Drugs modulating cholinesterase enzyme

Anticholinesterases

1. DRUGS MODULATING CHOLINESTERASE ENZYME ORGANOPHOSPHOROUS POISONING Dr. POOJA. M

2. DRUGS MODULATING CHOLINESTERASE ENZYME

3. ACETYLCHOLINE Acetic acid ester of choline CH 3 -CO-CH 2 -CH 2 N + (CH 3 ) 3 Cl - O ACh is synthesized in the axon terminal. Acetylation of choline with acetyl coenzyme A catalysed by enzyme choline acetyl transferase . Choline + acetyl coA Acetylcholine ChAT

4. Newly synthesized ACh is transported into the vesicle mediated by H + - ACh antiporter . Presynaptic action potential  rise in intracellular Ca 2+  release of ACh into the synaptic cleft. ACh in the synaptic cleft diffuses and binds to the muscarinic and nicotinic receptors producing the respective effects. Degradation of ACh is by the enzyme Acetylcholinesterase . Acetylcholine Choline + Acetic acid. Acetylcholinesterase

5. ANTICHOLINESTERASES

6. Anticholinesterases are the agents that bind to and inhibit AChE elevating the concentration of endogenously released ACh in the synaptic cleft. Accumulated ACh activates nearby cholinergic receptors. Also known as Indirectly acting ACh receptor agonists.

7. Classification REVERSIBLE Carbamates - Physostigmine Neostigmine Pyridostigmine Edrophonium Rivastigmine Donepezil Galantamine Acridine - Tacrine IRREVERSIBLE Organophosphates - Dyflos (DFP) Ecothiophate Malathion Diazinon Carbamates - Carbaryl Propoxur

8. CHEMISTRY Anti- ChEs are either esters of carbamic acid or derivatives of phosphoric acid. Carbamates may have a non polar tertiary amino N + ( Physostigmine ) or a quaternary N + ( Neostigmine ). Carbamates with tertiary N +  Lipid soluble Carbamates with quaternary N +  Lipid insoluble. All organophosphates are lipid soluble except echothiophate which is water soluble.

9. MECHANISM OF ACTION AChE is an extremely active enzyme. ACh binds to the enzyme’s active site, undergoes hydrolysis  choline + acetylated enzyme. Splitting of covalent acetylated enzyme bond with addition of water (Hydration). Cholinesterase inhibitors Inhibit AChE  Increase in concentration of endogenous ACh at cholinoceptors .

10. Carbamate esters ( Neostigmine and Physostigmine )  2 step hydrolysis similar to ACh . The covalent bond more resistant to hydration prolonged action (t 1/2 - 15-30 min) Edrophonium (quaternary alcohol) binds electrostatically and by hydrogen bonds to the active site. Covalent bond not involved (t 1/2 - 2-10 min)

11. Organophosphates  binding and hydrolysis phosphorylated active site. Covalent phosphorous enzyme bond- extremely stable, hydrolyses in water at a slow rate. Aging breaking of one oxygen-phosphorous bonds of the inhibitor and strengthening the phosphorous enzyme bond.

12. Once aging has occurred  enzyme inhibitor complex is more stable  difficult to break. Pralidoxime (Cholinesterase reactivator ) breaks the phosphorous enzyme bond if given before aging.

13. PHARMACOLOGICAL ACTIONS Anti- AChE’s act on muscarinic , ganglionic , skeletal muscles and CNS sites. Lipid soluble agents  more marked muscarinic and CNS effects. Stimulates ganglia but action on skeletal muscles is less prominent. Lipid insoluble agents  marked effect on skeletal muscles, stimulates ganglia. Muscarinic effect less prominent. No CNS effects.

14. CVS - Muscarinic action  bradycardia , hypotension Ganglionic stimulation increases heart rate and BP. Eye  Contraction of the circular muscle of iris Miosis Contraction of ciliary muscle spasm of accomodation , reduction in the intraocular tension.

15. Skeletal muscles  Accumulated ACh  rebinds with the cholinoceptors  twitching and fasciculations . Force of contraction is increased in myasthenic muscles. At higher doses, persistent depolarisation of endplates blockade of neuromuscular transmission weakness and paralysis.

16. GIT Tone and peristalsis in the GIT is increased, sphincters relax abdominal cramps, bowel evacuation. Bladder Contraction of detruser muscle, relaxation of bladder trigone and sphincter voiding

17. PHARMACOKINETICS Physostigmine - Rapidly absorbed from GIT and parenteral sites. Penetrates cornea freely. Crosses blood brain barrier. Hydrolysed by ChE .

18. PHARMACOKINETICS Neostigmine - Poorly absorbed orally. Does not penetrate cornea or BBB. Partially hydrolysed and partially excreted unchanged in the urine. Organophosphates- Absorbed from all sites including intact skin and lungs. Undergo hydrolysis in the body.

19. INDIVIDUAL COMPOUNDS PHYSOSTIGMINE Natural alkaloid from Physostigma venenosum . Tertiary amine derivative. Important use- Miotic Dose- 0.5- 1mg oral/ parenteral 0.1- 1% eye drops Duration of action- Systemic- 4- hrs In eye- 6-24hrs Adverse effect- convulsions, bradycardia , fall in cardiac output, paralysis of skeletal muscles.

