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CHOLINERGIC NERVOUS SYSTEMHISTORY1977 Fambrough, Devreotes and Card

- Chemically isolated by detergents - Nicotinic ACh receptors are hydrophobic glycoproteinCHOLINERGIC TRANSMISSION1. All preganglionic autonomic nerve ending (sympathetic & parasympathetic ).

2.Postganglionic neurons of Parasympathetic

3.Post ganglionic sympathetic ending innervating Sweat glands ,Piloerector muscles of hair, blood vessels.

4. NM Junction5.Parts of Brain Cerebral Cortex, thalamus, forebrain nucleiAch - synthesized in the terminal endings & varicosities of cholinergic nerve fibre.

CHOLINERGIC TRANSMISSION

Synthesis:

Acetyl-CoA + Choline AcetylCholine Choline acetyl transferase

Destruction:

Acetylcholine Choline + Acetate ion Acetylcholine esteraseBiochemical events at a cholinergic sysnapse

Types of Ach - esteraseAcetlycholine esterase/ True choline esterase

Pseudocholine esterase

DistributionFound in place where Ach is naturally found, e.g, Neuromuscular junction, ganglion synapses , Gray matter and RBCPlasma, Liver, Intestine, White matter2. HydrolysisVery FastSlow3. InhibitionMore sensitive to PhysostigmineMore sensitive to Organophosphate4. FunctionTermination of ACh actionHydrolysis of ingested estersTypes of Cholinergic ReceptorsMuscarinic action : - Ach acts like muscarine - an alkaloid from poisonous mushroom Amanita muscaria

Nicotinic action : - activates only nicotinic receptors

8Muscarinic Receptorssite: all effector cells stimulated by postganglionic cholinergic neurons of Parasympathetic /sympathetic N S.

TypesM1 brain, autonomic gangliaM2 heart M3 glands & smooth muscleM4 CNSM5 - CNS

M1Location: Autonomic ganglia, Gastric glands, CNSFunction: - Depolarization - Histamine release, acid secretion - Learning, memory, motor functionsNature G-protein coupled, 7-TMTransducer mechanism: - IP3/DAG- Cytosolic Ca2+ - PLA2 - PG synthesisAgonist: MCN-343A, OxotremorineAntagonist: Pirenzepine,TelenzepineM2Location: Heart (SAN, AVN, Atrium, Ventricle), Cholinergic nerve endings, Visceral smooth musclesFunction: -Heart: Hyperpolarization, rate of impulse generation, velocity of conduction & contractility - Cholinergic nerve ending: ACh release - CNS: tremor, analgesia - Visceral smooth muscle: contractionNature:G-protein coupled, 7-TMTransducer mechanism: K+ channel opening, cAMPAgonist: MethacolineAntagonist: Methoctramine, TripitramineM3Location: Visceral smooth muscle, Iris, Ciliary muscle, Exocrine gland, Vascular endotheliumFunction: - Smooth muscle contraction, Exocrine gland secretion - Vascular endothelium: Vasodilatation (release of NO)Nature G-protein coupled, 7-TMTransducer mechanism: - IP3/DAG- Cytosolic Ca2+ - PLA2 - PG synthesisAgonist: BethanecholAntagonist: Hexahydrosiladifenidol, DarifenacinActivation: Ach, Muscarine

Effects - Heart Inhibitory effect, H.R, Conduction in AVN - Smooth Muscle & Glands - Excitatory effect

Blockage atropine

Mechanism of Action - Heart SA Node inhibition of adenyl cyclase, leads to opening of K+ channels, slowing of spontaneous depolarization, & H.R.

- Smooth muscle & glands IP3 & intracellular Ca2+Nicotinic ReceptorsLocation: - Autonomic ganglia - Neuromuscular junction - Central nervous system - Adrenal Medulla

Nature: - Ligand gated ion channels

Mode of action:- quick in onset & brief in duration

Activation Acetylcholine, Nicotine

Effect ExcitationBlockade : - Ganglion blockers (block nicotinic receptors for Ach in autonomic ganglia but not at NM-junction) e.g, hexamethonium, trimethophan

Mechanism of Action- When stimulated the channel opens, permits Na+ & other cations producing DepolarisationNMNN1. Location & Function suservedNM Junction: depolarization of muscle end plate contraction of skeletal muscleAutonomic Ganglia: depolarization postganglionic impulseAdrenal Medulla: catecholamine releaseCNS: site specific excitation or inhibition2. NatureIntrinsic ion channel, pentamer 2 or y & subunitsIntrinsic ion channel, pentamer of only subunits3. Transducer mechanismOpening of Cation (Na+, K+) channelsOpening of Cation (Na+, K+, Ca2+) channels4. AgonistPTMA (Phenyl trimethyl ammonium), NicotineDMPP (Dimethyl phenyl piperazinum, Nicotine5.AntagonistTubocurarine, -BungarotoxinHexamethonium, TrimethaphanDRUGS1. Cholinomimetic or parasympathomimetic

2. Anticholinesterases

3. Anticholinergic or Parasympatholytic

Cholinomimetic or ParasympathomimeticDrugs producing similar actions that of ACh, either directly interacting with Cholinergic receptors (cholinergic agonist) or increasing availability of ACh at these sites (anticholine esterases)Cholinergic Agonist (Drugs acting on Cholinergic Effector Organs)

Choline esters - Acetylcholine - Methacholine - Carbachol - Bethanecol

Alkaloids - Muscarine - Pilocarpine - ArecolineAnticholinesteraseAnti-ChEs are agents inhibits ChE, protect ACh from hydolysis.

Reversible - Physostigmine - Neostigmine - Pyridostigmine - Edrophonium - Rivastigmine - Donepezil - Galantamine - TacrineIrreversible - Dyflos - Echothiophate - Parathion* - Malathion* - Diazinon* - Tabun - Sarin - SomanAnticholinergics or Parasympatholytic1.Natural Alkaloids - Atropine, Hyoscine(Scopolamine)

2. Semisynthetic deraivatives - Homatropine, - Atropine methonitrate, - Hyoscine butyl bromide, - Ipratropium bromide, - Tiotropium bromide,

Cont..3. Synthetic compounds (a) Mydriatics: Cyclopentolate, Tropicamide (b) Antisecretory-antispasmodics: - Propantheline, Oxyphenonium, Clidinum, Glycopyrolate, Isopropamide - Dicyclomine, Valethamete, Pirenzepine (c) Vasoselective: Oxybutynin, Flavoxate, Tolterodine (d) Antiparkinsonian: Trihexiphenidyl (Benzohexol), Procyclidine, BiperidenAPPLIEDGlaucomaMyasthenia gravisAlzheimers diseaseAnticholinesterase poisoningTHANK YOU