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Acetylcholinesterase Inhibitors

Acetylcholinesterase Inhibitors. Acetylcholinesterase Located in synapses Substrate selectivity: ACH. Plasma cholinesterase Located in plasma (non-neuronal) Substrate selectivity: ACH Succinylcholine Local anesthetics (procaine). Types of cholinesterases. Glu 327. His 440.

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Acetylcholinesterase Inhibitors

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  1. Acetylcholinesterase Inhibitors

  2. Acetylcholinesterase Located in synapses Substrate selectivity: ACH Plasma cholinesterase Located in plasma (non-neuronal) Substrate selectivity: ACH Succinylcholine Local anesthetics (procaine) Types of cholinesterases

  3. Glu 327 His 440 Hydrolysis of acetylcholine by AChE Phe 338 Anionic site Trp 86 Ser 203 Esteratic site

  4. Hydrolysis of acetylcholine by AChE Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site

  5. Glu 327 His 440 Hydrolysis of acetylcholine by AChE Phe 338 choline Anionic site Trp 86 Ser 203 Esteratic site

  6. Glu 327 His 440 Hydrolysis of acetylcholine by AChE Phe 338 Anionic site Trp 86 Ser 203 Esteratic site

  7. Glu 327 His 440 Hydrolysis of acetylcholine by AChE Phe 338 acetate Anionic site Trp 86 Ser 203 Esteratic site

  8. Action Potential Pharmacologic manipulation of AChE: No inhibition Ca2+ Na+ Muscarinic Receptor ACH ACH Acetylcholinesterase ACH ACH ACH ACH ACH ACH ACH ACH ACH Choline Acetate Presynaptic neuron Postsynaptic target

  9. Action Potential Pharmacologic manipulation of AChE: Inhibition by drugs Ca2+ ACH ACH Na+ ACH Muscarinic Receptor ACH ACH Acetylcholinesterase ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH Presynaptic neuron Postsynaptic target

  10. Acetylcholinesterase inhibitors • Tetraalkylammonium ions • Simplest structures • Bind to anionic site and block ACh binding • Reversible • Non-covalent R CH3 C2H5 C3H7 C4H9 Relative Potency 1.0 5.0 100 50

  11. Acetylcholinesterase inhibitors • Quaternary ammonium alcohol • Simplest structures • Bind to anionic site and block ACh binding • Reversible • Non-covalent

  12. Most basic Nitrogen; protonated at physiological pH. Acetylcholinesterase inhibitors • Carbamates • Quaternary or tertiary ammonium groups • Reversible • Covalent modification to AChE

  13. Inhibition of AChE by Neostigmine Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site

  14. Inhibition of AChE by Neostigmine Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site

  15. Inhibition of AChE by Neostigmine Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site

  16. Inhibition of AChE by Neostigmine Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site

  17. Inhibition of AChE by Neostigmine Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site

  18. Acetylcholinesterase inhibitors • Organophosphates • Irreversible • Covalent modification to AChE • Longer acting • Used in the treatment of glaucoma

  19. Acetylcholinesterase inhibitors • Organophosphates • Nerve gases • Irreversible • Covalent modification to AChE

  20. Acetylcholinesterase inhibitors • Organophosphates • Insecticides • Irreversible • Covalent modification to AChE • Rapidly inactivated in mammals

  21. Biotransformation of insecticides Cyt P450 Insects Carboxyesterase Mammals, Birds

  22. Inhibition of AChE by Organophosphates Why do these drugs selectively affect the cholinergic system? Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site

  23. Inhibition of AChE by Organophosphates Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site

  24. Inhibition of AChE by Organophosphates Aging Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site

  25. Antidote for AChE “poisoning” • Pralidoxime Chloride (Protopam; 2-pyridine aldoxime methyl chloride; 2-PAM) • Antidote for pesticide or nerve gas poisoning • Most effective if given within a few hours of exposure

  26. Regeneration of AChE by Pralidoxime Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site

  27. Regeneration of AChE by Pralidoxime Glu 327 Phe 338 His 440 Anionic site Trp 86 Ser 203 Esteratic site

  28. Glu 327 His 440 Regeneration of AChE by Pralidoxime Phe 338 Anionic site Trp 86 Ser 203 Esteratic site

  29. Clinical pharmacology of acetylcholinesterase inhibitors Type of Route of Drug inhibition 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

  30. Asthma COPD Peptic ulcer Obstruction of the urinary or GI tract Contraindications to the use of parasympathomimetic drugs

  31. SLUD Salivation Lacrimation Urination Defecation Also: Increased sweating Decreased heart rate Pupils constricted CNS activation Cholinergic agent side effects and toxicity • Treatment: • Cholinergic receptor antagonist (Atropine) • If irreversible AChE inhibitor, 2-PAM (Pralidoxime)

  32. Clinical Correlation:Alzheimer’s Disease • Most common cause of dementia after age 50 • Atrophy of brain • Widening of sulci and thinning of gyri • Improper processing of b-amyloid precursor protein (b-APP) leads to toxic form (b-A42) that promotes apoptosis • On pathological exam: • Senile plaques: b-amyloid • Neurofibrillary tangles • Loss of cholinergic neurons in brain

  33. Treatment of Alzheimer’s Disease • Bind to anionic site and block ACh binding • Reversible • Non-covalent • Enhances cognitive ability • Does not slow progression of disease • Newer agent: Donepezil (Aricept)

  34. Treatment of Alzheimer’s Disease • Reversible carbamate AChE inhibitor • Enhances cognitive ability by increasing cholinergic function • Loses effectiveness as disease progresses • Side Effects: Nausea, vomiting, anorexia, and weight loss • Newer long-acting carbamate: Eptastigmine

  35. Treatment of Alzheimer’s Disease • Reversible competitive AChE inhibitor • Extract from daffodil (Narcissus pseudonarcissus) bulbs • Loses effectiveness as disease progresses • May be a nicotinic receptor agonist • Inhibitors of P450 enzymes (3A4, 2D6) will increase galantamine bioavailability

  36. Treatment of Alzheimer’s Disease • N-methyl-D-aspartate (NMDA) receptor antagonist • NMDA receptors are activated by glutamate in the CNS in areas associated with cognition and memory • Neuronal loss in Alzheimer’s may be related to increased activity of glutamate • May slow progression of the disease • Favorable adverse effect profile

  37. Treatment of Alzheimer’s Disease On The Horizon: • Acetyl-L-carnitine - neuroprotective agent • -amyloid fibrillogenesis inhibitor (Alzhemed) - disease-modifying inhibitor of -amyloid fibril formation • Cerebrolysin – neurotrophic and neuroprotective agent • Phenserine – acetylcholinesterase and -amyloid precursor protein inhibitor • Xaliproden – neurotrophic agent

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