cholingeric and Anticholinesterase drug in detail .this ppt contains introduction ,mechanism of action ,pharmacological action ,uses and adverse effect of the drug

1. Mrs.M.Saranya M.Sc
Demonstrator
Department of pharmacology

2. Nervous system
Central nervous system
(CNS)
Peripheral nervous system
(PNS)
Autonomic nervous
system(ANS) Somatic nervous system
Sympathetic nervous system Parasympathetic nervous system

3. CHOLINERGIC AGENTS
• Ach is a major neurotransmitter at autonomic,
somatic as well as central sites
• Ach is the main physiological neurotransmitter in
the cholinergic system.
• The neuron that synthesize, store & release Ach
are called cholinergic neuron

4. ACETYLCHOLINE SYNTHESIS

5. ATP + Acetate + CoEn-A
Aectate activating reaction
choline
choline acetyl transferase
ACETYLCHOLINE + Co-En-A

6. • By the enzyme Choline Esterase
• Two types – True Choline Esterase
Pseudo choline Esterase
• Actylcholine – Choline + Acetic acid –CO2 & H2o
METABOLISM OF ACH

7. Two types of Cholinesterases
Acetylcholinesterase(true) Butyrylcholinesterase(pseudo)
Distribution All cholinergic sites, RBC,
Gray matter
Plasma, Liver, Intestine, white
matter
Hydrolysis of Ach Very fast Slow
Inhibition More sensitive to
physostigmine
More sensitive to
organophosphates
Function Termination of Ach action Hydrolysis of ingested esters

8. These are drugs which produce actions similar to that of
Ach.
 Directly - Acting directly on the cholinergic
receptors and activate them to produce the effect.
 Indirectly - which acts by
• Inhibiting the enzyme cholinesterase, thereby preventing the
hydrolysis of Ach .
• Result : more ACh is available at the receptors and produces a
parasympathomimetics action
CHOLINERGIC DRUGS
(Cholinomimetic, parasympathomimetic)

10. Cholinergic drugs
Directly acting Indirectly acting(Anticholinesterase)
Choline esters alkaloids
Reversible Irreversible
*carbaryl
*propoxur
(Baygon)
*parathion
*malathion
*nerve gases
*Dyflos
*Echothiophate
*physostigmine
*Neostigmine
*pyridostigmine
*Edrophonium
*Rivastigmine
*Donepezil
*Ach
*Bethanechol
* carbachol
• Pilocarpine
• muscarine
carbamates Organophosphorous(OP)

12. CHOLINERGIC RECEPTORS
• Muscarinic receptor subtypes with their locations
• Nicotinic receptor subtypes with their locations
M1
•Gastric glands
•Autonomic ganglia
•CNS
M2
Heart
M3
•Smooth muscle
•Exocrine glands
•Endothelial cells
NN
•Autonomic ganglia
•Adrenal medulla
NM
Neuromuscular
junction

13. ACTION OF Ach
The peripheral action of Ach is classifiable as muscarinic and
nicotinic.
I.Muscarinic
1. CVS : acts through M2 receptor
↓ heart rate.
↓ conduction
↓Force of contraction
2. Blood Vessels : acts through M3 receptor
↓ In BP due vasodilatation of blood vessels mediated
through the release of an endothelium dependent relaxing
factor(EDRF) which is NO

14. Cont..
3.SMOOTH MUSCLE : Ach increases the tone of all other
(nonvascular) smooth muscle.
* GIT: Tone and peristalsis is enhanced, sphincters are relaxed ,
resulting in rapid forward propulsion of intestinal contents
* Urinary Bladder: Detrusor muscle contracts and trigonal sphincter is
relaxed thus promotes voiding of urine
* RS : constricts the bronchial smooth muscle -bronchospasm.
4. SECRETORY GLANDS: Ach enhances the secretions of all glands; salivary,
lacrimal, nasopharyngeal, tracheobronchial, gastric and intestinal secretions

15. CONT….
5. EYES : contraction of
circular muscle of iris →
miosis
contraction of ciliary muscle
→spasm of accommodation,
 outflow facility,
↓ in intraocular tension

16. II . NICOTINIC
1. Autonomic ganglia: Ach stimulates sympathetic and
parasympathetic ganglia
2. Skeletal muscles: Ach brings about contraction of skeletal muscles
by stimulating the NM receptors present in NMJ.
Large doses cause persistent depolarization of skeletal muscles
resulting in paralysis
3 .CNS: Ach injected does not penetrate BBB and has no central
effects

