Acetylcholinesterase inhibitors : Dr Rahul Kunkulol

Dr Rahul Kunkulol's Power Point Presentations

1. ANTICHOLINESTERASESANTICHOLINESTERASES
DR.RAHULDR.RAHUL
ASSO.PROF, RMC.ASSO.PROF, RMC.

2. ANTICHOLINESTERASESANTICHOLINESTERASES
These are the agents which inhibit ChE, protect These are the agents which inhibit ChE, protect
ACH from hydrolysis-produce and potentiates ACH from hydrolysis-produce and potentiates
cholinergic effects .cholinergic effects .

3. Acetylcholinesterase InhibitorsAcetylcholinesterase Inhibitors
Reversible Reversible
Do not covalently modify ACHeDo not covalently modify ACHe
a)Carbamates:a)Carbamates: b)Acridineb)Acridine
Physostigmine (t)Physostigmine (t) TacrineTacrine
Neostigmine (q)Neostigmine (q)
PyridostigminePyridostigmine
EdrophoniumEdrophonium
Rivastigmine, DonepezilRivastigmine, Donepezil
IrreversibleIrreversible
Organophosphates & CarbamatesOrganophosphates & Carbamates

4. AcetylcholinesteraseAcetylcholinesterase
Cleaved

5. Mechanism of actionMechanism of action
Acetylated enzyme reacts with water very Acetylated enzyme reacts with water very
rapidly and the esteretic site is freed in fraction rapidly and the esteretic site is freed in fraction
of milli sec.of milli sec.
Carbamylated enzyme reacts slowly (reversible Carbamylated enzyme reacts slowly (reversible
inhibitors)inhibitors)
Phosphorylated enzyme reacts extremely slowly or Phosphorylated enzyme reacts extremely slowly or
not at all.not at all.
OPPs attaches only to the esteretic site whereas drugs OPPs attaches only to the esteretic site whereas drugs
like Tacrine & Endrophonium attaches to the anionic like Tacrine & Endrophonium attaches to the anionic
site.site.

6. Carbamate Inhibitors: Carbamate Inhibitors:
PhysostigminePhysostigmine
Physostigma venenosumPhysostigma venenosum
Natural alkaloid
Tertiary amine derivative
High lipid solubility
Rapidly absorbed from git
More marked muscarinic effect
Good CNS and corneal penetration

7. Carbamate Inhibitors : Carbamate Inhibitors :
NeostigmineNeostigmine
Neostigmine Neostigmine
synthetically prepared.synthetically prepared.
Quaternary amine
Less lipid soluble
Pyridostigmine resembles Pyridostigmine resembles
neostigmine but has neostigmine but has
longer DOAlonger DOA
Some are used as Some are used as
insecticides, Carbarylinsecticides, Carbaryl
PropoxurPropoxur

8. FEATURES PHYSOSTIGMINE NEOSTIGMINE
1.Source
2.Chemistry
3.Oral absorption
4.CNS action
5.Corneal penetration
6.Action on Nm
7.Prominent effect
8.USE
9.DOA
Natural
Tertiary amine
Good
Present
Good
Absent
Autonomic effectors
Miotic (Glaucoma)
0.5-1mg oral/ parental
0.5-1% eye drops
4-6 hrs
Synthetic
Quaternary ammonium
Poor
Absent
Poor
Present
Skeletal muscles
Myasthenia gravis
0.5-2.5mg im/sc
15-30mg orally
3-4 hrs
Physostigmine and NeostigminePhysostigmine and Neostigmine

9. Competitive Inhibitors : Competitive Inhibitors :
EdrophoniumEdrophonium
Alcohol bearing a Alcohol bearing a
quaternary ammoniumquaternary ammonium
Very short durationVery short duration
Rapidly excreted by the Rapidly excreted by the
kidneyskidneys
Resembles neostigmineResembles neostigmine
Suitable as diagnostic Suitable as diagnostic
agent for MGagent for MG

