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Medicine LibreTexts

3: Case Study - Anticholinesterase

  • Page ID
    10626
  • Case 1: AnticholinesteraseFebruary 3, 2005

    1. Cholinergic Pharmacology

    2. Anticholinesterase inhibitors

    3. Therapeutic use

    4. Managing toxicity

    Case: Organophosphate Poisoning

    A 55 yr old crop duster calls because he has lost control over his chronic twitch, and he is now beginning to have problems with blurry vision andcontrol of his bowels and bladder. He wants to go back to the airfield to finish his crop dusting, but his supervisor makes him call you first.

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    Synthesized from acetyl-CoA and choline by choline acetyltransferase (ChAT).

    Poor absorption and low lipophilicity due to charge on quaternary ammonium.

    Multiple systemic effects, esp autonomic pathways and at the neuromuscular junction (NMJ).

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    Acetylcholinesterase (AChE)

    Clears Ach from site of action (also degraded by plasma butyrylcholinesterase)

    Bound on post-synaptic membrane

    Rate = 400,000 per min

    Inhibition of AchE results in build up of Ach at muscarinic and nicotinic synapses!

    Screen Shot 2019-01-14 at 11.06.36 AM.png

    Step 1: Binding

    Step 2: Formation of covalent intermediate and release choline

    Step 3: Hydrolysis of acyl-enzyme intermediate

    Direct-acting agonists

    Mimics acetylcholine by binding Ach receptor and activating downstream signaling

    Examples: methacholine, carbachol, bethanechol, pilocarpine

    Indirect agonists

    Inhibits AchE from breaking down acetylcholine at synapse

    Quaternary alcoholsScreen Shot 2019-01-14 at 11.09.48 AM.png

    - competes w/ ACh for binding to AChE (step 1)

    Examples: edrophonium

    Carbamate estersScreen Shot 2019-01-14 at 11.11.18 AM.png

    - formation of carbamylated enzyme intermediate (step 2)

    Examples: neostigmine, pryidostigmine

    OrganophosphatesScreen Shot 2019-01-14 at 11.12.32 AM.png

    - formation of phosphorylated enzyme intermediate (step 2)

    Examples: parathion, malathion are insecticides soman, sarin are nerve agents

    AchE inhibitors: reversible versus irreversible

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    Inhibition by organophosphate: "Aging"

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    Pharmacokinetics of organophosphates

    Parathion and malathion are biotransformed in the liver to become active (insects perform this process more efficiently)

    Highly lipid soluble, widely distributed and penetrates CNS

    When used as insecticides, can be dispersed as aerosols or dusts and absorbed by all possible routes: GI, skin, mucous membranes, lungs

    Slow hepatic metabolism; urine excretion of hydrolysis products Lipid-soluble drug can remain in systems for weeks to months!

    Effects of acute O/P overdose

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    DUMBBELLS: Diarrhea (Diaphoresis), Urination, Miosis, Bronchospasm (secretion) Bradycardia, Excite skeletal muscle and CNS (Emesis), Lacrimation, Lethargy, Salivate

    Mode of death: respiratory failure via flaccid muscular paralysis exacerbated by bronchosecretion and bronchoconstriction

    Chronic Exposure to Low Doses: blurred vision, incontinence, twitching*** neuropathy associated with axonal demyelination

    Treatment

    Lethal Dose
    Remove contaminated clothing; remove from exposure site Wash skin with soap, bleach (alkaline hydrolysis) Respiratory support (O2, ventilatory assistance, treat Sz)

    Atropine – anti-muscarinic agent

    • reverses dangerous parasympathetic effects (respiratory)

    • 0.5-2 mg IV q15min until respiratory secretions dry (days!)

    Pralidoxime (2-PAM) - specific for organophosphate poisoning

    Therapeutic use of AchE inhibitors​​​​​​​

    Myasthenia gravis (edrophonium, pyridostigmine, neostigmine)

    Alzheimer's Disease (tacrine and donepezil)

    Reversal of neuromuscular blockers (neostigmine, physostigmine)

    Glaucoma (physostigmine, echothiophate)

    Summary of Key Points​​​​​​​

    Reversible versus irreversible inhibition of AchE causes build up of Ach at synapse

    Toxicity associated with AchE inhibitors (patient case!) include global nicotinic, muscarinic, & CNS effects (DUMBBELLS)

    Treatment for Exposure to Irreversible Inhibitors Atropine – counteract ACh agonism 2-Pralidoxime – prevent aging