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ADENOSINE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Adenosine is an endogenous nucleoside with antiarrhythmic activity.
    B) Adenosine, an endogenous coronary vasodilator, is used in a continuous infusion (0.140 mg/kg/min for 6 minutes) as a pharmacologic agent for Thallium stress testing. Adenosine causes more vasodilation in normal coronary arteries, leading to increased thallium uptake in normal myocardium versus ischemic areas.
    C) Adenosine is under investigation as an orphan drug in conjunction with carmustine for the treatment of brain tumors.
    D) Regadenoson is a low affinity adenosine receptor agonist, producing coronary vasodilation and increasing coronary blood flow via activation of the A2a adenosine receptor.

Specific Substances

    A) ADENOSINE
    1) 9-beta-D-ribofuranosyladenine
    2) SR-96225
    3) SUNY-4001
    4) CAS 58-61-7
    REGADENOSON
    1) CVT 3146
    2) CAS 313348-27-5

    1.2.1) MOLECULAR FORMULA
    1) C10H13N5O4

Available Forms Sources

    A) FORMS
    1) ADENOSINE is available as 6 mg/2 mL and 12 mg/4 mL in 2 mL and 4 mL plastic disposable syringes, respectively (Prod Info ADENOCARD(R)IV injection, 2005). Adenosine is also available as 60 mg/20 mL and 90 mg/30 mL in 20 mL and 30 mL single dose vials, respectively (Prod Info ADENOSCAN(R) IV injection, 2005).
    2) REGADENOSON is available as single use 5 mL vials and 5 mL pre-filled plastic syringes, each containing 0.08 mg/mL regadenoson (Prod Info LEXISCAN(TM) IV injection, 2008).
    B) USES
    1) ADENOSINE - is indicated for the use of conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT), including that associated with accessory bypass tracts (Wolff-Parkinson-White Syndrome). It should be used when appropriate vagal maneuvers had been shown to be unsuccessful (Prod Info ADENOCARD(R)IV injection, 2005). Adenosine is also indicated for thallium-201 myocardial perfusion scintigraphy in patients who are unable to exercise adequately (Prod Info ADENOSCAN(R) IV injection, 2005; Taillefer et al, 1996).
    2) ADENOSINE TRIPHOSPHATE - is not available or approved for the treatment of supraventricular tachycardia in the United States.
    3) REGADENOSON is a adenosine receptor agonist indicated for radionuclide myocardial perfusion imaging (MPI) in patients who are unable to undergo adequate exercise stress (Prod Info LEXISCAN(TM) IV injection, 2008).

Overview

Laboratory Monitoring

    A) No routine laboratory evaluation is indicated.
    B) Institute continuous cardiac monitoring, and obtain an ECG.
    C) If dysrhythmias develop, monitor electrolytes.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment for mild to moderate toxicity is symptomatic and supportive care. Duration of effect is extremely short, so treatment is usually unnecessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Duration is extremely short, so effects are typically self-limiting and short. However, if severe toxicity develops, support respiratory and cardiovascular function. Aminophylline, an adenosine receptor antagonist, has been used for regadenoson toxicity.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not indicated as these agents are administered parenterally.
    D) AIRWAY MANAGEMENT
    1) Airway management may be needed if cardiovascular compromise develops, but this is rare.
    E) ANTIDOTE
    1) There is no antidote for adenosine. Aminophylline, an adenosine receptor antagonist, has been used following regadenoson adverse reactions, at doses ranging from 50 to 250 mg IV, administered over 30 to 60 seconds.
    F) ENHANCED ELIMINATION
    1) Dialysis or other methods of enhanced elimination are not recommended.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: These medications are administered parenterally in a healthcare setting. There is no role for home management.
    2) OBSERVATION CRITERIA: Patients who develop adverse effects need to be observed in the emergency department until symptoms resolve.
    3) ADMISSION CRITERIA: Patients with severe or prolonged symptoms, those who develop new dysrhythmias, or requiring medication treatment should be admitted for further observation.
    4) CONSULT CRITERIA: Medical toxicology should be consulted in large and/or severe symptomatic exposures.
    H) PITFALLS
    1) Failure to monitor for new dysrhythmias and failure to institute continued cardiac monitoring.
    I) PHARMACOKINETICS
    1) Adenosine absorption is almost immediate when injected intravenously. Duration of effect is extremely short, usually less than 10 seconds, as it is rapidly taken up by most cells. Within cells, it is metabolized to adenosine monophosphate (AMP) by adenosine kinase. These metabolites elicit no electrophysiologic effects. Elimination half-life is less than 10 seconds. Regadenoson has a rapid onset of action, small volume of distribution (in the range of 16 to 58 liters), and is mostly excreted in the urine unchanged (57%). Elimination half-life of regadenoson is 2 to 4 minutes for the initial phase, 30 minutes for the intermediate phase, and 2 hours for the terminal phase.
    J) DIFFERENTIAL DIAGNOSIS
    1) Other antiarrhythmics and medications that can cause slowing through the AV node, such as calcium or beta blockers, and digoxin.

