Definition and Pathophysiology
Adenosine is an endogenous nucleoside present throughout the body that interacts with G protein-coupled A1 receptors located on the extracellular surface of cardiac cells. Through the guanine nucleotide regulatory proteins Gi and Go, adenosine activates potassium channels (IK.Ach, K.Ado) in a manner analogous to acetylcholine. The resulting increase in K+ conductance shortens the atrial action potential duration (APD), hyperpolarizes the membrane potential, and decreases atrial contractility. Analogous electrophysiological changes occur within the sinus and atrioventricular (AV) nodes.
In addition to these direct effects, adenosine antagonizes catecholamine-stimulated adenylate cyclase. This inhibition decreases the accumulation of cyclic adenosine monophosphate (cAMP), which in turn reduces the L-type calcium current (Ica.L) and the pacemaker current (If) in sinus node cells, accompanied by a decrease in Vmax. Consequently, shifts in the pacemaker site within the sinus node and sinus exit block may occur. In humans, adenosine initially slows the sinus rate, followed within seconds by a reflex increase in the sinus rate. In the AV node, adenosine produces a transient, rate-dependent prolongation of the A-H interval, frequently manifesting as transient first-, second-, or third-degree AV nodal block lasting up to a few seconds. His-Purkinje conduction is generally unaffected directly.
Adenosine does not typically affect conduction in normal accessory pathways. However, conduction may be blocked in unusual accessory pathways that possess long conduction times or decremental conduction properties. Furthermore, adenosine binds to four types of receptors. Binding to A2A receptors induces coronary vasodilation, whereas binding to the A1, A2B, and A3 receptors is responsible for the side effects of heart block, wheezing, and peripheral vasodilation, respectively.
Pharmacokinetics and Administration Technique
Adenosine is extensively and rapidly cleared from the plasma by cellular uptake into erythrocytes and vascular endothelial cells. It is removed from the extracellular space via washout, enzymatic degradation to inosine, phosphorylation to AMP, and reuptake into cells through a nucleoside transport system. Because of these highly efficient elimination pathways, adenosine has an extremely short elimination half-life of 1 to 6 seconds. Most of the drug's pharmacological effects are produced during its first passage through the circulation.
Due to this rapid clearance, adenosine must be administered as a rapid intravenous bolus. Unlike many other intravenous medications where rapid boluses risk hemodynamic instability or transiently toxic concentrations, adenosine requires a rapidly delivered bolus to achieve sufficiently high concentrations at its clinical site of action—the coronary artery perfusing the AV node—before the drug is eliminated. A flush should immediately follow the bolus injection to ensure rapid delivery to the central circulation. If the drug is injected into a central vein, the initial dose should be reduced.
Dosage and Dose Escalation
To terminate tachycardia, adenosine is rapidly injected intravenously at initial doses of 6 to 12 mg, followed by a flush. Doses as low as 2.5 mg may terminate some tachycardias, and doses of 12 mg or less successfully terminate 92% of supraventricular tachycardias (SVTs), usually within 30 seconds. Doses higher than 18 mg are unlikely to revert a tachycardia and should not be used.
Specific dosing adjustments are required in certain patient populations:
Pediatric patients: For patients weighing less than 50 kg, the dosing should be 0.05 to 0.3 mg/kg.
Central venous access: When injected into a central vein, the initial dose should be reduced to 3 mg.
Heart transplant patients: Due to denervation, which makes the sinus and AV nodes supersensitive to the drug, the initial dose should be reduced to 3 mg.
Dipyridamole therapy: Dipyridamole is a nucleoside transport blocker that inhibits the reuptake of adenosine, thereby delaying its clearance from the circulation or interstitial space and potentiating its effect. Smaller adenosine doses should be used in patients receiving dipyridamole, with the initial dose reduced to 3 mg.
Clinical Presentation and Symptoms
Adenosine is indicated as the drug of first choice to acutely terminate SVT, including AV nodal reentrant tachycardia (AVNRT) and AV reentrant tachycardia (AVRT). It is also useful in pediatric patients. The drug can produce AV nodal block or terminate atrial tachycardias (ATs) and sinus node reentry. In the setting of atrial flutter (AFL) or atrial fibrillation, adenosine results in only transient AV block, rendering it useful only for diagnostic purposes rather than therapeutic termination.
Adenosine also terminates a specific group of ventricular tachycardias (VTs) whose maintenance depends on adrenergic drive. These are most often located in the right ventricular outflow tract (RVOT) but can be found at other sites; however, idiopathic left septal VT rarely responds to adenosine.
When properly administered, adenosine usually causes transient hypotension, chest discomfort, and dyspnea. If a tachycardia persists in the absence of these expected effects, the drug may not have been administered correctly. Adenosine has less potential than verapamil for producing prolonged hypotension should the tachycardia persist after injection. Because of its effectiveness and extremely short duration of action, adenosine is generally preferable to verapamil, particularly in patients who have previously received intravenous beta-adrenoceptor blockers, in those with poorly compensated heart failure or severe hypotension, and in neonates. Verapamil might be chosen first in patients receiving drugs such as theophylline, in patients with active bronchoconstriction, and in those with inadequate venous access.
