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CHOLINERGIC

NERVOUS SYSTEM

HISTORY
1977 Fambrough,
Devreotes and Card
- Chemically isolated by
detergents
- Nicotinic ACh receptors are
hydrophobic glycoprotein

CHOLINERGIC TRANSMISSION
1. All preganglionic autonomic nerve
ending
(sympathetic
&
parasympathetic ).
2.Postganglionic
Parasympathetic

neurons

of

3.Post ganglionic sympathetic ending


innervating Sweat glands ,Piloerector
muscles of hair, blood vessels.
4. NM Junction
5.Parts of Brain

Cerebral

Cortex,

CHOLINERGIC TRANSMISSION
Ach - synthesized in the terminal
endings & varicosities of cholinergic nerve
fibre.

Synthesis:
Acetyl-CoA + Choline
AcetylCholine
Choline acetyl transferase

Destruction:
Acetylcholine
Acetate ion

Choline +

Acetylcholine esterase

Biochemical events at a cholinergic


sysnapse

Types of Ach - esterase


Acetlycholine esterase/
True choline
esterase

Pseudocholine
esterase

1. Distributio Found in place where Ach


n
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
M2
M3
M4
M5 -

brain, autonomic ganglia


heart
glands & smooth muscle
CNS
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,

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 NM Junction:
& Function depolarization of
suserved
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 of only
subunits

Intrinsic ion channel,


pentamer 2 or y
& subunits

3.
Opening of Cation
Transducer (Na+, K+) channels
mechanism

Opening of Cation
(Na+, K+, Ca2+)
channels

4. Agonist

PTMA (Phenyl trimethyl DMPP (Dimethyl phenyl


ammonium), Nicotine
piperazinum, Nicotine

5.Antagoni
st

Tubocurarine,
-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

Anticholinesterase
Anti-ChEs are agents inhibits ChE, protect
ACh from hydolysis.
Reversible
Irreversible
- Physostigmine
- Dyflos
- Neostigmine
- Echothiophate
- Pyridostigmine
- Parathion*
- Edrophonium
- Malathion*
- Rivastigmine
- Diazinon*
- Donepezil
- Tabun
- Galantamine
- Sarin
- Tacrine
- 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
Glaucoma
Myasthenia gravis
Alzheimers disease
Anticholinesterase poisoning

THANK YOU