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Acetylcholinesterase Inhibitors

PHM142 Fall 2013 Instructor: Dr. Jeffrey Henderson. Acetylcholinesterase Inhibitors. By: Rohini Bagchi , Janice Chan, John Chen, Melissa Taylor Date : December 4, 2013. Overview . Background Effects of AchE Inhibitors “Good” AChE Inhibitors “Bad” AChE Inhibitors. Background.

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Acetylcholinesterase Inhibitors

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  1. PHM142 Fall 2013 Instructor: Dr. Jeffrey Henderson Acetylcholinesterase Inhibitors By: RohiniBagchi, Janice Chan, John Chen, Melissa Taylor Date: December 4, 2013

  2. Overview • Background • Effects of AchE Inhibitors • “Good” AChE Inhibitors • “Bad” AChE Inhibitors

  3. Background • Acetylcholine (ACh) is a neurotransmitter with an important role in all divisions of the nervous system • 2 receptor types: nicotinic, muscarinic • Broken down in the synaptic cleft by acetylcholinesterase (AChE) • When AChE is inhibited, ACh remains intact in the synaptic cleft; thus its effects are enhanced

  4. Finkel, Richard, Luigi X. Cubeddu, and Michelle A. Clark, eds. Pharmacology. 4th ed. Baltimore: Lippincott Williams & Wilkins, 2009.

  5. Finkel, Richard, Luigi X. Cubeddu, and Michelle A. Clark, eds. Pharmacology. 4th ed. Baltimore: Lippincott Williams & Wilkins, 2009.

  6. Effects of AchE Inhibitors Some of the major effects of acetylcholinesterase inhibitors are: • Nausea • Vomiting • Diarrhea • Bronchoconstriction • Bradycardia • Gut hyposecretion • GI tract hypermotility • Muscle fasciculation and cramps • Decreased intraocular pressure • Loss of appetite and weight loss

  7. Deshpande, D.A., White, T.A., Dogan, S., Walseth, T.F., Panettieri, R.A, and Kannan, M.S. (2005). CD38/cyclic ADP-ribose signaling: role in the regulation of calcium homeostasis in airway smooth muscle. Am Jour Phys 288:733-788.

  8. Herring, N., Zaman, J. and Paterson, D. (2001). Natriuretic peptides like NO facilitate cardiac vagal neurotransmission and bradycardia via a cGMP pathway. Am. J. Physiol 28:2318-2327.

  9. Brown, T. Rapid Review Physiology, 2nd Ed. USA: Elsevier (2012).

  10. Gilhus, Nils, Iarnes, Michael and Brainin, Michael. European Handbook of Neurological Management. USA: John Wiley & Sons (2011).

  11. Good AChE Inhibitors • Alzheimers – Dementia -Donepezil** -Rivastigmine -Galantamine**

  12. Galantamine • Trade name: Razadyne • CompetitiveReversibleAChE inhibitor • Treatment of mild to moderate dementia • Nicotinic receptor agonist • Complete absorption (F=80-100%) • Long-term tolerability

  13. Donepezil Hydrochloride • Trade name: Aricept • ReversibleAChE Inhibitor • Treatment of mild to moderate dementia • Selective for AChEvsBChE (found outside CNS) • Complete absorption (F=100%) • Long halflife (70 hrs)

  14. Organophosphates • Esters/ thiolsderived from phosphoric, phosphonic, phosphinic or phosphoramidic acid • Usually irreversibly inactivates acetylcholinesterase disabled neurotransmission • General structure: Reference: Gahlaut, A., Gothwal, A., Chhillar, A., Hooda, V. “Electrochemical Biosensors for Determination of Organophosphorus Compounds: Review”. Open Journal of Applied Biosensor. 1 (2012): 1-8. doi: 10.4236/ojab.2012.11001.

  15. Organophosphate Examples -1 • Nerve Agents: Tabun, Soman, VX agent • SARIN • Phosphofluoridate • Colourless, odourless, classified as weapon of mass destruction (UN Resolution 687) • Can be ingested, inhaled + absorbed through skin • Recent Uses: Tokyo Subway Attack (1995), Syrian Civil War (2013)

  16. Mechanism of Sarin Ref: Soderberg, Tim. Organic Chemistry with a Biological Emphasis. Morris: University of Minnesota. 2005. 12.4C: Enzymatic ester hydrolysis: acetylcholinesterase and sarin nerve gas. Web: 29 Nov. 2013. http://chemwiki.ucdavis.edu/Organic_Chemistry/Organic_Chemistry_With_a_Biological_Emphasis/Chapter_12%3A_Acyl_substitution_reactions/Section_12.4%3A_Esters#Contributors • Symptoms: salivation, lacrimation, urination, defecation, GI issues, pupil contractions, bronchospasms, coma • Death occurs usually from asphyxia (stops nerve endings from switching off  hard to control muscles participating in breathing) • Antidotes: Atropine and Biperidine

  17. Ref: Gahlaut, A., Gothwal, A., Chhillar, A., Hooda, V. “Electrochemical Biosensors for Determination of Organophosphorus Compounds: Review”. Open Journal of Applied Biosensor. 1 (2012): 1-8. doi: 10.4236/ojab.2012.11001 Organophosphate Examples - 2 • Insecticides: • Parathion, Malathion • Risks: occupational exposure, leak into water supplies, non-target organism harm, human exposure from food • Causes impaired memory, headaches, insomnia, speech problems, influenza-like symptoms, neurotoxicity, etc.

