Acetylcholinesterase inhibitors
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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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Acetylcholinesterase inhibitors

Acetylcholinesterase Inhibitors


Types of cholinesterases

Acetylcholinesterase

Located in synapses

Substrate selectivity:

ACH

Plasma cholinesterase

Located in plasma (non-neuronal)

Substrate selectivity:

ACH

Succinylcholine

Local anesthetics (procaine)

Types of cholinesterases


Hydrolysis of acetylcholine by ache

Glu 327

His 440

Hydrolysis of acetylcholine by AChE

Phe 338

Anionic site

Trp 86

Ser 203

Esteratic site


Hydrolysis of acetylcholine by ache1

Hydrolysis of acetylcholine by AChE

Glu 327

Phe 338

His 440

Anionic site

Trp 86

Ser 203

Esteratic site


Hydrolysis of acetylcholine by ache2

Glu 327

His 440

Hydrolysis of acetylcholine by AChE

Phe 338

choline

Anionic site

Trp 86

Ser 203

Esteratic site


Hydrolysis of acetylcholine by ache3

Glu 327

His 440

Hydrolysis of acetylcholine by AChE

Phe 338

Anionic site

Trp 86

Ser 203

Esteratic site


Hydrolysis of acetylcholine by ache4

Glu 327

His 440

Hydrolysis of acetylcholine by AChE

Phe 338

acetate

Anionic site

Trp 86

Ser 203

Esteratic site


Acetylcholinesterase inhibitors

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


Acetylcholinesterase inhibitors

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


Acetylcholinesterase inhibitors1

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


Acetylcholinesterase inhibitors2

Acetylcholinesterase inhibitors

  • Quaternary ammonium alcohol

  • Simplest structures

  • Bind to anionic site and block ACh binding

  • Reversible

  • Non-covalent


Acetylcholinesterase inhibitors3

Most basic Nitrogen;

protonated at physiological pH.

Acetylcholinesterase inhibitors

  • Carbamates

  • Quaternary or tertiary ammonium groups

  • Reversible

  • Covalent modification to AChE


Inhibition of ache by neostigmine

Inhibition of AChE by Neostigmine

Glu 327

Phe 338

His 440

Anionic site

Trp 86

Ser 203

Esteratic site


Inhibition of ache by neostigmine1

Inhibition of AChE by Neostigmine

Glu 327

Phe 338

His 440

Anionic site

Trp 86

Ser 203

Esteratic site


Inhibition of ache by neostigmine2

Inhibition of AChE by Neostigmine

Glu 327

Phe 338

His 440

Anionic site

Trp 86

Ser 203

Esteratic site


Inhibition of ache by neostigmine3

Inhibition of AChE by Neostigmine

Glu 327

Phe 338

His 440

Anionic site

Trp 86

Ser 203

Esteratic site


Inhibition of ache by neostigmine4

Inhibition of AChE by Neostigmine

Glu 327

Phe 338

His 440

Anionic site

Trp 86

Ser 203

Esteratic site


Acetylcholinesterase inhibitors4

Acetylcholinesterase inhibitors

  • Organophosphates

  • Irreversible

  • Covalent modification to AChE

  • Longer acting

  • Used in the treatment of glaucoma


Acetylcholinesterase inhibitors5

Acetylcholinesterase inhibitors

  • Organophosphates

  • Nerve gases

  • Irreversible

  • Covalent modification to AChE


Acetylcholinesterase inhibitors6

Acetylcholinesterase inhibitors

  • Organophosphates

  • Insecticides

  • Irreversible

  • Covalent modification to AChE

  • Rapidly inactivated in mammals


Biotransformation of insecticides

Biotransformation of insecticides

Cyt P450

Insects

Carboxyesterase

Mammals, Birds


Inhibition of ache by organophosphates

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


Inhibition of ache by organophosphates1

Inhibition of AChE by Organophosphates

Glu 327

Phe 338

His 440

Anionic site

Trp 86

Ser 203

Esteratic site


Inhibition of ache by organophosphates2

Inhibition of AChE by Organophosphates

Aging

Glu 327

Phe 338

His 440

Anionic site

Trp 86

Ser 203

Esteratic site


Antidote for ache poisoning

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


Acetylcholinesterase inhibitors

Regeneration of AChE by Pralidoxime

Glu 327

Phe 338

His 440

Anionic site

Trp 86

Ser 203

Esteratic site


Acetylcholinesterase inhibitors

Regeneration of AChE by Pralidoxime

Glu 327

Phe 338

His 440

Anionic site

Trp 86

Ser 203

Esteratic site


Regeneration of ache by pralidoxime

Glu 327

His 440

Regeneration of AChE by Pralidoxime

Phe 338

Anionic site

Trp 86

Ser 203

Esteratic site


Clinical pharmacology of acetylcholinesterase inhibitors

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


Contraindications to the use of parasympathomimetic drugs

Asthma

COPD

Peptic ulcer

Obstruction of the urinary or GI tract

Contraindications to the use of parasympathomimetic drugs


Cholinergic agent side effects and toxicity

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)


Clinical correlation alzheimer s disease

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


Treatment of alzheimer s disease

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)


Treatment of alzheimer s disease1

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


Treatment of alzheimer s disease2

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


Treatment of alzheimer s disease3

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


Treatment of alzheimer s disease4

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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