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DUMBBELLS: Diarrhea (Diaphoresis), Urination, Miosis, Bronchospasm (Secretion) Bradycardia, Excite Skeletal Muscle and CNS (Emesis), Lacrimation, Lethargy, Salivate

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DUMBBELLS: Diarrhea (Diaphoresis), Urination, Miosis, Bronchospasm (Secretion) Bradycardia, Excite Skeletal Muscle and CNS (Emesis), Lacrimation, Lethargy, Salivate 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) O N+ Poor absorption and low lipophilicity due O to charge on quaternary ammonium Multiple systemic effects, esp autonomic pathways and at the neuromuscular junction (NMJ) Receptor class Locations 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 NM NMJ Nicotinic NN Pre-synaptic ANS ganglia, adrenal medulla, CNS Acetylcholinesterase (AChE) acetylcholine receptor(AChR) presynaptic Clears Ach from site of action (also degraded by plasma butyrylcholinesterase) OH postsynaptic Bound on post-synaptic membrane acetylcholine (ACh) acetate + choline Rate = 400,000 per min Inhibition of AchE results in build up of Ach at muscarinic and nicotinic synapses! reversible 1 Step 1: Binding Anionic Esterase binding ( ) Anionic Esterase OH CH3 OH H3C O Step 2: Formation of + N CH3 O acylation 2 covalent intermediate and O deacylation ( ) (3) release choline -O acetate Anionic Esterase CH+ 3 Step 3: Hydrolysis of H O N 2 O HO CH acyl-enzyme intermediate CH3 O choline 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 + CH CH HO N 2 3 - competes w/ ACh for binding to AChE (step 1) CH3 Examples: edrophonium edrophonium CH3 O Carbamate esters + H C CH 3 N O N 3 - formation of carbamylated enzyme intermediate (step 2) CH3 CH3 CH3 Examples: neostigmine, pryidostigmine neostigmine Organophosphates O - formation of phosphorylated enzyme intermediate (step 2) P O F O Examples: parathion, malathion are insecticides isoflurophate soman, sarin are nerve agents AchE inhibitors: reversible versus irreversible Quaternary alcohols reversible 1 Anionic Esterase binding ( ) Anionic Esterase OH CH3 OH H3C O + + N CH3 O acylation 2 O deacylation ( ) (3) -O acetate Anionic Esterase CH+ 3 H O N 2 O HO CH CH3 Organophosphates O choline Carbamate esters Anionic Esterase Anionic Esterase OR O NH P O 2 OR' O O half-life >100 hrs! half-life 1-6 hrs Inhibition by organophosphate: "Aging" Anionic Esterase "aging" Anionic Esterase O OR O OH P 1 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 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 Nicotinic Nicotinic CNS CNS Ciliary spasm, Miosis Weakness Confusion Bronchoconstriction Fasciculation Anxiety, Agitation Bronchosecretion Twitching Restlessness, Tremor Diaphoresis Flaccid Paralysis (resp.) Ataxia Salivation, Lacrimation Convulsions Bradycardia, Hypotension Respiratory depression Incontinence, Diarrhea Severe Cases: also include CV collapse GI spasms (cramping) conduction block, Coma Emesis, Nausea pulmonary edema 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 .
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