Range Of Toxicity

    A) TOXICITY: ADENOSINE: There is no data for a minimal toxic or lethal dose for adenosine. REGADENOSON: Flushing, dizziness, and increased heart rate have been reported at doses greater than 0.02 mg/kg.
    B) THERAPEUTIC DOSE: ADENOSINE: ADULTS: 6 mg IV peripheral bolus over 1 to 2 seconds; can increase to a maximum dose of 12 mg if needed. CHILDREN: Initial dose, 0.1 mg/kg rapid IV push or intraosseous, up to a maximum of 6 mg/dose; can repeat with 0.2 mg/kg, up to a maximum of 12 mg/dose. REGADENOSON: ADULTS: 0.4 mg (5 mL) of regadenoson administered as a rapid (approximately 10 seconds) intravenous injection.

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Adenosine is an endogenous nucleoside used for the conversion of paroxysmal supraventricular tachycardia to sinus rhythm. It is an endogenous coronary vasodilator and used for thallium stress testing. Regadenoson is a low affinity adenosine receptor agonist producing coronary vasodilation and increasing coronary blood flow used for myocardial perfusion imaging.
    B) PHARMACOLOGY: Adenosine depresses calcium-mediated slow-channel conduction and increases potassium conductance, thus depressing automaticity of the sinus node, Purkinje fibers, AV nodal conduction, and shortening and hyperpolarizing the atrial action potential.
    C) TOXICOLOGY: Overdose information is limited. In large doses, cardiac effects can occur which include atrial fibrillation, atrial flutter, bradycardia, and angina-like chest pain. However, adenosine has an ultra-short half-life which limits its toxicity. EPIDEMIOLOGY: Adenosine is commonly used, but toxicity is rarely seen.
    D) EPIDEMIOLOGY: Adenosine is commonly used, but toxicity is rarely seen.
    E) WITH THERAPEUTIC USE
    1) Hypotension, dyspnea, nausea, vomiting, abdominal discomfort, dizziness, facial flushing, and irritability have occurred with therapeutic dosing.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild toxicity can consist of hypotension, dyspnea, vomiting and retching, facial flushing, headaches, and irritability.
    2) SEVERE TOXICITY: Severe toxicity can cause bradycardia, sinus arrest, atrioventricular block, ventricular dysrhythmias, and bronchospasm. Seizures are rarely reported.
    0.2.20) REPRODUCTIVE
    A) Adenosine and regadenoson are classified as FDA pregnancy category C. There have been no reproductive studies in animals or humans with adenosine administration. Repeated administration of regadenoson in rats and rabbits resulted in reduced fetal body weights, microphthalmia, and skeletal malformations. It is unknown whether adenosine or regadenoson are excreted in human breast milk.

