Adenosine (Diagnostic) (adenosine)

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When possible, drugs that may augment or inhibit adenosine effects should be withheld for 5 half-lives prior to adenosine administration.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Adenosine; Hexobendine; Regadenoson/Xanthine Derivatives

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Xanthine derivatives may antagonize the effects of endogenous(1) and exogenous adenosine,(2,3) regadenoson,(4) and hexobendine.(5)

CLINICAL EFFECTS: Concurrent use of a xanthine derivative use may result in decreased effectiveness of adenosine, hexobendine and regadenoson. Aminophylline may increase the risk of adenosine-induced seizures.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with adenosine and a xanthine derivative should be monitored for decreased effectiveness of adenosine. The dosage of adenosine may need to be increased. Whenever possible, withhold xanthine derivatives for 5 half-lives prior to using adenosine in cardiac stress tests.(6) Methylxanthines should not be used to reverse the effects of adenosine in patients who experience adenosine-induced seizures.(3) Concurrent therapy with hexobendine and a xanthine oxidase derivative should also be monitored for decreased effectiveness of hexobendine.(5) The US manufacturer of regadenoson recommends that patients avoid methylxanthines (e.g. caffeine, pentoxifylline, and theophylline) for 12 hours prior to regadenoson administration. Aminophylline may be used to attenuate severe and/or persistent adverse reactions to regadenoson.(4)

DISCUSSION: In a study in six healthy subjects, theophylline significantly reduced the heart-rate response to adenosine. In addition, theophylline reduced the amount of abdominal and chest discomfort reported by subjects, allowing significantly higher infusion rates of adenosine.(7) Theophylline has also been reported to antagonize the vasorelaxant action of adenosine in human forearm arterioles.(8) In a study in five subjects, theophylline decreased the amounts of adenosine-induced side effects, including chest pain. There was no change in blood pressure or respiratory rate during concurrent adenosine and theophylline.(9) In a study in ten dog and twelve human subjects, the administration of adenosine after hexobendine increased coronary sinus blood flow. Aminophylline administration significantly decreased the coronary vasodilation response to adenosine and hexobendine.(5) In a study in ten healthy subjects, caffeine reduced the mean adenosine-induced increases in systolic blood pressure by 7.2 mmHg and heart rate by 8.4 beats/min when compared to placebo.(2) In another study in ten healthy subjects, caffeine was shown to lower the adenosine-induced response of blood pressure and heart rate.(3) Caffeine has also been reported to reduced adenosine-induced changes in minute ventilation and tidal volume.(3) Aminophylline has been shown to shorten the duration of coronary blood flow response to regadenoson.(3) Coronary flow reserve was 8% lower in patients who received caffeine (200 mg single dose) 2 hours prior to regadenoson administration when compared to subjects who received placebo instead of caffeine.(4)

Adenosine; Regadenoson/Dipyridamole

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Dipyridamole inhibits cellular transport of adenosine.(1-3) Also, dipyridamole has been shown to increase intrinsic adenosine levels indicating that dipyridamole inhibits the intrinsic metabolism of adenosine.(4) Regadenoson is a derivative of adenosine.(5)

CLINICAL EFFECTS: Concurrent dipyridamole may increase serum concentrations and potentiate the cardiovascular effects of adenosine. Conversely, significant bradycardia has occurred following rapid bolus injections of adenosine.(1-8) Dipyridamole may increase the effects of regadenoson.(1,2,5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The recommendations for concurrent use of adenosine or regadenoson with dipyridamole is dependent on the indication. -For Cardioversion: The Australian manufacturer of adenosine states the use of adenosine for cardioversion is contraindicated in patients receiving dipyridamole. Discontinue the use of dipyridamole 24 hours prior to adenosine bolus dosing.(7) The US manufacturer of adenosine states smaller doses of adenosine may be effective with dipyridamole.(6) Lower the dose of adenosine in patients receiving dipyridamole.(1,2) Monitor for increased effects of adenosine. -For Stress Testing: Clinical practice guidelines from the American Society of Nuclear Cardiology state dipyridamole use within the previous 48 hours is a contraindication to adenosine or regadenoson stress testing.(9,10) The US manufacturer of dipyridamole recommends stopping dipyridamole for 48 hours prior to stress testing with intravenous dipyridamole or other adenosinergic agents (e.g. adenosine or regadenoson).(1) The Australian manufacturer of dipyridamole recommends stopping dipyridamole for 24 hours prior to stress testing with adenosine.(2) The US manufacturer of regadenoson recommends withholding dipyridamole for at least 2 days prior to regadenoson administration.(5)

DISCUSSION: In a prospective, placebo-controlled single blinded study in eight healthy subjects, all patients were randomized to receive adenosine infusion on two separate days. Heart rate and skin temperature increased in a dose-related manner following adenosine administration. An increase in heart rate of 15 bpm occurred with 0.005 mg/kg/min of adenosine following administration of dipyridamole but did not change following saline. Blood pressure remained unchanged throughout the study.(11) According to another prospective, non-placebo controlled, non-blinded study, five healthy volunteers received a five-day course of oral dipyridamole 100 mg every 6 hours. Plasma adenosine levels were measured for a five day control period as a baseline and also during the five-day course of dipyridamole. It was found during the baseline studies that adenosine levels vary significantly between individuals but seem to be constant within the same individual. During the five-day course, the average increase in endogenous adenosine concentration was 60%. It was concluded that administration of oral dipyridamole significantly increases plasma adenosine levels in normal human subjects. Also, there was a positive correlation between adenosine and dipyridamole levels (p = 0.001).(12)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Adenosine/Carbamazepine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Both drugs may slow conduction through the AV node.(1-3)

