3. ACETYLCHOLINE
Acetic acid ester of choline
CH3-CO-CH2-CH2N+(CH3)3Cl-
O
ACh is synthesized in the axon terminal.
Acetylation of choline with acetyl coenzyme A catalysed by
enzyme choline acetyl transferase.
Choline + acetyl coA Acetylcholine
ChAT
4. Newly synthesized ACh is transported into the vesicle
mediated by H+ - ACh antiporter.
Presynaptic action potential rise in intracellular Ca2+
release of ACh into the synaptic cleft.
ACh in the synaptic cleft diffuses and binds to the
muscarinic and nicotinic receptors producing the respective
effects.
Degradation of ACh is by the enzyme Acetylcholinesterase.
Acetylcholine Choline+ Acetic acid.
Acetylcholinesterase
7. Anticholinesterases are the agents that bind to and
inhibit AChE elevating the concentration of
endogenously released ACh in the synaptic cleft.
Accumulated ACh activates nearby cholinergic
receptors.
Also known as Indirectly acting ACh receptor agonists.
9. CHEMISTRY
• Anti- ChEs are either esters of carbamic acid or derivatives
of phosphoric acid.
• Carbamates may have a non polar tertiary amino N+
(Physostigmine) or a quaternary N+ (Neostigmine).
• Carbamates with tertiary N+ Lipid soluble
• Carbamates with quaternary N+ Lipid insoluble.
• All organophosphates are lipid soluble except
echothiophate which is water soluble.
10. MECHANISM OF ACTION
• AChE is an extremely active enzyme.
• ACh binds to the enzyme’s active site, undergoes
hydrolysis choline + acetylated enzyme.
• Splitting of covalent acetylated enzyme bond with addition
of water (Hydration).
• Cholinesterase inhibitors Inhibit AChE Increase in
concentration of endogenous ACh at cholinoceptors.
11. • Carbamate esters (Neostigmine and Physostigmine) 2
step hydrolysis similar to ACh.
• The covalent bond more resistant to hydration
prolonged action (t1/2- 15-30 min)
• Edrophonium(quaternary alcohol) binds electrostatically
and by hydrogen bonds to the active site.
• Covalent bond not involved (t1/2- 2-10 min)
12. • Organophosphates binding and hydrolysis
phosphorylated active site.
• Covalent phosphorous enzyme bond- extremely stable,
hydrolyses in water at a slow rate.
• Aging breaking of one oxygen-phosphorous bonds of the
inhibitor and strengthening the phosphorous enzyme bond.
13. • Once aging has occurred enzyme inhibitor complex is
more stable difficult to break.
• Pralidoxime (Cholinesterase reactivator) breaks the
phosphorous enzyme bond if given before aging.
14. PHARMACOLOGICAL ACTIONS
• Anti-AChE’s act on muscarinic, ganglionic, skeletal muscles
and CNS sites.
• Lipid soluble agents more marked muscarinic and CNS
effects.
Stimulates ganglia but action on skeletal muscles is less
prominent.
• Lipid insoluble agents marked effect on skeletal
muscles, stimulates ganglia.
Muscarinic effect less prominent. No CNS effects.
15. • CVS-
Muscarinic action bradycardia, hypotension
Ganglionic stimulation increases heart rate and BP.
• Eye
Contraction of the circular muscle of iris Miosis
Contraction of ciliary muscle spasm of accomodation,
reduction in the intraocular tension.
16. • Skeletal muscles
Accumulated ACh rebinds with the cholinoceptors
twitching and fasciculations.
Force of contraction is increased in myasthenic muscles.
At higher doses, persistent depolarisation of endplates
blockade of neuromuscular transmission weakness and
paralysis.
17. • GIT
Tone and peristalsis in the GIT is increased, sphincters
relax abdominal cramps, bowel evacuation.
• Bladder
Contraction of detruser muscle, relaxation of bladder
trigone and sphincter voiding
20. PHARMACOKINETICS
• Neostigmine-
Poorly absorbed orally.
Does not penetrate cornea or BBB.
Partially hydrolysed and partially excreted unchanged in the
urine.
• Organophosphates-
Absorbed from all sites including intact skin and lungs.
Undergo hydrolysis in the body.
21. INDIVIDUAL COMPOUNDS
• PHYSOSTIGMINE
Natural alkaloid from Physostigma venenosum.
Tertiary amine derivative.
Important use- Miotic
Dose- 0.5- 1mg oral/ parenteral
0.1- 1% eye drops
Duration of action- Systemic- 4- hrs
In eye- 6-24hrs
Adverse effect- convulsions, bradycardia, fall in cardiac
output, paralysis of skeletal muscles.
23. • PYRIDOSTIGMINE
Resembles neostigmine
Less potent and long acting
Used in Myasthenia gravis
Duration of action- 3-6 hrs.
• EDROPHONIUM
Similar to neostigmine; more rapidly absorbed.
