Case 1: AnticholinesteraseFebruary 3, 2005
- Cholinergic Pharmacology
- Anticholinesterase inhibitors
- Therapeutic use
- 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.
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).
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!
Step 1: Binding
Step 2: Formation of covalent intermediate and release choline
Step 3: Hydrolysis of acyl-enzyme intermediate
Mimics acetylcholine by binding Ach receptor and activating downstream signaling
Examples: methacholine, carbachol, bethanechol, pilocarpine
Inhibits AchE from breaking down acetylcholine at synapse
- competes w/ ACh for binding to AChE (step 1)
- formation of carbamylated enzyme intermediate (step 2)
Examples: neostigmine, pryidostigmine
- formation of phosphorylated enzyme intermediate (step 2)
Examples: parathion, malathion are insecticides soman, sarin are nerve agents
AchE inhibitors: reversible versus irreversible
Inhibition by organophosphate: "Aging"
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
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
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