CLINICAL EFFECTS: When adenosine is used to slow conduction in the AV node or accessory pathways, the presence of carbamazepine may lead to prolonged or higher degrees of heart block.(1) When adenosine is used during diagnostic imaging studies, carbamazepine may increase the risk for symptomatic AV block.(3)

PREDISPOSING FACTORS: History of an underlying cardiac conduction disorder is a risk factor for carbamazepine-induced AV block.(2)

PATIENT MANAGEMENT: When used for supraventricular tachycardias, Advanced Cardiac Life Support (ACLS) Guidelines recommend lowering initial adenosine dose to 3 mg.(4) Unless a functioning pacemaker is in place, when adenosine is used for myocardial imaging studies, the provider should weigh the risks versus benefits of adenosine administration in patients receiving chronic carbamazepine therapy.(3)

DISCUSSION: Carbamazepine has a tricyclic structure which may be partly responsible for its effects on neuronal and cardiac conduction. Numerous case reports have documented the potential AV node blocking capabilities of carbamazepine. In most cases patients had underlying heart disease; however cases without known risk factors have been reported.(5,6) Although this specific interaction has not been documented, the interaction is plausible based upon the pharmacology of both agents.

There are no moderate interactions for this drug.

Known hypersensitivity to adenosine.

Second- or third-degree AV block (except in patients with a functioning artificial pacemaker).

Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker).

Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma).

There are no contraindication contraindications for this drug.

• Aortic valve stenosis
• Asthma
• Autonomic neuropathy
• Chronic obstructive pulmonary disease
• Complete atrioventricular block
• Hypotension
• Hypovolemia
• Left main coronary artery disease
• Mitral stenosis
• Myocardial ischemia
• Pericarditis
• Second degree atrioventricular heart block
• Seizure disorder
• Sick sinus syndrome
• Syncope due to bradycardia
• Unstable angina pectoris

• Cardiac transplantation
• Left-to-right cardiovascular shunt
• Respiratory alkalosis

Adverse effects reported in at least 1% of patients receiving adenosine for the treatment of PSVT in controlled clinical trials include facial flushing, shortness of breath/dyspnea, chest pressure, nausea, headache, lightheadedness, dizziness, numbness, and tingling in the arms.

Adverse effects reported in at least 1% of patients receiving adenosine as an adjunct to thallium stress testing in controlled and uncontrolled clinical trials include facial flushing; chest discomfort; dyspnea or urge to breathe deeply; headache; discomfort in the throat, neck, or jaw; GI discomfort; lightheadedness/dizziness; upper extremity discomfort; ST-segment depression; first-degree AV block; second-degree AV block; paresthesia; hypotension; nervousness; and arrhythmias.

More Frequent

• Cardiac arrhythmia
• Chest pain
• Dyspnea
• Premature atrial contractions
• Sinus bradycardia

Rare or Very Rare

• Acute myocardial infarction
• Acute respiratory failure
• Atrial fibrillation
• Blurred vision
• Bradycardia
• Bronchospastic pulmonary disease
• Cardiac arrest
• Cerebrovascular accident
• Heart block
• Hypertension
• Seizure disorder
• Throat constriction
• Torsades de pointes

More Frequent

• Dizziness
• Flushing
• Gastrointestinal irritation
• Headache disorder
• Neck pain

Less Frequent

• Hypotension
• Nervousness
• Pain in extremities
• Paresthesia

Rare or Very Rare

• Back pain
• Cough
• Drowsy
• Dysgeusia
• Earache
• Erythema
• Hyperhidrosis
• Hyperventilation
• Injection site sequelae
• Mood changes
• Nasal congestion
• Nausea
• Palpitations
• Scotomata
• Skin rash
• Sore tongue
• Tremor
• Urinary urgency
• Vaginal irritation
• Vomiting
• Xerostomia

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Although the manufacturer states that controlled studies establishing the safety and efficacy of adenosine for treatment of PSVT in pediatric patients are lacking, the drug has been used for the treatment of PSVT in neonates, infants, children, and adolescents, and some clinicians consider it a drug of choice for SVT in pediatric patients.

Safety and efficacy as an adjunct to thallium stress testing not established in children 18 years of age or younger.

Category C. Some clinicians suggest that because of its rapid onset and brief duration of action, adenosine may have advantages over other antiarrhythmic agents (e.g., verapamil, digoxin) in the acute treatment of PSVT in pregnant women in whom vagal maneuvers have failed. However, caution is advised because hypotension may compromise placental (fetal) blood flow.

It is not known whether adenosine is distributed into human milk. Because of the potential for serious adverse reactions from adenosine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. Some clinicians suggest that use of adenosine during lactation may be possible because of the drug's short half-life.

Insufficient experience in patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults. However, use with caution because increased sensitivity cannot be ruled out; some geriatric patients may have diminished cardiac function, nodal dysfunction, or concomitant disease or drug therapy that may alter hemodynamic function and result in severe bradycardia or AV block.