Adenosine

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Abstract
Adenosine (adenine riboside), administered either as the free base or as the 5′- triphosphate (ATP) by rapid intravenous bolus, depresses atrioventricular (AV) nodal conduction, resulting in transient A V block. Adenosine is the active agent and ATP is rapidly converted to adenosine after exogenous administration. By blocking the anterograde AV nodal limb of a re- entrant circuit, adenosine 6 to 12mg (or ATP 10 to 20mg) converts almost all episodes of paroxysmal supraventricular tachycardia (PSVT) involving the AV node within 30 seconds of administration. This is at least equivalent in efficacy to verapamil in adults, and superior to lanatoside C in children, with a considerably more rapid onset of action. Furthermore, if a dose of adenosine is ineffective, the exceptionally short plasma half- life of the adenyl nucleosides (< 10 sec) allows rapid upward dosage titration until PSVT is terminated. Because the induced conduction block primarily affects the AV node, adenosine is a useful diagnostic tool in patients with broad or narrow QRS complex tachycardia; it terminates arrhythmias dependent on the AV node, unmasks other supraventricular mechanisms during transient AV block, but almost always has no effect on ventricular tachycardia. Noncardiac adverse effects, i.e. flushing, dyspnoea and chest pain, may occur during acute arrhythmia termination or diagnosis with adenosine, and arrhythmias may develop; however, these effects are usually transient (lasting less than 1 minute). Adenosine has also been used to induce coronary vasodilation in patients undergoing thallium- 201 single photon emission computed tomography (201Tl SPECT), 2- dimensional echocardiography or positron emission tomography to evaluate suspected coronary artery disease. Intravenous infusion of adenosine 140 µg/kg/min for 6 minutes was generally associated with only mild adverse effects. These usually resolved within 1 to 2 minutes of discontinuing adenosine, although occasionally patients required aminophylline and/or nitroglycerin (glyceryl trinitrate). Diagnoses based on the results of scintigraphy were of a sensitivity, specificity and predictive accuracy comparable to those achieved with exercise- or dipyridamole- 201Tl SPECT. Adenosine is therefore particularly suitable for the diagnosis of tachycardias and the acute management of PSVT involving the AV node in all age groups, without the risks of cardiac arrest and hypotension associated with verapamil. Furthermore, intravenous adenosine infusion may be used to induce coronary vasodilation in patients unable to perform exercise stress tests for 201Tl scintigraphy, and is well tolerated. Adenosine is an endogenous nucleoside which is involved in many biological processes. Bolus administration of intravenous adenosine produces negative chronotropic and dromotropic effects, resulting from depression of the sinoatrial (SA) and atrioventricular (AV) nodes, respectively. These effects are almost immediate, transient (about 20 sec) and dose-proportional. The negative dromotropic effects of adenosine produce prolongation of the atrial-His (AH) interval and/or AV block without affecting conduction through atrial or His-ventricular (HV) tissues. Adenosine terminates supraventricular tachycardias involving the AV node via block in the AV node in patients with accessory pathways and AV reciprocating tachycardia (AVRT), and block of the anterograde slow pathway in patients with the common slow-fast form of AV nodal re-entrant tachycardia (AVNRT); less commonly adenosine terminates AVNRT by blocking the retrograde limb. The negative chronotropic effects of adenosine produce transient sinus bradycardia followed by transient, but longer lasting reflex sinus tachycardia. Adenosine infusion produces coronary vasodilation resulting in increased coronary blood flow velocity without increasing myocardial work. Adenosine infusion also lowers systemic vascular resistance and has been used to maintain controlled hypotension during surgery. In experimental models of reperfusion injury following coronary ischaemia, adenosine infusion has reduced infarct size and prevented the ‘no-reflow phenomenon’, probably via inhibition of neutrophil activities and improved endothelial cell preservation, in addition to providing a pool of adenine nucleotides to replace ATP degraded during ischaemia. Thus, adenosine may have a role as a cardioprotective adjunct to thrombolytic therapy in evolving myocardial infarction. Binding of adenosine to A1 purinergic receptors results in increased potassium outward current and hyperpolarisation in atrial tissues. Both A1 and A2 adenosine receptor subtypes have been implicated in the coronary vasodilatory effects of adenosine. Regulatory G proteins are implicated in signal transduction from both receptor types but the exact mechanism by which vasodilation is achieved is unknown. Adenosine has a very short half-life in human blood (less than 10 sec), with almost complete elimination observed after a single pass through the coronary circulation in the isolated perfused rat heart. This precludes measurement of many standard pharmacokinetic variables. Adenosine is rapidly taken up from plasma into erythrocytes and blood vessel endothelial cells where it is converted to adenosine-5′-monophosphate and/or inosine. ATP is rapidly converted to adenosine after exogenous administration. Rapid intravenous injection of adenosine 37.5 to 250 µg/kg or ATP 10 to 20mg terminated spontaneous or electrically induced episodes of AVRT or AVNRT in more than 90% of adult and paediatric patients. The very rapid plasma clearance of adenosine allowed the dosage to be