Adenosyl (abbreviated Ado or 5'-dAdo) is the chemical group formed by removal of the 5′-hydroxy (OH) group. It is found in adenosylcobalamin (an active form of vitamin B12[1]) and as a radical in the radical SAM enzymes.[2]
Fast rhythms of the heart that are confined to the atria (e.g., atrial fibrillation and 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.[7]
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.[8]
When given for the evaluation or treatment of a supraventricular tachycardia (SVT), the initial dose is 6 mg to 12 mg, depending on standing orders or provider preference,[10] 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 a flush of 10–20 mL of normal 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. 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 chronic liver disease or chronic kidney disease, and in elderly patients.
Drug interactions
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.[11]
Methylxanthines (e.g. caffeine found in coffee, theophylline found in tea, or theobromine found in chocolate) have a purine structure and bind to some of the same receptors as adenosine.[12] Methylxanthines act as competitive antagonists of adenosine and can blunt its pharmacological effects.[13] Individuals taking large quantities of methylxanthines may require increased doses of adenosine.
Caffeine acts by blocking binding of adenosine to the adenosine A1 receptor, which enhances release of the neurotransmitter acetylcholine.[14] Caffeine also increases cyclic AMP levels through nonselective inhibition of phosphodiesterase.[15] "Caffeine has a three-dimensional structure similar to that of adenosine," which allows it to bind and block its receptors.[16]
Asthma, traditionally considered an absolute contraindication. This is being contested, and it is now considered a relative contraindication (however, selective adenosine antagonists are being investigated for use in treatment of asthma)[17]
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, A2A, A2B, and A3).[18]
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 A2A receptors produces a constellation of responses that in general can be classified as anti-inflammatory.[19] Enzymatic production of adenosine can be anti-inflammatory or immunosuppressive.[20][21][22]
All adenosine receptor subtypes (A1, A2A, A2B, 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 Gi/o and decrease 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 (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.[23]
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 K+ efflux via inward rectifier K+ channels, subsequently inhibiting Ca2+ current.[25][26] 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.
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.[28] The 7-deaza-adenosine analog has been shown to inhibit the replication of the hepatitis C virus.[29]BCX4430 is protective against Ebola and Marburg viruses.[30] 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.[31][32] 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.[33]
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 neurotransmittersdopamine and glutamate.[34] Experimental evidence suggests that adenosine and adenosine agonists can activate Trk receptor phosphorylation through a mechanism that requires the adenosine A2A receptor.[35]
Hair
Adenosine has been shown to promote thickening of hair on people with thinning hair.[36][37] A 2013 study compared topical adenosine with minoxidil in male androgenetic alopecia, finding it was as potent as minoxidil (in overall treatment outcomes) but with higher satisfaction rate with patients due to “faster prevention of hair loss and appearance of the newly grown hairs” (further trials were called for to clarify the findings).[38]
Sleep
Adenosine is a key factor in regulating the body's sleep-wake cycle.[39] Adenosine levels rise during periods of wakefulness and lowers during sleep. Higher adenosine levels correlate with a stronger feeling of sleepiness, also known as sleep drive or sleep pressure.[40]Cognitive behavioral therapy for insomnia (CBT-I), which is considered one of the most effective treatments for insomnia, utilizes short-term sleep deprivation to raise and regulate adenosine levels in the body, for the intended promotion of consistent and sustained sleep in the long term.[41]
^Delacrétaz E (March 2006). "Clinical practice. Supraventricular tachycardia". The New England Journal of Medicine. 354 (10): 1039–1051. doi:10.1056/NEJMcp051145. PMID16525141.
^O'Keefe JH, Bateman TM, Silvestri R, Barnhart C (September 1992). "Safety and diagnostic accuracy of adenosine thallium-201 scintigraphy in patients unable to exercise and those with left bundle branch block". American Heart Journal. 124 (3): 614–621. doi:10.1016/0002-8703(92)90268-z. PMID1514488.
^"2014 Guidelines"(PDF). regionsems.com. April 2016. Retrieved 10 April 2023.
^Carter AJ, O'Connor WT, Carter MJ, Ungerstedt U (May 1995). "Caffeine enhances acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A1 receptors". The Journal of Pharmacology and Experimental Therapeutics. 273 (2): 637–642. PMID7752065.
^Katzung B (2012). Basic & Clinical Pharmacology (12th ed.). McGraw Hill. p. 245. ISBN978-0-07-176402-5.
^Miller-Patrick K, Vincent DL, Early RJ, Weems YS, Tanaka Y, Ashimine DT, et al. (1993). "Effects of the purine biosynthesis pathway inhibitors azaserine, hadacidin, and mycophenolic acid on the developing ovine corpus luteum". The Chinese Journal of Physiology. 36 (4): 245–252. PMID8020339.
^Oura H, Iino M, Nakazawa Y, Tajima M, Ideta R, Nakaya Y, et al. (December 2008). "Adenosine increases anagen hair growth and thick hairs in Japanese women with female pattern hair loss: a pilot, double-blind, randomized, placebo-controlled trial". The Journal of Dermatology. 35 (12): 763–767. doi:10.1111/j.1346-8138.2008.00564.x. PMID19239555. S2CID12289511.
^Faghihi G, Iraji F, Rajaee Harandi M, Nilforoushzadeh MA, Askari G (2013). "Comparison of the efficacy of topical minoxidil 5% and adenosine 0.75% solutions on male androgenetic alopecia and measuring patient satisfaction rate". Acta Dermatovenerologica Croatica. 21 (3): 155–159. PMID24183218.
^Sato A, Terata K, Miura H, Toyama K, Loberiza FR, Hatoum OA, et al. (April 2005). "Mechanism of vasodilation to adenosine in coronary arterioles from patients with heart disease". American Journal of Physiology. Heart and Circulatory Physiology. 288 (4): H1633–H1640. doi:10.1152/ajpheart.00575.2004. PMID15772334. S2CID71178.