Diagnostics and Electrophysiology
Adenosine is a valuable diagnostic tool in the evaluation of tachyarrhythmias. It can help differentiate among the causes of wide-QRS tachycardias because it terminates many SVTs with aberrancy or reveals the underlying atrial mechanism. Furthermore, it does not block conduction over an accessory pathway or terminate most VTs. However, tachycardia termination is not completely diagnostic of an SVT, as adenosine can terminate specific VTs, characteristically those of RVOT origin.
During ablative procedures designed to interrupt an accessory pathway, adenosine may be useful in differentiating conduction over the AV node from that over the accessory pathway. This distinction is not absolute, however, because adenosine can block conduction in slowly conducting accessory pathways and does not always produce a block in the AV node.
Adverse Effects and Precautions
Transient side effects occur in almost 40% of patients with SVT given adenosine. These typically consist of flushing, dyspnea, and chest pressure. These symptoms are fleeting, lasting less than one minute, and are generally well tolerated. Premature ventricular contractions (PVCs), transient sinus bradycardia, sinus arrest, and AV block are common when an SVT is terminated abruptly.
Atrial fibrillation is occasionally observed following adenosine administration—reported in 12% of patients in one study—likely due to the drug's effect in shortening atrial refractoriness. The induction of atrial fibrillation can be particularly problematic in patients with Wolff-Parkinson-White (WPW) syndrome and rapid AV conduction over an accessory pathway, as adenosine might transiently increase the ventricular response in these individuals.
Pharmacological Interactions
Important drug interactions occur with adenosine. Methylxanthines are competitive antagonists, and therapeutic concentrations of theophylline totally block the exogenous effects of adenosine. Conversely, dipyridamole potentiates the effect of adenosine by blocking its reuptake, necessitating a dose reduction.
Guideline Recommendations
Guideline-directed management of tachyarrhythmias relies on the patient's hemodynamic status as the primary decision point.
Supraventricular Tachycardia (AVNRT and Orthodromic AVRT)
For haemodynamically unstable patients presenting with AVNRT or AVRT, synchronized DC cardioversion is recommended (Class I, Level B).
For haemodynamically stable patients, vagal manoeuvres—preferably performed in the supine position with leg elevation—are recommended as the initial step (Class I, Level B). If vagal manoeuvres fail, an adenosine bolus of 6 to 18 mg intravenously is recommended (Class I, Level B). Should adenosine fail, intravenous verapamil, diltiazem, or beta-blockers (esmolol or metoprolol) may be considered (Class IIa). Synchronized DC cardioversion is recommended if drug therapy ultimately fails to convert or control the tachycardia (Class I, Level B). For long-term management, catheter ablation is recommended for symptomatic, recurrent AVNRT or symptomatic, recurrent AVRT involving an accessory pathway (Class I, Level B).
Wide QRS Tachycardia (Unknown Aetiology)
In the absence of an established diagnosis for a wide QRS tachycardia, synchronized DC cardioversion is recommended for haemodynamically unstable patients (Class I, Level B).
For haemodynamically stable patients, a 12-lead ECG during tachycardia is recommended (Class I, Level C), followed by vagal manoeuvres (Class I, Level C). Adenosine should be considered if vagal manoeuvres fail and there is no pre-excitation on a resting ECG (Class IIa, Level C). If vagal manoeuvres and adenosine fail, intravenous procainamide should be considered (Class IIa, Level B), and intravenous amiodarone may be considered (Class IIb, Level B). Synchronized DC cardioversion is recommended if drug therapy fails (Class I, Level B). Verapamil is not recommended in wide QRS-complex tachycardia of unknown aetiology (Class III, Level B).
Pharmacologic Stress Testing
Beyond its role in arrhythmia termination, adenosine is a commonly used vasodilator stress agent for radionuclide myocardial perfusion imaging (MPI) in patients unable to exercise adequately, and for the evaluation of residual ischemia in patients with recent acute coronary syndrome (ACS) or myocardial infarction (MI).
Adenosine is administered as a weight-based infusion of 140 µg/kg/min over 4 minutes. Vasodilator stress agents provoke maximal hyperemia and frequently cause symptoms in about 50% of patients, including an urge to breathe deeply, chest tightness, headache, flushing, a 10- to 20-beat increase in heart rate, and a decrease in systolic blood pressure of 10 mm Hg. With adenosine, these side effects occur acutely but are typically short-lived due to the drug's 3-second half-life and terminate when the infusion is completed. The addition of low-level treadmill exercise or other physical activity can improve symptoms, reduce the incidence of heart block (which is common during adenosine infusion), and improve the heart-to-liver radiotracer uptake ratio by counteracting splanchnic hyperemia.
Vasodilator agents, including adenosine, are contraindicated in patients with:
Active wheezing
High-grade AV block without a functioning pacemaker
Systolic blood pressure less than 90 mm Hg
Any general contraindications for stress testing (acute MI, unstable angina, aortic dissection, acute pulmonary embolism)
Methylxanthines are competitive agonists of the adenosine receptors and can reverse the vasodilatory effects of adenosine. Therefore, they must be held for at least 12 hours before vasodilator stress. If needed, intravenous aminophylline (1 to 2 mg/kg administered as a slow push over 1 to 2 minutes) serves as an antidote for the side effects of vasodilator stress agents. Vasodilator stress has been shown to be safe for the evaluation of myocardial ischemia within 24 to 48 hours after presentation with ACS or uncomplicated MI. When vasodilators are contraindicated or cannot be used due to caffeine intake, dobutamine stress testing is utilized as an alternative.
