Adenosine has several clinical uses including treating supraventricular tachycardia and ventricular tachycardia. It works by slowing conduction in the atrioventricular node. Its effects are short-lasting due to rapid uptake and breakdown. It can cause side effects like flushing but these are brief. Adenosine is also being studied for uses in pain management when administered intrathecally and shows potential for treating neuropathic pain.

1. ADENOSINE & ITS CLINICAL USES
-DR.RAVIKIRAN H M
Introduction:
Adenosine is a normal component of the body.
It’s a nucleoside.
Clinical Pharmacokinetics:
Adenosine is eliminated with a t1/2 of seconds by carrier-mediated uptake in most cell
types and subsequent metabolism by adenosine deaminase.
Adenosine probably is the only antiarrhythmic drug whose efficacy requires a rapid bolus
dose, preferably through a large central intravenous line; slow administration permits
elimination of the drug prior to its arrival at the heart.
Drug interaction:
The effects of adenosine are potentiated in patients receiving dipyridamole, an adenosine-
uptake inhibitor, and in patients with cardiac transplants owing to denervation
hypersensitivity.
Methylxanthines (e.g., theophylline and caffeine) block adenosine receptors; therefore,
larger than usual doses are required to produce an antiarrhythmic effect in patients who
have consumed these agents in beverages or as therapy.
Uses of adenosine:
1. SVT
2. Monomorphic VT
3. Stress testing
4. Hypotensive
5. To differentiate of type of VT
6. Diagnosis of CAD
7. To produce asystole for coronary stent placement
8. Cardiac preconditioning

2. 9. Pain management
10. Septic and hemorrhagic shock
Side-effects:
1. Flushing and hypotension, but because of their short duration these effects do not limit
the use of the drug.
2. Transient chest pain
3. Dyspnea (probably due to bronchoconstriction) may also occur.caution in asthmatics.
4. Transient asystole is common but usually lasts less than 5 seconds and is in fact the
therapeutic goal.
5. Rarely, an adenosine bolus can precipitate atrial fibrillation.
Physiological role:
1. Autoregulation in liver, coronaries
2. Brochoconstriction
3. Antiarrhythmic
4. It’s a neuromodulator
5. Antiplatlet action
6. Diuretic
ANTIARRYTHMIC
 Belongs to miscellaneous group of anti-arrhytmic drugs: ↑PR interval, no effect on QRS
duration & QT interval.
 When given in high doses (6–12 mg) as an intravenous bolus, the drug markedly slows or
completely blocks conduction in the atrioventricular node, probably by hyperpolarizing
this tissue (through increased IK1) and by reducing calcium current.
 Used for nodal reentry supraventricular arrhythmias.
 Blocks conduction for 10–15 s.
 Adenosine is extremely effective in abolishing AV nodal arrhythmia, and because of its
very low toxicity it has become the drug of choice for this arrhythmia.
 Adenosine has an extremely short duration of action (about 15 s).

3.  Rare cases of ventricular tachycardia in patients with otherwise normal hearts are thought
to be DAD(delayed after depolaristion)-mediated and can be terminated by adenosine.
 This drug is not effective in the treatment of atrial fibrillation, atrial flutter, or ventricular
tachycardia.
 The usual dose of adenosine is 6 mg IV followed, if necessary, by a repeat injection of 6
to 12 mg IV about 3 minutes later.
Pharmacological Effects:
 The effects of adenosine are mediated via specific GPCRs.
 Adenosine activates acetylcholine-sensitive K+ current in the atrium and sinus and AV
nodes, resulting in shortening of action potential duration, hyperpolarization, and slowing
of normal automaticity.
 Adenosine also inhibits the electrophysiological effects of increased cellular cyclic AMP
that occur with sympathetic stimulation. Because adenosine thereby reduces Ca2+
currents, it can be antiarrhythmic by increasing AV nodal refractoriness and by inhibiting
DADs elicited by sympathetic stimulation.
 Administration of an intravenous bolus of adenosine transiently slows sinus rate and AV
nodal conduction velocity and increases AV nodal refractoriness.
 A bolus of adenosine can produce transient sympathetic activation by interacting with
carotid baroreceptors; a continuous infusion can cause hypotension.

