Mechanism of Action
Adenosine is a potent vasodilator in most vascular beds, except in renal afferent
arterioles and hepatic veins where it produces vasoconstriction. Adenosine is
thought to exert its pharmacological effects through activation of purine receptors
(cell-surface A1 and A2 adenosine receptors). Although
the exact mechanism by which adenosine receptor activation relaxes vascular
smooth muscle is not known, there is evidence to support both inhibition of
the slow inward calcium current reducing calcium uptake, and activation of adenylate
cyclase through A2 receptors in smooth muscle cells. Adenosine may
also lessen vascular tone by modulating sympathetic neurotransmission. The intracellular
uptake of adenosine is mediated by a specific transmembrane nucleoside transport
system. Once inside the cell, adenosine is rapidly phosphorylated by adenosine
kinase to adenosine monophosphate, or deaminated by adenosine deaminase to inosine.
These intracellular metabolites of adenosine are not vasoactive.
Myocardial uptake of thallium-201 is directly proportional to coronary blood flow. Since Adenoscan significantly increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, Adenoscan causes relatively less thallium-201 uptake in vascular territories supplied by stenotic coronary arteries i.e., a greater difference is seen after Adenoscan between areas served by normal and areas served by stenotic vessels than is seen prior to Adenoscan.
Hemodynamics
Adenosine produces a direct negative chronotropic, dromotropic and inotropic
effect on the heart, presumably due to A1-receptor agonism, and produces
peripheral vasodilation, presumably due to A2-receptor agonism. The
net effect of Adenoscan in humans is typically a mild to moderate reduction
in systolic, diastolic and mean arterial blood pressure associated with a reflex
increase in heart rate. Rarely, significant hypotension and tachycardia have
been observed.
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 ecto-form
of adenosine deaminase. As Adenoscan 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 Trials
In two crossover comparative studies involving 319 subjects who could exercise
(including 106 healthy volunteers and 213 patients with known or suspected coronary
disease), Adenoscan and exercise thallium images were compared by blinded observers.
The images were concordant for the presence of perfusion defects in 85.5% of
cases by global analysis (patient by patient) and up to 93% of cases based on
vascular territories. In these two studies, 193 patients also had recent coronary
arteriography for comparison (healthy volunteers were not catheterized). The
sensitivity (true positive Adenoscan divided by the number of patients with
positive (abnormal) angiography) for detecting angiographically significant
disease ( ≥ 50% reduction in the luminal diameter of at least one vessel)
was 64% for Adenoscan and 64% for exercise testing, while the specificity (true
negative divided by the number of patients with negative angiograms) was 54%
for Adenoscan and 65% for exercise testing. The 95% confidence limits for Adenoscan
sensitivity were 56% to 78% and for specificity were 37% to 71%.
Intracoronary Doppler flow catheter studies have demonstrated that a dose of intravenous Adenoscan of 140 mcg/kg/min produces maximum coronary hyperemia (relative to intracoronary papaverine) in approximately 95% of cases within two to three minutes of the onset of infusion. Coronary blood flow velocity returns to basal levels within one to two minutes of discontinuing the Adenoscan infusion.
Last updated on RxList: 1/13/2009