10. Organophosphate DrugsOrganophosphate Drugs

11. b. Organophosphate Insecticidesb. Organophosphate Insecticides

12. Mechanism of ActionMechanism of Action
Phosphorylating the active
Site of serine.
Covalent modification
Duration: days

13. ““Aging” of Organophosphates Aging” of Organophosphates

By the loss of one of the By the loss of one of the
alkyl group the phosporylated alkyl group the phosporylated
enzyme may become enzyme may become
resistant to hydrolysis thus resistant to hydrolysis thus
causing irreversibility.causing irreversibility.
Reactivation time of Reactivation time of
carbamylated enzyme is carbamylated enzyme is
less(30mins) whereas less(30mins) whereas
phospory. E is more than phospory. E is more than
regeneration time.regeneration time.

14. c. Organophosphate Weaponsc. Organophosphate Weapons
Chemical warfare agents-nerve gasesChemical warfare agents-nerve gases
TabunTabun
Serin Serin
SomanSoman

15. Pharmacology of AChE InhibitorsPharmacology of AChE Inhibitors
Act at both muscarinic and nicotinic Act at both muscarinic and nicotinic
synapsessynapses
They potentiates synaptic transmission both They potentiates synaptic transmission both
parasympathetic and sympathetparasympathetic and sympatheticic

16. PHARMACOLOGICAL ACTIONSPHARMACOLOGICAL ACTIONS
a.a. Central nervous system Central nervous system: :
 Ache inhibitors are Lipid soluble Ache inhibitors are Lipid soluble
(Physostigmine and Ops) Cross BBB(Physostigmine and Ops) Cross BBB
 Low doses: CNS activationLow doses: CNS activation
 High: coma and respiratory arrestHigh: coma and respiratory arrest
b.b. Eye, respiratory tract, GI & urinary tract:Eye, respiratory tract, GI & urinary tract:
 The same as muscarinic agonists The same as muscarinic agonists
(regulated by parasympathetic neurons)(regulated by parasympathetic neurons)

17. PHARMACOLOGICAL ACTIONSPHARMACOLOGICAL ACTIONS
c. c. Cardiovascular:Cardiovascular:
ComplexComplex
Bradycardia, decrease contraction, cardiac outputBradycardia, decrease contraction, cardiac output
Blood vessels? No effectBlood vessels? No effect
d. d. Neuromuscular junction:Neuromuscular junction:
Increase force of contraction (low dose)Increase force of contraction (low dose)
Muscle fasciculation and depolarizing blockade Muscle fasciculation and depolarizing blockade
(high dose) weakness and paralysis(high dose) weakness and paralysis

18. Therapeutic UsesTherapeutic Uses
A. Eye: A. Eye:
Miosis and constriction of the ciliary muscle, and are Miosis and constriction of the ciliary muscle, and are
used to treat glaucomaused to treat glaucoma
B. GI and urinary tractB. GI and urinary tract: : Neostigmine 0.5-1mg s.cNeostigmine 0.5-1mg s.c..
Paralysis of the stomach and intestines Paralysis of the stomach and intestines
(paralytic illeus)(paralytic illeus)
Postpartum urinary retentionPostpartum urinary retention

19. C. Neuromuscular junctionC. Neuromuscular junction::
Myastenia Gravis----Neostigmine 0.5-2mg i.v.Myastenia Gravis----Neostigmine 0.5-2mg i.v.
Post operative decurarization induced by NMBPost operative decurarization induced by NMB
Cobra biteCobra bite
D. CNSD. CNS::
Belladona poisoningBelladona poisoning
Alzheimer’s diseaseAlzheimer’s disease
Overdose of phenothiazides, TCAsOverdose of phenothiazides, TCAs

