Acetylcholinesterase inhibitors : Dr Rahul Kunkulol


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Acetylcholinesterase inhibitors : Dr Rahul Kunkulol

  2. 2. ANTICHOLINESTERASESANTICHOLINESTERASES  These are the agents which inhibit ChE, protectThese are the agents which inhibit ChE, protect ACH from hydrolysis-produce and potentiatesACH from hydrolysis-produce and potentiates cholinergic effects .cholinergic effects .
  3. 3. Acetylcholinesterase InhibitorsAcetylcholinesterase Inhibitors ReversibleReversible 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. 4. AcetylcholinesteraseAcetylcholinesterase Cleaved
  5. 5. Mechanism of actionMechanism of action  Acetylated enzyme reacts with water veryAcetylated enzyme reacts with water very rapidly and the esteretic site is freed in fractionrapidly and the esteretic site is freed in fraction of milli sec.of milli sec.  Carbamylated enzyme reacts slowly (reversibleCarbamylated enzyme reacts slowly (reversible inhibitors)inhibitors)  Phosphorylated enzyme reacts extremely slowly orPhosphorylated enzyme reacts extremely slowly or not at all.not at all.  OPPs attaches only to the esteretic site whereas drugsOPPs attaches only to the esteretic site whereas drugs like Tacrine & Endrophonium attaches to the anioniclike Tacrine & Endrophonium attaches to the anionic
  6. 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. 7. Carbamate Inhibitors :Carbamate Inhibitors : NeostigmineNeostigmine  NeostigmineNeostigmine synthetically prepared.synthetically prepared.  Quaternary amine  Less lipid soluble  Pyridostigmine resemblesPyridostigmine resembles neostigmine but hasneostigmine but has longer DOAlonger DOA  Some are used asSome are used as insecticides, Carbarylinsecticides, Carbaryl PropoxurPropoxur
  8. 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. 9. Competitive Inhibitors :Competitive Inhibitors : EdrophoniumEdrophonium  Alcohol bearing aAlcohol bearing a quaternary ammoniumquaternary ammonium  Very short durationVery short duration  Rapidly excreted by theRapidly excreted by the kidneyskidneys  Resembles neostigmineResembles neostigmine  Suitable as diagnosticSuitable as diagnostic agent for MGagent for MG
  10. 10. Organophosphate DrugsOrganophosphate Drugs
  11. 11. b. Organophosphate Insecticidesb. Organophosphate Insecticides
  12. 12. Mechanism of ActionMechanism of Action Phosphorylating the active Site of serine. Covalent modification Duration: days
  13. 13. ““Aging” of OrganophosphatesAging” of Organophosphates  By the loss of one of theBy the loss of one of the alkyl group the phosporylatedalkyl group the phosporylated enzyme may becomeenzyme may become resistant to hydrolysis thusresistant to hydrolysis thus causing irreversibility.causing irreversibility.  Reactivation time ofReactivation time of carbamylated enzyme iscarbamylated enzyme is less(30mins) whereasless(30mins) whereas phospory. E is more thanphospory. E is more than regeneration time.regeneration time.
  14. 14. c. Organophosphate Weaponsc. Organophosphate Weapons  Chemical warfare agents-nerve gasesChemical warfare agents-nerve gases TabunTabun SerinSerin SomanSoman
  15. 15. Pharmacology of AChE InhibitorsPharmacology of AChE Inhibitors  Act at both muscarinic and nicotinicAct at both muscarinic and nicotinic synapsessynapses  They potentiates synaptic transmission bothThey potentiates synaptic transmission both parasympathetic and sympathetparasympathetic and sympatheticic
  16. 16. PHARMACOLOGICAL ACTIONSPHARMACOLOGICAL ACTIONS a.a. Central nervous systemCentral nervous system::  Ache inhibitors are Lipid solubleAche 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 agonistsThe same as muscarinic agonists (regulated by parasympathetic neurons)(regulated by parasympathetic neurons)
  17. 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 blockadeMuscle fasciculation and depolarizing blockade (high dose) weakness and paralysis(high dose) weakness and paralysis
  18. 18. Therapeutic UsesTherapeutic Uses A. Eye:A. Eye:  Miosis and constriction of the ciliary muscle, and areMiosis 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 intestinesParalysis of the stomach and intestines (paralytic illeus)(paralytic illeus)  Postpartum urinary retentionPostpartum urinary retention
