cholinergic transmission

1. Sarvarsh Singh Saini
57-
3rd Course

2. Nervous System:Overview
NervousSystem (NS)
CentralNervous
System(CNS)
Cerebrum,Cerebellum,
Brainstem,SpinalCord
Peripheral NervousSystem
(PNS)
Somatic Nervous
System
AutonomicNervous
System (ANS)
Sympathetic Nervous
System
ParasympatheticNervous
System

3. Autonomic Nervous System:
Organization

4. Sympathetic vs Parasympathetic NS
Sympathetic NS Parasympathetic NS
Thoracolumbar outflow
Most ganglions are nearer
to vertebral column
Shorter preganlionic fibres
Craniosacral outflow
Ganglions are within or near
to target organ
Longer preganglionic fibers
PreganglionicNT:
Acetylcholine
PreganglionicNT:
Acetylcholine
Postganlionic NT:
Norepinephrine
(Noradrenaline);
Acetylcholine at some sites
Postganglionic NT:
Acetylcholine; Nitric oxide
at some sites

5. Cholinoceptors
• Muscarinic (G ProteinCoupled
Receptor)
• SelectiveAgonist: Muscarine
• Antagonist:Atropine
• FiveSubtypes: M1-M5
• M1, M3, M5: excitatory
• Nicotinic (Ligand gated cation
channel)
• SelectiveAgonist: Nicotine
• Antagonist: d-tubocurarine
• Two subtypes: NN & NM
• Usually excitatory

6. CholinergicTransmission
Site Type of Receptor SelectiveAgonist SelectiveAntagonist
All postganglionic
parasympathetic(parasym).
Few postganglionic
sympathetic (sym)1
Muscarinic Muscarine Atropine
Ganglia(sym. & parasym.)
Adrenal Medulla
Nicotinic(NN)
Dimethyl Phenyl
Piperazinium (DMPP)
Hexamethonium
Skeletal Muscles Nicotinic (NM)
PhenylTrimethyl
Ammonium(PTMA)
d-tubocurarine
CNS (cortex, basal ganglia,
spinal cord, others)
Muscarinic Muscarine/Oxotremorine Atropine
Nicotinic Carbachol d-tubocurarine

7. CholinergicTransmission
• Synthesised from Acetyl CoA and
Choline in presence of Choline Acetyl
Transferase
• Stored in vesicles
• Released when impulses arrives by
exocytosis
• Degraded byAcetylcholinesterase
(AChE)

8. MuscarinicCholinoceptors
Features M1 M2 M3
Location&
Function
Autonomic ganglia:
depolarization1
Gastric glands: increased
secretion
CNS (learning, memory,
motor function)
Heart: Decrease rate, force
Nerve endings: Decrease
ACh release
CNS: tremor, analgesia
Visceral smooth muscle:
contraction
Visceral smooth muscle:
contraction
Iris: constriction of pupil
Ciliary muscle: contraction2
Exocrine glands: secretion
Vascular endothelium:
vasodilatation
Nature Gq protein coupled Gi/G0 protein coupled Gq protein coupled
Transducer
mechanism
IP3/DAG – increaseCa++
PLA2 increasd – PG
synthesis
K+channel opening,
decreased cAMP
IP3/DAG – increaseCa++
PLA2 increasd – PG synthesis
Agonists Oxotremorine, MCN 343A Methacholine Bethanechol
Antagonists Pirenzepine,Telenzepine Methotramine,
Triptiramine
Solifenacin, Darifenacin

9. NicotinicCholinoceptors
Features NM NN
Location &
Function
Neuromuscular 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
Nature
Intrinsic ion channel, pentamer
of α2 β ε or γ and δ, each with
4 transmembrane segments
Intrinsic ion channel, pentamer of only α
or α,β subunit, each with 4
transmembrane segments
Transducer
mechanism
Opening of cation channels
(Na+ K+)
Opening of cation (Na+ K+ Ca++) channels
Agonists PTMA, nicotine DMPP, nicotine
Antagonists Tubocurarine, α-Bungarotoxin Hexamethonium,Trimethaphan

10. Cholinergic (Cholinomimetic /
Parasympathomimetic) Drugs
CholinergicAgonists Anti-cholinesterases
Choline esters Alkaloids Reversible Irreversible
Acetylcholine Pilocarpine Carbamates:Physostigmine,
Neostigmine,
Pyridostigmine,
Edrophonium, Rivastigmine,
Donepezil, Galantamine
Carbamates:
Carbaryl, Propoxur
Methacholine Arecoline Organophosphates:
Dyflos,
Echothiophate,
Malathion, Diazinon,
Tabun, Sarin, Soman
Carbachol Muscarine
Bethanechol Acridine:Tacrine

