Adenosine's activity (Figure 2) can be divided into 3 components:

Mechanism of Formation
Adenosine, a naturally occurring purine, is produced in small amounts as part of normal cellular metabolism by dephosphorylation of adenosine monophosphate (AMP) and intracellular degradation of S-adenosyl-homocysteine (SAH). Adenosine is released from the cell upon formation.

Mechanism of Action
Extracellular adenosine accumulates and binds to cell-surface A₁ and A₂ purine receptors where it is thought to induce vasodilation. Factors known to increase extracellular adenosine concentrations are:

• introduction of exogenous adenosine (eg, Adenoscan).
• increased production as a result of tissue ischemia (eg, exercise).
• decreased cellular re-uptake as a result of the blocking effects of nucleoside transport
inhibitors (eg, dipyridamole).

Although the exact mechanism is not known, there is evidence that vasodilation is related to the inhibition of the slow inward calcium current, reducing calcium uptake, and activation of adenylate cyclase by A₂ receptors in smooth muscle cells. Adenosine may also lessen vascular tone by modulating sympathetic neurotransmission.

Methylxanthines such as caffeine and theophylline are competitive antagonists of adenosine, competing for A₂ cell-surface receptor sites. As such, adenosine vasoactivity is reduced in the presence of these substances.

Mechanism of Removal
Adenosine is rapidly cleared from extracellular sites by cellular uptake. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical. Excessive amounts of extracellular adenosine may be deaminated by an ecto-form of adenosine deaminase.

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 K_m and V_max than adenosine deaminase, deamination plays a significant role only when the cytosolic adenosine saturates the phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, or, ultimately, uric acid. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool.

Because 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.

FIGURE 2. Adenosine uptake and metabolism.³



Pharmacokinetics
The half-life of adenosine in human blood is less than 10 seconds in vitro.^4,5 This very short time frame has precluded the investigation of many of the standard pharmacokinetic variables. The half-life in the circulation is probably much less than the half-life in vitro because of the presence of blood-vessel endothelial cells that rapidly remove adenosine from plasma.⁵

Adenosine is metabolized intracellularly, with AMP as the main metabolite at physiologic concentrations, although inosine predominates at higher adenosine concentrations. Since adenosine salvage and elimination pathways are very efficient, the biologic effects of exogenously administered adenosine are very short-lived.

It has, therefore, been impossible to measure an increase in adenosine levels in the circulation or in the coronary artery after exogenous administration. However, clinical trials^6-8 provide evidence that Adenoscan elicits the expected effect when administered intravenously and that this effect is dose dependent and terminates rapidly when the infusion is discontinued.

FIGURE 3. Hemodynamic effects of adenosine. Changes in systolic and diastolic blood pressure and heart rate in patients who received Adenoscan infusion at 140 mcg/kg/min for 6 minutes.⁷



Hemodynamics
Adenosine is a potent vasodilator in most vascular beds, except in renal afferent arterioles and hepatic veins, where it produces vasoconstriction. Adenosine exerts negative chronotropic, dromotropic, and inotropic effects on the heart. At higher (bolus) doses, adenosine is associated with transient bradycardia and decreased atrioventricular (AV) conduction. Therefore, adenosine has found utility in terminating paroxysmal supraventricular tachycardia when the AV node is part of the re-entry circuit.⁹ During slow infusion (140 mcg/kg/min), adenosine produces a modest increase in heart rate and decreases in systolic and diastolic blood pressure (Figure 3).⁷

Adenosine has a rapid onset of action, produces peak vasodilatory effects soon thereafter, and is metabolized quickly via cellular re-uptake (Table 3).

Table 3. Pharmacologic Characteristics of Adenoscan

Parameter Half-life4 <10 sec Mean time to peak coronary flow velocity10 55 ± 34 sec Duration of vasodilatory effect10 154 ± 88 sec

Hemodynamic studies
When adenosine was infused at a rate of 140 mcg/kg/min into healthy subjects and changes in coronary blood flow velocity were assessed using an intracoronary Doppler flow catheter, Wilson et al⁶ found that coronary blood flow velocity increased 3- to 4-fold over baseline. This corresponded to the maximal coronary vasodilation that was caused by intracoronary papaverine.*

Adenosine caused coronary hyperemia to reach maximal or near maximal levels in 92% of patients. Coronary blood flow velocity peaked within 2 minutes and returned to baseline levels within 2.5 minutes after the infusion was stopped.⁶

In 2 separate studies involving healthy individuals, Adenoscan was found to increase myocardial thallium-201 uptake significantly, to 1.3 times that of exercise.^11,12

*Prolonged infusion of papaverine is impractical, because it must be injected via an intracoronary route, causes systemic hypotension, and prolongs the QT interval.