This document discusses anticholinesterases, which are agents that inhibit cholinesterase and protect acetylcholine from hydrolysis. It describes their mechanism of action, classification, and examples. Anticholinesterases are either esters of carbamic acid or derivatives of phosphoric acid. They act by reversibly or irreversibly inhibiting the active site of acetylcholinesterase. Examples mentioned include physostigmine, neostigmine, pyridostigmine, edrophonium, tacrine, and donepezil. Their uses include treatment of glaucoma, myasthenia gravis, postoperative ileus, and Alzheimer's disease. The document also discusses their pharmacokinetics,

1. Anticholinestrases
Dr. Pramod P Bhalerao (M.D.)
Asst. Professor
Dept. of Pharmacology

2. Introduction
• Anticholinesterases (anti-ChEs)
are agents which inhibit ChE,
protect ACh from hydrolysis.

3. Anticholinetrases- Mechanism of Action

4. Classification of Anticholinestrases

5. Chemistry of Anticholinestrases
• Anti-ChEs are either esters of carbamic acid or derivatives of
phosphoric acid.

6. Mechanism of action
• The active region of AChE forms
a gorge which contains
• an anionic site (near glutamate)
and
• an esteratic site formed by serine
and histidine.
Acetylcholinestrases enzyme

7. • Hydrolysis of ACh involves electrostatic attraction of positively
charged N+ of ACh to the anionic site and nucleophilic
attack by serine-OH which is activated by the adjacent histidine
leading to acetylation of serine.

8. • The acetylated enzyme reacts with water extremely rapidly to produce
acetic acid and choline.
• The esteratic site is freed in a fraction of a millisecond.

9. • The carbamylated enzyme (reversible inhibitors) reacts slowly with
H2O and the phosphorylated enzyme (irreversible inhibitors) reacts
extremely slowly with H2O or not at all.

10. Pharmacological actions
• Lipid-soluble agents (physostigmine and organophosphates) have
more marked muscarinic and CNS effects; but action on skeletal
muscles is less prominent.

11. Pharmacological actions
• Lipid-insoluble agents (neostigmine and other quaternary ammonium
compounds) produce more marked effect on the skeletal muscles
(direct action on muscle endplate cholinoceptors as well), but
muscarinic effects are less prominent.
• They do not penetrate CNS and have no central effects.

12. Pharmacokinetics
• Physostigmine
• It is rapidly absorbed from g.i.t. and parenteral sites.
• Applied to the eye, it penetrates cornea freely.
• It crosses blood-brain barrier.

13. Pharmacokinetics
• Neostigmine and congeners
• These are poorly absorbed orally;
• oral dose is 20–30 times higher than parenteral dose.
• They do not effectively penetrate cornea or cross blood-brain barrier.

14. Pharmacokinetics
• Organophosphates
• These are absorbed from all sites including intact skin and lungs.

15. Individual compounds

16. • Physostigmine
• 0.25% eye drops
• Neostigmine
• 15 mg tab, 0.5 mg/ml in 1 ml and 5 ml inj

18. • Pyridostigmine
• Resembles neostigmine in all respects but is dose to dose less potent
and longer acting.
• less frequent dosing is required in myasthenia gravis.

19. • Edrophonium
• Resembles neostigmine in action, has a brief duration (10–30 min),
suitable only as a diagnostic agent for myasthenia gravis.

20. • Tacrine
• It is a lipophilic acridine compound which interacts with ChE.
• It crosses blood-brain barrier and has a longer duration of action.
• By increasing brain ACh levels it was found to produce some
symptomatic improvement in Alzheimer’s disease, but has gone
into disuse due to hepatotoxicity.

21. • Donepezil
• Another centrally acting anti-AChE that has produced cognitive and
behavioral improvement in AD.
• It is long-acting and suitable for once daily administration.

22. Precautions
• Anti-ChEs are contraindicated in sick sinus, A-V conduction defects
and hypotensive states.
• They are to be used cautiously in peptic ulcer, asthma, COPD

23. Uses of anticholinestrases
• 1. As miotic
• 2. Myasthenia gravis
• 3. Postoperative paralytic ileus/urinary retention
• 4. Postoperative decurarization
• 5. Cobra bite
• 6. Belladonna poisoning
• 7. Alzheimer’s disease

24. 1. As miotic
• (a) 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 --- i.o.t. falls in
open angle glaucoma.
• Miotics are now 3rd choice drugs, used only as add on therapy in
advanced cases.

26. Uses of anticholinestrases- 1. As miotic
• (b) To reverse the effect of
mydriatics after refraction
testing.

27. Uses of anticholinestrases- 1. As miotic
• (c) 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. 2. Myasthenia gravis
• Weakness and easy fatigability on
repeated activity, with recovery after
rest.