11. MuscarinicActions of CholinergicAgonists (ACh)
Organ Receptor
Involved
Mechanism Effect
Heart
Blood
Vessels
M2 Hyperpolarization of SA Node Bradycardia, cardiac arrest
M2 Increased Refractory Period at AV
node and His-Purkinje Fibres
Delayed conduction,
Prolonged P-R interval, Heart
Block
PLc – IP3/DAG mediated EDRF
(NO release):Vasodilation
Fall in BP, flushing
M3 Vasoconstriction
Release of NO – dilatation of
cavernous sinus
Erection of penis

12. MuscarinicActions of CholinergicAgonists (ACh)
Organ Receptor
Involved
Mechanism Effects
Smooth
Muscle
M3 + M2 Increased tone and peristalsis
ofGIT, sphincters relaxed
Abdominal cramps, evacuation of
bowels
M3 Increased peristalsis in
ureters, detrusor contracts,
trigone & sphincter relaxes
Voiding of bladder
M3 Constriction of bronchial
muscles
Bronchospams, dyspnoea,
asthamatic attack

13. MuscarinicActions of CholinergicAgonists (ACh)
Organ
Receptor
Involved
Mechanism Effects
Glands M3 + M2 Increased secretion Salivation, sweating, lacrimation,
increased tracheobronchial and gastric
secretions
Eyes M3
Contraction of circular
muscle of iris
Miosis
Contraction of ciliary
muscle
Blurring of near vision, increased
aqueous outflow, decreased intra ocular
pressure in glaucomatous eye

14. NicotinicActions of Cholinergic Drugs (ACh)
Organ Receptor Involved Mechanism & Effects
AutonomicGanglia NN
• Stimulation of
(higher doses)
sym. & parasym. ganglia
Skeletal Muscles NM
• Iontophoreic application of ACh to muscle end
plate: contraction of fibres
• Intra-arterial injection: twitching and
fasciculations

15. CNSAction of ACh
• Intravenous injection: No central effects
• Direct injection into brain: arousal response followed by depression
• Complex neurological and behavioural effects

16. Drug interactions
Synergism Antagonism
Anticholinesterases: potentiation Atropine,Atropine like substances
Methacholine: potentiation (lesser
extent)
Adrenaline
Carbachol, bethanechol: additive

17. Choline esters: Uses and Side Effects
• Uses:
• Rarely used (evanescent
and non selective action)
non-
urinary
neurogenic
• Bethanechol:
obstructive
retention,
bladder
• Side effects:
• Belching, colic
• Involuntary
urination/defecation
• Flushing, sweating
• Fall in BP
• Bronchospasm

18. CholinomimeticAlkaloids
Pilocarpine
• Source: Pilocarpus microphyllus
• Prominent muscarinic actions;
ganglionic action via M1 receptors
• CVS Effects:
• Small dose – fall in BP (muscarinic, ?M2)
• Higher dose – rise in BP and tachycardia
(ganglion mediated; M1)
• Eyes:
• Local application – penetrates cornea,
miosis, ciliary muscle contraction, fall in
intraocular tension (M3)
• Use:As Miotics (counteract
mydriatics used for refraction, along
with mydriatics to prevent/break
adhesions), In open angle glaucoma,
• S/E: marked sweating, salivation,
increased secretions

19. Arecholine
• Source: betel nut Areca catechu
• Muscarinic as well as Nicotinic actions
• No therapeutic use
CholinomimeticAlkaloids

20. Muscarine
•Source: mushrooms Amanita muscaria, Inocybe sps.
•Only muscarinic actions
•Not used therapeutically, has toxicological importance
CholinomimeticAlkaloids

21. Mushroom Poisoning
Early type (Muscarinic) HallucinogenicType Late type (Phalloidin)
Toxic principle Inocybe and related sps. Muscimol; isoxazole
(A. muscaria)
Peptide toxin of A.
phalloides,Galerina
Mechanism Blocks M receptors in
CNS
Inhibit RNA and protein
synthesis
Features Muscarinic Hallucinogenic,
central manifestations
Damage to GIT, liver,
kidney
Presentation Within an hour of eating After hours of ingestion
Treatment Atropine Nonspecific, Atropine
contraindicated
Supportive

22. Anti-cholinesterases (AChE)
•InhibitsCholinesterases (ChE)  protectsACh from
hydrolysis  cholinergic effects
•Some have additional direct action on Nicotinic
receptors