20. GlaucomaGlaucoma
Group of disease characterized by progressive Group of disease characterized by progressive
optic nerve damage ass. with raised IOT optic nerve damage ass. with raised IOT
Treatment aims:Treatment aims:
Lower IOT by Lower IOT by :1.Reducing aqueous secretion :1.Reducing aqueous secretion
2. Promoting its drainage.2. Promoting its drainage.
TypesTypes--
Open angle glaucoma Open angle glaucoma (wide angle, chronic simple)(wide angle, chronic simple)
Closed angle glaucoma Closed angle glaucoma (narrow angle, acute congestive)(narrow angle, acute congestive)

23. Drugs used in glaucomaDrugs used in glaucoma
Open angle glaucomaOpen angle glaucoma
1.Beta adrenergic blockers-1.Beta adrenergic blockers-
Timolol(B1+B2)Timolol(B1+B2)
Betaxolol (B1)Betaxolol (B1)
LevobunololLevobunolol
2.Miotics-2.Miotics-
PilocarpinePilocarpine
PhysostigminePhysostigmine
3.Alpha agonists3.Alpha agonists
Adrenaline, Dipivefrine, Adrenaline, Dipivefrine,
apraclonidine, apraclonidine,
4.Carbonic anhydrase inhibitors4.Carbonic anhydrase inhibitors
5.latanoprost-PG analogue5.latanoprost-PG analogue
Angle closure glaucomaAngle closure glaucoma
Narrow iridocorneal angle and shallowNarrow iridocorneal angle and shallow
ant. Chamberant. Chamber
1.Beta adrenergic blockers1.Beta adrenergic blockers
`Timolol(B1+B2)`Timolol(B1+B2)
2.Miotics2.Miotics-Pilocarpine-Pilocarpine
3.iv.20% Mannitol3.iv.20% Mannitol
4.Acetazolamide 4.Acetazolamide

24. Myasthenia GravisMyasthenia Gravis
Myasthenia Gravis is an autoimmune Disease that is
characterized by a decrease in number of AChR

25. Myasthenia GravisMyasthenia Gravis
Myasthenia gravis (MG) is the most common primary disorder of neuromuscular
transmission. The usual cause is an acquired immunological abnormality, but
some cases result from genetic abnormalities at the neuromuscular junction

26. Myasthenia Gravis – Effect on the Myasthenia Gravis – Effect on the
Neuromuscular JunctionNeuromuscular Junction
NormalNormal Myasthenia gravisMyasthenia gravis

27. Myasthenia GravisMyasthenia Gravis
Symptoms: Symptoms:
Specific muscle weakness, and not of Specific muscle weakness, and not of
generalized fatigue. Ocular motor generalized fatigue. Ocular motor
disturbances, ptosis or diplopia, disturbances, ptosis or diplopia,
Oropharyngeal muscle weakness, difficulty Oropharyngeal muscle weakness, difficulty
chewing, swallowing, or talking, limb chewing, swallowing, or talking, limb
weakness. weakness.
The severity of weakness fluctuates during the The severity of weakness fluctuates during the
day, usually being least severe in the morning day, usually being least severe in the morning
and worse as the day progresses, especially and worse as the day progresses, especially
after prolonged use of affected muscles.after prolonged use of affected muscles.
Prognosis:Prognosis:
With treatment, most MG patients will have With treatment, most MG patients will have
excellent improvement of their muscle excellent improvement of their muscle
weakness.weakness.

28. Drugs Used in Myasthenia GravisDrugs Used in Myasthenia Gravis
Diagnosis: Diagnosis:
EdrophoniumEdrophonium iv (improvement)iv (improvement)5-15 min5-15 min
TreatmentTreatment: :
ANTICHOLINESTERASESANTICHOLINESTERASES
Neostigmine Neostigmine 0.5-2 hours0.5-2 hours
Pyridostigmine Pyridostigmine 3-6 hours3-6 hours
CORTICOSTEROIDS AND THYMECTOMYCORTICOSTEROIDS AND THYMECTOMY

29. Alzheimer’s Disease - SymptomsAlzheimer’s Disease - Symptoms
AD is a neurodegenerative disorder AD is a neurodegenerative disorder
Charcterized by progressive dementia Charcterized by progressive dementia
primarily affecting cholinergic neurones primarily affecting cholinergic neurones
in the brain.in the brain.

