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Anticholinesterase: Revision

Harvard-MIT Division of Health Sciences and Technology 
HST.151: Principles of Pharmocology 
Instructor: Dr. Carl Rosow, Dr. David Standaert and Prof. Gary Strichartz 
Case 1: Anticholinesterase

February 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 and 
control 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. Acetylcholine
Synthesized from acetyl-CoA and choline 
by choline acetyltransferase (ChAT) 
N
Poor absorption and low lipophilicity due 
to charge on quaternary ammonium 
Multiple systemic effects, esp autonomic 
pathways and at the neuromuscular 
junction (NMJ) 
Receptor class

Muscarinic M1 
Post-synaptic ANS ganglia, CNS 
Muscarinic M2 
Heart, smooth muscle 
Muscarinic M3 
Vessels (smooth muscle), exocrine glands 
Muscarinic M4 CNS 
Muscarinic M5 CNS 
Nicotinic N
M NMJ 
Nicotinic NN 
Pre-synaptic ANS ganglia, adrenal medulla, CNS 
Locations
Acetylcholinesterase (AChE)

Clears Ach from site of action (also 
degraded by plasma butyrylcholinesterase) 
presynaptic 
postsynaptic 
acetylcholine (ACh) 
acetylcholine receptor(AChR) 
acetate + choline 
OH
Bound on post-synaptic membrane

Rate = 400,000 per min 
Inhibition of AchE results in build up of Ach at 
muscarinic and nicotinic synapses! 
reversible 
Step 1: Binding 
Anionic Esterase 
binding (1) 
Anionic Esterase 
Step 2: Formation of 
covalent intermediate and 
release choline 
CH3 
acyl-enzyme intermediate 
CH3
OH OH H3
CH3 
CH3 
Anionic Esterase 
acylation 
(2) 
HO 
-O 
acetate 
deacylation 
(3) 
choline 
Step 3: Hydrolysis of 
CH 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 alcohols 
CH2
CH3
- competes w/ ACh for binding to AChE (step 1) 
HO N
CH3 
Examples: edrophonium 
edrophonium 
CH3 
Carbamate esters 
O + 
CH3
N O N
- formation of carbamylated enzyme intermediate (step 2)
H3
CH3
CH3 
CH3 
Examples: neostigmine, pryidostigmine 
neostigmine 
Organophosphates 
- formation of phosphorylated enzyme intermediate (step 2)
O
P O 
O
Examples: parathion, malathion are insecticides isoflurophate

 soman, sarin are nerve agents
AchE inhibitors: reversible versus irreversible

Quaternary alcohols 
reversible 
CH3 
Anionic Esterase 
OH 
Anionic Esterase 
OH H3
CH3 
CH3 
binding (1) 
Anionic Esterase 
acylation 
(2) 
HO 
-O 
acetate 
deacylation 
(3) 
CH 
CH3 
Organophosphates 
choline 
Carbamate esters 
Anionic Esterase 
OR 
OR' 
NH2 
half-life >100 hrs! 
half-life 1-6 hrs 
Anionic Esterase 
P Inhibition by organophosphate: "Aging"

Anionic Esterase Anionic Esterase 
O OH 
"aging" 
OR1 
OR2 
OR2 
NOH 
untreatable 
Pralidoxime (2-PAM) 
can regenerate free 
N+ 
enzyme if given 
CH3 
before aging 
Anionic Esterase 
OH 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

Muscarinic
 Muscarinic
Ciliary spasm, Miosis
Bronchoconstriction
Bronchosecretion
Diaphoresis
Salivation, Lacrimation
Bradycardia, Hypotension
Incontinence, Diarrhea
GI spasms (cramping)
Emesis, Nausea
Nicotinic
 Nicotinic
Weakness
Fasciculation
Twitching
Flaccid Paralysis (resp.)
Severe Cases: also include Severe Cases: also include
conduction block, conduction block, 
pulmonary edema
CNS

Confusion
Anxiety, Agitation
Restlessness, Tremor
Ataxia
Convulsions
Respiratory depression
CV collapse CV collapse 
Coma
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

Photos removed for copyright reasons. 
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