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