Clinical Effects

Summary Of Exposure

    A) USES: Adenosine is an endogenous nucleoside used for the conversion of paroxysmal supraventricular tachycardia to sinus rhythm. It is an endogenous coronary vasodilator and used for thallium stress testing. Regadenoson is a low affinity adenosine receptor agonist producing coronary vasodilation and increasing coronary blood flow used for myocardial perfusion imaging.
    B) PHARMACOLOGY: Adenosine depresses calcium-mediated slow-channel conduction and increases potassium conductance, thus depressing automaticity of the sinus node, Purkinje fibers, AV nodal conduction, and shortening and hyperpolarizing the atrial action potential.
    C) TOXICOLOGY: Overdose information is limited. In large doses, cardiac effects can occur which include atrial fibrillation, atrial flutter, bradycardia, and angina-like chest pain. However, adenosine has an ultra-short half-life which limits its toxicity. EPIDEMIOLOGY: Adenosine is commonly used, but toxicity is rarely seen.
    D) EPIDEMIOLOGY: Adenosine is commonly used, but toxicity is rarely seen.
    E) WITH THERAPEUTIC USE
    1) Hypotension, dyspnea, nausea, vomiting, abdominal discomfort, dizziness, facial flushing, and irritability have occurred with therapeutic dosing.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild toxicity can consist of hypotension, dyspnea, vomiting and retching, facial flushing, headaches, and irritability.
    2) SEVERE TOXICITY: Severe toxicity can cause bradycardia, sinus arrest, atrioventricular block, ventricular dysrhythmias, and bronchospasm. Seizures are rarely reported.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) ADENOSINE
    1) Atrial fibrillation or atrial flutter have been observed in several patients receiving adenosine in doses higher than those required to produce tachycardia termination or atrioventricular (AV) block; the dysrhythmias lasted less than 60 seconds (DiMarco et al, 1985).
    2) In a study of 198 patients with paroxysmal supraventricular tachycardia treated with adenosine. A 12% incidence of atrial fibrillation or atrial flutter was observed with 12 mg doses. The duration of atrial fibrillation or atrial flutter resulting from adenosine administration was approximately 5 to 6 minutes. While most episodes will convert to sinus rhythm spontaneously, some patients required cardioversion or other interventions (Strickberger et al, 1997).
    b) REGADENOSON: Rhythm or conduction abnormalities, including premature atrial contractions, premature ventricular contractions, atrial fibrillation/flutter, wandering atrial pacemaker, supraventricular or ventricular dysrhythmias, and AV block, were reported in 26% of patients (n=1275) who received regadenoson during clinical trials (Prod Info Lexiscan(R) IV injection, 2011).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) ADENOSINE
    1) Severe bradycardia has been only rarely observed with adenosine following termination of supraventricular tachycardia (Overholt et al, 1988; Clarke et al, 1987).
    2) CASE REPORT: Severe sinus bradycardia was observed in a 10-year-old boy with Down syndrome, complete atrioventricular canal, and pulmonary hypertension following the administration of intravenous adenosine 150 mcg/kg for orthodromic reciprocating tachycardia (Overholt et al, 1988).
    3) The bradycardia persisted for 2 to 3 minutes and required temporary pacing, but did not occur a second time on rechallenge with the same dose.
    2) WITH POISONING/EXPOSURE
    a) ADENOSINE
    1) CASE REPORT/FETAL EXPOSURE: A 37-year-old 25 week primigravida with a history of paroxysmal supraventricular tachycardia for over 17 years was treated initially with adenosine (6 mg) with no change in maternal heart rate. A repeat dose of 12 mg resulted in a 5-second episode of fetal bradycardia to 40 to 50 beats/minute with rapid return to baseline. The patient was then treated with diltiazem and delivered a viable male at 39 weeks (Dunn & Brost, 2000).
    C) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) ADENOSINE
    1) INOTROPIC EFFECTS: Adenosine reportedly lacks negative inotropic effects. The nucleoside has been used safely in hemodynamically compromised patients (Griffith et al, 1988; Clarke et al, 1987). Unlike verapamil, no significant hemodynamic disturbances were observed in patients with ventricular tachycardia after adenosine administration (Griffith et al, 1988).
    D) ANGINA
    1) WITH THERAPEUTIC USE
    a) ADENOSINE
    1) Infusion of adenosine causes angina-like chest pain in susceptible persons without EKG signs of ischemia (Johnston et al, 1995; Crea et al, 1990; Griffith et al, 1988). Chest pain with adenosine has been occasionally reported in association with dyspnea (Griffith et al, 1988).
    2) INCIDENCE: In controlled US trials, 1% or less of patients developed chest pain following intravenous adenosine administration (Prod Info ADENOCARD(R) IV injection, 2009).
    3) INCIDENCE/STRESS TESTING: In a large study (n=2,000) comparing the effects of adenosine and dipyridamole for pharmacologic stress testing, 53% of the adenosine patients developed chest pain compared with 30% in the dipyridamole group (Johnston et al, 1995).
    4) Angina-like chest pain was reported following adenosine therapy administration to healthy volunteers by Sylven et al (1989). Chest pain occurred after coronary vasodilation and was followed by tachycardia and elevated systolic pressure, but diastolic pressure remained unchanged. The results were compatible with a myocardial origin for the pain by a mechanism separate from vasodilation (Sylven et al, 1989).
