Adenosine is a nucleoside consisting of adenine connected to a ribose (ribofuranose) β-N 9 - glycosidic bond [1] . It is part of some enzymes , ATP and nucleic acids.
| Adenosine | |
|---|---|
 | |
| Chemical compound | |
| IUPAC | (2R, 3R, 4R, 5R) -2- (6-aminopurin-9-yl) - 5- (hydroxymethyl) oxolan-3,4-diol |
| Gross formula | C 10 H 13 N 5 O 4 |
| Molar mass | 267.242 g / mol |
| Cas | |
| PubChem | |
| Drugbank | |
| Classification | |
| ATX | |
| Pharmacokinetics | |
| Bioavailable | Quickly removed from circulation by cell uptake |
| Plasma Protein Binding | Not |
| Metabolism | Rapidly converted to inosine and adenosine monophosphate |
| The half-life. | in purified plasma <30 seconds - half-life <10 seconds |
| Excretion | May leave the cell unchanged, or converted to hypoxanthine, xanthine or uric acid |
| Route of administration | |
| Intravenously or intramuscularly | |
Adenosine plays an important role in biochemical processes such as energy transfer ( ATP and ADP ) and signals ( cAMP ). Adenosine is also an inhibitory type of neurotransmitter. It is believed that it plays a role in stimulating sleep and suppressing vigor, since its concentration increases during prolonged wakefulness of the body and decreases during subsequent sleep [2] [3] .
Content
Pharmacological effects
Adenosine is an endogenous purine nucleoside that modulates many physiological processes. Cell signaling occurs through 4 known subtypes of adenosine receptors (A1, A2A, A2B, and A3) [4] , which include 7 transmembrane receptors associated with the G-protein . A more detailed classification within these four subtypes is based on their ability to stimulate or inhibit adenylate cyclase activity. The A2A and A2B receptors are associated with Gάs and mediate the activation of adenylate cyclase. Adenosine receptors of types A1 and A3 are associated with Gάi, which inhibits adenylate cyclase activity. In addition, type A1 receptors are coupled to the Gάo protein, which is reported to mediate inhibition of calcium conductivity by adenosine. At the same time, receptors of types A2B and A3 are conjugated to Gάq and stimulate phospholipase activity. An extracellular concentration of adenosine near normal cells is approximately 300 nM. However, in response to cell damage (for example, in inflamed or ischemic tissues), adenosine concentration rapidly increases to 600–1200 nM. Thus, in response to stress or injury, adenosine mainly exhibits a cytoprotective effect, protecting tissues from damage in cases of hypoxia, ischemia or seizures. Activation of type A2A receptors elicits a wide range of responses that can be generally classified as anti-inflammatory.
Brain Effects
In the synaptic cleft, ecto-ATPases cleave a fraction of ATP, forming adenosine. It activates K-channels through A1 receptors, hyperpolarizing the membrane of a neuron. Also, ATP through the P2X7 protein mediates the production of TNF, IL-1 and ATP (a new fraction). TNF activates the NFkB factor (Kappa B nuclear factor) in neurons, resulting in increased neuronal susceptibility to adenosine (A1 receptor sensitivity).
Intensive brain function leads to the accumulation of adenosine, which causes hyperpolarization of neurons, which weakens the transmission of information. It is important to note that the further action of adenosine is not due to its accumulation in neurons, but because of an increase in sensitivity to it by the above mechanism.
Anti-inflammatory properties
Adenosine is a potent anti-inflammatory agent acting on 4 receptors associated with the G-protein. It has been shown that topical application of adenosine for the treatment of limb wounds in laboratory animals suffering from diabetes mellitus significantly accelerates tissue healing. Topical use of adenosine for delayed wound healing and diabetes in humans is currently undergoing clinical trials.
