Adenosine is a
purineA purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
nucleosideNucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
comprising a
moleculeA molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
of
adenineAdenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
attached to a
riboseRibose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
sugar molecule (ribofuranose) moiety via a β-N
9-
glycosidic bondIn chemistry, a glycosidic bond is a type of covalent bond that joins a carbohydrate molecule to another group, which may or may not be another carbohydrate....
.
Adenosine plays an important role in
biochemicalBiochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
processes, such as energy transfer—as
adenosine triphosphateAdenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP) and
adenosine diphosphateAdenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
(ADP)—as well as in
signal transductionSignal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
as
cyclic adenosine monophosphateCyclic adenosine monophosphate is a second messenger important in many biological processes...
, cAMP. It is also an inhibitory neurotransmitter, believed to play a role in promoting sleep and suppressing arousal, with levels increasing with each hour an organism is awake.
Adenosine is often abbreviated
Ado.
Pharmacological effects
Adenosine is an endogenous purine nucleotide 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
hypoxiaHypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
,
ischemiaIn medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
, and seizure activity. Activation of A2A receptors produces a constellation of responses that in general can be classified as anti-inflammatory.
Adenosine receptors
The different adenosine receptor subtypes (A1, A2A, A2B, and A3) are all seven transmembrane spanning G-protein coupled receptors. These four receptor subtypes are further classified based on their ability to either stimulate or inhibit
adenylate cyclaseAdenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
activity. The A2A and A2B receptors couple to G
s and mediate the stimulation of adenylate cyclase, while the A1 and A3 adenosine receptors couple to G
i which inhibits adenylate cyclase activity. Additionally, A1 receptors couple to G
o, which has been reported to mediate adenosine inhibition of Ca2+ conductance, whereas A2B and A3 receptors also couple to G
q and stimulate phospholipase activity.
Anti-inflammatory properties
Adenosine is believed to be an
anti-inflammatoryAnti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
agent at the A(2A) receptor. Topical treatment of adenosine to foot wounds in
diabetes mellitusDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
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.
MethotrexateMethotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
's anti-inflammatory effect may be due to its stimulation of adenosine release.
Action on the heart
When administered intravenously, adenosine causes transient
heart blockA heart block can be a blockage at any level of the electrical conduction system of the heart .* Blocks that occur within the sinoatrial node are described as SA nodal blocks....
in the
Atrioventricular (AV) nodeThe atrioventricular node is a part of the electrical control system of the heart that coordinates heart rate. It electrically connects atrial and ventricular chambers...
. This is mediated via the A1 receptor, inhibiting adenylyl cyclase, reducing cAMP and so causing cell hyperpolarization by increasing outward K+ flux. 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
endotheliumThe endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
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.
In individuals suspected of suffering from a
supraventricular tachycardiaSupraventricular tachycardia is a general term that refers to any rapid heart rhythm originating above the ventricular tissue. Supraventricular tachycardias can be contrasted to the potentially more dangerous ventricular tachycardias - rapid rhythms that originate within the ventricular...
(SVT), adenosine is used to help identify 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),
AV nodal reentrant tachycardiaAV nodal reentrant tachycardia , or atrioventricular nodal reentrant tachycardia, is a type of tachycardia of the heart. It is a type of supraventricular tachycardia , meaning that it originates from a location within the heart above the bundle of His. AV nodal reentrant tachycardia is the most...
(AVNRT). In addition,
atrial tachycardiaAtrial tachycardia is a type of atrial arrhythmia in which the heart's electrical impulse comes from an ectopic atrial pacemaker rather than from the SA node. Atrial tachycardias are characterized by very regular rates ranging from 140–220 bpm....
can sometimes be terminated with adenosine.
Adenosine has an indirect effect on atrial tissue causing a shortening of the refractory period. When administered via a central lumen catheter, adenosine has been shown to initiate
atrial fibrillationAtrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
because of its effect on atrial tissue. In individuals with accessory pathways, the onset of atrial fibrillation can lead to a life-threatening
ventricular fibrillationVentricular fibrillation is a condition in which there is uncoordinated contraction of the cardiac muscle of the ventricles in the heart, making them quiver rather than contract properly. Ventricular fibrillation is a medical emergency and most commonly identified arrythmia in cardiac arrest...
.
Fast rhythms of the heart that are confined to the
atriaIn anatomy, the atrium , sometimes called auricle , refers to a chamber or space. For example, the term is used for a portion of the lateral ventricle in the brain and the blood collection chamber of the heart...
(e.g.,
atrial fibrillationAtrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
,
atrial flutterAtrial flutter is an abnormal heart rhythm that occurs in the atria of the heart. When it first occurs, it is usually associated with a fast heart rate or tachycardia , and falls into the category of supra-ventricular tachycardias. While this rhythm occurs most often in individuals with...
) or
ventriclesIn the heart, a ventricle is one of two large chambers that collect and expel blood received from an atrium towards the peripheral beds within the body and lungs. The Atria primes the Pump...
(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 IV antiarrhythmic agent. When adenosine is used to
cardiovertCardioversion is a medical procedure by which an abnormally fast heart rate or cardiac arrhythmia is converted to a normal rhythm, using electricity or drugs. Synchronized electrical cardioversion uses a therapeutic dose of electric current to the heart, at a specific moment in the cardiac cycle...
an abnormal rhythm, it is normal for the heart to enter ventricular
asystoleIn medicine, asystole is a state of no cardiac electrical activity, hence no contractions of the myocardium and no cardiac output or blood flow...
for a few seconds. This can be disconcerting to a normally conscious patient, and is associated with angina-like sensations in the chest.
