This is an lecture presentation for MBBS Semester 1 students. Here we discuss cholinergic agonists and anticholinesterase drugs. We end up discussing about OP poisoning in brief.

1. Drugs acting on
Cholinergic System-I
Dr. Pravin Prasad
M.B.B.S., MD Clinical Pharmacology
Lecturer, Lumbini Medical College & TH
8 February 2019 (25 Magh 2075), Friday

2. Possible drug targets
Choline transporter
Hemicholinium
Vesicle associated
transporter
Vesamicol
Inhibit Exocytosis
Botulinium toxin

3. Possible drug targets
Deplete Acetylcholine
(ACh)
Black widow spider toxin
Bind to post-synaptic
receptors
Cholinergic agonists
Inhihbit hydrolysis of ACh
Anticholinesterase
(AChE)

4. Cholinergic Agonists
Choline esters Alkaloids
Acetylcholine Pilocarpine
Methacholine Arecoline
Carbachol Muscarine
Bethanechol

5. Anticholinesterases (AChE)
Reversible Irreversible
Carbamates Non-
carbamates
Carbamates Organo-
phosphates
Physostigmine Edrophonium Carbaryl Dyflos
Neostigmine Tacrine Propoxur Echothiophate
Pyridostigmine Donepezil Malathion
Rivastigmine Galantamine Diazinon

6. Choline esters
Acetylcholine, Methacholine, Carbachol,
Bethanechol
Has peripheral and central actions
Peripheral actions: muscarinic and nicotinic
• Nicotinic actions at higher doses
Central actions: seen on direct injection into the
brain
Difference in hydrolysis by ChE and actions

7. Choline esters
Choline esters Hydrolysis by Actions
Selective
action on
AChE BuChE Muscarinic Nicotinic
ACh +++ ++ ++ +
Non-
selective
Methacholine + - ++ +/- CVS
Carbachol - - + ++ GIT, bladder
Bethanechol - - + - GIT, bladder

8. Choline esters
Interactions:
Anticholinesterase
• Potentiates ACh, methacholine
• Additive action: Carbachol, Bethanechol
Atropine: competitive antagonist at M receptors
Adrenaline: physiological antagonist

9. Choline esters
Uses:
Bethanechol: non-obstructive urinary retention,
neurogenic bladder
Side effects:
Belching, colic
Involuntary urination/defecation
Flushing, sweating
Fall in BP, Bronchospasm

10. Cholinergic alkaloids
Pilocarpine
Eyes: Seen with local application
• Miosis
• Ciliary muscle contraction
• Fall in intraocular tension

11. Cholinergic alkaloids
Pilocarpine
Use:
• Open angle glaucoma (third line)
• To counteract mydriatics
Side Effects:
• Initial stinging sensation
• Painful spasm of accomodation

12. Anticholinesterase
Carbamates, organophosphates
Mechanism of action:
Inhibits Cholinesterase (ChE) 
Protects ACh from hydrolysis (Amplification of
endogenous ACh) 
Cholinergic effects
Additional direct action on Nicotinic receptors
(some compounds)

13. AChE: Mechanism of Action

14. AChE: Mechanism of Action

15. AChE: Pharmacological Actions
Characteristics
(Example)
Muscarinic
Nicotinic
CNS
Ganglia
Skeletal
Muscle
Lipid soluble
(Physostigmine,
organo-
phosphates)
+++ + Less
prominent
+++
Lipid insoluble
(Neostigmine)
Less
prominent
+ +++ none

16. AChE: Pharmacological Actions
Organ System Low dose High dose
Skeletal muscle Twitching and
fasciculations
Weakness and
paralysis
Ganglia Stimulation Blockade
Central Nervous
System
General arousal confusion

17. AChE: Pharmacological Actions
Cardiovascular effects:
Muscarinic: bradycardia, hypotension
Ganglia stimulation: increase heart rate and BP
• High dose: transmission blockade
Medullary centres: stimulation followed by
depression
Unpredictable and variable effects!!!

18. AChE: Individual compounds
Physostigmine:
Rapid absorption (oral, parenteral, topical in eye)
Crosses BBB, central effects
Metabolism by hydrolysis
Eye drops prepared freshly

19. AChE: Individual compounds
Neostigmine, Pyridostigmine:
Poor oral absorption (20-30 times parenteral dose)
Does not cross BBB, cornea
Partially hydrolysed and partially excreted unchanged in
urine
Edrophonium:
Brief duration of action (10-30 mins)
Diagnostic purpose only

20. AChE: individual compounds
Rivastigmine, Donepezil, Galantamine
Centrally acting AChE
• Galantamine: additional agonistic action on
nicotinic receptors
Use: Alzeheimer’s disease

21. AChE: Individual compounds
Organophosphates:
Dyflos, Echothiophate
• Previously used as miotics
Absorbed from all sites
Hydrolysed and oxidised and then excreted

22. AChE: Precautions
Use cautiously in:
Peptic ulcer
Hypertension
Asthma
COPD
Seizure patients
Contraindications:
Sick sinus
A-V conduction
defects
Hypotensive states

23. AChE: Uses
As Miotic
Glaucoma (Open angle as well as angle closure):
Third line drugs
Physostigmine 0.1% - supplement pilocarpine
Effective in aphakic glaucoma
Reversal of mydriasis after refraction
Prevent/break adhesions: In conjunction with
mydriatics

24. AChE: Uses
In Myasthenia gravis(MG)
Treatment
Neostigmine
• 15 mg orally 6 hourly
• Adjusted according to response
• Dose requirement fluctuates
Pyridostigmine

25. AChE: Uses
In Myasthenia gravis(MG)
Diagnostic Tests
Ameliorative Test:
• 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
Provocative Test

26. 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.
Cobra bite
Neostigmine + Atropine to prevent respiratory
paralysis can be used

27. AChE: Uses
Belladona poisoning/Dhatura poisoning
Physostigmine 0.5-2 mg i.v. repeat as required
Neostigmine safer
Drug Overdose (TCA, phenothiazines,
antihistamines)
Alzheimer’s Disease
Cerebro-selective (rivastigmine, donepezil,
galantamine)

28. Anticholinesterase poisoning
Commonly available
compounds
Organophosphates
Carbamates
Mushrooms
DUMBBELLSS

29. Anticholinesterase poisoning
Local action at the site of
application
Systemic effects:
Muscarinic
Nicotinic
Central
Death due to respiratory
failure DUMBBELLSS

30. Anticholinesterase poisoning
Treatment:
Termination of further exposure
Maintain airway, breathing and circulation
Supportive measures
Specific antidotes:
• Atropine
• Cholinergic reactivators (Pralidoxime,
Obidoxime)

31. Conclusion
Activities of ACh can be mimicked by using
cholinergic agonists and anticholinesterase
Bethanechol is useful for post operative/ post
partum urinary retention
Pilocarpine is used as eye drop for glaucoma and as
a miotic
Carbamates and organophosphates are the
anticholinergics that have therapeutic as well as
toxicological implication

32. Thank you
Any Queries?
Assignment:
Recent newspaper articles on organophosphorus
poisoning in Nepal
Next class:
Monday- Anticholinergics Drugs