Adenosine
Adenosine is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of four nucleoside building blocks to RNA, which is essential for all life. Its derivatives include the energy carriers adenosine mono-, di-, and triphosphate. Cyclic adenosine monophosphate is pervasive in signal transduction. Adenosyl is the radical formed by removal of the 5'-hydroxy group. Ad is found in vitamin B12 and the radical SAM enzymes. Adenosine is also used as a drug.
Medical uses
Supraventricular tachycardia
In individuals with supraventricular tachycardia, adenosine is used to help identify and convert the rhythm.Certain SVTs can be successfully terminated with adenosine. This includes any re-entrant arrhythmias that require the AV node for the re-entry, e.g., AV reentrant tachycardia, AV nodal reentrant tachycardia. In addition, atrial tachycardia can sometimes be terminated with adenosine.
Fast rhythms of the heart that are confined to the atria or ventricles and do not involve the AV node as part of the re-entrant circuit are not typically converted by adenosine. However, the ventricular response rate is temporarily slowed with adenosine in such cases.
Because of the effects of adenosine on AV node-dependent SVTs, adenosine is considered a class V antiarrhythmic agent. When adenosine is used to cardiovert an abnormal rhythm, it is normal for the heart to enter ventricular asystole for a few seconds. This can be disconcerting to a normally conscious patient, and is associated with angina-like sensations in the chest.
Nuclear stress test
Adenosine is used as an adjunct to thallium or technetium myocardial perfusion scintigraphy in patients unable to undergo adequate stress testing with exercise.Dosage
When given for the evaluation or treatment of a supraventricular tachycardia, the initial dose is 6 mg to 12 mg, depending on standing orders or provider preference, given as a rapid parenteral infusion. Due to adenosine's extremely short half-life, the IV line is started as proximal to the heart as possible, such as the antecubital fossa. The IV push is often followed with a flush of 10–20 mL of normal saline. If this has no effect, a dose of 12 mg can be given 1–2 minutes after the first dose. When given to dilate the arteries, such as in a "stress test", the dosage is typically 0.14 mg/kg/min, administered for 4 or 6 minutes, depending on the protocol.The recommended dose may be increased in patients on theophylline, since methylxanthines prevent binding of adenosine at receptor sites. The dose is often decreased in patients on dipyridamole and diazepam because adenosine potentiates the effects of these drugs. The recommended dose is also reduced by half in patients presenting congestive heart failure, myocardial infarction, shock, hypoxia, and/or chronic liver disease or chronic kidney disease, and in elderly patients.
Drug interactions
potentiates the action of adenosine, requiring the use of lower doses.'s principal mode of action is as an antagonist of adenosine receptors in the brain.
Methylxanthines have a purine structure and bind to some of the same receptors as adenosine. Methylxanthines act as competitive antagonists of adenosine and can blunt its pharmacological effects. Individuals taking large quantities of methylxanthines may require increased doses of adenosine.
Contraindications
Common contraindications for adenosine include- Asthma, traditionally considered an absolute contraindication. This is being contended and it is now considered a relative contraindication
Side effects
Pharmacological effects
Adenosine is an endogenous purine nucleoside that modulates many physiological processes. Cellular signaling by adenosine occurs through four known adenosine receptor subtypes.Extracellular adenosine concentrations from normal cells are approximately 300 nM; however, in response to cellular damage, these concentrations are quickly elevated. Thus, in regard to stress or injury, the function of adenosine is primarily that of cytoprotection preventing tissue damage during instances of hypoxia, ischemia, and seizure activity. Activation of A2A receptors produces a constellation of responses that in general can be classified as anti-inflammatory. Enzymatic production of adenosine can be anti-inflammatory or immunosuppressive.
Adenosine receptors
All adenosine receptor subtypes are G-protein-coupled receptors. The four receptor subtypes are further classified based on their ability to either stimulate or inhibit adenylate cyclase activity. The A1 receptors couple to Gi/o and decreases cAMP levels, while the A2 adenosine receptors couple to Gs, which stimulates adenylate cyclase activity. In addition, A1 receptors couple to Go, which has been reported to mediate adenosine inhibition of Ca2+ conductance, whereas A2B and A3 receptors also couple to Gq and stimulate phospholipase activity.Researchers at Cornell University have recently shown adenosine receptors to be key in opening the blood-brain barrier.
Mice dosed with adenosine have shown increased transport across the BBB of amyloid plaque antibodies and prodrugs associated with Parkinson's disease, Alzheimer's, multiple sclerosis, and cancers of the central nervous system.
Ghrelin/growth hormone secretagogue receptor
Adenosine is an endogenous agonist of the ghrelin/growth hormone secretagogue receptor. However, while it is able to increase appetite, unlike other agonists of this receptor, adenosine is unable to induce the secretion of growth hormone and increase its plasma levels.Mechanism of action
When it is administered intravenously, adenosine causes transient heart block in the atrioventricular node. This is mediated via the A1 receptor, inhibiting adenylyl cyclase, reducing cAMP and so causing cell hyperpolarization by increasing K+ efflux via inward rectifier K+ channels, subsequently inhibiting Ca2+ current. It also causes endothelial-dependent relaxation of smooth muscle as is found inside the artery walls. This causes dilation of the "normal" segments of arteries, i.e. where the endothelium is not separated from the tunica media by atherosclerotic plaque. This feature allows physicians to use adenosine to test for blockages in the coronary arteries, by exaggerating the difference between the normal and abnormal segments.The administration of adenosine also reduces blood flow to coronary arteries past the occlusion. Other coronary arteries dilate when adenosine is administered while the segment past the occlusion is already maximally dilated, which is a process called coronary steal. This leads to less blood reaching the ischemic tissue, which in turn produces the characteristic chest pain.
Metabolism
Adenosine used as a second messenger can be the result of de novo purine biosynthesis via adenosine monophosphate, though it is possible other pathways exist.When adenosine enters the circulation, it is broken down by adenosine deaminase, which is present in red blood cells and the vessel wall.
Dipyridamole, an inhibitor of adenosine nucleoside transporter, allows adenosine to accumulate in the blood stream. This causes an increase in coronary vasodilatation.
Adenosine deaminase deficiency is a known cause of immunodeficiency.
Research
Viruses
The adenosine analog NITD008 has been reported to directly inhibit the recombinant RNA-dependent RNA polymerase of the dengue virus by terminating its RNA chain synthesis. This interaction suppresses peak viremia and rise in cytokines and prevents lethality in infected animals, raising the possibility of a new treatment for this flavivirus. The 7-deaza-adenosine analog has been shown to inhibit the replication of the hepatitis C virus. BCX4430 is protective against Ebola and Marburg viruses. Such adenosine analogs are potentially clinically useful since they can be taken orally.Anti-inflammatory properties
Adenosine is believed to be an anti-inflammatory agent at the A2A receptor. Topical treatment of adenosine to foot wounds in diabetes mellitus has been shown in lab animals to drastically increase tissue repair and reconstruction. Topical administration of adenosine for use in wound-healing deficiencies and diabetes mellitus in humans is currently under clinical investigation.Methotrexate's anti-inflammatory effect may be due to its stimulation of adenosine release.
Central nervous system
In general, adenosine has an inhibitory effect in the central nervous system.Caffeine's stimulatory effects are credited primarily to its capacity to block adenosine receptors, thereby reducing the inhibitory tonus of adenosine in the CNS. This reduction in adenosine activity leads to increased activity of the neurotransmitters dopamine and glutamate. Experimental evidence suggests that adenosine and adenosine agonists can activate Trk receptor phosphorylation through a mechanism that requires the adenosine A2A receptor.