This document summarizes cholinergic transmission and the actions of acetylcholine (ACh) as a neurotransmitter. It discusses ACh synthesis, storage, release and metabolism by acetylcholinesterase. It describes the two classes of cholinergic receptors - muscarinic and nicotinic receptors. The document outlines the pharmacological actions and uses of parasympathomimetic drugs like pilocarpine, muscarine, and anticholinesterases. It also discusses the treatment of myasthenia gravis and organophosphate poisoning using anticholinesterases.

1. Moderator :-
Dr. Afroz Abidi
Presented By:-
Dr. Roohana Hasan

2. CHOLINERGIC TRANSMISSION
 Acetylcholine (ACh) is a major neurohumoral
transmitter at autonomic, somatic as well as central
sites.
 It has virtually no systemic therapeutic applications
because its actions are diffuse, and its hydrolysis,
catalyzed by both acetylcholinesterase (AChE) and
plasma butyrylcholinesterase, is rapid.

3. Synthesis, Storage And Release

4. Metabolism
 Acetylcholine is hydrolysed by an enzyme called
acetylcholinesterase to choline and acetic acid and thus
its actions are terminated.
 Choline is then recycled in acetylcholine biosysthensis.
 The cholinergic sysnapse is very rich in
acetylcholinesterase and therefore, the t 1/2 of Ach is
very short.

5.  Cholinesterase is of two types:-
1. True Acetylcholinesterase- membrane bound
enzyme present in the cholinergic synaptic cleft.
Hydrolyses Ach and other acetylesters. Eg:-
Methacholine.
2. Plasma Cholinesterase- synthesised in liver and
found in plasma and in intestines.
Hydrolyses benzoylcholine and butyrylcholine esters.
Genetic variations are commonly seen with these
enzymes.

6. Cholinoceptors
 Two classes of receptors for ACh are recognised –
 Muscarinic - a G protein coupled receptor.
M1,M3,M5- Gq
M2,M4- Gi- decreased cAMP
 Nicotinic- a ligand gated cation channel.
Nm and Nn receptors.

7. Subtypes and characteristics of
cholinoceptors.
Gastric secretion
Gi motility
gastric Gastric
paracrine cells

8. CHOLINERGIC AGONISTS
 Choline Esters
Acetylcholine
Methacholine
Carbachol
Bethanechol
 Alkaloids
Muscarine
Pilocarpine
Arecoline

9. ACTIONS - Muscarinic
 Eye – Circular muscle of iris, ciliary muscle and lacrimal
glands possess M3 receptors.
 Contraction of circular muscle of iris - Miosis.
 Contraction of ciliary muscle –
Loosen the sensory ligaments
Lens more convex
Accomodated for near vision
 It also opens the canal of schlemn- drainage of aqueous
humor- reducing intra ocular pressure.
 Lacrimation Glands- Lacrimation.

10.  Heart – Parasympathetic supply is only upto SA node,
atria and AV node.
 Effect of M2 receptors activation at SA node and
Atria causes decrease in heart rate and decrease in
force of contraction respectively.
 At AV node causes decrease in conduction velocity
and increase in refractory period.

11.  Blood Vessels- Areteries have no parasympathetic
innervation but M3 receptors.
 If a cholinomimetic drug is given exogenously, a
transient but a marked fall in BP ( due to vasodilatation)
can be observed.
 The endothelium of most blood vessels releases EDRF.
Eg Nitric Oxide, which causes vasodilatation due to M3
receptors activation by exogenously administered
cholinomimetic.
 The fall in BP evokes baroreceptor reflex, resulting in
compensatory sympathetic discharge at the heart.