    b) REGADENOSON: Angina/ST segment depression and nonspecific chest pain were reported in 12% and 7% of patients (n=1337), respectively, who received regadenoson during clinical trials (Prod Info Lexiscan(R) IV injection, 2011).
    E) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) ADENOSINE
    1) Hypotension is not usually a complication during adenosine therapy (Griffith et al, 1988; DiMarco et al, 1985; DiMarco et al, 1983); slight blood pressure elevations may occur after conversion to sinus rhythm (DiMarco et al, 1983).
    2) INCIDENCE: In controlled US trials, 1% or less of patients developed hypotension following intravenous adenosine administration (Prod Info ADENOCARD(R) IV injection, 2009).
    b) REGADENOSON: Decreased systolic blood pressure of greater than 35 mmHg and decreased diastolic blood pressure of greater than 25 mmHg were reported in 7% and 4% of patients, respectively, during clinical trials. The onset of hypotension was observed approximately 45 minutes after regadenoson administration (Prod Info Lexiscan(R) IV injection, 2011).
    F) HEART BLOCK
    1) WITH THERAPEUTIC USE
    a) ADENOSINE
    1) SUMMARY: During therapeutic use, adenosine exerts its effect by decreasing conduction through the AV-node and may produce short periods of first-, second- or third-degree heart block. Due to its short half-life, effects are usually self-limiting (Prod Info ADENOCARD(R) IV injection, 2009).
    b) REGADENOSON: Asymptomatic first degree AV block (PR prolongation greater than 220 msec) occurred in 3% of patients (n=1209), during clinical trials, within 2 hours following regadenoson administration (Prod Info Lexiscan(R) IV injection, 2011). Transient asymptomatic second degree AV block occurred in 1 patient who received regadenoson during the same clinical trial.
    G) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) ADENOSINE TRIPHOSPHATE
    1) Adenosine triphosphate may be associated with a higher incidence of adverse effects than adenosine. A high frequency of cardiac adverse effects have been observed, including sinus bradycardia, sinus arrest, sinus tachycardia, and varying degrees of atrioventricular (AV) block upon termination of the tachycardia (Sharma et al, 1990).
    2) These effects occur a few seconds following administration and persist for a similar time period. Patients are usually asymptomatic, and intervention is not required (Belhassen & Pelleg, 1985; Belhassen & Pelleg, 1984; Belhassen & Pelleg, 1984a).
    3) Only rarely has a thoracic blow been required to restore normal sinus rhythm during symptomatic cardiac pauses (Belhassen & Pelleg, 1985).
    H) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) REGADENOSON: An increased heart rate was reported in healthy volunteers who received regadenoson at doses greater than 0.02 mg/kg (Prod Info Lexiscan(R) IV injection, 2011).
    I) INTRA-ARTERIAL INJECTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT/ADENOSINE: A 12-year-old girl, with Wolff-Parkinson-White syndrome, experienced blurred vision, dizziness, nausea, transient pain, and mottling of the skin of her forearm after an IV cannula was inadvertently placed in her left brachial artery and adenosine, 150 mcg/kg, was administered intraarterially intended to treat supraventricular tachycardia. The cannula was removed and the adverse effects disappeared within 10 minutes. A new IV cannula was placed, adenosine was administered intravenously, and the patient subsequently converted to sinus rhythm. Examination of the patient's left arm indicated no abnormalities (ter Schure & de Vries, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) ADENOSINE
    1) Dyspnea has been frequently reported with intravenous adenosine used for stress testing (Johnston et al, 1995; Griffith et al, 1988; Overholt et al, 1988)Watt et al, 1986; (DiMarco et al, 1985).
    2) This effect is transient in most patients and persists for only a few seconds. The dyspnea is most likely due to the weak bronchoconstrictor effects of adenosine (Cushley et al, 1985).
    3) Until further data are available, adenosine should be used with caution in asthmatic patients.
    4) INCIDENCE: In controlled US trials, 12% of patients developed dyspnea following intravenous adenosine administration (Prod Info ADENOCARD(R) IV injection, 2009).
    5) CASE SERIES/STRESS TESTING: 25% of patients developed dyspnea during pharmacologic stress testing (Johnston et al, 1995).
    6) DiMarco et al (1985) reported transient dyspnea in 9 of 46 patients (20%) who received adenosine for the treatment of supraventricular dysrhythmias (DiMarco et al, 1985).
    b) REGADENOSON
    1) During clinical trials, dyspnea was a frequent occurrence, reported in 28% of patients (n=1337) who received regadenoson administration (Prod Info Lexiscan(R) IV injection, 2011).
    2) In a randomized placebo-controlled trial involving 467 patients with stable COPD and 532 patients with asthma, dyspnea occurred in 18% of the COPD patients (n=316) and in 10.7% of the asthma patients (n=356) who received regadenoson, as compared with 4% (n=151) and 1.1% (n=176) in each of the placebo groups, respectively (Prod Info Lexiscan(R) IV injection, 2011).
    B) HYPERVENTILATION
    1) WITH THERAPEUTIC USE
    a) ADENOSINE: In controlled US trials, 1% or less of patients developed hyperventilation following intravenous adenosine administration (Prod Info ADENOCARD(R) IV injection, 2009).
    b) ADENOSINE TRIPHOSPHATE: Hyperpnea and cough have been seen with adenosine triphosphate. This effect is generally benign and short-lasting (Belhassen & Pelleg, 1985; Belhassen & Pelleg, 1984a).
    C) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) ADENOSINE