20. NEOSTIGMINE Synthetic quaternary ammonium compound. Important use- Myasthenia gravis Dose- 0.5- 2.5 mg IM/SC 15-30 mg orally Duration of action- 3-4 hrs Adverse effects- Generalised cholinergic stimulation  salivation, flushing, fall in BP, nausea, pain abdomen, diarrhea, bronchospasm .

21. PYRIDOSTIGMINE Resembles neostigmine Less potent and long acting Used in Myasthenia gravis Duration of action- 3-6 hrs. EDROPHONIUM Similar to neostigmine ; more rapidly absorbed. Short duration of action- 10-20 min Used in the diagnosis of Myasthenia gravis Dose- 2-10mg IV

22. RIVASTIGMINE Cerebroselective ChE inhibitor Highly lipid soluble Indicated in mild- moderate AD DONEPEZIL Cerebroselective and reversible Can be used in severe cases of AD

23. GALANTAMINE Natural alkaloid, cerebroselective Has direct agonistic action on nicotinic receptors Produces cognitive and behavioural benefits in AD.

24. ECHOTHIOPHATE Organophosphates with quaternary structure Potent, long acting Water soluble Uses- Treatment of open angle galucoma

25. USES Ophthalmic uses- Physostigmine is used- for the treatment of open angle glaucoma for reversal of mydriasis to prevent adhesions between pupils and lens

26. Myasthenia gravis- Neostigmine 15mg orally 6 hourly. Pyridostigmine is an alternative, needs less frequent dosing. Intolerable muscarinic effects can be blocked by Atropine. Corticosteroids- immunosuppresant activity. - inhibit production of antibodies  increasing synthesis of nicotine receptors. - Initally 30-60 mg/day followed by 10 mg daily or alternate days as maintainance therapy

27. Azathioprine and cyclosporine inhibit NR-antibody synthesis by affecting T-cells. Plasmapheresis Thymectomy Myasthenic crisis??

28. Overtreatment with anti- ChEs - Overdose  persistent depolarisation of muscle endplate weakness Cholinergic crisis. Edrophonium test- to differentiate cholinergic crisis and myasthenic crisis. Edrophonium 2mg IV-- Improvement- Myasthenic crisis No improvement/ worsening- Cholinergic crisis

29. Alzheimers disease-

30. Post operative paralytic ileus / urinary retention- 0.5-1 mg SC neostigmine . Cobra bite- Neostigmine + atropine prevents respiratory paralysis Belladona poisoning- 0.5-2 mg IV Physostigmine is a specific antidote for poisoning with belladona or other anticholinergics .

31. Case Scenario A 50-year-old farmer is brought to the emergency department in a semiconscious state and having garlic like smell. A bottle of pesticide containing Organophosphorous compound was found beside him says the attender . O/E, the patient has pinpoint pupils, large amounts of secretions pouring from his mouth. His heart rate is 120 bpm , BP 90/60 mmHg, and oxygen saturation 65%. His chest has widespread crackles and rhonchi . Fine fasciculations are apparent in his peri -orbital, chest, and leg muscles. He also has incontinence of urine and faeces.

32. ORGANOPHOSPHOROUS POISONING

33. Easily available, extensively used as agricultural and household insecticides. Accidental as well as suicidal and homicidal poisoning is common. OP  inhibits acetylcholinesterases  rise in ACh activity at nicotinic and muscarinic receptors in CNS.

34. Clinical Features GI symptoms- Abdominal cramps, diarrhea, vomiting. Excessive salivation, sweating, lacrimation , miosis . Involuntary defecation and urination. Initial tachycardia followed by bradycardia , fall in BP

35. Irritability, disorientation, unsteadiness, tremor, ataxia, convulsions, coma Skeletal muscle weakness aggravated by excessive bronchial secretions  respiratory arrest and death. Diagnosis should be suspected in patients presenting with miosis , sweating, hyperperistalsis and a characteristic garlic like odour . Serum and red blood cell cholinesterase activity is usually depressed at least 50% below baseline in those who have severe intoxication.

36. Treatment Termination of further exposure to poison Maintain patent airway, positive pressure respiration Supportive measures- maintain BP, hydration, control of convulsions with use of diazepam Specific antidotes- Atropine, Pralidoxime

37. ATROPINE Highly effective in counteracting muscarinic symptoms. High doses required to antagonise central effects. Atropine 2mg IV every 10 min till signs of atropinisation occur Continued treatment with maintainance dose may be required for 1-2 weeks.

38. CHOLINESTERASE REACTIVATORS Pralidoxime , contains a quaternary ammonium group attaches to the anionic site of the enzyme. Oxime end reacts with the phosphorous atom attached to the esteric site. Oxime-phosphonate formed diffuses leaving the reactivated ChE . Treatment should be started early before the phosphorylated enzyme has undergone ‘aging’ and become resistant to hydrolysis

39. Pralidoxime 1-2g slow IV; Children- 20-40mg/kg 30 mg/kg IV loading dose followed by 8-10 mg/kg/hour continuous infusion till recovery.

40. REFERENCES Basic and clinical pharmacology – Katzung . Lippincott’s illustrated reviews. David E Golan’s Principles of pharmacology. K D Tripathi H L Sharma

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