Adenosine
DESCRIPTION:
Adenosine is an endogenous nucleoside occurring in all cells of the body. It is
chemically 6-amino-9-(beta)-D-ribofuranosyl-9-H-purine.
C10H13N5O4 267.24
Adenosine is a white crystalline powder. It is soluble in water and practically
insoluble in alcohol. Solubility increases by warming and lowering the pH.
Adenosine is not chemically related to other antiarrhythmic drugs. Adenoject
(adenosine) is a sterile solution for rapid bolus intravenous injection. Each mL
contains 3 mg adenosine and 9 mg sodium chloride in Water for Injection. The pH
of the solution is between 5.5 and 7.5.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
Adenoject (adenosine) slows conduction time through the A-V node, can interrupt
the reentry pathways through the A-V node, and can restore normal sinus rhythm
in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT
associated with Wolff-Parkinson-White Syndrome.
Adenoject is antagonized competitively by methylxanthines such as caffeine and
theophylline, and potentiated by blockers of nucleoside transport such as
dipyridamole. Adenoject is not blocked by atropine.
HEMODYNAMICS
The usual intravenous bolus dose of 6 or 12 mg Adenoject (adenosine) will have
no systemic hemodynamic effects. When larger doses are given by infusion,
adenosine decreases blood pressure by decreasing peripheral resistance.
PHARMACOKINETICS
Intravenously administered adenosine is rapidly cleared from the circulation via
cellular uptake, primarily by erythrocytes and vascular endothelial cells. This
process involves a specific transmembrane nucleoside carrier system that is
reversible, nonconcentrative, and bidirectionally symmetrical. Intracellular
adenosine is rapidly metabolized either via phosphorylation to adenosine
monophosphate by adenosine kinase, or via deamination to inosine by adenosine
deaminase in the cytosol. Since adenosine kinase has a lower Km and Vmax than
adenosine deaminase, deamination plays a significant role only when cytosolic
adenosine saturates the phosphorylation pathway. Inosine formed by deamination
of adenosine can leave the cell intact or can be degraded to hypoxanthine,
xanthine, and ultimately uric acid. Adenosine monophosphate formed by
phosphorylation of adenosine is incorporated into the high-energy phosphate
pool. While extracellular adenosine is primarily cleared by cellular uptake with
a half- life of less than 10 seconds in whole blood, excessive amounts may be
deaminated by an ectoform of adenosine deaminase. As Adenoject requires no
hepatic or renal function for its activation or inactivation, hepatic and renal
failure would not be expected to alter its effectiveness or tolerability.
CLINICAL STUDIES:
CLINICAL TRIAL RESULTS
In controlled studies in the United States, bolus doses of 3, 6, 9, and 12 mg
were studied. A cumulative 60% of patients with paroxysmal supraventricular
tachycardia had converted to normal sinus rhythm within one minute after an
intravenous bolus dose of 6 mg Adenoject (some converted on 3 mg and failures
were given 6 mg), and a cumulative 92% converted after a bolus dose of 12 mg.
Seven to sixteen percent of patients converted after 1-4 placebo bolus
injections. Similar responses were seen in a variety of patient subsets,
including those using or not using digoxin, those with Wolff-Parkinson-White
Syndrome, males, females, blacks, Caucasians, and Hispanics.
Adenosine is not effective in converting rhythms other than PSVT, such as atrial
flutter, atrial fibrillation, or ventricular tachycardia, to normal sinus
rhythm. To date, such patients have not had adverse consequences following
administration of adenosine.
INDICATIONS AND USAGE:
Intravenous Adenoject (adenosine) is indicated for the following.
Conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT),
including that associated with accessory bypass tracts (Wolff-Parkinson-White
Syndrome). When clinically advisable, appropriate vagal maneuvers (e.g.,
Valsalva maneuver), should be attempted prior to Adenoject administration.
It is important to be sure the Adenoject solution actually reaches the systemic
circulation (see DOSAGE AND ADMINISTRATION).
Adenoject does not convert atrial flutter, atrial fibrillation, or ventricular
tachycardia to normal sinus rhythm. In the presence of atrial flutter or atrial
fibrillation, a transient modest slowing of ventricular response may occur
immediately following Adenoject administration.
CONTRAINDICATIONS:
Intravenous Adenoject (adenosine) is contraindicated in:
1. Second- or third-degree A-V block (except in patients with a functioning
artificial pacemaker).
2. Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia
(except in patients with a functioning artificial pacemaker).
3. Known hypersensitivity to adenosine.
WARNINGS:
HEART BLOCK
Adenoject (adenosine) exerts its effect by decreasing conduction through the A-V
node and may produce a short lasting first-, second- or third-degree heart
block. In extreme cases, transient asystole may result (one case has been
reported in a patient with atrial flutter who was receiving carbamazepine).
Appropriate therapy should be instituted as needed. Patients who develop high-
level block on one dose of Adenoject should not be given additional doses.
Because of the very short half-life of adenosine, these effects are generally
self-limiting.
Rarely, ventricular fibrillation has been reported following Adenoject
administration, including both resuscitated and fatal events. In most instances,
these cases were associated with the concomitant use of digoxin and, less
frequently with digoxin and verapamil. Although no causal relationship or drug-
drug interaction has been established, Adenoject should be used with caution in
patients receiving digoxin or digoxin and verapamil in combination. Appropriate
resuscitative measures should be available.
ARRHYTHMIAS AT TIME OF CONVERSION
At the time of conversion to normal sinus rhythm, a variety of new rhythms may
appear on the electrocardiogram. They generally last only a few seconds without
intervention, and may take the form of premature ventricular contractions,
atrial premature contractions, sinus bradycardia, sinus tachycardia, skipped
beats, and varying degrees of A-V nodal block. Such findings were seen in 55% of
patients.
BRONCHOCONSTRICTION
Adenoject (adenosine) is a respiratory stimulant (probably through activation of
carotid body chemoreceptors) and intravenous administration in man has been
shown to increase minute ventilation (Ve) and reduce arterial PCO2 causing
respiratory alkalosis.
Adenosine administered by inhalation has been reported to cause
bronchoconstriction in asthmatic patients, presumably due to mast cell
degranulation and histamine release. These effects have not been observed in
normal subjects. Adenoject has been administered to a limited number of patients
with asthma and mild to moderate exacerbation of their symptoms has been
reported. Respiratory compromise has occurred during adenosine infusion in
patients with obstructive pulmonary disease. Adenoject should be used with
caution in patients with obstructive lung disease not associated with
bronchoconstriction (e.g., emphysema, bronchitis, etc.) and should be avoided in
patients with bronchoconstriction or bronchospasm (e.g., asthma). Adenoject
should be discontinued in any patient who develops severe respiratory
difficulties.
PRECAUTIONS:
DRUG INTERACTIONS
Intravenous Adenoject (adenosine) has been effectively administered in the
presence of other cardioactive drugs, such as quinidine, beta- adrenergic
blocking agents, calcium channel blocking agents, and angiotensin converting
enzyme inhibitors, without any change in the adverse reaction profile. Digoxin
and verapamil use may be rarely associated with ventricular fibrillation when
combined with Adenoject (see WARNINGS). Because of the potential for additive or
synergistic depressant effects on the SA and AV nodes, however, Adenoject should
be used with caution in the presence of these agents. The use of Adenoject in
patients receiving digitalis may be rarely associated with ventricular
fibrillation (see WARNINGS).
The effects of adenosine are antagonized by methylxanthines such as caffeine and
theophylline. In the presence of these methylxanthines, larger doses of
adenosine may be required or adenosine may not be effective. Adenosine effects
are potentiated by dipyridamole. Thus, smaller doses of adenosine may be
effective in the presence of dipyridamole. Carbamazepine has been reported to
increase the degree of heart block produced by other agents. As the primary
effect of adenosine is to decrease conduction through the A-V node, higher
degrees of heart block may be produced in the presence of carbamazepine.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Studies in animals have not been performed to evaluate the carcinogenic
potential of Adenoject (adenosine). Adenosine was negative for genotoxic
potential in the Salmonella (Ames Test) and Mammalian Microsome Assay.
Adenosine, however, like other nucleosides at millimolar concentrations present
for several doubling times of cells in culture, is known to produce a variety of
chromosomal alterations. In rats and mice, adenosine administered
intraperitoneally once a day for five days at 50, 100, and 150 mg/kg (10-30
(rats) and 5-15 (mice) times human dosage on a mg/M(squared) basis) caused
decreased spermatogenesis and increased numbers of abnormal sperm, a reflection
of the ability of adenosine to produce chromosomal damage.