12.  Salivary Glands- M3 receptors
Increased watery saliva- vasodilation resulting from
release of bradykinin.
 Lungs- Smooth muscles of bronchi and mucus glands
possess M3 receptors.
Stimulation of smooth muscles of bronchi –
bronchoconstriction
Stimulation of mucus glands- Increased bronchial
secretion.
 Urinary Bladder- M3 receptors
Contraction of Detrusor muscle
Relaxation of sphincters- leading to urination

13.  Gastrointestinal System- GIT smooth muscles,
sphincters and gastric glands have M3 receptors.
 Gastric Parietal cells- M1 receptors.
 Activation of M3 – increase in motility and tone of GIT
smooth muscle, relaxation of sphincters, and increased
secretions from gastric glands- leading to defaecation.
 Activation of M1 receptors- promotes gastric acid
secretions.
 Pancreas- Acini cells – M3 receptors
Increased secretion of pancreatic juice.
 Sweat Glands- M3 receptors
Increased sweating.
The innervation is sympathetic in origin but cholinergic
in character.

14.  Central Nervous System-
 Nicotinic Effects- Ataxia, behavioural disturbances,
and restlessness.
 Muscarinic Effects- Tremors and convulsions.

15. Actions - Nicotinic
 Stimulation of sympathetic as well as parasympathetic
ganglia ( Nn receptors), which ultimately results in
discharge of either Ach or NE from the respective
postganglionic neurons. Since most organs have a dual
innervation, the net result of discharge would promote
the dominant tone of that particular organ.
 Stimualtion of Nm receptors – spasm of skeletal
muscle.
Prolonged activation causes fasciculations followed by
paralysis.

16. Classification of
Parasympathomimetic Drugs

17. CHOLINOMIMETIC ALKALOIDS
 Pilocarpine- It is obtained from the leaves of Pilocarpus
microphyllus and other species. It has prominent
muscarinic actions and also stimulates ganglia-mainly
through ganglionic muscarinic receptors.
 Pilocarpine causes marked sweating, salivation and
increases other secretions as well.
 Cardiovascular effects are complex. Small doses generally
cause fall in BP (muscarinic), but higher doses elicit rise
in BP and tachycardia which is probably due to
ganglionic stimulation (through ganglionic muscarinic
receptors).

18.  Applied to the eye, it penetrates cornea and promptly
causes miosis, ciliary muscle contraction and fall in
intraocular tension lasting 4-8 hours.
 Stinging sensation, painful spasm of accomodation are
frequent side effects.
 Other uses as a miotic are - to counteract mydriatics after
they have been used for testing refraction
 To prevent, adhesions of iris with lens or cornea by
alternating it with mydriatics.

19.  Muscarine- It occurs in poisonous mushrooms
Animata muscaria and Inocybe species and has only
muscarinic actions. It is not used therapeutically but is
of toxicological importance.
 Mushroom poisoning- Depending on the toxic
principle present in the particular species, at least 3
types of mushroom poisoning is known.
 Muscarine type (Early mushroom poisoning) due
to Inocybe and related species.
Symptoms characterstic of muscarinic actions appear
within an hour of eating mushroom, and are promptly
reversed by atropine.

20.  Hallucinogenic type It is due to muscimol and
isoxazole compounds which are present in A.muscaria
and related mushrooms in much larger quantities
therefore actions are muscarine.
 These compounds activate amino acid receptors, and
block muscarinic receptors and have hallucinogenic
property.
 Manifestations of poisoning are primarily central.
 There is no specific treatment atropine is
contraindicated.
 Another hallucinogenic mushroom is Psilocybe
mexicana whose active principle psilocybine is a
tryptaminergic (5-HT related) compound.

21.  Phalloidin type (Late mushroom poisoning) lt is
due to peptide toxins found in A. phalloides, Galerina
and related species.
 These inhibit RNA and protein synthesis.
 The symptoms start after many hours and are due to
damage to the gastrointestinal mucosa, liver and
kidney.
 Treatment consists of supportive measures.
 Thioctic acid may have some antidotal effect.

22. ANTICHOLINESTERASES
Anticholinesterases (anti-ChEs) are agents which inhibit ChE, protect
ACh from hydrolysis.

23. Mechanism Of Action

24. PHARMACOLOGICAL ACTIONS
Ganglia- Local hydrolysis of ACh is less important in
ganglia: inactivation occurs partly by diffusion and
hydrolysis in plasma.
 Anti-ChEs stimulate ganglia primarily through
muscarinic receptors present there.
 High doses cause persistent depolarization of the
ganglionic nicotinic receptors and blockade of
transmission.
 CVS Cardiovascular effects are complex. Whereas
muscarinic action would produce bradycardia and
hypotension, ganglionic stimulation would tend to
increase heart rate and BP.