29. 2. Myasthenia gravis
• Myasthenia gravis is an autoimmune
disorder affecting about 1 in 10,000
population, due to development of
antibodies directed to the nicotinic
receptors (NR) at the muscle endplate ---
reduction in number of free Nm
cholinoceptors to 1/3 of normal or less
and structural damage to the
neuromuscular junction.
• This results in weakness and easy
fatigability on repeated activity, with
recovery after rest.

30. • Neostigmine and its congeners improve muscle contraction by
allowing Ach released from prejunctional endings to accumulate
and act on the receptors over a larger area.
• Treatment is usually started with neostigmine 15 mg orally 6 hourly;
• Pyridostigmine is an alternative which needs less frequent dosing.

31. Diagnostic tests for myasthenia gravis:
Tensilon Test
• Initially edrophonium 2 mg is injected i.v. as a test dose.
• If nothing untoward happens, the remaining 8 mg is injected after 30–
60 sec.
• Reversal of weakness and shortlasting improvement in the strength of
affected muscles occurs only in myasthenia gravis and not
in other muscular dystrophies.

32. 3. Postoperative paralytic ileus/urinary
retention
• This may be relieved by 0.5–1 mg s.c. neostigmine.

33. 4. Postoperative decurarization
• Neostigmine 0.5–2.0 mg (30–50 µg/kg) i.v.,, rapidly reverses muscle
paralysis induced by competitive neuromuscular blockers.
Curare like Arrow
Poison
Rocuronium- competitive
neuromuscular blocker

34. 5. Cobra bite
• Cobra venom has a curare like neurotoxin.
• Though specific antivenom serum is the
primary treatment, neostigmine + atropine
prevent respiratory paralysis.

35. 6. 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.
Atropa belladona

36. 7. Alzheimer’s disease
• Characterized by progressive dementia,
• AD is a neurodegenerative disorder,
• Primarily affecting cholinergic neurons in the brain.
• The relatively cerebroselective anti-ChEs, rivastigmine, donepezil and
galantamine are now commonly used.

37. Anticholinesterase poisoning
• Anticholinesterases are easily available and extensively used as
agricultural and household insecticides;
• Accidental as well as suicidal and homicidal poisoning is common.

38. Anticholinesterase poisoning
• Local muscarinic manifestations at the site of exposure (skin, eye,
g.i.t.) occur immediately.
• followed by complex systemic effects due to muscarinic, nicotinic and
central actions.

39. Anticholinesterase poisoning- Signs and
Symptoms
• Lacrimation,
• Salivation,
• Sweating,
• Copious tracheo-bronchial secretions,
• Miosis, Blurring of vision,
• Bronchospasm, Breathlessness,
• Colic, involuntary defecation and urination.

40. Anticholinesterase poisoning- Signs and
Symptoms
• Fall in BP, bradycardia or tachycardia, cardiac arrhythmias, vascular
collapse.
• Muscular fasciculations, weakness, respiratory paralysis (central as
well as peripheral)
• Irritability, disorientation, unsteadiness, tremor, ataxia, convulsions,
coma and death.
• Death is generally due to respiratory failure.

41. Treatment
1. Termination of further exposure to the poison— fresh air, wash the skin
and mucous membranes with soap and water, gastric lavage according to
need.
2. Maintain patent airway, positive pressure respiration if it is failing.
3. Supportive measures—maintain BP, hydration, control of convulsions with
judicious use of diazepam.
4. Specific antidotes— (a) Atropine
(b) Cholinesterase reactivators

42. Specific antidotes—
• (a) Atropine
• It is highly effective in counteracting the muscarinic symptoms, but
higher doses are required to antagonize the central effects.
• It does not reverse peripheral muscular paralysis which is a nicotinic
action.
• All cases of anti-ChE (carbamate or organophosphate) poisoning must
be promptly given atropine 2 mg i.v. repeated every 10 min till dryness
of mouth or other signs of atropinization appear.

43. Specific antidotes—
• (b) Cholinesterase reactivators
• 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 = N–OH) are provided, reactivation occurs more than a
million times faster.

44. • Pralidoxime (2-PAM) has a positively charged quaternary nitrogen:
attaches to the anionic site of the enzyme which remains unoccupied
in the presence of organophosphate inhibitors.
• Its oxime end reacts with the phosphorus atom attached to the esteratic
site: the oxime-phosphonate so formed diffuses away leaving the
reactivated ChE.

45. Pralidoxime (2-PAM)
• Pralidoxime is ineffective as an antidote to carbamate anti-ChEs
(physostigmine, neostigmine, carbaryl, propoxur) in which case the
anionic site of the enzyme is not free to provide attachment to it.

46. Pralidoxime (2-PAM)
• Pralidoxime is injected i.v. slowly in a dose of 1–2 g (children 20–40
mg/kg).
• Treatment should be started as early as possible (within few hours),
before the phosphorylated enzyme has undergone ‘aging’ and become
resistant to hydrolysis.
• The use of oximes in organophosphate poisoning is secondary to that
of atropine.

47. Thank You