30. Alzheimer’s Disease PathologyAlzheimer’s Disease Pathology

31. Cholinergic NeuronsCholinergic Neurons

32. AChE Inhibitors Used to Treat AChE Inhibitors Used to Treat
Alzheimer’s DiseaseAlzheimer’s Disease
The first to become The first to become
available available
The first to become The first to become
passpasséé

33. AChE Inhibitors Used to Treat AChE Inhibitors Used to Treat
Alzheimer’s DiseaseAlzheimer’s Disease

34. Are They Worth It?Are They Worth It?
Effect of Rivastigmine in Alzheimer’s DiseaseEffect of Rivastigmine in Alzheimer’s Disease
RivastigmineRivastigmine Placebo Placebo
ImprovedImproved 37%37% 20% 20%
Adverse EffectsAdverse Effects23%23% 7% 7%

35. Toxicity of AChE InhibitorsToxicity of AChE Inhibitors
Organophosphorous poisoningOrganophosphorous poisoning
Autonomic Nervous System:Autonomic Nervous System:
Eye: Eye: Miosis, blurred visionMiosis, blurred vision
 Cardiovascular: Cardiovascular: Bradycardia, hypotensionBradycardia, hypotension
Glands: Glands: Extreme salivation, lacrimation, Extreme salivation, lacrimation,
sweatingsweating
Gastrointestinal:Gastrointestinal:Anorexia, nausea, vomiting, diarrheaAnorexia, nausea, vomiting, diarrhea
 Respiratory: Respiratory: Bronchoconstriction, bronchial secretion Bronchoconstriction, bronchial secretion

36. Organophosphorous poisoningOrganophosphorous poisoning
Skeletal MuscleSkeletal Muscle:: Fasciculations, weakness, paralysis Fasciculations, weakness, paralysis
CNSCNS:: Ataxia, confusion, convulsions, coma, paralysisAtaxia, confusion, convulsions, coma, paralysis
Death:Death:
Respiratory depression due to bronchoconstriction, Respiratory depression due to bronchoconstriction,
increased secretions, paralysis of diaphragm and increased secretions, paralysis of diaphragm and
intercostal muscles and central respiratory depressionintercostal muscles and central respiratory depression

37. Treatment of AChE PoisoningTreatment of AChE Poisoning
Atropine:Atropine:
Reverses muscarinic but not nicotinicReverses muscarinic but not nicotinic
2 mg i.v. repeated every 10 mins till 2 mg i.v. repeated every 10 mins till
signs of full atropinization i.e dilatation signs of full atropinization i.e dilatation
of pupils ,tachycardia.of pupils ,tachycardia.
Pralidoxime (2-PAM):Pralidoxime (2-PAM):

38. Mechanism of Action of PralidoximeMechanism of Action of Pralidoxime

39. Clinical pharmacology of acetylcholinesterase inhibitorsClinical pharmacology of acetylcholinesterase inhibitors
Drug
Type of
inhibition
Route of
administrationClinical Use
Edrophonium Rev IM or IV Diagnostic for Myasthenia Gravis
Neostigmine Rev IM, IV, or oralMyasthenia Gravis, post-operative ileus and
bladder distention, surgical adjunct
Physostigmine Rev IM, IV, or localGlaucoma, Alzheimer’s disease, antidote to
anticholinergic overdose
Tacrine Rev Oral Alzheimer’s disease
Donepezil Rev Oral Alzheimer’s disease
Isofluorophate Irrev Local Glaucoma
Echothiophate Irrev Local Glaucoma