  19. 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. 20. GlaucomaGlaucoma  Group of disease characterized by progressiveGroup of disease characterized by progressive optic nerve damage ass. with raised IOToptic nerve damage ass. with raised IOT  Treatment aims:Treatment aims: Lower IOT byLower IOT by :1.Reducing aqueous secretion:1.Reducing aqueous secretion 2. Promoting its drainage.2. Promoting its drainage. TypesTypes--  Open angle glaucomaOpen angle glaucoma (wide angle, chronic simple)(wide angle, chronic simple)  Closed angle glaucomaClosed angle glaucoma (narrow angle, acute congestive)(narrow angle, acute congestive)
  21. 21. 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.Acetazolamide4.Acetazolamide
  22. 22. Myasthenia GravisMyasthenia Gravis Myasthenia Gravis is an autoimmune Disease that is characterized by a decrease in number of AChR
  23. 23. 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
  24. 24. Myasthenia Gravis – Effect on theMyasthenia Gravis – Effect on the Neuromuscular JunctionNeuromuscular Junction NormalNormal Myasthenia gravisMyasthenia gravis
  25. 25. Myasthenia GravisMyasthenia Gravis Symptoms:Symptoms:  Specific muscle weakness, and not ofSpecific muscle weakness, and not of generalized fatigue. Ocular motorgeneralized fatigue. Ocular motor disturbances, ptosis or diplopia,disturbances, ptosis or diplopia, Oropharyngeal muscle weakness, difficultyOropharyngeal muscle weakness, difficulty chewing, swallowing, or talking, limbchewing, swallowing, or talking, limb weakness.weakness.  The severity of weakness fluctuates during theThe severity of weakness fluctuates during the day, usually being least severe in the morningday, usually being least severe in the morning and worse as the day progresses, especiallyand 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 haveWith treatment, most MG patients will have excellent improvement of their muscleexcellent improvement of their muscle weakness.weakness.
  26. 26. Drugs Used in Myasthenia GravisDrugs Used in Myasthenia Gravis  Diagnosis:Diagnosis: EdrophoniumEdrophonium iv (improvement)iv (improvement) 5-15 min5-15 min  TreatmentTreatment::  ANTICHOLINESTERASESANTICHOLINESTERASES NeostigmineNeostigmine 0.5-2 hours0.5-2 hours PyridostigminePyridostigmine 3-6 hours3-6 hours  CORTICOSTEROIDS AND THYMECTOMYCORTICOSTEROIDS AND THYMECTOMY
  27. 27. Alzheimer’s Disease - SymptomsAlzheimer’s Disease - Symptoms AD is a neurodegenerative disorderAD is a neurodegenerative disorder Charcterized by progressive dementiaCharcterized by progressive dementia primarily affecting cholinergic neuronesprimarily affecting cholinergic neurones in the the brain.
  28. 28. Alzheimer’s Disease PathologyAlzheimer’s Disease Pathology
  29. 29. Cholinergic NeuronsCholinergic Neurons
  30. 30. AChE Inhibitors Used to TreatAChE Inhibitors Used to Treat Alzheimer’s DiseaseAlzheimer’s Disease  The first to becomeThe first to become availableavailable  The first to becomeThe first to become passpasséé
  31. 31. AChE Inhibitors Used to TreatAChE Inhibitors Used to Treat Alzheimer’s DiseaseAlzheimer’s Disease
  32. 32. Are They Worth It?Are They Worth It? Effect of Rivastigmine in Alzheimer’s DiseaseEffect of Rivastigmine in Alzheimer’s Disease RivastigmineRivastigmine PlaceboPlacebo ImprovedImproved 37%37% 20%20% Adverse EffectsAdverse Effects 23%23% 7%7%
  33. 33. 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 secretionBronchoconstriction, bronchial secretion
  34. 34. Organophosphorous poisoningOrganophosphorous poisoning Skeletal MuscleSkeletal Muscle:: Fasciculations, weakness, paralysisFasciculations, 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 andincreased secretions, paralysis of diaphragm and intercostal muscles and central respiratory depressionintercostal muscles and central respiratory depression
  35. 35. 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 till2 mg i.v. repeated every 10 mins till signs of full atropinization i.e dilatationsigns of full atropinization i.e dilatation of pupils ,tachycardia.of pupils ,tachycardia.  Pralidoxime (2-PAM):Pralidoxime (2-PAM):
  36. 36. Mechanism of Action of PralidoximeMechanism of Action of Pralidoxime
  37. 37. Clinical pharmacology of acetylcholinesterase inhibitorsClinical pharmacology of acetylcholinesterase inhibitors Drug Type of inhibition Route of administration Clinical Use Edrophonium Rev IM or IV Diagnostic for Myasthenia Gravis Neostigmine Rev IM, IV, or oral Myasthenia Gravis, post-operative ileus and bladder distention, surgical adjunct Physostigmine Rev IM, IV, or local Glaucoma, 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