Adenosine

Adenosine

Systematic (IUPAC) name
(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
Clinical data
Trade names	Adenocard; Adenocor; Adenic; Adenoco; Adeno-Jec; Adenoscan; Adenosin; Adrekar; Krenosin
AHFS/Drugs.com	monograph
Pregnancy category	B (adenosine may appear to be safe to the fetus in pregnant women)
Legal status	℞ (Prescription only)
Routes of administration	Intravenous
Pharmacokinetic data
Bioavailability	Rapidly cleared from circulation via cellular uptake
Protein binding	No
Metabolism	Rapidly converted to inosine and adenosine monophosphate
Biological half-life	cleared plasma <30 seconds – half-life <10 seconds
Excretion	can leave cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid
Identifiers
CAS Number	58-61-7 Y
ATC code	C01EB10 (WHO)
PubChem	CID: 60961
IUPHAR/BPS	2844
DrugBank	DB00640 Y
ChemSpider	54923 Y
UNII	K72T3FS567 Y
KEGG	C00212 Y
ChEBI	CHEBI:16335 Y
ChEMBL	CHEMBL477 N
Synonyms	SR-96225 (developmental code name)
Chemical data
Formula	C10H13N5O4
Molecular mass	267.241 g/mol
SMILES n2c1c(ncnc1n(c2)[C@@H]3O[C@@H]([C@@H](O)[C@H]3O)CO)N
InChI InChI=1S/C10H13N5O4/c11-8-5-9(13-2-12-8)15(3-14-5)10-7(18)6(17)4(1-16)19-10/h2-4,6-7,10,16-18H,1H2,(H2,11,12,13)/t4-,6-,7-,10-/m1/s1 Y Key:OIRDTQYFTABQOQ-KQYNXXCUSA-N Y
NY (what is this?)  (verify)

Adenosine is a purine nucleoside composed of a molecule of adenine attached to a ribose sugar molecule (ribofuranose) moiety via a β-N₉-glycosidic bond. Adenosine is widely found in nature and plays an important role in biochemical processes, such as energy transfer — as adenosine triphosphate (ATP) and adenosine diphosphate (ADP) — as well as in signal transduction as cyclic adenosine monophosphate (cAMP). It is also a neuromodulator, believed to play a role in promoting sleep and suppressing arousal. Adenosine also plays a role in regulation of blood flow to various organs through vasodilation.

In addition to adenosine's endogenous forms, it is also used as a medication, specifically, as an antiarrhythmic agent, to treat a number of forms of supraventricular tachycardia that do not improve with vagal maneuvers. Common side effects include chest pain, feeling faint, shortness of breath along with tingling of the senses . Serious side effects include a worsening dysrhythmia and low blood pressure. It appears to be safe in pregnancy.

Medical uses

Diagnosis of supraventricular tachycardia

When it is administered intravenously, adenosine causes transient heart block in the atrioventricular (AV) node. This is mediated via the A₁ receptor, inhibiting adenylyl cyclase, reducing cAMP and so causing cell hyperpolarization by increasing inward K+ flux 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. This leads to less blood reaching the ischemic tissue, which in turn produces the characteristic chest pain.

In individuals suspected of suffering from a supraventricular tachycardia (SVT), adenosine is used to help identify the rhythm.

Antiarrhythmic agent

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 (AVRT), AV nodal reentrant tachycardia (AVNRT). In addition, atrial tachycardia can sometimes be terminated with adenosine.

An electrocardiogram showing the conversion of SVT with adenosine

Fast rhythms of the heart that are confined to the atria (e.g., atrial fibrillation, atrial flutter) or ventricles (e.g., monomorphic ventricular tachycardia) 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.

Thallium stress test

Adenosine is used an adjunct to thallous (thallium) chloride TI 201 myocardial perfusion scintigraphy (thallium stress test) in patients unable to undergo adequate stress testing with exercise.

Dosage

When given for the evaluation or treatment of a supraventricular tachycardia (SVT), the initial dose is 6 mg, given as a rapid parenteral infusion. Due to adenosine's extremely short half-life, the IV line is started as proximal (near) to the heart as possible, such as the antecubital fossa. The IV push is often followed with an immediate flush of 10-20 ccs of saline. If this has no effect (i.e., no evidence of transient AV block), a dose of 12 mg can be given 1–2 minutes after the first dose. Some clinicians may prefer to administer a higher dose (typically 18 mg), rather than repeat a dose that apparently had no effect. 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 (Persantine) and diazepam (Valium) 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 hepatic or renal insufficiency, and in elderly patients.