17. Bethanechol and Carbachol
Choline esters of carbamic acid
Resistant to hydrolysis by cholinesterase so have longer duration of
action.
Clinical use:
• Methacholine : PSVT
• Bethanechol :
• Muscarinic action only
• Postoperative or postpartum urinary retention
Dose 10-40 mg oral or 2.5-5mg s.c.
• Neurogenic bladder, congenital megacolon and
gastroesophageal reflux.
• Carbachol :
• Chronic open-angle glaucoma
• Miosis during ophthalmic surgery

18. Anticholinesterases
(Cholinesterase Inhibitors)
• Anti-ChEs are the agents which inhibit the
cholinesterase that is responsible for hydrolysis of Ach.
Thus Ach is not metabolized & get accumulated at
muscarinic and nicotinic sites
They are two types:
• Reversible
Bind to cholinesterase for a period of minutes to hours. Than
release from it.
• Irreversible
- Bind to cholinesterase and form a permanent covalent bond
- The body must make new cholinesterase to break these
bonds

19. MOA of Anticholinesterases
Anionic siteEsteratic site
ACh
- AChE -
choline acetate
Rapid metabolism
Anionic site
- AChE
Esteratic site
Irreversible antiAChE
-
No metabolism!
Covalent binding blocks esteratic
site
+

20. PHARMACOLOGICAL ACTIONS
Pharmacology of Anti-ChEs  similar to direct
cholinergic stimulants But varies in muscarinic,
ganglionic, neuromuscular & CNS actions
Ganglia:
 Stimulation via muscarinic receptors
 High doses  persistent depolarization leads to
neuromuscular block via NM
CVS: [complex direct + via ganglia]
 Muscarinic action  bradycardia, hypotension
 Ganglia  tachycardia, hypertension
 Overall effect unpredictable and depend on the agent
and its dose

21. Skeletal muscles
• Sustained contractions  twitches, fasciculations
• Strengthens muscles in myasthenia gravis
• High doses  persistent depoloarisation 
neuromuscular block  weakness, paralysis
Other effects: on GIT, Eye etc
• peristalsis, bronchoconstriction, miosis, etc

22. Reversible Cholinesterase Inhibitors
Physostigmine:
• It is an alkaloid obtained from Physostigma Venenosum.
• Tertiary amine & has good penetration through tissues
• Actions similar to cholinergic agents
USES:
• Glaucoma
• Atropine poisoning

23. NEOSTIGMINE
• It is a synthetic anticholinesterase agent
• It has both direct & indirect actions
Comparative aspects of physostigmine & neostigmine
Physostigmine Neostigmine
Natural alkaloid synthetic
Tertiary amine, has good penetration
through tissues
Quaternary ammonium compound,
has poor penetration
Crosses BBB & produces both central &
peripheral effects
Does not cross BBB, hence no central
effects
USES: glaucoma
Atropine poisoning
USES: myasthenia gravis
Postoperative urinary retention
Curare poisoning

24. Edrophonium
• Reversibly binds anionic site on AChE
• Prevents hydrolysis of acetylcholine (Ach) while bound to
enzyme
• Short-acting
• Duration of action: 5-10 minutes
• Clinical use:
• Diagnosis of Myasthenia gravis
• Used to differentiate myasthenic crisis from cholinergic
crisis
• In curare poisoning, preferred because of it rapid onset of
action

25. Indirect Acting Agents used to treat Alzheimer’s
disease
Tacrine
 Lipophilic acridine derivative : crosses BBB
 Longer duration of action
 Use: symptomatic therapy in Alzheimer’s
Rivastigmine
 Lipophilic  cerebroselective ChE inhibitor
 Use: Alzheimer’s
Donepezil: Centrally acting
 Long acting; once daily doses
 Use: cognitive & behavioural improvement in AD
Galantamine : [Alkaloid inhibitor of cerebral ChE]
 Symptomatic relief in AD

26. Therapeutic uses
1. Miotic
1. Glaucoma
2. Counteracts mydriatics after eye tests
3. Prevents adhesions between iris & lens or cornea
4. To break adhesions formed by iritis, corneal ulcer [ miotic &
mydriatic used alternatively]
2. Myasthenia Gravis
3. Post operative
1. paralytic ileus / urinary retention
2. post op decurarisation
4. Poisoning
1. Cobra bite
2. Belladonna poisoning
3. Drug overdosages
4. Alzheimer’s Disease