    1) SUMMARY: Adenosine is a respiratory stimulant (possibly through activation of the carotid body chemoreceptors), and intravenous administration has resulted in increases in minute ventilation (Ve) and reduced arterial PCO(2) resulting in respiratory alkalosis. Respiratory compromise has developed in patients with obstructive lung diseases following adenosine administration; it should be avoided in patients with bronchoconstriction or bronchospasm (eg, asthma) (Prod Info ADENOCARD(R) IV injection, 2009).
    2) CASE REPORTS: Sudden bronchospasm developed in 2 asthmatic patients following several intravenous doses of adenosine (Drake et al, 1994). It is thought that adenosine can produce bronchoconstriction by enhancing IgE-dependent release of preformed mediators from mast cells.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) ADENOSINE TRIPHOSPHATE: Seizures have been rarely seen with adenosine triphosphate usage (Belhassen & Pelleg, 1985; Belhassen & Pelleg, 1984a).
    B) MALAISE
    1) WITH THERAPEUTIC USE
    a) ADENOSINE TRIPHOSPHATE: Malaise has been seen with adenosine triphosphate. This effect is generally benign and short-lasting (Belhassen & Pelleg, 1985; Belhassen & Pelleg, 1984a).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) ADENOSINE: In controlled US trials, 2% of patients developed headache following intravenous adenosine administration (Prod Info ADENOCARD(R) IV injection, 2009).
    b) ADENOSINE TRIPHOSPHATE: Headache has been seen with adenosine triphosphate. This effect is generally benign and self-limiting (Belhassen & Pelleg, 1985; Belhassen & Pelleg, 1984a).
    c) REGADENOSON: Headache was a common occurrence with regadenoson administration, reported in 26% of patients (n=1337) during clinical trials. The onset of symptoms generally occurred shortly after dosing, with resolution of the headache usually occurring within 30 minutes (Prod Info Lexiscan(R) IV injection, 2011).
    D) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) ADENOSINE: In controlled US trials, lightheadedness (2%), dizziness (less than 1%), tingling in arms (less than 1%), and numbness (less than 1%) were reported in patients following intravenous adenosine administration (Prod Info ADENOCARD(R) IV injection, 2009).
    b) REGADENOSON: During clinical trials, dizziness was reported in 8% of patients (n=1337) following regadenoson administration (Prod Info Lexiscan(R) IV injection, 2011).
    2) WITH POISONING/EXPOSURE
    a) REGADENOSON: Dizziness was reported in healthy volunteers who received regadenoson at doses greater than 0.02 mg/kg (Prod Info Lexiscan(R) IV injection, 2011).
    E) FEELING NERVOUS
    1) WITH THERAPEUTIC USE
    a) ADENOSINE
    1) Irritability was reported in children who received adenosine (Overholt et al, 1988).
    2) INCIDENCE: In controlled US trials, less than 1% of patients developed apprehension following intravenous adenosine administration (Prod Info ADENOCARD(R) IV injection, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) ADENOSINE
    1) Nausea is an infrequent adverse effect of adenosine (Griffith et al, 1988).
    2) INCIDENCE: In controlled US trials, 3% of patients developed nausea and less than 1% experienced a metallic taste following intravenous adenosine administration (Prod Info ADENOCARD(R) IV injection, 2009).
    b) REGADENOSON: Nausea was reported in 6% of patients (n=1337) who received regadenoson during clinical trials (Prod Info Lexiscan(R) IV injection, 2011).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) ADENOSINE TRIPHOSPHATE: Vomiting and retching have been seen with adenosine triphosphate. This effect is generally benign and short-lasting (Belhassen & Pelleg, 1985; Belhassen & Pelleg, 1984a).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Facial flushing is a common adverse effect of adenosine and regadenoson, occurring in up to 45% of patients (Prod Info Lexiscan(R) IV injection, 2011; Prod Info ADENOSCAN(R) IV injection, 2010; Johnston et al, 1995; Griffith et al, 1988; Overholt et al, 1988)Watt et al, 1986; (DiMarco et al, 1985; DiMarco et al, 1983). This effect is transient, subsiding in most patients in several seconds, and is most likely related to the cutaneous vasodilating properties of adenosine (DiMarco et al, 1985).
    b) INCIDENCE: In controlled US trials, 18% of patients developed facial flushing following intravenous adenosine administration (Prod Info ADENOCARD(R) IV injection, 2009).
    2) WITH POISONING/EXPOSURE
    a) REGADENOSON: Flushing was reported in healthy volunteers who received regadenoson doses greater than 0.02 mg/kg (Prod Info Lexiscan(R) IV injection, 2011).
    B) MOTTLING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT/ADENOSINE: A 12-year-old girl, with Wolff-Parkinson-White syndrome, experienced blurred vision, dizziness, nausea, transient pain, and mottling of the skin of her forearm after an IV cannula was inadvertently placed in her left brachial artery and adenosine, 150 mcg/kg, was administered intraarterially intended to treat supraventricular tachycardia. The cannula was removed and the adverse effects disappeared within 10 minutes. A new IV cannula was placed, adenosine was administered intravenously, and the patient subsequently converted to sinus rhythm. Examination of the patient's left arm indicated no abnormalities (ter Schure & de Vries, 2011).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) ADENOSINE
    1) CASE REPORT: A 61-year-old woman developed anaphylactic symptoms (urticarial rash on the face, arms, and chest with mild facial swelling) within minutes of receiving a second dose of intravenous adenosine (Fata et al, 1996). Symptoms resolved with medical management.

