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Case 1: Anticholinesterase
February 3, 2005
1. Cholinergic Pharmacology
2. Anticholinesterase inhibitors
3. Therapeutic use
4. Managing toxicity
Case: Organophosphate Poisoning
acetylcholine receptor(AChR)
presynaptic Clears Ach from site of action (also
degraded by plasma butyrylcholinesterase)
postsynaptic
OH
Bound on post-synaptic membrane
acetylcholine (ACh)
acetate + choline Rate = 400,000 per min
reversible
Step 1: Binding Anionic Esterase binding (1) Anionic Esterase
OH CH3
H 3C O OH
N
Step 2: Formation of +
CH3 O acylation
covalent intermediate and O deacylation (2)
(3)
release choline -O
acetate CH3
Anionic Esterase +
Step 3: Hydrolysis of H2O
O HO
N
CH
acyl-enzyme intermediate CH3
O choline
Direct-acting agonists
Indirect agonists
Carbamate esters O
+
H3C CH3
- formation of carbamylated enzyme intermediate (step 2) N
CH3
O N
CH3
CH3
Examples: neostigmine, pryidostigmine neostigmine
Organophosphates
O
- formation of phosphorylated enzyme intermediate (step 2) P O
F
Examples: parathion, malathion are insecticides O
isoflurophate
Quaternary alcohols
reversible
Anionic Esterase binding (1) Anionic Esterase
OH CH3
H 3C O OH
+ N
CH3 O acylation
O deacylation (2)
(3)
-O
acetate CH3
Anionic Esterase +
H2O N
O HO CH
CH3
Organophosphates O choline
Carbamate esters
Anionic Esterase
Anionic Esterase
O OR
O NH2
P
OR' O O
half-life >100 hrs! half-life 1-6 hrs
Inhibition by organophosphate: "Aging"
O OR1 O OH
P P
O OR2 O OR2
untreatable
Pralidoxime (2-PAM) NOH
can regenerate free N+
enzyme if given CH3
before aging Anionic Esterase
OH
Pharmacokinetics of organophosphates
Muscarinic
Muscarinic
Nicotinic
Nicotinic
CNS
CNS
Lethal Dose
Remove contaminated clothing; remove from exposure site
Wash skin with soap, bleach (alkaline hydrolysis)
Respiratory support (O2, ventilatory assistance, treat Sz)