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Dr.S.P.Dhanya Anticholinesterases


Acknowledgements Dr.Anupama-JR,Govt.TDMCA Dr. Kumarasingam -PG Pharmacology Larrey keeley , MUSOMGraphic designs for videos


Anticholinesterases Physostigmine Galantamine Neostigmine Pyridostigmine Edrophonium Rivastigmine Donepezil Tacrine Dyflos Echothiophate Parathion Malathion Diazinon Tabun , Sarin , Soman Carbaryl Propoxur

ACh is broken by AChE:

ACh is broken by AChE

Removal of Acetylcholine :

Removal of Acetylcholine   Acetylcholine + Acetylcholinestrase H2O Choline + H+ acetate

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MECHANISM OF ACTION Acetylcholinesterase inhibitors - inhibit the AChE , responsible for breakdown of ACh increased cholinergic activity -both nicotinic and muscarinic receptors


(1) AchE + phosphates Phosphorylated enzyme Ageing-Loss of alkyl gp -resistant to hydrolysis (extremely slow reaction)

‘Ageing’ on Phosphorylated enzyme:

‘Ageing’ on Phosphorylated enzyme


(2) AchE + carbamates Carbamylated enzyme + H2O Free enzyme + carbamic acid (slow reaction) ½ life of reactivation - carbamylated enz - 30 mins -less than synthesis of fresh enzyme Edrophonium & Tacrine – attach in anionic site & does not involve hydrolysis BUT DIFFUSION action brief.

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Carbamates Binds to both sites OP Binds to esteratic site EDROPHONIUM TACRINE Hydrostatic bond E A A E E A


EFFECTS OF ACETYLCHOLINESTEASE INHIBITION Lipid soluble agent : Physostigmine , organophosphates except edrophonium Muscarinic & CNS action Skeletal muscle less prominent Lipid insoluble agent : Neostigmine , other ammonium compounds Skeletal muscle & ganglia Muscarinic effect less prominent


SKELETAL MUSCLE Ach released not degraded – Rebinds to R  repetitive firing  Twitching & Fasciculations Force of contraction in partially curarised & myasthenic muscles ↑ High doses  Persistent depolarisation in end plate  Blockade of NM transmission weakness & paralysis DIRECT action of neostigmine on end plate

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EYE : miosis GI : diarrhea, urination, vomiting, salivation RESPIRATORY : bronchoconstriction , bronchial secretion CNS : tremor, anxiety, convulsions, coma CVS : bradycardia , hypotension Skeletal muscle : fasciculation

Pharmacokinetics :

Pharmacokinetics Physostigmine Rapidly absorbed in g.i.t / parenteral Eye – penetrate the cornea Cross the BBB Disposed after hydrolysed by chE Neostigmine & congeners Poorly absorbed orally Cornea / BBB – penetration low Partially hydrolysed & partially excreted unchanged in urine Organophosphates Absorbed all sites – including intact skin & lung Hydrolysed & oxidised in the body Little is excreted unchanged form

Organophosphate poisoning:

Organophosphate poisoning Bronchoconstriction , secretions Sweating,Salivation , Lacrimation Bradycardia,Hypotention Miosis , Blurring of vision Urinary incontinence,Defecation Muscular fasciculation Tachycardia Hypertension Restlessness,Confusion Insomnia Tremors, Ataxia Convulsions Circulatory collapse Respiratory depression Signs and symptoms :

Treatment :

Treatment Termination of further exposure fresh air, wash the skin & mucosa with soap & water, gastric lavage Maintain airway- PPV if its failing Supportive measures Maintain BP Hydration control of convulsions -diazepam


SPECIFIC ANTIDOTES Atropine Highly effective -counteracting Muscarinic symptoms, higher doses antagonise central effects 2 mg IV repeated every 10 minutes till dryness of mouth Dilatation of pupil and HR upto 140 Doesnt reverse peripheral muscle paralysis


CHOLINE ESTERASE REACTIVATORS 2.OXIMES Phosphorylated enzyme reacts very slowly with water Hydrolysis occurs a million times faster if more reactive OH groups in the form of oximes are given Restore NM transmission PRALIDOXIME Quarternary N : Attaches to Anionic site – which remains unoccupied in OP poisoning

