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Adenosine (
symbol A symbol is a mark, sign, or word that indicates, signifies, or is understood as representing an idea, object, or relationship. Symbols allow people to go beyond what is known or seen by creating linkages between otherwise very different conc ...
A) is an
organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. Th ...
that occurs widely in nature in the form of diverse derivatives. The molecule consists of an
adenine Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deriv ...
attached to a
ribose Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, , is a component of the ribonucleotides from which RNA is built, and so this com ...
via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside building blocks of RNA (and its derivative deoxyadenosine is a building block of DNA), which are essential for all life. Its derivatives include the energy carriers adenosine mono-, di-, and triphosphate, also known as AMP/ADP/ATP. Cyclic adenosine monophosphate (cAMP) is pervasive in
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
. Adenosine is used as an intravenous medication for some
cardiac arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adult ...
s. 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) and as a radical in radical SAM enzymes.


Medical uses


Supraventricular tachycardia

In individuals with supraventricular tachycardia (SVT), 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 (AVRT) and AV nodal reentrant tachycardia (AVNRT). In addition,
atrial tachycardia Atrial tachycardia is a type of heart rhythm problem in which the heart's electrical impulse comes from an ectopic pacemaker (that is, an abnormally located cardiac pacemaker) in the upper chambers ( atria) of the heart, rather than from the sin ...
can sometimes be terminated with adenosine. 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 Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period ...
), 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 Asystole (New Latin, from Greek privative a "not, without" + ''systolē'' "contraction") is the absence of ventricular contractions in the context of a lethal heart arrhythmia (in contrast to an induced asystole on a cooled patient on a heart-lu ...
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 Thallium is a chemical element with the symbol Tl and atomic number 81. It is a gray post-transition metal that is not found free in nature. When isolated, thallium resembles tin, but discolors when exposed to air. Chemists William Crookes an ...
(TI 201) or technetium (Tc99m)
myocardial perfusion scintigraphy Myocardial perfusion imaging or scanning (also referred to as MPI or MPS) is a nuclear medicine procedure that illustrates the function of the heart muscle (myocardium). It evaluates many heart conditions, such as coronary artery disease (CAD), ...
(nuclear 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 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 (near) to the heart as possible, such as the
antecubital fossa The cubital fossa, chelidon, or elbow pit, is the triangular area on the anterior side of the upper limb between the arm and forearm of a human or other hominid animals. It lies anteriorly to the elbow (Latin ) when in standard anatomical positio ...
. 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 Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
,
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...
,
shock Shock may refer to: Common uses Collective noun *Shock, a historic commercial term for a group of 60, see English numerals#Special names * Stook, or shock of grain, stacked sheaves Healthcare * Shock (circulatory), circulatory medical emerge ...
, 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. Methylxanthines (e.g.
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class. It is mainly recreational drug use, used recreationally as a Nootropic, cognitive enhancer, increasing alertness and attentional perfor ...
found in coffee, theophylline found in tea, or
theobromine Theobromine, also known as xantheose, is the principal alkaloid of '' Theobroma cacao'' (cacao plant). Theobromine is slightly water- soluble (330 mg/L) with a bitter taste. In industry, theobromine is used as an additive and precursor to ...
found in chocolate) have a
purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...
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.
Caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class. It is mainly recreational drug use, used recreationally as a Nootropic, cognitive enhancer, increasing alertness and attentional perfor ...
acts by blocking binding of adenosine to the adenosine A1 receptor, which enhances release of the neurotransmitter
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
. Caffeine also increases cyclic AMP levels through nonselective inhibition of phosphodiesterase. "Caffeine has a three-dimensional structure similar to that of adenosine," which allows it to bind and block its receptors.


Contraindications

Common contraindications for adenosine include *
Asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
, traditionally considered an absolute contraindication. This is being contended and it is now considered a relative contraindication (however, selective adenosine antagonists are being investigated for use in treatment of asthma)


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). 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 Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems w ...
, 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 (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 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 (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 Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, ...
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...
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 Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...
and increase its plasma levels.


Mechanism of action

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. 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 The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
is not separated from the tunica media by
atherosclerotic plaque An atheroma, or atheromatous plaque, is an abnormal and reversible accumulation of material in the inner layer of an arterial wall. The material consists of mostly macrophage cells, or debris, containing lipids, calcium and a variable amount ...
. 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 Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first m ...
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 Adenosine deaminase (also known as adenosine aminohydrolase, or ADA) is an enzyme () involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues. Its primary function ...
, which is present in
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
s and the vessel wall. Dipyridamole, an inhibitor of
adenosine nucleoside transporter Nucleoside transporters (NTs) are a group of membrane transport proteins which transport nucleoside substrates like adenosine across the membranes of cells and/or vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (bi ...
, allows adenosine to accumulate in the blood stream. This causes an increase in coronary vasodilatation.
Adenosine deaminase deficiency Adenosine deaminase deficiency (ADA deficiency) is a metabolic disorder that causes immunodeficiency. It is caused by mutations in the ADA gene. It accounts for about 10–15% of all cases of autosomal recessive forms of severe combined immuno ...
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
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s 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 Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after becom ...
and
Marburg Marburg ( or ) is a university town in the German federal state (''Bundesland'') of Hesse, capital of the Marburg-Biedenkopf district (''Landkreis''). The town area spreads along the valley of the river Lahn and has a population of approximat ...
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 Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
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 Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
'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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS).
Caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class. It is mainly recreational drug use, used recreationally as a Nootropic, cognitive enhancer, increasing alertness and attentional perfor ...
'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
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...
s 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.


Hair

Adenosine has been shown to promote thickening of hair on people with thinning hair. 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).


Sleep

The principal component of
cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: '' Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternative ...
delta-9-tetrahydrocannabinol (THC) and the endocannabinoid anandamide (AEA) induce
sleep Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited Perception, sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefuln ...
in rats by increasing adenosine levels in the basal forebrain. They also significantly increase slow-wave sleep during the third hour, mediated by CB1 receptor
activation Activation, in chemistry and biology, is the process whereby something is prepared or excited for a subsequent reaction. Chemistry In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical o ...
. These findings identify a potential therapeutic use of cannabinoids to induce sleep in conditions where sleep may be severely attenuated.


Vasodilation

It also plays a role in regulation of blood flow to various organs through vasodilation.


See also

* Adenosine receptor * Adenosine reuptake inhibitor *
List of growth hormone secretagogues A ''list'' is any set of items in a row. List or lists may also refer to: People * List (surname) Organizations * List College, an undergraduate division of the Jewish Theological Seminary of America * SC Germania List, German rugby unio ...


References

{{Authority control Adenosine receptor agonists Antiarrhythmic agents Chemical substances for emergency medicine Drugs acting on the cardiovascular system Ghrelin receptor agonists Nucleosides Purines Vasodilators Hydroxymethyl compounds