Short duration of action- 10-20 min
Used in the diagnosis of Myasthenia gravis
Dose- 2-10mg IV
24. • RIVASTIGMINE
Cerebroselective ChE inhibitor
Highly lipid soluble
Indicated in mild- moderate AD
• DONEPEZIL
Cerebroselective and reversible
Can be used in severe cases of AD
25. • GALANTAMINE
Natural alkaloid, cerebroselective
Has direct agonistic action on nicotinic receptors
Produces cognitive and behavioural benefits in AD.
26. • ECHOTHIOPHATE
Organophosphates with quaternary structure
Potent, long acting
Water soluble
Uses- Treatment of open angle galucoma
27.
28. USES
• Ophthalmic uses- Physostigmine is used-
for the treatment of open angle glaucoma
for reversal of mydriasis
to prevent adhesions between pupils and lens
29. • Myasthenia gravis-
Neostigmine 15mg orally 6 hourly.
Pyridostigmine is an alternative, needs less frequent
dosing.
Intolerable muscarinic effects can be blocked by Atropine.
Corticosteroids- immunosuppresant activity.
- inhibit production of antibodies increasing
synthesis of nicotine receptors.
- Initally 30-60 mg/day followed by 10 mg daily or
alternate days as maintainance therapy
30. Azathioprine and cyclosporine inhibit NR-antibody
synthesis by affecting T-cells.
Plasmapheresis
Thymectomy
Myasthenic crisis??
31. • Overtreatment with anti-ChEs-
Overdose persistent depolarisation of muscle
endplate weakness Cholinergic crisis.
Edrophonium test- to differentiate cholinergic crisis
and myasthenic crisis.
Edrophonium 2mg IV--
Improvement-
Myasthenic crisis
No improvement/
worsening- Cholinergic
crisis
33. • Post operative paralytic ileus/ urinary retention- 0.5-1
mg SC neostigmine.
• Cobra bite- Neostigmine+ atropine prevents respiratory
paralysis
• Belladona poisoning- 0.5-2 mg IV Physostigmine is a
specific antidote for poisoning with belladona or other
anticholinergics.
34. Case Scenario
• A 50-year-old farmer is brought to the emergency department
in a semiconscious state and having garlic like smell. A bottle
of pesticide containing Organophosphorous compound was
found beside him says the attender. O/E, the patient has
pinpoint pupils, large amounts of secretions pouring from his
mouth. His heart rate is 120 bpm, BP 90/60 mmHg, and
oxygen saturation 65%. His chest has widespread crackles and
rhonchi. Fine fasciculations are apparent in his peri-orbital,
chest, and leg muscles. He also has incontinence of urine and
faeces.
36. • Easily available, extensively used as agricultural and
household insecticides.
• Accidental as well as suicidal and homicidal poisoning is
common.
• OP inhibits acetylcholinesterases rise in ACh activity
at nicotinic and muscarinic receptors in CNS.
37. Clinical Features
• GI symptoms- Abdominal cramps, diarrhea, vomiting.
• Excessive salivation, sweating, lacrimation, miosis.
• Involuntary defecation and urination.
• Initial tachycardia followed by bradycardia, fall in BP
38. • Irritability, disorientation, unsteadiness, tremor, ataxia,
convulsions, coma
• Skeletal muscle weakness aggravated by excessive
bronchial secretions respiratory arrest and death.
• Diagnosis should be suspected in patients presenting with
miosis, sweating, hyperperistalsis and a characteristic
garlic like odour.
• Serum and red blood cell cholinesterase activity is usually
depressed at least 50% below baseline in those who have
severe intoxication.
39. • Treatment
Termination of further exposure to poison
Maintain patent airway, positive pressure respiration
Supportive measures- maintain BP, hydration, control of
convulsions with use of diazepam
Specific antidotes- Atropine, Pralidoxime
40. • ATROPINE
Highly effective in counteracting muscarinic symptoms.
High doses required to antagonise central effects.
Atropine 2mg IV every 10 min till signs of atropinisation
occur
Continued treatment with maintainance dose may be
required for 1-2 weeks.
41. • CHOLINESTERASE REACTIVATORS
Pralidoxime, contains a quaternary ammonium group
attaches to the anionic site of the enzyme.
Oxime end reacts with the phosphorous atom attached to
the esteric site.
Oxime-phosphonate formed diffuses leaving the
reactivated ChE.
Treatment should be started early before the
phosphorylated enzyme has undergone ‘aging’ and become
resistant to hydrolysis
42. • Pralidoxime 1-2g slow IV; Children- 20-40mg/kg
• 30 mg/kg IV loading dose followed by 8-10
mg/kg/hour continuous infusion till recovery.
43. REFERENCES
Basic and clinical pharmacology – Katzung.
Lippincott’s illustrated reviews.
David E Golan’s Principles of pharmacology.
K D Tripathi
H L Sharma
