PRESENTATION ON PURINE RECEPTORS

Presented by-Vinay k. DubeyM. Pharm. (P’cology)H.S.K. College of PHARMACY

INTRODUCTIONNucleosides (adenosine) & nucleotides (ADP and ATP)

produce a wide range of pharmacological effects that are

unrelated to their role in energy metabolism.

1929 adenosine injected In anaesthetised animals causes

• bradycardia

• Fall in blood pressure

• Vasodilation

• Inhibition of intestinal movements

Purines are participate in many physiological control

mechanisms

• Regulation of coronary flow

• Immune responses

• Neurotransmission in both CNS & PNS.

ATP AS A NEUROTRANSMITTER

ATP acts both as a primary mediator & as a co-transmitter

in the noradrenergic nerve terminals.

ATP is contained in synaptic vesicles of both adrenergic

and cholinergic neurons, produces the action by stimulation

of autonomic nerves that are not caused by ACh or NA.

these action includes relaxation of intestinal smooth muscles

evoked by sympathetic stimulation, and contraction of

bladder produced by parasympathetic nerves.

Burnstock and his colleagues have shown that ATP is

released in Ca2+ dependent fashion on nerve stimulation.

ATP is present in all cells in millimolar concentrations and

is released independently of exocytosis, if the cells are

damage.

Dephosphorylation

ATP released from cells is rapidly dephosphorylated by a

range of tissue specific nucleotidases, producing ADP and

ADENOSINE, both of which produce a wide variety of

receptor-mediated effects.

Adenosine as a mediator

Adenosine differs from ATP in that it is not stored in

storage vescicles and released from secretary vesicles.

It exist free in cytosol of all cells and it is transported in

and out of cells mainly via a membrane transporter.

Adenosine in tissues comes partly from this source and

partly from extracellular hydrolysis of ATP or ADP.

Adenosine produce many pharmacological effects both in

the periphery and in the CNS.

Adenosine acts only on different P1 receptors.

Adenosine is taken up within a few seconds of I.V

administration. This uptake is blocked by dipyridamole (a

vasodilator & antiplatelet drug)

SYNTHESIS and RELEASE OF ATP and

ADENOSINE

FIGURE 19-2: Purine release and metabolism. Although ATP is used as an energy source, it is also released as a signaling molecule. ATP ispackaged into vesicles by vesicular nucleotide transporter (VNUT), which provides an exocytotic release pathway. ATP can also be released bychannels and transporters. In the extracellular space ATP is rapidly hydrolyzed to adenosine by ectoenzymes. Purines have actions through P1, P2X

and P2Y receptors. Adenosine is taken back up into cells via equilibrative or concentrative nucleoside transporters (ENT, CNT) where it ismetabolized to uric acid or via the action of adenosine kinase to AMP and ultimately to ATP. Metabolism through adenosine kinase dominatesover adenosine deaminase. Hypoxanthine can be metabolized to IMP and subsequently to AMP via the action of hypoxanthine-guaninephosphoribosyltransferase (HPGRT). Equilibrative transport of adenosine allows bidirectional flow of adenosine and consequently the metabolicstate of the cell to regulate extracellular adenosine. Under normoxic conditions, adenosine kinase phosphorylates intracellular adenosine,causing a concentration gradient of adenosine into the cell and its uptake via ENT. However, under hypoxic conditions, or during periods ofmetabolic demand, intracellular adenosine accumulation leads to its release through ENTs. (Blue). Mutations in adenosine deaminase areassociated with changes in sleep, presumably resulting from increased intracellular adenosine leading to release of this purine via ENTs and toextracellular adenosine accumulation (see Fig. 19-3). Increased expression of adenosine kinase in rodent models of epilepsy lead to enhancedclearance of adenosine and removal of this natural anticonvulsant. Lesch-Nyhan Syndrome is an inherited disorder with mutations in HPGRT.

CLASSIFICATION OF PURINE

RECEPTORS

FUNCTION OF PURINE RECEPTORS

Action of adenosine on different P1 receptor

MECHAINSM OF ADENOSINE BY A1

RECEPTOR ON HEART

• Adenosine binding tothe A1 receptors of S-Anode cell will decreasethe spontaneous firingrate & causesNEGATIVECHRONOTROPHY &DROMOTROPY

ROLE OF ADENOSINE IN SLEEP

(inhibitory action in brain)

Adenosine accumulates during period of ATP use by the

nervous system.

Adenosine binds to A1 receptors and inhibits

cholinergic neurons of RAS ( reticular activating system) that participate in the arousal.

Thus adenosine inhibits RAS activity and induces sleep.

A2B action

Ado

MECHANISM OF ACTION OF A3

RECEPTOR

ATP affinity

•Group 1: P2X1 and P2X3- high affinity to ATP.

•Group 2: P2X2, P2X4, P2X5 and P2X6- low affinity for

ATP.

•Group 3 : P2X7- very low affinity to ATP.

Action of adenosine on different P2X receptor

MECHANISM OF P2X RECEPTOR ON

SMOOTH MUSCLES

ATP binds to P2X receptors

OPENS Ca2+ channels

Ca2+ ion concentration increases

contraction of smooth muscles

MECHANISM OF P2Y RECEPTOR ON

SMOOTH MUSCLES

MECHANISM OF P2Y RECEPTOR

When ATP binds to P2Y receptor (Gq) P2Y receptor (Gi)

PLC activated cAMP

leading to formation of IP3 Ca2+

release Ca2+ ion from storage sites k+

activates MLCK hyperpolarisation

vasoconstriction

SMOOTH MUSCLE RELAXATION

THERAPEUTIC USES AND ADVERSE

EFFECTS OF DRUGS

TREATMENT OF TACHYCARDIA

adenosine binds to S-A node (A1) receptors(Gi)

Decrease cyclic AMP

opens potassium channels inhibits L-type calcium channels

Hyperpolarization inhibits calcium ions

inhibits the pacemaker current of SA node

decreasing its spontaneous firing rate

(negative chronotropy)(BRADYCARDIA)

TREATMENT OF PULMONARY

HYPERTENSION

ATP cAMP 5-AMP

AC phosphodiesterase

Phosphodiesterase converts cAMP to 5-AMP thus decreasing cAMPconc. which leads to vasoconstriction resulting in pulmonary hypertension

ATP cAMP 5-AMP

AC phosphodiesterase

METHYL XANTHINE

Methyl xanthine inhibits phosphodiesterase enzyme thus increasing cAMP conc. which induces VASODILATION. Thus treating pulmonary hypertension

REFERENCES• PHARMACOLOGY BY RANG AND DALE,

6th EDITION

• ESSENTIAL OF MEDICAL

PHARMACOLOGY BY K.D. TRIPATHI, 6th

EDITION

• INTERNET SOURCES

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