27. Myasthenia Gravis
 Autoimmune disorder [incidence 1 in 10,000]
 Autoantibodies to NM receptors 
• NM receptors to one third of normal
• Structural damage to neuromuscular junction.
• Leads to weakness , easy fatigue
 Diagnosis
• Ameliorative test: edrophonium iv  muscle strength
in myasthenia [not other muscle Dystrophies]
• Provocative test: 0.5 mg d-tubocurarine  profound
weakness in myasthenia patients
• Anti NM antibodies in plasma or muscle biopsy
specimen

28. Therap Uses of Anti ChE
Post op paralytic ileus
• 0.5 - 1 mg sc neogstigmine
Post op decurarisation
• Neostigmine 05 – 2 mg [after atropinisation]
Cobra bite [curare like neurotoxin]
• Neostigmine + atropine  prevent resp paralysis
Belladonna poisoning
• Physostigmine blocks CNS + peripheral cholinergic poisoning
Drug poisoning
• Tricyclics, Phenothiazine, Antihistaminics have cholinergic action
• Physostigmine : 1overdose of diazepam, Gen anesthetics
Alzheimer’s : Cerebroselective anti ChE
• Tacrine, Rivastigmine, Donepezil, Galantamine

29. IRREVESIBLE ANTICHOLINESTERASES
ORGANOPHOSPHORUS(OP) INSECTICIDES
• All OP compounds except Echothiophate have no
therapeutic applications.
• It is used in resistant cases of glaucoma.
• OP compounds have only toxicological importance
• OP poisoning is one of the most common poisoning all
over the world. Common OP compounds are
• Parathion, malathion, dyflos, etc
• They irreversibly inhibit cholinesterases & cause
accumulation of Ach at muscarinic & Nicotinic sites

30. MOA of Anticholinesterases
Anionic siteEsteratic site
ACh
- AChE -
choline acetate
Rapid metabolism
Anionic site
- AChE
Esteratic site
Irreversible antiAChE
-
No metabolism!
Covalent binding blocks esteratic
site
+

31. Signs and Symptoms
1. Muscarinic effects: profuse sweating, salivation, lacrimation , increased
bronchial secretions, bronchospasm, vomiting, miosis, abdominal cramps,
hypotension, bradycardia, involuntary urination & defecation
2. Nicotinic effects: twichings, fasciculations, muscle weakness & paralysis
3. Central effects: restlessness, confusion, convulsions, coma & death due to
respiratory failure

33. DIAGNOSIS
OP poisoning can be diagnosed by:
• History of exposure
• Characteristic signs & symptoms
• Estimation of cholinesterase activity in blood, which is reduced to less
than 50% of normal

34. TREATMENT
GENERAL MEASURES:
• Remove the contaminated cloths, and wash the skin with soap &
water
• Gastric lavage should be continued till the returning fluid is clear
• Airway should be maintained
• Artificial respiration is given, if necessary
• Diazepam should be used cautiously by slow I.V inj to control
convulsions.

35. SPECIFIC MEASURE:
1. Atropine: is the drug of choice in OP poisoning.
Inject 2mg i.v. stat, and should be repeated every 5-10 min doubling dose
if necessary, till the patient is fully atropinized (fully dilated pupil,
tachycardia etc) atropine should be coutinued for 7-10 days
2. Oximes: atropine is not effective to reverse the neuromuscular paralysis.
Neuromuscular transmission can be improved by giving cholinesterase
reactivators such as pralidoxime, obidoxime & diacetyl monoxime(DAM).

36. Interactions
• Anticholinergics, antihistamines,
sympathomimetics
• Antagonize cholinergic drugs, resulting in decreased
responses
• Other cholinergic drugs
• Additive effects

37. Important Question
1.Classify anticholinesterases.
write in detail about the uses of anticholinesterases,
Elaborate on organophosphate poisoning.
2.Explain acetylcholine synthesis ,storage and release of
acetylcholine.write in detail about the cholinergic receptor and
cholinergic drugs.
Short note
1.Botulinum toxin
2.Mysthenia gravis
3.Organophosphate poisoning

38. Reference book
• K.d.tripath-Essentials of pharmacology
• Tara shanbrug-
• Web source