Adenosine

Mechanism of Action

Adenosine is a purine nucleoside base, most commonly recognized with the molecule adenosine triphosphate, or ATP, and is used thoroughly throughout the entire body in general metabolism.[6] Adenosine’s use as a pharmacological drug works through receptors called purinergic adenosine receptors found throughout the body. Samsel et al. describe four types of adenosine receptors: A1, A2a, A2B, and A3, affecting the immune, nervous, circulatory, respiratory, and urinary systems. Most notably, receptors found in the cardiac atrioventricular (AV) nodal tissue and within the peripheral vasculature exhibit clinical manifestations when administering adenosine.[7][8]

Adenosine further classifies as a miscellaneous antiarrhythmic drug outside the Vaughan-Williams classification scheme. It acts on receptors in the cardiac AV node, significantly slowing conduction time.[8] This effect occurs by activation of specific potassium channels, driving potassium outside of cells, and inhibition of calcium influx, disrupting the resting potential of the slow nodal cardiac myocyte. Driving potassium outside of the cell causes hyperpolarization of the resting membrane potential while slowing calcium influx causes suppression of calcium-dependent action potentials, all requiring a longer time for depolarization to occur and thus slowing down conduction within these cells, which is useful in supraventricular tachycardia (SVT). SVT is defined as any arrhythmia originating above and including the bundle of His and specifically excludes atrial fibrillation by the ACC/AHA 2015 guidelines.[9]

Usually narrow complex, SVT consists of several specific arrhythmias, which are difficult to diagnose at a high rate (greater than 150 beats per minute). Adenosine has a role in slowing down the heart rate enough to assist in diagnosis. It can also terminate specific reentrant tachycardia involving the AV node, including AV nodal reentrant tachycardia (AVNRT), orthodromic AV reentrant tachycardia (AVRT), and antidromic AVRT. However, extreme caution is necessary when administering adenosine for antidromic AVRT as it should be used only if the diagnosis is certain.

The objective of a cardiac stress test is to evaluate the patient for significant, stable coronary artery disease and/or prognosis through the induction of ischemia. Adenosine’s role in the cardiac stress test is a pharmacologic component of stressing the heart through vasodilation, causing ischemia through a mechanism called a coronary steal.[10] Adenosine, with the use of a radiotracer for imaging, composes a nuclear cardiac stress test. The use of adenosine in cardiac testing is favorable for evaluating patients with a baseline left bundle branch block morphology on the electrocardiogram. Its limitations, however, are that it can not assess prognosis through functional status as there is no exercise component to the cardiac stress test with adenosine.

Drug Metabolism

Adenosine has a rapid onset of action with a very short half-life and undergoes rapid intracellular metabolism, either by phosphorylation, forming adenosine monophosphate, or deamination. Phosphorylation via adenosine kinase allows adenosine to be further metabolized as cellular energy, while deamination occurs by adenosine deaminase, eventually forming xanthine and further metabolizing into uric acid.

Adenosine and its chemical analogs have potential anticancer properties.[11] Tumors possess properties of immune evasion or suppression. Adrenosinergic signaling in the tumor microenvironment is one mechanism of immunosuppression.[12] Adenosine receptor antagonists might have anti-tumor properties.

Epilepsy affects about 70 million patients worldwide. Endogenous adenosine is thought to play a role in the pathophysiology of epilepsy or seizures.[13] Increased activity of adenosine kinase can reduce adenosine concentration in the CNS leading to more seizure activity. Therefore, medications that increase adenosine’s CNS concentrations could be effective antiseizure drugs for treating epilepsy.

Adenosine receptors have a role in glucose and lipid metabolism. Adenosine receptor agonists and antagonists can affect the balance between glucose and lipid metabolism[14] and thus could be used in future treatments of diabetes mellitus.

Researchers conducted a small clinical trial on eleven (nine men and two women) conscious subjects.[15] The subjects received randomized doses of adenosine (4 to 512 micrograms) or placebo via a diagnostic catheter located in the carotid artery. Adenosine increased minute ventilation, systolic blood pressure, mean blood pressure, and decreased heart rate. Researchers conclude that adenosine has an excitatory role in carotid bodies, which can help further study carotid body activity in humans.

