Acetylcholinesterase Inhibitors

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Acetylcholinesterase Inhibitors
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Types of cholinesterases

• Acetylcholinesterase
• Located in synapses
• Substrate selectivity
• ACH

• Plasma cholinesterase
• Located in plasma (non-neuronal)
• Substrate selectivity
• ACH
• Succinylcholine
• Local anesthetics (procaine)

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Hydrolysis of acetylcholine by AChE
Phe 338
Anionic site
Trp 86
Ser 203
Esteratic site
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Hydrolysis of acetylcholine by AChE
Glu 327
Phe 338
His 440
Anionic site
Trp 86
Ser 203
Esteratic site
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Hydrolysis of acetylcholine by AChE
Phe 338
choline
Anionic site
Trp 86
Ser 203
Esteratic site
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Hydrolysis of acetylcholine by AChE
Phe 338
Anionic site
Trp 86
Ser 203
Esteratic site
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Hydrolysis of acetylcholine by AChE
Phe 338
acetate
Anionic site
Trp 86
Ser 203
Esteratic site
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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
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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
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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
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Acetylcholinesterase inhibitors

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

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Acetylcholinesterase inhibitors

• Carbamates
• Quaternary or tertiary ammonium groups
• Reversible
• Covalent modification to AChE

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

• Organophosphates
• Irreversible
• Covalent modification to AChE
• Longer acting
• Used in the treatment of glaucoma

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Acetylcholinesterase inhibitors

• Organophosphates
• Nerve gases
• Irreversible
• Covalent modification to AChE

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Acetylcholinesterase inhibitors

• Organophosphates
• Insecticides
• Irreversible
• Covalent modification to AChE
• Rapidly inactivated in mammals

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Biotransformation of insecticides
Cyt P450
Insects
Carboxyesterase Mammals, Birds
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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
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Inhibition of AChE by Organophosphates
Glu 327
Phe 338
His 440
Anionic site
Trp 86
Ser 203
Esteratic site
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Inhibition of AChE by Organophosphates
Aging
Glu 327
Phe 338
His 440
Anionic site
Trp 86
Ser 203
Esteratic site
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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

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Regeneration of AChE by Pralidoxime
Glu 327
Phe 338
His 440
Anionic site
Trp 86
Ser 203
Esteratic site
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Regeneration of AChE by Pralidoxime
Glu 327
Phe 338
His 440
Anionic site
Trp 86
Ser 203
Esteratic site
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Regeneration of AChE by Pralidoxime
Phe 338
Anionic site
Trp 86
Ser 203
Esteratic site
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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, Alzheimers disease, antidote to
anticholinergic overdose
Tacrine
Rev
Oral
Alzheimers disease
Donepezil
Rev
Oral
Alzheimers disease
Isofluorophate
Irrev
Local
Glaucoma
Echothiophate
Irrev
Local
Glaucoma
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Contraindications to the use of
parasympathomimetic drugs

• Asthma
• COPD
• Peptic ulcer
• Obstruction of the urinary or GI tract

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Cholinergic agent side effects and toxicity

• SLUD
• Salivation
• Lacrimation
• Urination
• Defecation

• Also
• Increased sweating
• Decreased heart rate
• Pupils constricted
• CNS activation

• Treatment
• Cholinergic receptor antagonist (Atropine)
• If irreversible AChE inhibitor, 2-PAM
  (Pralidoxime)

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Clinical CorrelationAlzheimers 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

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Treatment of Alzheimers 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)

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Treatment of Alzheimers 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

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Treatment of Alzheimers 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

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Treatment of Alzheimers 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 Alzheimers may be related to
  increased activity of glutamate
• May slow progression of the disease
• Favorable adverse effect profile

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Treatment of Alzheimers 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