4. Figure 1: Components of the membrane action potential (AP) in a typical Purkinje or ventricular cardiac cell. The
deflections of the AP, designated as phases 0–3, are generated by several ionic currents. The actions of the sodium
pump and sodium–calcium exchanger are mainly involved in maintaining ionic steady state during repetitive
activity. Note that small but significant currents occur during diastole (phase 4) in addition to the pump and
exchanger activity. In non-pacemaker cells, the outward potassium current during phase 4 is sufficient to maintain a
stable negative resting potential as shown by the solid line at the right end of the tracing. In pacemaker cells,
however, the potassium current is smaller and the depolarizing currents (sodium, calcium, or both) during phase 4
are large enough to gradually depolarize the cell during diastole (dashed line). ATP, adenosine triphosphate.
PAIN MANAGEMENT
 In the spinal cord, adenosine receptors are located in the superficial layers of the dorsal
horn. Adenosine shows antinociceptive activity at adenosine A1 receptors located in
laminae I and II of the dorsal horn of the spinal cord.
 Another proposed mechanism is enhancement of spinal norepinephrine release.
 Initial studies confirmed relative safety of intrathecal administration of adenosine in
human volunteers with no reported clinical toxicity.
 Intrathecal adenosine does not inhibit acute pain but is effective in treating allodynia and
hyperalgesia.

5.  Experimental hyperalgesia and allodynia is reduced by intrathecal adenosine in a non–
dose-dependent fashion; however, in clinical settings, it did not change the anesthetic
requirement or postoperative analgesia.
 Similarly, in combination with an opioid, intrathecal adenosine did not prolong analgesia
during labor.
 Adenosine appears be effective in the treatment of neuropathic pain.
 Intrathecal adenosine is not associated with hypotension, motor blockade, or sedation.
 Following many clinical trials involving animal subjects, intrathecal adenosine 500 to
2,000 mcg in human volunteers was shown to decrease allodynia in phase I clinical trials.
 The only side effect observed was transient lumbar pain after a dose of 2,000 mcg.
 The role of neuraxial adenosine in the armamentarium for treatment of acute or chronic
pain awaits further delineation.
Figure 2: Adenosine, dopamine (DA), glutamate, g-aminobutyric acid (GABA), prostaglandins, and enkephalins
influence neurally-mediated release of neurotransmitters, in part by altering the function of prejunctional ion
channels.

6. Figure 3: As with the other cotransmitters, ATP can act prejunctionally to modify its own release via receptors for
ATP or via its metabolic breakdown to adenosine that acts on P1 (adenosine) receptors. ATP is cleared from the
synapse primarily by releasable nucleotidases (rNTPase) and by cell-fixe ectonucleotidases. Adenosine, generated
from the released ATP by ectoenzymes and releasable nucleotidases, acts as a modulator, causing feedback
inhibition of release of the transmitter. Methyxanthies blocks adenosine receptor. Adenosine can act presynaptically
throughout the cortex and hippocampal formation to inhibit the release of amine and amino acid transmitters.

7. Figure 4: Sites of action of neuroleptics and lithium. presynaptic A2 adenosine receptors (A2R) activate AC and, via
the cyclic AMP–PKA pathway, Tyroxine hydroxylase activity. Many of caffeine’s effects are believed to occur by
means of competitive antagonism at adenosine receptors. The mild sedating effects that occur when adenosine
activates particular adenosine-receptor subtypes can be antagonized by caffeine. PGD2 also appears to act on
arachnoid trabecular cells in the basal forebrain to mediate an increase in extracellular adenosine that, in turn,
facilitates induction of sleep.
BRONCHODILATION BY THIOPHYLLINE:
Theophylline is also a competitive antagonist at adenosine receptors. Adenosine can act
as an autacoid and transmitter with myriad biological actions. Of particular relevance to
asthma are the observations that adenosine can cause bronchoconstriction in asthmatics
and potentiate immunologically induced mediator release from lung mast cells. Inhibition
of the actions of adenosine therefore also must be considered when attempting to explain
the mechanism of action of theophylline.
Both adenosine receptor antagonism and PDE inhibition are likely involved in the
bronchodilating effect of theophylline.

8. AUTOREGULATORY METABOLIC FACTORS such as adenosine: heart, liver[hepatic
artery buffer response-HABR]
Figure5: Platelet aggregation is triggered by a variety of endogenous mediators that include the prostaglandin
thromboxane, adenosine diphosphate (ADP), thrombin, and fibrin. Substances that increase intracellular cyclic
adenosine monophosphate (cAMP; eg, the prostaglandin prostacyclin, adenosine) inhibit platelet aggregation.

