leads; however, cardiac enzyme values were normal. Following supportive care, including therapy with IV aminophylline 250 mg, and continuous infusion of dopamine, her ECG, blood pressure, and PT normalized (Chen et al, 1994).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Severe bronchospasm leading to respiratory arrest has been reported in asthmatic patients receiving intravenous dipyridamole (Eagle & Boucher, 1989).
    B) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) Pulmonary edema was noted during dipyridamole-thallium imaging. The patient also had prolonged, reversible post-ischemic regional ventricular dysfunction (Lette et al, 1989).
    C) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In a study of 1,000 patients given dipyridamole before myocardial perfusion imaging, dyspnea developed in 250 patients (25%) (Johnston et al, 1995).
    b) Dyspnea was reported in 2.6% of patients in a study of adjunct IV dipyridamole used with thallium myocardial perfusion imaging (n=3911) (Prod Info dipyridamole IV injection, 2007).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 23-year-old woman developed weakness, dyspnea, and loss of consciousness after ingesting 70 dipyridamole 25 mg tablets (total: 1.75 g). On admission, she was hypotensive (BP 70/30 mmHg) and developed respiratory arrest shortly after arrival. Laboratory results revealed metabolic acidosis, prothrombin time (PT) of 16.4 s, (control value: 11.9 s), and a partial thromboplastin time (PTT) of 37.6 s (control value: 26.4 s). An ECG showed deep ST depression (2.5 mm) and T wave inversion over the precordial and the limb leads; however, all cardiac enzyme values were normal. Following supportive care, including therapy with IV aminophylline 250 mg, and continuous infusion of dopamine, her ECG, blood pressure, and PT normalized (Chen et al, 1994).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In 2 heart valve replacement studies, dizziness was reported in 13.6% of patients receiving dipyridamole tablets plus warfarin (n=147), compared with 8.2% of patients receiving warfarin and placebo (n=170) (Prod Info dipyridamole oral tablets, 2008).
    b) Dizziness was reported in 11.8% of patients in a study of adjunct IV dipyridamole used with thallium myocardial perfusion imaging (n=3911) (Prod Info dipyridamole IV injection, 2007).
    2) WITH POISONING/EXPOSURE
    a) Dizziness may occur with overdose (Prod Info dipyridamole oral tablets, 2008).
    B) ASTHENIA
    1) WITH POISONING/EXPOSURE
    a) Weakness may occur with overdose (Prod Info dipyridamole oral tablets, 2008; Chen et al, 1994).
    C) RESTLESSNESS
    1) WITH POISONING/EXPOSURE
    a) Restlessness may occur with overdose (Prod Info dipyridamole oral tablets, 2008).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a study of 1,000 patients given dipyridamole before myocardial perfusion imaging, headache developed in 202 patients (20%) (Johnston et al, 1995).
    E) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been associated with IV dipyridamole administration (Prod Info dipyridamole IV injection, 2007).
    F) LOSS OF CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 23-year-old woman developed weakness, dyspnea, and loss of consciousness after ingesting 70 dipyridamole 25 mg tablets (total: 1.75 g). On admission, she was hypotensive (BP 70/30 mmHg) and developed respiratory arrest shortly after arrival. Laboratory results revealed metabolic acidosis, prothrombin time (PT) of 16.4 s, (control value: 11.9 s), and a partial thromboplastin time (PTT) of 37.6 s (control value: 26.4 s). An ECG showed deep ST depression (2.5 mm) and T wave inversion over the precordial and the limb leads; however, all cardiac enzyme values were normal. Following supportive care, including therapy with IV aminophylline 250 mg, and continuous infusion of dopamine, her ECG, blood pressure, and PT normalized (Chen et al, 1994).