Reproductive

    3.20.1) SUMMARY
    A) Adenosine and regadenoson are classified as FDA pregnancy category C. There have been no reproductive studies in animals or humans with adenosine administration. Repeated administration of regadenoson in rats and rabbits resulted in reduced fetal body weights, microphthalmia, and skeletal malformations. It is unknown whether adenosine or regadenoson are excreted in human breast milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) REGADENOSON
    a) RATS - In studies of pregnant rats treated during organogenesis with regadenoson doses equivalent to 10 and 20 times the maximum recommended human dose (MRHD) on a mg/m(2) basis, fetal body weights were significantly reduced, and ossification in limb phalanges and metatarsals was significantly delayed. Maternal toxicity also occurred at these doses; the no-effect dose level for maternal toxicity was 2 times the MRHD (Prod Info LEXISCAN(TM) IV injection, 2008).
    b) RABBITS - In studies of pregnant rabbits treated during major organogenesis with regadenoson doses equivalent to 4 times the MRHD, there was no evidence of teratogenicity; however, maternal toxicity occurred. At regadenoson doses equivalent to 12 and 20 times the MRHD, maternal toxicity, increased embryo/fetal loss and fetal malformations were observed. The no-effect dose was 4 times the MRHD for fetal toxicity and was not identified for maternal toxicity (Prod Info LEXISCAN(TM) IV injection, 2008).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Adenosine is classified by the manufacturer as FDA pregnancy category C (Prod Info ADENOSCAN intravenous injection, 2014).
    2) Regadenoson is classified by the manufacturer as FDA pregnancy category C (Prod Info LEXISCAN(TM) IV injection, 2008).
    B) CASE REPORT
    1) ADENOSINE/FETAL EXPOSURE - A 37-year-old 25 week primigravida with a history of paroxysmal supraventricular tachycardia for over 17 years was treated initially with adenosine (6 mg) with no change in maternal heart rate. A repeat dose of 12 mg resulted in a 5-second episode of fetal bradycardia to 40 to 50 beats/minute with rapid return to baseline (approximately 140 bpm). The patient was then treated with diltiazem and delivered a viable male at 39 weeks (Dunn & Brost, 2000).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) ADENOSINE: Based on adenosine's short serum half-life, it is unlikely that any of the drug will pass into milk (Briggs et al, 1998). However, it is unknown whether adenosine is excreted into breast milk. Because many drugs are excreted into human milk and the potential for serious adverse reactions exists in nursing infants exposed to adenosine, it is recommended to either discontinue nursing or adenosine, considering the importance of the drug to the mother (Prod Info ADENOSCAN intravenous injection, 2014).
    2) REGADENOSON - Lactation studies with regadenoson have not been conducted in humans and it is unknown whether the drug is excreted into human milk. Based on regadenoson pharmacokinetics, the drug should be cleared 10 hours after administration. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to interrupt nursing for 10 hours after regadenoson administration or to not administer regadenoson, taking into consideration the importance of the drug to the mother (Prod Info LEXISCAN(TM) IV injection, 2008).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No routine laboratory evaluation is indicated.
    B) Institute continuous cardiac monitoring, and obtain an ECG.
    C) If dysrhythmias develop, monitor electrolytes.
    4.1.2) SERUM/BLOOD
    A) If dysrhythmias develop, monitor electrolytes.
    B) OTHER
    1) The duration of electrophysiologic and clinical effects with adenosine is extremely short, usually less than 10 seconds, due to rapid cellular uptake and metabolism. Laboratory measures are not likely to be useful in an intoxication.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Continuous electrocardiogram monitoring is recommended, especially in patients capable of rapid atrioventricular (AV) conduction.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with severe or prolonged symptoms, those who develop new dysrhythmias, or requiring medication treatment should be admitted for further observation.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) These medications are administered parenterally in a healthcare setting. There is no role for home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Medical toxicology should be consulted in large and/or severe symptomatic exposures.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients who develop adverse effects need to be observed in the emergency department until symptoms resolve.