Drug interactions

Dopamine may precipitate toxicity in the patient. Carbamazepine may increase heart block. Dipyridamole potentiates the action of adenosine, requiring the use of lower doses.

Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain.

Theophylline and caffeine (methylxanthines) competitively antagonize adenosine's effects; an increased dose of adenosine may be required. By nature of caffeine's purine structure, it binds to some of the same receptors as adenosine. With the proviso that theophylline and theobromine cross the blood-brain barrier very poorly (thus, a low CNS effects on the heart), the pharmacological effects of adenosine may therefore be blunted in individuals taking large quantities of methylxanthines (e.g., caffeine, found in coffee, or theophylline in tea, or theobromine, as found in chocolate).

Contraindications

Common contraindications for adenosine are:

• Second- or third-degree heart block (without a pacemaker)
• Sick sinus syndrome (without a pacemaker)
• Long QT syndrome
• Severe hypotension
• Decompensated heart failure
• Asthma, traditionally considered an absolute CI. This is being contended and it is now considered a relative CI (however, selective adenosine antagonists are being investigated for use in treatment of asthma)
• Poison/drug-induced tachycardia

When administered via a central lumen catheter, adenosine has been shown to initiate atrial fibrillation because of its effect on atrial tissue. In individuals with accessory pathways, the onset of atrial fibrillation can lead to a life-threatening ventricular fibrillation. However, adenosine may be administered if equipment for cardioversion is immediately available as a backup.

Side-effects

Many individuals experience facial flushing, a temporary rash on the chest, lightheadedness, diaphoresis, or nausea after administration of adenosine due to its vasodilatory effects. Metallic taste is a hallmark side-effect of adenosine administration. These symptoms are transitory, usually lasting less than one minute. It is classically associated with a sense of "impending doom", more prosaically described as apprehension. This lasts a few seconds after administration of a bolus dose, during transient asystole induced by intravenous administration. In some cases, adenosine can make patients' limbs feel numb for about 2–5 minutes after administration intravenously depending on the dosage (usually above 12 mg).

Pharmacological effects

Adenosine is an endogenous purine nucleoside that modulates many physiological processes. Cellular signaling by adenosine occurs through four known adenosine receptor subtypes (A₁, A_2A, A_2B, and A₃).

Extracellular adenosine concentrations from normal cells are approximately 300 nM; however, in response to cellular damage (e.g. in inflammatory or ischemic tissue), these concentrations are quickly elevated (600–1,200 nM). 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 A_2A receptors produces a constellation of responses that in general can be classified as anti-inflammatory.

In the US, Adenosine is marketed as Adenocard. In India Adenosine is sold as Adenoscan (Cipla)

Adenosine receptors

Main article: Adenosine receptor

All adenosine receptor subtypes (A₁, A_2A, A_2B, and A₃) 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 G_i/o and decreases cAMP levels, while the A₂ adenosine receptors couple to G_s, which stimulates adenylate cyclase activity. In addition, A₁ receptors couple to G_o, which has been reported to mediate adenosine inhibition of Ca²⁺ conductance, whereas A_2B and A₃ receptors also couple to G_q and stimulate phospholipase activity. Researchers at Cornell University have recently shown adenosine receptors to be key in opening the blood-brain barrier (BBB). 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.

Metabolism

Adenosine used as a second messenger can be the result of de novo purine biosynthesis via adenosine monophosphate (AMP), though it is possible other pathways exist.

When adenosine enters the circulation, it is broken down by adenosine deaminase, which is present in red cells and the vessel wall.

Dipyridamole, an inhibitor of adenosine nucleotide 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

See also: nucleoside analog

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 suppresses peak viremia and rise in cytokines and prevented infected animal from death, 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 A_2A 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 (CNS). Caffeine's stimulatory effects are credited primarily (although not entirely) 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 A_2A receptor.

Hair

Adenosine has been shown to promote thickening of hair on people with thinning hair. A 2013 study compared topical adenosine to minoxidil for in male androgenetic alopecia, finding it was not superior to minoxidil and further trials were needed.

See also

• Adenosine receptors
• Adenosine reuptake inhibitor