25. Skeletal muscles -After treatment with antiChEs, the
ACh released by a single nerve impulse is not
immediately destroyed-rebinds to the same receptor,
diffuses to act on neighbouring receptors and activates
prejunctional fibres - repetitive firing - twitching and
fasciculations.
 Force of contraction in partially curarized and
myasthenic muscles is increased.
 Higher doses cause persistent depolarization of
endplates resulting in blockade of neuromuscular
transmission - weakness and paralysis.

26. Uses
1. As miotic
 In glaucoma: Miotics increase the tone of ciliary
muscle (attached to scleral spur) and sphincter pupillae
which pull on and somehow improve alignment of the
trabeculae so that outflow facility is increased therefore,
i.o.t. falls in open angle glaucoma.
Pilocarpine is the preferred miotic. The action is rapid
and short lasting (4-6 hr); 6-8 hourly instillation is
required and even then i.o.t. may fluctuate in between.
Diminution of vision especially in dim light (due to
constricted pupil), spasm of accommodation and brow
pain are frequent side effects. Systemic effects-nausea,
diarrhoea, sweating and bronchospasm may occur with
higher concentration eye drops.

27.  To reverse the effect of mydriatics after refraction
testing.
 To prevent formation of adhesions between iris and
lens or iris and cornea, and even to break those which
have formed due to iritis, corneal ulcer, etc.-a miotic is
alternated with a mydriatic.

28. Myasthenia Gravis
(Myo + asthenia)
 Autoimmune disorder affecting 1
in 10,000 population
 reduction in number of free NM
receptors
 Causes: Development of
antibodies directed to Nicotinic
receptors at muscle end plate –
reduction in number by 1/3rd of
NM receptors-Structural damage
to NM junction-weakness and
easy fatigability on repeated
activity, with recovery after rest.

30. Myasthenia gravis – Treatment
 Neostigmine and its congeners improve muscle
contraction by allowing ACh released from prejunctional
endings to accumulate and act on receptors over a larger
area, and by directly depolarizing the endplate.
 Neostigmine – 15 to 30 mg. orally every 6 hrly
 Dose frequency is Adjusted according to the response
 Pyridostigmine – less frequency of dosing
 These drugs have no effect on the basic disorder which
often progresses; ultimately it may not be possible to
restore muscle strength adequately with antiChEs alone.

31.  Other drugs: Corticosteroids (prednisolone 30-60 mg
/day induces remission and 10 mg daily or on alternate
days can be used for maintenance therapy. ) –
immunosuppression
 Inhibits production of NR antibodies and may increase
synthesis or NRs
Both azathioprine and cyclosporine also inhibit NR-
antibody synthesis by affecting T-cells.
Removal of antibodies by plasmapheresis (plasma
exchange) is another therapeutic approach.

32. Myasthenic crisis
 Myasthenic crisis is characterized by acute weakness of
respiratory muscles.
 Managed by:-
 Tracheobronchial intubation and mechnical ventilation
 Methylprednisolone IV with withdrawal of AChE for 2-3
days.
 Gradual reintroduction of AChE
 Thymectomy- produces gradual improvement in majority
of cases. Even complete remission has been obtained.
Thymus may contain modified muscle cells with NRs on
their surface, which may be the source of the antigen for
production of anti-NR antibodies in myasthenic patients.

33. Overtreatment with anti-ChEs
 Produces weakness by causing persistent
depolarization of muscle endplate: this is called
cholinergic weakness.
 Late cases with high anti-ChE dose requirements often
alternately experience myasthenic and cholinergic
weakness and these may assume crisis proportions.