    G) CEREBROVASCULAR ACCIDENT
    1) WITH THERAPEUTIC USE
    a) Stroke and transient cerebral ischemia have been associated with IV dipyridamole administration (Prod Info dipyridamole IV injection, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance with dipyridamole therapy, nausea and vomiting have been reported rarely (Prod Info dipyridamole oral tablets, 2008). Nausea was reported in 4.6% of patients in a study of adjunct IV dipyridamole used with thallium myocardial perfusion imaging (n=3911) (Prod Info dipyridamole IV injection, 2007).
    B) ABDOMINAL DISCOMFORT
    1) WITH THERAPEUTIC USE
    a) In 2 heart valve replacement studies, abdominal distress was reported in 6.1% of patients receiving dipyridamole tablets plus warfarin (n=147), compared with 3.5% of patients receiving warfarin and placebo (n=170) (Prod Info dipyridamole oral tablets, 2008).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In uncontrolled trials with dipyridamole, diarrhea has been reported (Prod Info dipyridamole oral tablets, 2008).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) Increased hepatic enzymes have been reported with dipyridamole therapy (Prod Info dipyridamole oral tablets, 2008).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance with dipyridamole therapy, thrombocytopenia has rarely been reported (Prod Info dipyridamole oral tablets, 2008).
    B) BLEEDING
    1) WITH THERAPEUTIC USE
    a) In rare cases, increased bleeding during or after surgery has been reported in patients receiving dipyridamole (Prod Info dipyridamole oral tablets, 2008).
    C) BLOOD COAGULATION DISORDER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 23-year-old woman developed weakness, dyspnea, and loss of consciousness after ingesting 70 dipyridamole 25 mg tablets (total: 1.75 g). On admission, she was hypotensive (BP 70/30 mmHg) and developed respiratory arrest shortly after arrival. Laboratory results revealed metabolic acidosis, prothrombin time (PT) of 16.4 s, (control value: 11.9 s), and a partial thromboplastin time (PTT) of 37.6 s (control value: 26.4 s). An ECG showed deep ST depression (2.5 mm) and T wave inversion over the precordial and the limb leads; however, cardiac enzyme values were normal. Following supportive care, including therapy with IV aminophylline 250 mg, and continuous infusion of dopamine, her ECG, blood pressure, and PT normalized (Chen et al, 1994).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH POISONING/EXPOSURE
    a) Flushing and warm feeling may occur with overdose (Prod Info dipyridamole oral tablets, 2008).
    B) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Sweating may occur with overdose (Prod Info dipyridamole oral tablets, 2008).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance with dipyridamole therapy, hypersensitivity reactions, such as rash, pruritus, urticaria, severe bronchospasm, and angioedema, have been reported rarely (Prod Info dipyridamole oral tablets, 2008; Prod Info dipyridamole IV injection, 2007).
    b) CASE REPORT: In one case, periorbital pruritus was observed about 1 hour following a dipyridamole infusion. Shortly afterwards, the patient developed neck tightness, dyspnea, and facial swelling, which subsided after promethazine and hydrocortisone injections (Angelides et al, 1999).
    B) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylactoid reaction has been reported with IV dipyridamole administration (Prod Info dipyridamole IV injection, 2007).