Monitoring

    A) No routine laboratory evaluation is indicated.
    B) Institute continuous cardiac monitoring, and obtain an ECG.
    C) If dysrhythmias develop, monitor electrolytes.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not indicated as these agents are administered parenterally.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) See the PARENTERAL EXPOSURE treatment section for further information.

Enhanced Elimination

    A) DIALYSIS
    1) Dialysis or other methods of enhanced elimination are not recommended.

Range Of Toxicity

Summary

    A) TOXICITY: ADENOSINE: There is no data for a minimal toxic or lethal dose for adenosine. REGADENOSON: Flushing, dizziness, and increased heart rate have been reported at doses greater than 0.02 mg/kg.
    B) THERAPEUTIC DOSE: ADENOSINE: ADULTS: 6 mg IV peripheral bolus over 1 to 2 seconds; can increase to a maximum dose of 12 mg if needed. CHILDREN: Initial dose, 0.1 mg/kg rapid IV push or intraosseous, up to a maximum of 6 mg/dose; can repeat with 0.2 mg/kg, up to a maximum of 12 mg/dose. REGADENOSON: ADULTS: 0.4 mg (5 mL) of regadenoson administered as a rapid (approximately 10 seconds) intravenous injection.

Therapeutic Dose

    7.2.1) ADULT
    A) ADENOSINE
    1) RAPID INTRAVENOUS BOLUS
    a) An initial dose of 6 mg should be given as a rapid IV bolus over 1 to 2 seconds directly into a vein or into the most proximal site of an IV catheter (Prod Info ADENOCARD(R)IV injection, 2005).
    1) Repeat administration: A second and third dose of 12 mg can be given after a one- to two-minute interval, if tachycardia persists. Single doses exceeding 12 mg are not recommended (Prod Info ADENOCARD(R)IV injection, 2005).
    2) MAXIMUM - Doses greater than 12 mg are NOT recommended for adult and pediatric patients (Prod Info ADENOCARD(R)IV injection, 2005).
    b) In 2 studies, the use of gradually increasing doses was effective, beginning with an IV bolus of 30 to 40 mcg/kg and increasing by increments of 37.5 mcg/kg every 1 to 3 minutes. This continues until arrhythmia termination or atrioventricular (AV) block is observed (DiMarco et al, 1983; DiMarco et al, 1985).
    c) Negative chronotropic and dromotropic effects are only seen with rapid administration (Belhassen & Pelleg, 1985). The route of administration is also important. It is unlikely that the oral or intramuscular routes would be effective; therefore, the drug should be given IV (DiMarco et al, 1985).
    2) CENTRAL LINE
    a) Lower doses should be employed for central administration due to the shorter amount of time required for the drug to reach the heart. In both of these studies, the mean range of effective doses was 80 to 90 mcg/kg or 2 to 23 mg. In most patients, the dose required to terminate TACHYCARDIA is less than or equal to the dose needed to produce bradycardia or AV block (DiMarco et al, 1983; DiMarco et al, 1985).
    b) Tachycardia termination has occurred more rapidly when adenosine was administered via a central vein or into the right atrium as opposed to a peripheral vein (Leclercq & Coumel, 1978) (Belhassen et al, 1983; Belhassen & Pelleg, 1985).
    3) INTRAVENOUS INFUSION
    a) The recommended dose for adenosine as an adjunct to thallium myocardial perfusion scintigraphy is 0.14 mg/kg/min as a continuous peripheral intravenous infusion over a 6-minute period (total infused dose, 0.84 mg/kg) (Prod Info ADENOSCAN intravenous injection, 2014).
    4) DISEASE STATE
    a) SUPRAVENTRICULAR TACHYCARDIA
    1) The intravenous dose of adenosine to terminate supraventricular tachycardia has been variable in clinical studies.
    a) In one study, a 7-fold range of effective doses was observed when the dose was calculated as mcg/kg; a 10-fold range was seen when only the number of milligrams required was considered (DiMarco et al, 1985).
    b) This variability was related to several factors that affected the concentration that reached the cardiac adenosine receptor, including speed of injection, circulation time from injection site to the heart, and the volume of the central compartment. The level of adrenergic or vagal tone that noncompetitively antagonizes or enhances the effect of adenosine could also account for the wide range in effective doses (DiMarco et al, 1985).
    B) ADENOSINE TRIPHOSPHATE
    1) Intravenous bolus doses of adenosine triphosphate 10 to 20 mg in adults (3 to 15 mg in children) have successfully terminated 89% to 98% (mean, 95%) of paroxysmal supraventricular tachycardia in available clinical investigations (Belhassen & Pelleg, 1984).
    2) Adenosine triphosphate was comparable to IV verapamil in one study involving pediatric patients, with each agent terminating approximately 90% of arrhythmias (Greco et al, 1982).
    C) REGADENOSON
    1) The recommended dose is 0.4 mg (5 mL) of regadenoson administered as a rapid (approximately 10 seconds) IV injection into a peripheral vein (Prod Info LEXISCAN(R) intravenous injection, 2014).
    7.2.2) PEDIATRIC
    A) ADENOSINE
    1) PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA CONVERSION
    a) INITIAL DOSE: 0.1 mg/kg rapid IV push or intraosseous; maximum 6 mg/dose (Kleinman et al, 2010; Bouhouch et al, 2008; Losek et al, 1999; Reyes et al, 1992).
    b) REPEAT DOSES: If conversion of PSVT does not occur after 30 seconds, repeat with 0.2 mg/kg for the second dose (and subsequent doses, if necessary); maximum 12 mg/dose (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Losek et al, 1999).
    c) Prospective and retrospective case reviews of success rates of various initial doses of adenosine in infants and children have shown better termination rates with higher initial doses. Based on this, some clinicians advocate use of higher initial doses of 0.15 to 0.3 mg/kg and a minimum of 0.1 mg/kg (Gandhi & Uzun, 2006; Rosenthal, 2006; Dixon et al, 2005; Losek et al, 1999).
    2) HEART TRANSPLANTATION
    a) The adult literature has noted a supersensitivity of the transplanted heart to the effects of adenosine; denervated transplanted sinus and AV nodes have an exaggerated response to adenosine (Toft et al, 1998; Anderson et al, 1993; Ellenbogen et al, 1990). It has been suggested that the dose of adenosine used to treat SVT in heart transplant patients be decreased by one-third to one-fifth (Ellenbogen et al, 1990). Other experts consider adenosine contraindicated in pediatric heart transplant patients (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    3) ADJUNCT TO THALLIUM-201 MYOCARDIAL PERFUSION SCINTIGRAPHY
    a) Safety and efficacy in the pediatric population have not been established (Prod Info ADENOSCAN intravenous injection, 2014).
    B) REGADENOSON
    1) Safety and efficacy in the pediatric population have not been established (Prod Info LEXISCAN(R) intravenous injection, 2014).