23. AChE: Mechanism of Action
• Normally, after showing its activity, ACh is
degraded by hydrolysis by
Cholinesterase(ChE) into choline and acetic
acid
• Hydrolysis of AChEs
(carbamates, about 30
is either slow
mins) or extremely
slow (organophosphates, days), hence the
enzyme ChE is rendered inactive  normal
ACh at the junction cannot be hydrolysed 
prolonged action of ACh (cholinomimetic
action)
• Hydrolysis after ageing not possible, new ChE
needs to be formed

24. AChE: PharmacologicalActions
Characteristics
• Due to amplification of endogenousAch
• Intensity of action on muscarinic, nicotinic andCNS varies
among different agents
Nicotinic
CNS
Ganglia
Skeletal
Muscle
Lipid soluble
Example Muscarinic
Physostigmine, +++
organophosphates
+ Less
prominent
+++
Lipid insolube Neostigmine Less
prominent
+ +++ none

25. AChE: PharmacologicalActions
• Ganglia: stimulation at low dose, blockade at high dose
• Stimulation via M1 receptors
• High dose: persistent depolarization  depletion ofACh  blockade of transmission
• CVS: complex, unpredictable effects
• Muscarinic: bradycardia, hypotension;Ganglionic: tachycarida, hypertension
• Action on medullary centres(stimulation then depression), ganglion blockade at high doses
• Skeletal Muscles: twitching and fasciculations at low dose, weakness and paralysis at
high dose
• Prolonged action ofACh on motor end plates and prejunctional fibres twitching and fasciculations
• High dose: persistent depolarization  neuromuscular transmission blockade  weakness and paralysis
• CNS: general arousal at low dose, excitement, confusion at high dose
• Lipophilic agent: generalised alerting response, improved cognition inAlzheimer’s Disease
• Higher doses: excitement, mental confusion, disorientation, tremors, convulsions, coma

26. AChE: Pharmacokinetics
• Physostigmine:
• Rapid absorption (oral,
parenteral, topical in eye)
• Crosses BBB, central effects
• Metabolism by hydrolysis
• Neostigmine:
• Poor oral absorption (20-30
times parenteral dose)
• Does not cross BBB, cornea
• Partially hydrolysed and
partially excreted unchanged
in urine
• Organophosphates:
• Absorbed from all sites
• Hydrolysed and oxidised and
then excreted

27. AChE:Uses
As Miotic
• Glaucoma:
• Increases tone of ciliary muscle and sphincter pupillae  opening of trabeculae 
intra ocular tension (iot) falls in open angle glaucoma
• Pilocarpine – rapid and short lasting (4-6hrs), 6-8hrly instillation required; fluctuation
of iot in between seen,S/E: diminution of vision especially in dim light, spasm of
accommodation, brow pain; nausea, diarrhoea, sweating, bronchospasm with higher
concentration; also used in combination for angle closure glaucoma
• Physostigmine 0.1% - supplement pilocarpine
• Reversal of mydriasis after refraction
• Prevent/break adhesions (iris-lens, iris-cornea): in conjunction with mydriatics

28. AChE:Uses
• Myasthenia gravis(MG):
• Treatment
• Neostigmine 15 mg orally 6 hrly, adjusted
according to response, dose requirement
fluctuates in accordance to remission and
exacerbation
• Pyridostigmine
• Atropine if muscarinic side effects seen,
cholinergic weakness/crisis if dose
adjustment not adequate
• DiagnosticTests
• AmeliorativeTest: Inj Edrophonium
2mg i.v. (test dose) followed by 8 mg
i.v. after 30-60 sec. reversal of
weakness and short lasting
improvement of strength: +ve for MG
• ProvocativeTest: hazardous – not
performed
• Demonstration of anti-NR antibodies in
plasma or muscle biopsy specimen

29. AChE:Uses
• Post-operative paralytic ileus/urinary retention: Inj. Neostigmine 0.5-1 mg s.c.
• Post-operative decurarization: Neostigmine 0.5-2 mg i.v. preceeded by atropine to block
muscarinic effects  rapidly reversal of muscle paralysis induced by competitive
neuromuscular blockers
• Cobra bite: Neostigmine +Atropine to prevent respiratory paralysis can be used
• Belladona poisoning/Dhatura poisoning: Physostigmine 0.5-2 mg i.v. repeat as required
(S/E – hypotension, arrhythmia, undesireable central effects: last resort), Neostigmine
safer
• DrugOverdose:TCA, phenothiazines, antihistaminics – Physostigmine (rare)
• Alzheimer’s Disease: cerebroselectiveAChE (rivastigmine, donepezil, galantamine)

30. Phew!!!!
• That will be all for today
• Please revise the topic….
• Next class:Thursday 31st December, 2015;Topic:Anticholinergics Drugs