Reproductive

    3.20.1) SUMMARY
    A) Dipyridamole is classified as US Food and Drug Administration (FDA) pregnancy category B; dipyridamole/aspirin combination is FDA pregnancy category D. Limited human data indicated a congenital anomaly occurred in one infant whose mother used the drug during the first trimester. Teratogenicity has not been reported in mice, rabbit, and rat reproduction studies. No reports describing the use of dipyridamole during human lactation are available and the effects on a nursing infant from exposure are unknown. The manufacturer states that dipyridamole is excreted in human milk. In rats, high doses of dipyridamole caused a reduction in implantations and live fetuses.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) The outcomes of 8 patients with prosthetic heart valves who received dipyridamole and aspirin at some point during their pregnancy were reported. One pregnancy resulted in abortion at 13 weeks, and a second pregnancy aborted at 22 weeks after 9 weeks of warfarin therapy. The second case received dipyridamole from the first to 12th week of pregnancy. The other six pregnancies resulted in live births, one of which had incurving fifth fingers bilaterally. All eight patients received dipyridamole during the first trimester (Chen et al, 1982).
    B) LACK OF EFFECT
    1) Four normal pregnancies resulted in patients with heart valve prostheses who were given dipyridamole 300 mg/day and aspirin 1.5 grams/day. The neonates had no congenital abnormalities and were of normal weight. Treatment was begun in the first trimester in 3 patients and during the 23rd week in the fourth patient (Biale et al, 1980).
    C) ANIMAL STUDIES
    1) There was no evidence of harm to the fetus after mice, rabbits, and rats were given up to 125 mg/kg, 40 mg/kg, and 1000 mg/kg, respectively, of oral dipyridamole. The doses represented approximately 1.5, 2, and 25 times the maximum recommended daily human oral dose (MRHD), respectively, on a mg/m(2) basis (Prod Info dipyridamole oral tablets, 2008).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified dipyridamole as US Food and Drug Administration pregnancy category B (Prod Info dipyridamole oral tablets, 2008).
    2) The manufacturer has classified dipyridamole/aspirin combination as US Food and Drug Administration pregnancy category D (Prod Info AGGRENOX(R) oral capsules, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) No reports describing the use of dipyridamole during human lactation are available and the effects on the nursing infant from exposure to the drug in milk are unknown. It is not known whether dipyridamole affects the quantity and composition of breast milk. Although citing no data, the manufacturer states that dipyridamole is excreted in human milk (Prod Info dipyridamole oral tablets, 2008).
    B) BREAST MILK
    1) Although citing no data, the manufacturer states that dipyridamole is excreted in human milk (Prod Info dipyridamole oral tablets, 2008).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Fertility studies in male and female rats indicated oral dipyridamole doses of 1250 mg/kg/day, which represented more than 30 times the maximum recommended daily human oral dose (MRHD) on a mg/m(2) basis, caused a significant reduction in the number of corpora lutea and a reduction in implantations and live fetuses. Oral doses up to 500 mg/kg/day (12 times the MRHD on a mg/m(2) basis) did not cause impaired fertility (Prod Info dipyridamole oral tablets, 2008).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturers do not report any carcinogenic potential for dipyridamole or dipyridamole/aspirin in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) There was no evidence of carcinogenesis in mice and rats after dipyridamole at doses up to 75 mg/kg/day was added to the feed for up to 111 weeks (male and female mice), up to 128 weeks (male rats), and up to 142 weeks (female rats). On a mg/m(2) basis, the dose was approximately equivalent to the maximum recommended daily human oral dose (MRHD) for the mice and about twice the MRHD for the rats (Prod Info dipyridamole oral tablets, 2008; Prod Info AGGRENOX(R) oral capsules, 2009).