PREGNANCY CATEGORY C
Animal reproduction studies have not been conducted with adenosine; nor have
studies been performed in pregnant women. As adenosine is a naturally occurring
material, widely dispersed throughout the body, no fetal effects would be
anticipated. However, since it is not known whether Adenoject can cause fetal
harm when administered to pregnant women, Adenoject should be used during
pregnancy only if clearly needed.
PEDIATRICS
No controlled studies have been conducted in pediatric patients.
DRUG INTERACTIONS:
Intravenous Adenoject (adenosine) has been effectively administered in the
presence of other cardioactive drugs, such as quinidine, beta- adrenergic
blocking agents, calcium channel blocking agents, and angiotensin converting
enzyme inhibitors, without any change in the adverse reaction profile. Digoxin
and verapamil use may be rarely associated with ventricular fibrillation when
combined with Adenoject (see WARNINGS). Because of the potential for additive or
synergistic depressant effects on the SA and AV nodes, however, Adenoject should
be used with caution in the presence of these agents. The use of Adenoject in
patients receiving digitalis may be rarely associated with ventricular
fibrillation (see WARNINGS).
The effects of adenosine are antagonized by methylxanthines such as caffeine and
theophylline. In the presence of these methylxanthines, larger doses of
adenosine may be required or adenosine may not be effective. Adenosine effects
are potentiated by dipyridamole. Thus, smaller doses of adenosine may be
effective in the presence of dipyridamole. Carbamazepine has been reported to
increase the degree of heart block produced by other agents. As the primary
effect of adenosine is to decrease conduction through the A-V node, higher
degrees of heart block may be produced in the presence of carbamazepine.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
The following reactions were reported with intravenous Adenoject (adenosine)
used in controlled U.S. clinical trials. The placebo group had a less than 1%
rate of all of these reactions.
CARDIOVASCULAR
Facial flushing, (18%),
headache (2%),
sweating, palpitations, chest pain, hypotension (less than 1%).
RESPIRATORY
Shortness of breath/dyspnea (12%),
chest pressure (7%),
hyperventilation, head pressure (less than 1%).
CENTRAL NERVOUS
Lightheadedness (2%),
dizziness, tingling in arms,
SYSTEM
numbness (1%),
apprehension, blurred vision, burning
sensation, heaviness in arms, neck and back pain (less than 1%).
GASTROINTESTINAL
Nausea (3%),
metallic taste, tightness in throat, pressure in groin (less than 1%).
In post-market clinical experience with Adenoject, cases of prolonged asystole,
ventricular tachycardia, ventricular fibrillation, transient increase in blood
pressure, bradycardia, hypotension, atrial fibrillation, and bronchospasm, in
association with Adenoject use, have been reported.
OVERDOSAGE:
The half-life of Adenoject (adenosine) is less than 10 seconds. Thus, adverse
effects are generally rapidly self-limiting. Treatment of any prolonged adverse
effects should be individualized and be directed toward the specific effect.
Methylxanthines, such as caffeine and theophylline, are competitive antagonists
of adenosine.
DOSAGE AND ADMINISTRATION:
For rapid bolus intravenous use only.
ADENOJECT (ADENOSINE) INJECTION SHOULD BE GIVEN AS A RAPID BOLUS BY THE
PERIPHERAL INTRAVENOUS ROUTE. TO BE CERTAIN THE SOLUTION REACHES THE SYSTEMIC
CIRCULATION, IT SHOULD BE ADMINISTERED EITHER DIRECTLY INTO A VEIN OR, IF GIVEN
INTO AN IV LINE, IT SHOULD BE GIVEN AS CLOSE TO THE PATIENT AS POSSIBLE AND
FOLLOWED BY A RAPID SALINE FLUSH.
The dose recommendation is based on clinical studies with peripheral venous
bolus dosing. Central venous (CVP or other) administration of Adenoject has not
been systematically studied.
The recommended intravenous doses for adults are as follows:
INITIAL DOSE: 6 mg given as a rapid intravenous bolus (administered over a 1-2
second period).
REPEAT ADMINISTRATION: If the first dose does not result in elimination of the
supraventricular tachycardia within 1-2 minutes, 12 mg should be given as a
rapid intravenous bolus. This 12 mg dose may be repeated a second time if
required.
DOSES GREATER THAN 12 MG ARE NOT RECOMMENDED.
NOTE: Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration.