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This presentation provides an overview of agents that inhibit acetylcholinesterase. This lecture was delivered to 2nd year pharmacy students enrolled in a pharmacology & toxicology course and accompanies chapter 10 of Goodman & Gillman (12e).

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  • Pronunciation: fahy-soh-stig-meen
  • Sarin is a organophosphorus compound developed in an attempt to produce a pesticide. Japanese terrorist group conducted 5 attacks simultaneously.
  • Pr: doe NEP e zil
  • Anticholinesterase

    1. 1. Anticholinesterase Agents Brian J. Piper, Ph.D., M.S.
    2. 2. Goals• Synthesis & Breakdown of Acetylcholine• Therapeutics & Toxicology
    3. 3. Dietary Sources of Choline
    4. 4. Biosynthesis of Acetylcholine ACh: Acetylcholine AcCoA: acetyl coenzyme A CAT: choline acetyltransferase Stahl (2008). Essential Psychopharmacology. p. 914.
    5. 5. Stahl (2008). Essential Psychopharmacology.
    6. 6. Anatomy of cholinergic pathways• Nucleas basilis (Basal Forebrain): connections to frontal cortex, important for cognition• Caudate-Putamen: important for motor function Meyer & Quezner (2001). Psychopharmacology.
    7. 7. Acetylcholine (ACh) in PNS Receptors N: Nicotinic M: MuscarinicKatzung et al. (2012). Basic & Clinical Pharmacology. p 80.
    8. 8. Acetylcholine Breakdown BuChE: butyrylcholinesterase (pseudo), liver, plasma VAChT: Vesicular Acetylcholine Transporter See also Animation: Cholinergic Neuroeffector Junction Stahl (2008). Essential Psychopharmacology. p. 915.
    9. 9. Oneata Gorge, ORAcetycholinesterase (AChE) GorgeStructure Colombia River Acyl Pocket (AP): Pheylalanine 295 & 297 Choline Subsite (CS): Tryptophan 86 CS Glutamic Acid 202 Tyrosine 337 AP CT Catalytic Triad (CT): Glutamic Acid 334 Histidine 447 Serine 203 (phophorylation)Bourne et al. (1995). Cell, 83, 493-506.
    10. 10. AcetycholinesteraseGorge Structure PBS Acyl Pocket (AP): Choline Subsite (CS): Catalytic Triad (CT): CS Peripheral (Rim) Binding Site (PBS): Tryptophan 286 AP CT Tryptophan 124 Tryptophan 72Bourne et al. (1995). Cell, 83, 493-506.
    11. 11. Physostigmine • Found in seed (Calabar bean) of African plant Physostigma venenosum • Reversible acetylcholinesterase inhibitor • Ordeal Poison: accusation of demonic possession – Winner: vomited (or didn’t chew beans) – Loser: miosis, excessive salivation, decreased bowel/bladder control, seizures, asphyxiation! • Used for glaucoma & belladonna overdosePronunciation:
    12. 12. Sarin (GB)• Colorless, odorless, liquid named after German scientists (Schrader, Ambros, Rudinger & Van der LINde) in 1938• Used in Subway Sarin Incident of 1995 (killed 13, injured 50)• Inhalation & skin absorption
    13. 13. Pesticides• herbicides (plants), fungicides, pediculicides (lice), acaracide (ticks & mites), biocides (microorganisms), rodenticides• Insecticides – Organophosphates (malathion): long-acting, irreversible, phosphorylate active site – Carbamates: short-acting, reversible, carbamylation of active site – “One-million people are poisoned by ACh-E inhibitor insecticides and several hundred thousand die” (world- wide)Gupta et al. (2012). Organophosphate and carbamate pesticides. In Reproductive Toxicology.
    14. 14. Organophosphate Pesticide (OP)
    15. 15. Chyka (2008). Clinicical toxicology. In Pharmacotherapy: A Pathophysiological Approach.
    16. 16. Antidote(s) to Acetycholinesterase Inhibitors• Atropine: mACh antagonist• Diazepam: GABAA allosteric modulator, seizures• Reactivators: attach to inhibitor & separate inhibitor from acetylcholinesterase (dephosphorylate) – Examples: pralidoxime (2-PAM), HI-6 – Concern: not one reactivator for all AChE-InhibitorsBagjar (2010). Acta Medica, 53, 207-211.
    17. 17. Myasthenia Gravis• Autoimmune disorder caused by antibodies against nicotinic Acetycholine receptors• Therapies include 1) neostigmine & pyridostigmine; 2) immunosuppresive; 3) thymectomy Ptosis (toe sis)0:00 to 0:45 with Jade:
    18. 18. Alzheimer’s Disease (AD)• Neurodegenerative disease• Nucleas basilis is one region affected early• AChE Inhibitors may provide some symptomatic improvement – Tacrine: short acting, infrequently used – Donepezil: long acting, commonly used
    19. 19. Stahl (2008). Essential Psychopharmacology. p. 921.
    20. 20. Stahl (2008). Essential Psychopharmacology. p. 922.
    21. 21. Alzheimer’s Disease Assessment Scale: Cognitive• Word Recall: memorize list of words for immediate recall• Orientation: name, day of week, year, place• Praxis: copy geometric pattern• Word Recognition: get list (A), differentiate A from other words (B)
    22. 22. Subtle Benefits for AD• Multi-site (23) randomized, controlled trial (N=468/273) for 3 months.• ADAS-Cognitive is clinician rated measure of memory, --------------------------------------- language, and movement (max score = 70).• Adverse effect (sweating, ↑micturition) were 34% (placebo) versus 51% (Tacrine)Farlow et al. (1992). JAMA, 268(18), 2523-2529.
    23. 23. Organophosphates & ADHD? • Parents of nationally representative sample of children were interviewed for symptoms of Attention Deficit Hyperactivity Disorder (ADHD) using the Diagnostic Interview Schedule for Children (DISC) • Child urine was analyzed for levels of organophospate metabolites (DEAP & DMAP) • Odd’s Ratio: 1.0 events equal, <.5, >1.5 statistically sigBouchard et al. (2010). Pediatrics, 125(6), e1270-1277.
    24. 24. Refresher on Goodwin Terminology I (p. 185-194)antiporter (p. 187): protein that moves two different molecules (e.g. ions) in oppositedirections across a plasma membranesatellite cells (p. 189): small progenitor cells found in muscleplexus: intricate network (nerves or blood vessels)myenteric plexus (p. 189): plexus of unmyelinated fibers and postganglionicautonomic cell bodies found in the muscular coat of the esophagus, stomach, &intestines miosis mydriasis
    25. 25. Refresher on Goodwin Terminology II (Chapter 10)reversible enzyme inhibitors (p. 239): molecules that bind to enzymes weakly (non-covalent bonds)irreversible enzyme inhibitors (p. 239): molecules that bind to enzymes strongly with covalent bondsEdrophonium (p. 241): reversible acetylcholinesterase inhibitor, used to differentiate myashthenia gravis from acholinergic crisisschistosomias (p. 245): disease caused by parasitic worm (Schistosoma), associated with unsanitary H2Oconjunctiva (p. 246): mucous membrane that covers eyeballachalasia (p. 246): inability of muscle to relaxatony (p. 246): lack of tone, muscular weaknessantidromic (p. 246): conduction of nerve impulse in the direction opposite of the usual onefasciculation (p. 246): small, localized, involuntary muscle contractionhypoxemia (p. 246): deficiency of oxygen in arterial bloodalkyl: carbon and hydrogenureter (p. 246): duct conveying urine from kidney to bladderalkoxy group (p. 249): alkyl group singly bonded to an oxygenstoichiometry (p. 249): branch of chemistry that deals with relative quantities of reactants & products inchemical reactionspesticide: substance intended for preventing, controlling, or destroying any pest including herbicides (plants),fungicides, pediculicides (lice), biocides (microorganism), & rodenticidesdysuria (p. 250): painful urinationesters: chemical compounds consisting of a carbonyl (C=0) adjacent to an ether (R-O-R’)salutary (p. 246): favorable to or promoting health
    26. 26. Alzheimer’s Disease Assessment Scale: Cognitive Schultz et al. (2001). Braz J of Med & Bio Res, 34, 1295-1302.