Genotoxicity

    A) Mutagenicity tests in bacterial and mammalian cell systems were negative for dipyridamole (Prod Info dipyridamole oral tablets, 2008). Dipyridamole and aspirin combined (1:5 ratio) tested negative in the following tests: Ames test, in vivo chromosome aberration test (mice and hamsters), oral micronucleus test (mice and hamsters), and oral dominant lethal test (mice) (Prod Info AGGRENOX(R) oral capsules, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea or hypotension.
    E) Monitor coagulation studies after in patients with severe overdose.
    F) Monitor serial troponin and ECG in patients with chest pain.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted. Patients with unstable vital signs and/or life-threatening cardiac dysrhythmias should be admitted to an intensive care unit.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be referred to a healthcare facility for evaluation and treatment. Patients should be observed for 6 hours with frequent monitoring of vital signs and cardiac function. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea or hypotension.
    E) Monitor coagulation studies after in patients with severe overdose.
    F) Monitor serial troponin and ECG in patients with chest pain.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Dipyridamole is also available in combination with aspirin. Refer to "SALICYLATES" management for information on aspirin overdose.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Consider using a xanthine derivative (eg, aminophylline 50 to 240 mg) to reverse the hemodynamic effects of dipyridamole overdose. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Obtain an ECG, and institute continuous cardiac monitoring.
    4) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea or severe overdose.
    5) Monitor serial troponin and ECG in patients with chest pain.
    6) Monitor coagulation studies in patients with severe overdose.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) AMINOPHYLLINE
    1) Dipyridamole produces vasodilation via inhibition of adenosine reuptake, leading to accumulation in plasma and tissues.
    2) Hemodynamic effects of dipyridamole overdose may be reversed by the use of xanthine derivatives (eg, aminophylline 50 to 240 mg) (Prod Info AGGRENOX(R) oral capsules, 2009; Chen et al, 1994).
    a) CASE REPORT: A 23-year-old woman developed weakness, dyspnea, and loss of consciousness after ingesting 70 dipyridamole 25 mg tablets (total: 1.75 g). On admission, she was hypotensive (BP 70/30 mmHg) and developed respiratory arrest shortly after arrival. Laboratory results revealed metabolic acidosis, prothrombin time (PT) of 16.4 s, (control value: 11.9 s), and a partial thromboplastin time (PTT) of 37.6 s (control value: 26.4 s). An ECG showed deep ST depression (2.5 mm) and T wave inversion over the precordial and the limb leads; however, all cardiac enzyme values were normal. Following supportive care, including therapy with IV aminophylline 250 mg, and continuous infusion of dopamine, her ECG, blood pressure, and PT normalized (Chen et al, 1994).
    b) Adenosine-mediated adverse effects, such as bronchoconstriction and angina, have been reversed with intravenous aminophylline administration (Eagle & Boucher, 1989; Blumenthal & McCauley, 1988).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Dipyridamole is highly protein-bound. Hemodialysis is not expected to be of value in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: CHILDREN: Ingestion of 625 mg in a 19-month-old produced toxicity, while ingestion of 400 mg in a child weighing 30 pounds (29 mg/kg) produced no signs of toxicity. ADULTS: Doses of up to 2000 mg/day have been used therapeutically. Acute ingestions of 200 to 1250 mg have produced toxicity. A woman with long-standing angina developed non-ST elevation myocardial infarction after ingesting approximately 5 g of dipyridamole tablets. Loss of consciousness, hypotension, deep ST depression and T wave inversion, elevated PT and PTT, respiratory arrest developed in a woman after ingesting 1.75 g of dipyridamole.
    B) THERAPEUTIC DOSES: ADULTS: Thallium myocardial perfusion: 0.142 mg/kg/min (0.57 mg/kg total) as an IV infusion over 4 minutes prior to thallium; a total dose in excess of 60 mg will most likely not be necessary. Thrombosis prophylaxis, heart valve replacement: 75 to 100 mg orally 4 times daily as an adjunct to warfarin therapy. Stroke prevention: One capsule of extended-release dipyridamole 200 mg/aspirin 25 mg orally twice daily. CHILDREN: Safety and effectiveness of dipyridamole have not been established in pediatric patients. Oral doses of 1 to 4.2 mg/kg/day have been used in children with platelet dysfunction and cardiac valve replacement. Oral doses of 4 to 10 mg/kg/day have been used investigationally to treat proteinuria in pediatric renal disease.

Therapeutic Dose

    7.2.1) ADULT
    A) DIPYRIDAMOLE
    1) THALLIUM MYOCARDIAL PERFUSION: 0.142 mg/kg/min (0.57 mg/kg total) as an IV infusion over 4 minutes prior to thallium; MAX: 60 mg (Prod Info dipyridamole intravenous injection, 2011)
    2) THROMBOSIS PROPHYLAXIS, HEART VALVE REPLACEMENT: 75 to 100 mg orally 4 times daily as an adjunct to warfarin therapy (Prod Info dipyridamole oral tablets, 2013)
    B) DIPYRIDAMOLE/ASPIRIN
    1) STROKE PREVENTION: One capsule (200 mg dipyridamole/aspirin 25 mg)) orally twice daily in the morning and evening (Prod Info AGGRENOX(R) oral extended release capsules, 2012)
    7.2.2) PEDIATRIC
    A) DIPYRIDAMOLE
    1) THALLIUM MYOCARDIAL PERFUSION: Safety and effectiveness in the pediatric or adolescent population have not been established (Prod Info dipyridamole intravenous injection, 2011).
    2) THROMBOSIS PROPHYLAXIS, HEART VALVE REPLACEMENT
    a) 12 YEARS AND OLDER: 75 to 100 mg orally 4 times daily as an adjunct to warfarin therapy (Prod Info dipyridamole oral tablets, 2013).
    b) 11 YEARS AND YOUNGER: Safety and efficacy in the pediatric population 11 years and younger have not been established (Prod Info dipyridamole oral tablets, 2013).
    B) DIPYRIDAMOLE/ASPIRIN
    1) Safety and efficacy in the pediatric or adolescent population have not been established. Due to the aspirin content, use is not recommended (Prod Info AGGRENOX(R) oral extended release capsules, 2012).

