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CLASS - 2
CHOLINERGIC NERVOUS SYSTEM
DR. LAXMIKANTA SAY
HISTORY
• 1977 – Fambrough, Devreotes and Card
- Chemically isolated by detergents
- Nicotinic ACh receptors are hydrophobic glycoprotein
CHOLINERGIC 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
nuclei
• Ach - 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 esterase
Biochemical events at a cholinergic sysnapse
Types of Ach - esteraseAcetlycholine esterase/
True choline esterase
Pseudocholine esterase
1. Distribution
Found in place where Ach is naturally found, e.g, Neuromuscular junction, ganglion synapses , Gray matter and RBC
Plasma, Liver, Intestine, White matter
2. Hydrolysis Very Fast Slow
3. Inhibition More sensitive to Physostigmine
More sensitive to Organophosphate
4. Function Termination of ACh action Hydrolysis of ingested esters
Types of Cholinergic Receptors
• Muscarinic action : - Ach acts like muscarine - an alkaloid from poisonous
mushroom “Amanita muscaria”
• Nicotinic action : - activates only nicotinic
receptors
Muscarinic Receptors• site: all effector cells stimulated
by postganglionic cholinergic neurons of Parasympathetic /sympathetic N S.
• Types• M1– brain, autonomic ganglia• M2 – heart • M3 – glands & smooth muscle• M4 – CNS• M5 - CNS
M1
• Location: Autonomic ganglia, Gastric glands, CNS
• Function:
- Depolarization
- Histamine release, acid secretion - Learning, memory, motor functions• Nature – G-protein coupled, 7-TM• Transducer mechanism: - IP3/DAG- Cytosolic Ca2+ - PLA2 - PG synthesis• Agonist: MCN-343A, Oxotremorine• Antagonist: Pirenzepine,Telenzepine
M2• Location: Heart (SAN, AVN, Atrium, Ventricle),
Cholinergic nerve endings, Visceral smooth muscles• Function:
-Heart: Hyperpolarization, rate of impulse generation, velocity of conduction & contractility
- Cholinergic nerve ending: ACh release - CNS: tremor, analgesia - Visceral smooth muscle: contraction• Nature:G-protein coupled, 7-TM• Transducer mechanism: K+ channel opening,
cAMP• Agonist: Methacoline• Antagonist: Methoctramine, Tripitramine
M3• Location: Visceral smooth muscle, Iris, Ciliary
muscle, Exocrine gland, Vascular endothelium• Function:
- Smooth muscle contraction, Exocrine gland secretion
- Vascular endothelium: Vasodilatation (release of NO)
• Nature – G-protein coupled, 7-TM
• Transducer mechanism: - IP3/DAG- Cytosolic Ca2+ - PLA2 - PG synthesis• Agonist: Bethanechol• Antagonist: Hexahydrosiladifenidol,
Darifenacin
• Activation: 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 Receptors• Location: - 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 – Excitation• Blockade : - 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 Depolarisation
NM NN
1. Location & Function suserved
•NM Junction: depolarization of muscle end plate – contraction of skeletal muscle
•Autonomic Ganglia: depolarization – postganglionic impulse•Adrenal Medulla: catecholamine release•CNS: site specific excitation or inhibition
2. Nature Intrinsic ion channel, pentamer α2β ε or y & δ subunits
Intrinsic ion channel, pentamer of only αβ subunits
3. Transducer mechanism
Opening of Cation (Na+, K+) channels
Opening of Cation (Na+, K+, Ca2+) channels
4. Agonist PTMA (Phenyl trimethyl ammonium), Nicotine
DMPP (Dimethyl phenyl piperazinum, Nicotine
5.Antagonist
Tubocurarine, α-Bungarotoxin
Hexamethonium, Trimethaphan
DRUGS
• 1. Cholinomimetic or parasympathomimetic
• 2. Anticholinesterases
• 3. Anticholinergic or Parasympatholytic
Cholinomimetic or
Parasympathomimetic
• Drugs 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 - Arecoline
AnticholinesteraseAnti-ChEs are agents inhibits ChE, protect
ACh from hydolysis.• Reversible - Physostigmine - Neostigmine - Pyridostigmine - Edrophonium - Rivastigmine - Donepezil - Galantamine - Tacrine
• Irreversible - Dyflos - Echothiophate - Parathion* - Malathion* - Diazinon* - Tabun - Sarin - Soman
Anticholinergics or Parasympatholytic• 1.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, Biperiden
APPLIED
GlaucomaMyasthenia gravis
Alzheimer’s diseaseAnticholinesterase poisoning
THANK YOU
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