34.  The two types of weakness require opposite
treatments. They can be differentiated by
edrophonium test-
 Inject edrophonium (2 mg. i.v.) worsening-cholinergic
crisis
improvement-
myasthenic crisis worsening-cholinergic
crisis

35. Diagnostic tests for Myasthenia
Gravis
 (a) Ameliorative test: edrophonium 2-10 mg injected
slowly i.v. improves muscle strength only in
myasthenia gravis and not in other muscular
dystrophies.
 (b) Provocative test: myasthenics are highly sensitive
to d-tubocurarine; 0.5 mg i.v. causes marked weakness
in them but is ineffective in non-myasthenics. This
test is hazardous: facilities for positive pressure
respiration must be at hand before performing it.

36.  Postoperative paralytic ileus/urinary retention
This can be relieved by 0.5-1 mg s.c. neostigmine,
provided no organic obstruction is present.
 Postoperative decurarization Neostigmine 0.5-2.0
mg i.v.,preceded by atropine to block muscarinic
effects, rapidly reverses muscle paralysis induced by
competitive neuromuscular blockers.
 Cobra bite- Cobra venom has a curare like neurotoxin.
Though specific antivenom serum is the primary
treatment, neostigmine + atropine prevent respiratory
paralysis.
Other Uses

37.  Belladonna poisoning -Physostigmine 0.5-2 mg i.v.
repeated as required is the specific antidote for
poisoning with belladonna or other anticholinergics.
It penetrates blood-brain barrier and antagonizes both
central and peripheral actions.
However, physostigmine often itself induces
hypotension and arrhythmias; is employed only as a
last resort. Neostigmine does not block the central
effect, but is less risky.

38.  Alzheimer's disease -Characterized by progressive
dementia, is a neurodegenerative disorder, primarily
affecting cholinergic neurons in the brain.
 The relatively cerebroselective anti-ChEs- tacrine
rivastigmine, donepezil and galantamine have been
approved for clinical use.

39. Pharmacotherapy of
Organophosphate Poisoning
• Complex effects – Muscarinic, Nicotinic and CNS
• Signs and symptoms:
1. Irritationof eye, lacrmation, salivation, tracheo-
bronchial secretions, colic, blurring of vision,
defaecation and urination
2. Fall in BP, tachy or bradycardia and CVS collapse
3. Muscular fasciculations, weakness, and respiratory
paralysis
4. Irritability, disorientation, ataxia, tremor, convulsins
and coma

40. • Treatment:
1. Decontamination and termination of further exposure –
gastric lavage if needed
2. Airway maintenance – endotrachial intubation
3. Supportive measures – for BP/fluid and electrolyte
4. Specifc antidote – Atropine – highly effective in
counteracting muscarinic symptoms- antagonizes central
effects.
2mg IV every 10 minutes till dryness of mouth or othe
signs of atropinization occur(upto 200 mg/day)
Continued treatment with maintenance doses may be
required for 1-2 weeks.

41.  Cholinesterase reactivators –
Oximes are used torestore neuromuscular
transmission in case of organophosphate anti-ChE
poisoning.
The phosphorylated ChE reacts very slowly or not at all
with water. However, if more reactive OH groups in
the form of oximes (generic formula R-CH = NH-OH )
are provided, reactivation occurs more than a million
times faster .
Pralidoxime – 1-2 g is given by slow IV infusion over 15-
30 mins to reactivate and to regenerate the AchE.

42. Mechanism Of Action Of Oximes

43. Limitations of use of Oximes in OPP
 Reactivation of the phosphorylated AchE is no longer
possible if it has undergone the process of ageing.
 Ineffective in Carbamated poisoning.
 Pralidoxime and Obidoxime do not cross BBB and
hence cannot reactivate the AchE inhibited in the
brain.
 Diacetylmono-oxime(DAM) can cross BBB.

44. Summary
 Acetylcholine (ACh) is a major neurohumoral
transmitter.
 2 types of cholinoceptors- muscaranic and nicotinic.
 Actions of Ach on different organs.
 Cholinomimetic Alkaloids.
 Mechanism of action of Anticholinesterases.
 Myasthenia gravis
• Organophosphate poisoning
• Oximes