Maximum Tolerated Exposure

    A) ADENOSINE: Adverse effects have been seen at therapeutic levels; however, the half-life of adenosine is less than 10 seconds and effects are usually rapidly self-limiting (Prod Info ADENOCARD(R)IV injection, 2005).
    B) REGADENOSON: Flushing, dizziness, and an increased heart rate were reported in healthy volunteers who received regadenoson at doses greater than 0.02 mg/kg (Prod Info LEXISCAN(TM) IV injection, 2008)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) ADENOSINE
    1) Adenosine is an endogenous nucleoside primarily formed as a degradation product of adenosine triphosphate (ATP) (Anon, 1985). As an intermediate metabolite in several biochemical pathways, adenosine contributes to the regulation of numerous physiologic processes, including platelet function, coronary and systemic vascular tone, and lipolysis in adipocytes (Arch & Newsholme, 1978; DiMarco et al, 1983).
    2) Early studies in animals demonstrated that adenosine produced a transient slowing of the sinus rate and atrioventricular (AV) block (Drury & Szent-Gyorgyi, 1929). Subsequently, numerous studies have confirmed that both adenosine and adenosine triphosphate (ATP) exert transient negative dromotropic and chronotropic effects in animals and humans (Belardinelli et al, 1980; DiMarco et al, 1983; Leclerq & Coumel, 1978; Berne et al, 1984; Belhassen & Pelleg, 1984a; Belhassen & Pelleg, 1985).
    3) In experimental preparations, the electrophysiologic effects of adenosine have included depression of automaticity of the sinus node and Purkinje fibers, depression of AV nodal conduction, shortening and hyperpolarization of the atrial action potential, and antagonism of the effects of isoproterenol on the action potential of ventricular myocytes (DiMarco et al, 1985; Rosen et al, 1983; Belardinelli & Isenberg, 1983; DiMarco et al, 1983).
    a) These effects appear to be mediated by depression of calcium-mediated slow-channel conduction, an increase in potassium conductance, and possibly by indirect antiadrenergic effects (Belhassen & Pelleg, 1984; Belardinelli & Isenberg, 1983; Schrader et al, 1975; Belardinelli et al, 1982).
    4) The strong depressant effects of adenosine and adenosine triphosphate (ATP) on the atrioventricular (AV) node following bolus injection account for the efficacy of both agents in either terminating AV reentrant tachycardia or in slowing ventricular rate during atrial tachyarrhythmias (Belhassen & Pelleg, 1984; Belhassen & Pelleg, 1985).
    a) Both agents produce a transient AV block, which breaks the reentrant circuit within the AV node (Anon, 1985). Adenosine has no effect on anterograde conduction over accessory pathways in patients with Wolff-Parkinson-White syndrome.
    b) The sinus and AV nodes are very sensitive to adenosine in physiologic doses and the drug is effective in terminating acute episodes of paroxysmal supraventricular tachycardia involving the AV node (DiMarco et al, 1983). Adenosine and ATP also produce potent vasodilation (Sollevi, 1986; Belhassen & Pelleg, 1984).
    c) This effect has been used therapeutically to produce controlled hypotension during surgical procedures (Sollevi et al, 1984). Although some animal studies have suggested vagal involvement in the mechanism of action of ATP, human studies indicate that the actions of both ATP and adenosine are not vagally-mediated (Belhassen & Pelleg, 1984).
    d) Some studies have suggested that the effects of ATP result from its rapid degradation to adenosine (Belhassen & Pelleg, 1984).
    5) The selective antiarrhythmic activity of adenosine has diagnostic implications.
    a) Differentiation of supraventricular tachycardia with intraventricular aberrancy from ventricular tachycardia can be accomplished with adenosine administration (Belhassen & Pelleg, 1984a).
    b) The high-grade transient atrioventricular (AV) block produced in patients with a supraventricular arrhythmia not requiring AV nodal conduction can allow a clear demonstration of atrial activity, a useful diagnostic maneuver in patients with fibrillation, or multiple accessory pathways (DiMarco et al, 1985).
    6) REVIEW ARTICLES: Sollevi (1986) reviewed the cardiovascular effects and potential clinical applications of adenosine (Sollevi, 1986a).
    a) Pelleg & Porter (1990) have provided an extensive review on the pharmacology of adenosine (Pelleg & Porter, 1990).
    b) Parker & McCollam (1990) reviewed the clinical use of adenosine (Parker & McCollam, 1990).
    B) REGADENOSON
    1) Regadenoson, an A(2A) adenosine receptor agonist, produces coronary vasodilation. It causes a rapid increase in coronary blood flow that is of short duration. Mean average peak velocity of coronary blood flow is increased to greater than twice the baseline level by 30 seconds and decreased to less than twice the baseline level within 10 minutes (Prod Info LEXISCAN(TM) IV injection, 2008).
    2) The affinity of regadenoson for the A(2A) adenosine receptor is low (K(i) approximates 1.3 micromoles (mcM)), with at least a 10-fold lower affinity for the A(1) adenosine receptor (K(i) greater than 16.5 mcM). Its affinity for the A(2B) and A(3) adenosine receptors, if any, is weak (Prod Info LEXISCAN(TM) IV injection, 2008).

Physicochemical

Physical Characteristics

    A) Adenosine is a white crystalline powder that is soluble in water and practically insoluble in alcohol (Prod Info ADENOSCAN(R) IV injection, 2009).

Ph

    A) 4.5 to 7.5 (Prod Info ADENOSCAN(R) IV injection, 2009)

Molecular Weight

    A) 267.24 (Prod Info ADENOSCAN(R) IV injection, 2009)

References

General Bibliography

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    44) Product Information: ADENOCARD(R) IV injection, adenosine IV injection. Astellas Pharma US, Inc, Deerfield, IL, 2009.
    45) Product Information: ADENOCARD(R)IV injection, adenosine injection. Hospira,Inc., Lake Forest, IL, 2005.
    46) Product Information: ADENOSCAN intravenous injection, adenosine intravenous injection. Astellas Pharma US, Inc. (per FDA), Northbrook, IL, 2014.
    47) Product Information: ADENOSCAN(R) IV injection, adenosine IV injection. Hospira,Inc, Lake Forest, IL, 2005.
    48) Product Information: ADENOSCAN(R) IV injection, adenosine IV injection. Astellas Pharma US, Inc, Deerfield, IL, 2009.
    49) Product Information: ADENOSCAN(R) IV injection, adenosine IV injection. Astellas Pharma US, Inc, Deerfield, IL, 2010.
    50) Product Information: LEXISCAN(R) intravenous injection, regadenoson intravenous injection. Astellas Pharma US, Inc. (per FDA), Northbrook, IL, 2014.
    51) Product Information: LEXISCAN(TM) IV injection, regadenoson IV injection. Astellas Pharm US Inc, Deerfield, IL, 2008.
    52) Product Information: Lexiscan(R) IV injection, regadenoson IV injection. Astellas Pharma US, Inc. (per FDA), Deerfield, IL, 2011.
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    66) Toft J, Mortensen J, & Hesse B: Risk of atrioventricular block during adenosine pharmacologic stress testing in heart transplant recipients. Am J Cardiol 1998; 82(5):696-697.
    67) ter Schure JM & de Vries TW: Accidental intra-arterial injection of adenosine in a patient with supraventricular tachycardia. Cardiol Young 2011; 21(5):601-601.