9. Figure 6: Tubule transport systems in the kidney and sites of action of diuretics. If the concentration of NaCl is too
high, the macula densa sends a chemical signal (perhaps adenosine or ATP) to the afferent arteriole of the same
nephron, causing it to constrict. This, inturn, causes a reduction in glomerular filtration rate (GFR). This homeostatic
mechanism, known as tubuloglomerular feedback (TGF), serves to protect the organism from salt and volume
wasting. Both adenosine and prostaglandins mediate the macula densa pathway; the former is released when Na+
transport increases, and the latter is released when NaCl transport decreases. Adenosine, acting via the A1 adenosine
receptor, inhibits renin release, while prostaglandins stimulate renin release.

10. Figure 7: Schematic portrayal of the three major physiological pathways regulating renin release. MD, macula
densa; PGI2/PGE2 prostaglandins I2 and E2; NSAIDs, nonsteroidal anti-inflammatory drugs; AngII, angiotensin II;
ACE, angiotensin-converting enzyme, AT1 R, angiotensin subtype 1 receptor; NE/Epi, norepinephrine/ epinephrine;
JGCs, juxtaglomerular cells. B. Possible mechanisms by which the macula densa regulates renin release.
Both acute changes in tubular delivery of NaCl to the macula densa and chronic changes in dietary sodium intake
cause appropriate signals to be conveyed from macula densa to the juxtaglomerular cells. Chronic sodium depletion
up-regulates neuronal nitric oxide synthase (nNOS) and inducible cyclooxygenase (COX-2) in the macula densa.
nNOS increases nitric oxide (NO) production, and NO reacts with superoxide anion (O2 –) to form peroxynitrite, an
activator of COX-2. In addition, COX-2 may be rapidly, although indirectly, inhibited and stimulated by increases
and decreases in NaCl transport, respectively, across the macula densa. Arachidonic acid (AA) is converted to
prostaglandins (PGs), which diffuse to nearby juxtaglomerular cells to stimulate adenylyl cyclase (AC) via
prostaglandin receptors, such as EP4 and IP, that couple to Gs.
Circulating and locally released catecholamines also stimulate adenylyl cyclase via b1 receptors. Cyclic AMP
(cAMP) augments renin release. Increased NaCl transport depletes ATP and increases adenosine (ADO) levels in
the macula densa. ADO diffuses to the juxtaglomerular cells and activates the AT1-Gi pathway, inhibiting AC and
reducing cellular cAMP. Increased NaCl transport in the macula densa augments the efflux of ATP through
basolateral maxianion channels, and ATP is converted to adenosine in the extracellular compartment and inhibits

11. adenylyl cyclase via A1 receptors. In addition, ATP released from the macula densa may inhibit renin release
directly by binding to P2Y receptors coupled to Gq on juxtaglomerular cells. Activation of Gq increases intracellular
Ca2+, which inhibits renin release.
Circulating AngII binds to AT1 receptors on juxtaglomerular cells and inhibits renin release via Gq-induced
increases in intracellular Ca2+.
AngII–induced vasoconstriction of preglomerular microvessels is enhanced by endogenous adenosine.
Note:
Receptors that have constitutive activity and are sensitive to inverse agonists include
benzodiazepine, histamine, opioid, cannabinoid, dopamine, b adrenergic, calcitonin,
bradykinin, and adenosine receptors.
Melarsoprol resistance(antiprotozoal agent) likely involves transport defects. The P2
adenine–adenosine transporter has activity on melarsoprol as well as pentamidine and
berenil; point mutations in this transporter are found in melarsoprol-resistant isolates.
Tenofovir is a derivative of adenosine 5′-monophosphate lacking a complete ribose ring
and is the only nucleotide analog currently marketed for the treatment of HIV infection; it
is active against HIV-1, HIV-2, and HBV.
The pyrimidine antimetabolites encompass a diverse group of drugs that inhibit RNA
and DNA function in a variety of ways. Some, such as the fluoropyrimidines and the
purine base analogs (6-mercaptopurine and 6-thioguanine) inhibit the synthesis of
essential precursors of DNA. Others, particularly the cytidine and adenosine nucleoside
analogs, become incorporated into DNA and block its further elongation and its function.
Other metabolic effects of these analogs may contribute to their cytotoxicity and even
their ability to induce differentiation. Inhibition of ADA by pentostatin leads to
accumulation of intracellular adenosine and deoxyadenosine nucleotides, which can
block DNA synthesis by inhibiting ribonucleotide reductase. Deoxyadenosine also
inactivates S-adenosyl homocysteine hydrolase. The resulting accumulation of S-
adenosyl homocysteine is particularly toxic to lymphocytes.

12. References:
1. Katzung pharmacology
2. Goodman & Gilman
3. Stoelting pharmacology