By nature of
caffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
's
purineA purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
structure it binds to some of the same receptors as adenosine. The pharmacological effects of adenosine may therefore be blunted in individuals who are taking large quantities of methylxanthines (e.g.,
caffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
, found in coffee and tea, or
theobromineTheobromine , also known as xantheose, is a bitter alkaloid of the cacao plant, with the chemical formula C7H8N4O2. It is found in chocolate, as well as in a number of other foods, including the leaves of the tea plant, and the kola nut...
, as found in chocolate).
Action in the central nervous system
Generalized, adenosine has an inhibitory effect in the
central nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS).
CaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
's stimulatory effects, on the other hand, are primarily (although not entirely) credited to its inhibition of adenosine by binding to the same receptors, and therefore effectively blocking adenosine receptors in the CNS. This reduction in adenosine activity leads to increased activity of the
neurotransmitterNeurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and glutamate.
Dosage
When given for the evaluation or treatment of a
supraventricular tachycardiaSupraventricular tachycardia is a general term that refers to any rapid heart rhythm originating above the ventricular tissue. Supraventricular tachycardias can be contrasted to the potentially more dangerous ventricular tachycardias - rapid rhythms that originate within the ventricular...
(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
cubital fossaThe cubital fossa is the triangular area on the anterior view of the elbow of a human or other hominid animal. It is colloquially known as the "elbow pit".-Boundaries:...
. The IV push is often followed with an immediate flush of 10-20ccs of saline. If this has no effect (i.e. no evidence of transient AV block), a 12 mg dose can be given 1–2 minutes after the first dose. AHA 2010 IS NO LONGER RECOMMENDING A SECOND DOSE OF 12MG. PLEASE VIEW ALGORITHM AS CONFIRMATION. 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 who are presenting
congestive heart failureHeart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...
,
myocardial infarctionMyocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, shock,
hypoxiaHypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
, and/or hepatic or renal insufficiency, and in elderly patients.
Drug interactions
Dopamine may precipitate toxicity in the patient.
Carbamazepine may increase heart block.
Theophylline and caffeine (methylxanthines) competitively antagonize adenosine's effects; an increased dose of adenosine may be required.
Dipyridamole potentiates the action of adenosine, requiring the use of lower doses.
Contraindications
Common
ContraindicationIn medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...
s for adenosine are:
- 2nd or 3rd degree heart block
A heart block can be a blockage at any level of the electrical conduction system of the heart .* Blocks that occur within the sinoatrial node are described as SA nodal blocks....
(without a pacemaker)
- Sick sinus syndrome
Sick sinus syndrome, also called sinus node dysfunction, is a group of abnormal heart rhythms presumably caused by a malfunction of the sinus node, the heart's primary pacemaker...
(without a pacemaker)
- Long QT syndrome
The long QT syndrome is a rare inborn heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsade de pointes . These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation...
- Severe hypotension
- Decompensated heart failure
- Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, traditionally an absolute CI this is being contended and it is now considered relative (however, selective adenosine agonists are being investigated for use in treatment of asthma)
- Poison/drug-induced tachycardia
In
Wolff-Parkinson-White syndromeWolff–Parkinson–White syndrome is a disorder of the heart in which the ventricles of the heart contract prematurely due to an accessory pathway known as the bundle of Kent. This accessory pathway is an abnormal electrical communication from the atria to the ventricles...
, 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,
diaphoresisDiaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions.Diaphoretic is the state of perspiring profusely, or something that has the power to cause increased perspiration....
, 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
asystoleIn medicine, asystole is a state of no cardiac electrical activity, hence no contractions of the myocardium and no cardiac output or blood flow...
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).
Metabolism
Adenosine used as a second messenger can be the result of
de novo purine biosynthesis via
adenosine monophosphateAdenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
(AMP), though it is possible other pathways exist.
When adenosine enters the circulation, it is broken down by
adenosine deaminaseAdenosine deaminase 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.-Reactions:...
, which is present in
red cellRed blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s and the vessel wall.
DipyridamoleDipyridamole is a drug that inhibits thrombus formation when given chronically and causes vasodilation when given at high doses over a short time.-Mechanism and effects:...
, an inhibitor of
adenosine deaminaseAdenosine deaminase 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.-Reactions:...
, allows adenosine to accumulate in the blood stream. This causes an increase in coronary vasodilatation.
Adenosine deaminase deficiencyAdenosine deaminase deficiency, also called ADA deficiency or ADA-SCID, is an autosomal recessive metabolic disorder that causes immunodeficiency. It occurs in fewer than one in 100,000 live births worldwide....
is a known cause of immunodeficiency.
Analogs and viruses
The adenosine analog, NITD008 has been reported to directly inhibit the recombinant an RNA-dependent
RNA polymeraseRNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
of the
dengue virusDengue virus in one of four serotypes is the cause of dengue fever. It is a mosquito-borne single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus...
by terminating its RNA chain synthesis. This suppresses peak
viremiaViremia is a medical condition where viruses enter the bloodstream and hence have access to the rest of the body. It is similar to bacteremia, a condition where bacteria enter the bloodstream.- Primary versus Secondary :...
, rise in
cytokineCytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s and prevented infected animal from death raising the possibility of a new treatment for this
flavivirusFlavivirus is a genus of the family Flaviviridae. This genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, and several other viruses which may cause encephalitis....
. The 7-deaza-adenosine analog has been shown to inhibit the replication of the
hepatitis C virusHepatitis C virus is a small , enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae...
. Such adenosine analogs are potentially clinically useful since they can be taken orally.
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