Cholinergics-2

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Pharmacology

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Anticholinesterases:

Dr.S.P.Dhanya Anticholinesterases

Acknowledgements:

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

Anticholinesterases:

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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H2O

MECHANISM OF ACTION:

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

(1):

(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):

(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:

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:

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:

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:

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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Hydrolysis

PowerPoint Presentation:

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:

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:

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

TACRINE:

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:

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 :

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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