Heart Effects
When administered intravenously, adenosine causes temporary blockage of the heart in the atrioventricular node. This effect is transmitted through receptor A1, which inhibits adenylate cyclase and decreases the concentration of cAMP , thus causing hyperpolarization of cells through an increase in the flow of K + ions from the outside. It also causes endothelial-dependent relaxation of the smooth muscles located inside the walls of the arteries. The consequence of this is the expansion of the "normal" segments of the arteries in which the endothelium is not separated from the tunica media by atherosclerotic plaques. This property of adenosine allows its use in the diagnosis of blockade of coronary arteries, since it increases the difference between normal and abnormal segments of the arteries.
Adenosine is used to identify rhythm in people presumably suffering from supraventricular tachycardia (SVT). Some types of CBT can be successfully stopped by adenosine. They include any recurrent arrhythmias (e.g., AVRT and AVNRT ). In some cases, atrial tachycardia can be stopped by adenosine.
Adenosine has an indirect effect on atrial tissue , causing a shortened refractory period. It has been shown that when administered through a central catheter, adenosine causes atrial fibrillation. In people with additional conduction channels, the onset of atrial fibrillation can lead to ventricular fibrillation .
Fast heart rhythms located in the atria or ventricles that do not affect the AV node usually do not stop after the administration of adenosine, but it can cause a temporary decrease in the rate of response of the ventricles.
Due to the effect that adenosine has on AV- dependent supraventricular tachycardia, it is considered a class V antiarrhythmic drug. When using adenosine as a means to stop arrhythmia, ventricular asystole is considered a normal effect for several seconds. This effect can disorient the patient, who is conscious, and is associated with unpleasant sensations in the chest.
The pharmacological effect may be dulled in people taking large amounts of methylxanthines , such as caffeine or theophylline .
The stimulating effect of caffeine occurs mainly due to the inhibition of the action of adenosine upon binding to the same receptors. By the nature of its purine structure, caffeine binds to part of the adenosine receptors in the central nervous system , effectively blocking them. A decrease in the activity of adenosine leads to an increased activity of the neurotransmitters dopamine and glutamate .
Dosage
For the diagnosis and treatment of SVT, the initial dose is 6 mg with rapid intravenous or intraosseous administration. Due to the very short half-life, intravenous injection is done most proximal to the heart, for example into the ulnar fossa. Intravenous administration of adenosine is often followed by immediate administration of 5-10 ml of isotonic solution. In the absence of effect, an additional dose (12 mg) can be administered after 1-2 minutes. Another 12 mg can be administered after 1-2 minutes in the absence of effect. Some doctors prefer to administer a larger dose (usually 18 mg) than repeating the same amount of the drug. To expand the arteries, a dosage of 0.14 mg / kg / min is usually used for 4-6 minutes.
The recommended dose may be increased in the case of patients taking theophylline. The dose should be reduced in the case of patients taking dipyridamole or valium , since adenosine potentiates the effect of these drugs. The dose is halved for patients with heart failure , myocardial infarction , shock , hypoxia , liver or kidney failure, as well as for elderly patients.
Notes
- ↑ Makeeva E.N. , Mezenko A.M. , Cartel N.A. Genetics. Encyclopedic Dictionary . - Litres, 2011 .-- S. 34 .-- 992 p. - ISBN 9789850813114 .
- ↑ Huang ZL , Urade Y. , Hayaishi O. The role of adenosine in the regulation of sleep. (English) // Current topics in medicinal chemistry. - 2011 .-- Vol. 11, no. 8 . - P. 1047-1057. - PMID 21401496 .
- ↑ Huang ZL , Zhang Z. , Qu WM Roles of adenosine and its receptors in sleep-wake regulation. (English) // International review of neurobiology. - 2014 .-- Vol. 119. - P. 349-371. - DOI : 10.1016 / B978-0-12-801022-8.00014-3 . - PMID 25175972 .
- ↑ Haskó G. et al. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases (eng.) // Nature reviews. Drug discovery: magazine. - 2016 .-- 21 December ( vol. 7 , iss. 9 ). - P. 759-770 . - ISSN 1474-1776 . - DOI : 10.1038 / nrd2638 .
Links
- Dubynin V. Glycine and adenosine . Publishing House PostNauka (November 11, 2016). - lecture. Date of treatment November 21, 2016.