  18. Carbamate Insecticides • Similar mechanism to organophosphates except reversible inhibitors of AchE • Spontaneous recovery within 4 hours for humans and mammals (pulse rate change, sweating, abdominal pain, headache, breathing issues, etc.) • Used in resistant insects, broad spectrum of pest control • Examples: Bendiocarb, Carbaryl, Methomyl Ref.: Fukuto, T. “Mechanism of Action of Organophosphorous and Carbamate Insecticides”. Environmental Health Perspectives. 87 (1990): 245-254.

  19. Summary Slide • Ach is a neurotransmitter • Broken down by AchE in the synpatic cleft • It is the primary NT at the neuromuscular junction and the autonomic nervous system • Side effects of AchE inhibitors arise from increased activation of Ach receptors • Muscarinic receptors: bronchoconstriction, bradycardia • Nicotinic receptors: muscle fasciculation and cramps • Increased levels of Ach caused hypersecretion of HCl in the stomach • Donepezil, Galantamine are better than Rivastigmine • Galantamine: competitive and reversible inhibitor, nicotinic receptor agonist • Donepezil: reversible inhibitor, highly selective for AchE • Organophosphates irreversibly bind to acetylcholinesterase and inactivate it (nerve gases and pesticides) • Sarin: phosphorylates serine active site on enzyme, loss of muscle control used in breathing leading to death by asphyxia • Symptoms: salivation, lacrimation, urination, defecation, GT issues • Carbamates reversibly bind to acetylcholinesterase, and spontaneous recovery in humans occur within 4 hours, usually used as insecticies

  20. References • Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Db. Syst. Rev.2006;1:CD005593 • Brown, T. Rapid Review Physiology, 2nd Ed. USA: Elsevier (2012). • Colovic, M., Kristic, D., Lazarevic-Pasti, T., Bondzic, A., Vasic, V. “Acetylcholinesterase Inhibitors: Pharmacology and Toxicology”. Current Neuropharmacology. 11 (2013): 315-355. • Dani, John A., and Daniel Bertrand. "Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system." Annu. Rev. Pharmacol. Toxicol. 47 (2007): 699-729. • Deshpande, D.A., White, T.A., Dogan, S., Walseth, T.F., Panettieri, R.A, and Kannan, M.S. (2005). CD38/cyclic ADP-ribose signaling: role in the regulation of calcium homeostasis in airway smooth muscle. Am Jour Phys 288:733-788. • "Facts About Sarin".Centers for Disease Control and Prevention, 17 May 2004. Web: 29 December 2013.. http://www.bt.cdc.gov/agent/sarin/basics/facts.asp • Finkel, Richard, Luigi X. Cubeddu, and Michelle A. Clark, eds. Pharmacology. 4th ed. Baltimore: Lippincott Williams & Wilkins, 2009. • Fukuto, T. “Mechanism of Action of Organophosphorous and Carbamate Insecticides”. Environmental Health Perspectives. 87 (1990): 245-254. • Gahlaut, A., Gothwal, A., Chhillar, A., Hooda, V. “Electrochemical Biosensors for Determination of Organophosphorus Compounds: Review”. Open Journal of Applied Biosensor. 1 (2012): 1-8. doi: 10.4236/ojab.2012.11001. • Gilhus, Nils, Iarnes, Michael and Brainin, Michael. European Handbook of Neurological Management. USA: John Wiley & Sons (2011). • Herring, N., Zaman, J. and Paterson, D. (2001). Natriuretic peptides like NO facilitate cardiac vagal neurotransmission and bradycardia via a cGMP pathway. Am. J. Physiol 28:2318-2327. • Holden, Mark, and Cornelius Kelly. "Use of cholinesterase inhibitors in dementia." Advances in Psychiatric Treatment. 8. (2002): 89-96. doi: 10.1192/apt.8.2.89. • International Programme on Chemical Safety, Environmental Health Criteria 64: "Carbamate Pesticides: A General Introduction". World Health Organization, Geneva, 1986. • Masuda, Y. (2004). Cardiac Effect of cholinesterase inhibitors used in Alzheimer’s disease – from basic research to bedside. Curr Alzheimer Res 4:315-321. • Soderberg, Tim. Organic Chemistry with a Biological Emphasis. Morris: University of Minnesota. 2005. 12.4C: Enzymatic ester hydrolysis: acetylcholinesterase and sarin nerve gas. Web: 29 Nov.2013. http://chemwiki.ucdavis.edu/Organic_Chemistry/Organic_Chemistry_With_a_Biological_Emphasis/Chapter_12%3A_Acyl_substitution_reactions/Section_12.4%3A_Esters#Contributors • Uchiyama, T. and Chess-Williams, R. (2004). Muscarinic receptor subtypes of the bladder and gastrointestinal tract. J Smooth Muscle Res 40(6): 237-247.

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