Maximum Tolerated Exposure

    A) ADULT
    1) Acute ingestion of more than 200 mg has resulted in minor symptoms. A 50-year-old woman ingested 1,250 mg and recovered (Personal Communication, 1985).
    2) CASE REPORT: A 62-year-old woman with a history of angina presented with severe chest pain 6 hours after ingesting approximately 50 dipyridamole 100 mg tablets. On presentation, she had a heart rate of 92 beats/min and blood pressure of 140/90 mmHg. An initial ECG revealed sinus rhythm with left bundle branch block. Laboratory results revealed elevated creatine kinase of 583 Units/L (normal range: less than 175 Units/L), MB isoenzyme greater than 8% (normal range: less than 6% to 8% CK). The creatine kinase increased to 924 Units/L 6 hours later. She remained hemodynamically stable and was discharged several hours later against medical advice (Jahangiri & Holdright, 1992).
    3) CASE REPORT: A 23-year-old woman developed weakness, dyspnea, and loss of consciousness after ingesting 70 dipyridamole 25 mg tablets (total: 1.75 g). On admission, she was hypotensive (BP 70/30 mmHg) and developed respiratory arrest shortly after arrival. Laboratory results revealed metabolic acidosis, prothrombin time (PT) of 16.4 s, (control value: 11.9 s), and a partial thromboplastin time (PTT) of 37.6 s (control value: 26.4 s). An ECG showed deep ST depression (2.5 mm) and T wave inversion over the precordial and the limb leads; however, all cardiac enzyme values were normal. Following supportive care, including therapy with IV aminophylline 250 mg, and continuous infusion of dopamine, her ECG, blood pressure, and PT normalized (Chen et al, 1994).
    B) PEDIATRIC
    1) Acute ingestion of at least 400 mg produced no symptoms in a child weighing 30 pounds (29 mg/kg) (Personal Communication, 1985).
    C) INFANT
    1) Ingestion of 625 mg in a 19-month-old produced toxicity with complete recovery. Another 6 children ingested unspecified amounts and recovered (Prod Info Dipyridamole (Persantine(R)), 1968).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 2150 mg/kg(RTECS , 2002)
    B) LD50- (ORAL)RAT:
    1) 6000 mg/kg(Prod Info Dipyridamole (Persantine(R)), 1968)
    C) LD50- (ORAL)RAT:
    1) 8400 mg/kg(RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes resulting in an increase in local concentrations of adenosine. By acting on the platelet A(2)–receptor, the increase in concentration of adenosine stimulates platelet adenylate cyclase and in turn increases the levels of cyclic–3',5'–adenosine monophosphate (cAMP). Stimulated by various stimuli such as platelet activating factor (PAF), collagen, and adenosine diphosphate (ADP), this mechanism inhibits platelet aggregation. At therapeutic concentrations (0.5-1.9 micrograms/milliliter (mcg/mL)), dipyridamole inhibits cyclic-3',5'-guanosine monophosphate phosphodiesterase (cGMP-PDE) in various tissues. This enhances the increase in cGMP produced by nitric oxide(Prod Info dipyridamole oral tablets, 2013).

Physicochemical

Physical Characteristics

    A) Dipyridamole is an intensely yellow crystalline powder or needles that is very soluble in methanol, in alcohol, and in chloroform; slightly soluble in water; and very slightly soluble in acetone and in ethyl acetate (Prod Info dipyridamole oral tablets, 2008).

Ph

    A) 2.2 to 3.2 (injection solution) (Prod Info dipyridamole IV injection, 2007)

Molecular Weight

    A) 504.63 (Prod Info dipyridamole oral tablets, 2008)

References

General Bibliography

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