Acetylcholine and An.cholinesterase Drugs. Nicholas J. Silvestri, M.D. Assistant Professor of Neurology
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1 Acetylcholine and An.cholinesterase Drugs Nicholas J. Silvestri, M.D. Assistant Professor of Neurology
2 Acetylcholine Major neurotransmi?er Involved in both central, autonomic, and peripheral nervous system func.on
3 Acetylcholine Synthesis and degrada.on Choline Acetyltransferase Acetyl CoA + Choline à Acetylcholine Acetylcholinesterase Acetylcholine à Choline + Acetate
4 Acetylcholine Receptors Nico.nic Muscarinic
5 Acetylcholine Receptors Nico.nic Brain Skeletal Muscle Autonomic Ganglia (pre- ganglionic- both parasympathe.c and sympathe.c) Muscarinic Parasympathe.c end organs Sweat glands (only post- ganglionic sympathe.c func.on mediated by ACh)
6 Acetylcholine
7 Physiology Acetylcholine
8 Skeletal Muscle
9 Autonomic Nervous System
10 Acetylcholinesterase Func.on: Breaks down acetylcholine in order to prevent excessive ac.vity (toxicity)
11 Acetylcholinesterase Inhibitors Physiologic effects: CNS: modulate pathways involved in cogni.on, memory, execu.ve func.oning Eye: miosis, lacrima.on Cardiac: bradycardia GI: increased produc.on of saliva, increased mo.lity, relaxa.on of sphincters, s.mulates gastric acid secre.on
12 Acetylcholinesterase Inhibitors Physiologic effects, con.nued GU: s.mula.on of bladder detrusor muscle, relaxa.on of urinary sphincter muscles Lung: bronchoconstric.on, increases bronchial secre.ons Sweat glands: increase swea.ng Skeletal muscle: enhance neuromuscular transmission
13 Acetylcholinesterase Inhibitors Therapeu.c uses Disorders of neuromuscular transmission Demen.a Non- therapeu.c uses Nerve gases Pes.cides
14 Acetylcholinesterase Inhibitors Precau.ons Asthma or COPD Cardiac conduc.on defects, par.cularly bradyarrhythmias History of GI ulcers GI or GU tract obstruc.on Hyperthyroidism
15 Acetylcholineseterase Inhibitors Disorders of Neuromuscular Transmission Myasthenia gravis, Lambert- Eaton syndrome Symptoma.c treatment Commonly used drugs Pyridos.gmine Neos.gmine Physos.gmine Edrophonium (no longer commercially available)
16 Acetylcholinesterase Inhibitors Most commonly used acetylcholinesterase inhibitor in myasthenia is pyridos.gmine (Mes.non) Ini.ated at dose of 30-60mg t.i.d. Gradually.trated to effect, most adults require mg q4-6h Doses exceeding 600mg/day typically ineffec.ve and produce side effects
17 Acetylcholinesterase Inhibitors Demen.a Alzheimer s disease, Lewy body demen.a Loss of cholinergic neurons in nucleus basalis of Meynert Medica.ons used to increase amount of acetylcholine in brain Modest benefit in slowing disease course
18 Demen.a Commonly used medica.ons: Donepezil (Aricept) Galantamine (Reminyl) Rivas.gmine (Exelon) Available both p.o. and transdermal patch
19 Non- therapeu.c Acetylcholinesterase Inhibitors Pes.cides Organophosphates: phosphorylate AChE, inhibi.ng its ac.on Nerve gases
20 Acetylcholinesterase Inhibitor Toxicity Causes Inadvertent overdose of therapeu.c agent Inten.onal or uninten.onal exposure to non- therapeu.c agents
21 Acetylcholinesterase Inhibitor Toxicity Signs: CNS: Confusion (encephalopathy) Eye: miosis, excessive lacrima.on Cardiac: bradycardia (which may lead to asystole) GI: sialorrhea, dyspepsia, abdominal cramping, diarrhea
22 Acetylcholinesterase Inhibitor Toxicity Signs, con.nued GU: urinary incon.nence Lung: bronchoconstric.on, increased bronchial secre.ons Sweat glands: increased swea.ng Skeletal muscle: fascicula.ons, depolarizing blockade leading to paralysis (cholinergic crisis)
23 Acetylcholinesterase Toxicity Treatment Emergency stabiliza.on Atropine: compe..ve inhibitor of ACh at muscarinic sites 2 PAM (pralidoxime): binds to and then removes inhibitor from AChE
24 Ques.ons?
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