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Pralidoxime Oxime end reacts with Phosphorous : Oxime Phosphonate diffuses away- leaving reactivated Ach E Not effective in Carbamate poisoning Anionic site is not free Weak Anti CHE activity of its own Contraindicated- Doesnt reactivate carbamylated enzyme More activation of skeletal muscle than autonomic fn NO CNS action- doesnot cross BBB Given within 24 hrs before aging sets in Dose-1-2g for adults –slow iv infusion OBIDOXIME & DAM (Crosses BBB)

Delayed neurotoxicity of organophosphorus compounds:

Delayed neurotoxicity of organophosphorus compounds Fluorine containing group – dyflos , mipafox Severe polyneuropathy Mild sensory disturbances Ataxia Weakness Muscle fatigue & twitching Reduced tendon reflexes Flaccid paralysis & muscle wasting

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PHYSOSTIGMINE Natural -Alkaloid Physostigma Venenosum Tertiary amine Oral abs  Good CNS action + Penetrates cornea No DIRECT action NMJ IMP USE : MIOTIC NEOSTIGMINE Synthetic Quarternary ammonium Oral abs  Poor CNS action (-) Cornea(-) DIRECT action NMJ+ MYASTHENIA GRAVIS


PYRIDOSTIGMINE -- Neostigmine LESS Potent Longer acting EDROPHONIUM Brief dur( 10- 30 min) Diagnostic agent in Myasthenia Post operative Decurarization AMBENONIUM Another long acting congener Used in Myasthenia


RIVASTIGMINE Lipophilic Relative cerebroselective Alzheimers disease GALANTAMINE Natural Alkaloid Weak agonistic action on N Used in Alzheimers


TACRINE Lipophilic acridine compd Crosses BBB Longer duration of action ↑Brain Ach- partial improvement in AD Hepatotoxic DONEPEZIL Centrally acting Cognitive & behavioural improvement in AD


ECHOTHIOPHATE OP + Quarternary structure Water soluble, Local irritant ↓ Used -Resistant cases of glaucoma Long acting DYFLOS Very potent, Long acting Used as miotic Not used now - Irritant

Uses of anticholinesterases:

Uses of anticholinesterases 1.MIOTIC A) GLAUCOMA ↑ tone of ciliary mus ( attached to scleral spur) & ↑ tone of Sphincter pupillae  pull on & improve alignment of trabeculae  outflow facility is ↑ Physostigmine (0.1 %) Aphakic glaucoma B ) TO REVERSE EFFECT OF MYDRIATICS C ) TO PREVENT FORM OF ADHESIONS

2.Myasthenia gravis:

2.Myasthenia gravis Autoimmune disorder Nicotinic receptor antibodies obliterate the nicotinic receptors – muscle endplate Population of nicotinic receptors are reduce


MOA Anti AchE Inhibit AchE Frequency of Ach-NR interaction ↑ Muscle contraction

Treatment :

Treatment Anticholinesterases Neostigmine – 15mg oral 6 hourly-fast action Pyridostigmine-60 mg TDS-Preferred-long but delayed onset Immunosupressives Corticosteroids – prednisolone -↓AB and ↑ R-30-60mg-Better for ocular myasthenics and those not fit for surgery Azathioprine / cyclosporine Thymectomy -Remission 80%-3-5years Plasmapheresis -Removal of AB by plasma exchange

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3.POST OP PARALYTIC ILEUS / URINARY RETENTION Neostigmine 4.POST OP DECURARIZATION Atropine ( Block M ) Followed by Neostigmine 5.COBRA BITE Neostigmine + Atropine  prev Resp Paralysis 6.BELLADONA POISONING-? Physostigmine 7.ANTI CHOLINERGIC OVERDOSAGE TCA, Phenothiazine, Anti Histamine – Physostigmine 8.ALZHEIMERS DISEASE Tacrine , Donepezil , Rivastigmine, Galantamine

Alzheimer’s disease:

Alzheimer’s disease Neurodegenerative disorder-atrophy of cerebral cortex Cardinal features Dementia ,diminished Cognitive functions Progressive loss of memory+short -term memory Neurofibrillary tangles Treatment Tacrine - Not used - HEPATOTOXICITY Rivastigmine,Galantamine,Donepezil Memantine -NMDA receptor blocker

Thank You:

Thank You

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