Administration

Adenosine is administered intravenously in specific clinical cases. To manage supraventricular tachycardia (SVT), adenosine is ideally given through a peripheral intravenous (IV) access as a 6 mg dose followed by a 20 mL saline flush for rapid infusion. Subsequent doses start at 12 mg, followed by 20 mL of saline for rapid infusion.[16] The initial dose of adenosine is reduced to a 3 mg bolus if given through an intravenous line that accesses the central circulation, those on dipyridamole or carbamazepine, or if the patient is a cardiac transplant recipient.

Administration for pharmacological cardiac stress testing is intravenously as well; however, in a continuous fashion rather than bolus therapy as with SVT. The dose of adenosine used in cardiac stress testing is weight-based and usually administered as 140 mcg/kg per minute.[16]

Adverse Effects

The adverse effects of adenosine are secondary to the activation of adenosine receptors found on vascular tissue, causing vasodilation. Symptoms of skin flushing, lightheadedness, nausea, sweating, nervousness, numbness, and feeling of impending doom have all been described; however, these effects are very transient and short-lived secondary to adenosine’s short half-life.[16]

More severe symptoms are cardiac-related and include the development of cardiac arrhythmia, including premature atrial contractions and premature ventricular contractions, development of AV block, cardiac ischemia, hypotension, and prolonged asystole. Before any administration, the clinician should communicate information to the patient regarding these possible effects. A 68-year-old man with possible coronary artery stenosis was undergoing fractional flow reserve measurement using adenosine administered via intracoronary injection, which immediately caused atrial fibrillation.[17] The patient required drug-induced cardioversion for treatment. The patient had no history of arrhythmias.

Although presenting a lesser adverse effect, it is essential to review specific drug-drug interactions involving adenosine. The effects of adenosine can be blocked by caffeine and theophylline, which fall under a class of drugs called methylxanthines. Methylxanthines derive from another purine base, xanthine, which has a chemical structure sufficiently similar to that of adenine, that they can bind to adenosine receptors acting as a competitive antagonist to adenosine. Patients on these drugs may require larger doses.[18]

Other drug-drug interactions to consider when administering adenosine is the simultaneous use of carbamazepine and dipyridamole. Both these drugs may enhance the adverse effects of adenosine; the clinician should use a decreased initial dose. 

Contraindications

Absolute contraindications include known hypersensitivity to adenosine, heart block, or clinical active bronchospasm, either secondary to reactive airway disease, chronic obstructive pulmonary disease (COPD), or asthma.[19]

Extreme caution is necessary with adenosine administration in any patient with supraventricular tachycardia (SVT) involving an accessory pathway, including Wolf-Parkinson-White (WPW) syndrome. In general, the clinician should not use adenosine in irregular or polymorphic wide-complex tachycardias, a class III recommendation, as the administration can cause degeneration into ventricular fibrillation. Even in the setting of known antidromic AVRT, because of underlying atrial fibrillation, blocking the AV nodal tissue can cause unhindered conduction from the atria to the ventricle through this accessory pathway. While adenosine can slow conduction through the AV node, it does not affect accessory pathways. In such cases, this can cause severe tachycardia that can deteriorate to a non-perfusing rhythm, leading to cardiac arrest.

Of note, pregnancy is not a deterrent for adenosine administration.[20]

Toxicity

Due to the rapidly short half-life of adenosine, the toxic effects of adenosine are kept to a minimum, although there have been reports of severe effects involving prolonged asystole, development of heart block, and cardiac ischemia with adenosine. There is no reversal agent; however, unless the patient sustains a permanent injury, these effects are transient, and patients should receive appropriate supportive measures.

Enhancing Healthcare Team Outcomes

Healthcare workers, including cardiologists, nurse practitioners, and pharmacists, who plan to use adenosine, should be very familiar with the indications and contraindications. Any patient receiving adenosine should be on a form of cardiac monitoring. Patients receiving treatment for supraventricular tachycardia (SVT) are often on a 12-lead electrocardiogram rhythm monitoring to assess the underlying rhythm, while adenosine actively affects the AV node. In cases of Wolf-Parkinson-White (WPW) syndrome, a defibrillator should be available in case of rapid decompensation. If one has never used adenosine before, it is important to first speak to a cardiologist.

It would also benefit the clinician to consult a cardiology board-certified pharmacist to ensure proper dosing for the application at hand. Cardiology specialty-trained nurses can also assist in administering the drug, helping during a pharmacological stress test, or following up when using adenosine therapeutically. Open communication must exist between the clinician, cardiologist, nurses, and pharmacists so that an interprofessional team works on the case and the patient receives the optimal benefit. [Level 5]