increased by 37.5 or 50 µg/kg every 1 or 2 minutes until a response occurred, without drug accumulation, but also resulted in a wide range of effective doses. Tachycardia was routinely terminated as a consequence of transient (< 10 sec) AV nodal conduction block in the anterograde limb of the re-entrant circuit in patients with AVRT or AVNRT, although block in the retrograde limb occasionally occurred. PSVT recurred in up to 37% of patients soon after re-establishment of sinus rhythm, but was often terminated by a further dose of adenosine or ATP. In comparisons with verapamil, the adenyl nucleosides were effective in a similar, if not slightly greater, proportion of patients, with a more rapid onset of action. Importantly, rapid dosage titration was possible. Similarly, significantly more children and infants responded compared to treatment with the cardiac glycoside lanatoside C, and in a significantly shorter time. Adenosine and ATP produced transient AV block in arrhythmias sustained without obligatory AV nodal involvement (e.g. atrial flutter, atrial fibrillation, intra-atrial re-entry, sinus node re-entry and ectopic atrial tachycardias), but generally did not restore sinus rhythm. The selective transient AV block induced by adenosine and ATP is valuable in the differential diagnosis of the mechanism of broad and narrow QRS complex tachycardias in adults and children. Adenosine has a sensitivity of 90%, specificity of 94% and predictive accuracy of 92% as a test for supraventricular origin of broad complex tachycardia. An arrhythmia terminated by adenosine is likely to be a PSVT involving obligatory AV nodal conduction (i.e. AV or AV nodal reentry), although in a few instances atrial flutter, ectopic atrial tachycardia and exercise-induced ventricular tachycardia in a normal heart may also be terminated. Adenosine and ATP do not normally restore sinus rhythm in patients with PSVT without obligatory AV nodal involvement, but during transient AV block the underlying mechanism is revealed on the surface ECG. Ventricular tachycardias in patients with structural abnormalities (e.g. ischaemic heart disease) are almost never affected by adenosine and ATP. Significantly, the nucleosides can be used to elucidate the mechanism of any broad or narrow complex tachycardia, whereas verapamil may result in cardiac arrest and hypotension, particularly in patients with ventricular tachycardia misdi-agnosed from the ECG as PSVT with aberrancy. Adenosine has also been used in the noninvasive assessment of patients with suspected coronary artery disease. Increased coronary blood flow produced by adenosine infusion permitted 201thallium single photon emission computed tomography (201Tl SPECT), 2-dimensional echocardiography (2DE) or positron emission tomography in patients unable to undergo adequate exercise stress testing. Myocardial uptake and redistribution of 201Tl is assessed following adenosine infusion, permitting identification of ischaemic and scarred areas of myocardium. Sensitivity, specificity and predictive accuracy appear to be similar to those achieved with exercise stress testing or dipyridamole-mediated vasodilation. About 18% of patients given a rapid intravenous injection of adenosine or ATP experienced flushing, with dyspnoea and respiration-associated chest discomfort occurring in 12% and 7%, respectively; symptoms were transient (< 1 min) and usually mild. Asymptomatic atrial or ventricular extrasystoles occurred soon after conversion to sinus rhythm in 33 to 44% of patients, and may reinitiate PSVT. Transient atrial fibrillation has also been reported following adenosine or ATP. Intravenous adenosine infusion produces more frequent adverse effects than rapid injection, which resolve within 1 to 2 minutes of discontinuing the infusion. These effects are usually well tolerated, although aminophylline administration has been required in a few patients. Prolongation of the PR interval may occur, with first-degree AV block in some patients. ECG changes indicative of ischaemia may also occur but are also usually mild and transient. Heart rate may increase significantly and diastolic blood pressure may decrease. For both diagnosis and treatment of PSVT in adults, it is recommended adenosine be administered rapidly (over 1 or 2 seconds) as an intravenous bolus of 6mg into a peripheral vein. If no effect is noticed within 2 minutes a further bolus of 12mg may be given, and repeated if necessary after another 1 or 2 minutes; however, upward dose titration every 1 to 2 minutes in 2.5 or 3mg (37.5 or 50 µg/kg) increments until arrhythmia termination or to a maximum dose of 20mg (300 µg/kg) has been widely used in clinical trials. Lower doses may be required if the drug is administered into a central vein, or if the patient is also receiving dipyridamole, while those taking methylxanthines may require larger doses. Caution should be exercised when using adenosine in asthmatic patients. In clinical trials the per kilogram dosage requirements of children and infants were similar to those in adults. The above recommendations also hold for ATP, which is given as a 10mg rapid intravenous bolus, followed by 15mg and then 20mg after 1 or 2 minutes if the first dose is ineffective. In patients undergoing cardiac imaging or 2DE, a 6-minute intravenous infusion of adenosine 140 µg/kg/min is recommended to induce coronary vasodilation. 201Tl is administered as a bolus at 3 minutes and imaging performed 5 minutes and 4 hours after infusion completion. The infusion should be discontinued if myocardial ischaemia or other severe symptoms develop, and aminophylline and/or nitroglycerin administered if required.

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