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Cholinergic class 4th.ppt


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Cholinergic class 4th.ppt

  1. 1. Cholinergic Acting Drugs Associate prof. PhD Yulia Sorokina
  2. 2. Prescription writing 1. 0,1% solution of Physostigmine salicylate as eye drops, bottle 10 ml 2. 10 tablets of Neostigmine methylsulfate, 0,015; BID 3. 0,01% solution of Atropine sulfate for SC injection; 5 ampoules 1 ml each. OD
  3. 3. Autonomic Nervous System
  4. 4. Sites of Cholinergic Activity -Preganglionic synapses of both sympathetic and parasympathetic ganglia - Parasympathetic postganglionic neuroeffector junctions - All somatic motor end plates on skeletal muscles M2 M4 M5 M3 M1 Gi Go Adenylyl cyclase cAMP Hyperpolarization (heart) Cardiac inhibition Antagonism of smooth muscle relaxation RECEPTOR INTRACELLULAR TRANSDUCER ELECTRICAL MECHANICAL PHYSIOLOGICAL RESPONSES Gq Phospholipase C Diacyl-glycerol IP3 Depolarization Smooth muscle contraction Glandular secretion
  5. 5. Nicotinic Receptors (Activated by nicotine from tobacco) M2 (Heart & SM) M3 (Heart & SM) M4 (SM & Glands) M5 (CNS) NM (Neuromuscular) NN Autonomic ganglia, Adrenal medulla & CNS (Blocked by Trimethaphan) (Blocked by Tubocurarine) Muscarinic Receptors (Activated by muscarine from Amanita muscaria) Cholinergic Receptors: Receptors Activated by Ach M1 (Nerve Cells)
  6. 6. Muscarinic receptor types experiments that led to their discovery M1 - CNS excitation, gastric secretion M2 - bradycardia, tremor, autoinhibition of release in several brain regions M3 - Smooth muscle contraction, gland secreation, pupil dilation, ocular accommodation food intake M4 and M5 – Central Nervous System (CNS) roles, Enhanced locomotion
  7. 7. Parasympathetic Responses
  8. 8. Classes of cholinergic stimulants Direct-acting Receptor agonists Choline esters ACETYLCHOLINE BETHANECOL CARBACOL Alkaloids PILOCARPINE Cholinesterase inhibitors Carbamates PHYSOSTIGMINE NEOSTIGMINE PYRIDOSTIGMINE EDROPHONIUM Phosphates ISOFLUROPHATE Indirect-acting
  9. 9. Cholinergic Agents • Direct acting - act on the receptors to activate a tissue response • Indirect acting - inhibit the action of the enzyme Acetylcholinesterase:
  10. 10. Chemical Structure of Cholinergic agonists Tertiary amines Quaternary ammonium
  11. 11. Cholinergic System - Agonists Parasympathomimetics The extremely short half-life of AcCholine makes it therapeutically useless => • CARBACHOL: – Not hydrolyzed by AcCholinesterase – Also activates N receptors • BETHANECHOL: – Not hydrolyzed by AcCholinesterase – Does not activate N receptors – Lacks cardiovascular effects – Treatment of urinary retention Bethanechol
  12. 12. Cholinergic System - Agonists Muscarinic Parasympathomimetics Pilocarpine: – Topically ! – Used to treat glaucoma Ciliary muscle contraction=>increased outflow of aqueous humor => reduction in intraocular pressure
  13. 13. Side effects - Eyes: contraction of ciliary muscle and smooth muscle of the iris sphincter (miosis) – aqueous humor outflow, drainage of the anterior chamber - Cardiovascular: Bradycardia (possibly preceded by tachycardia), vasodilation (all vascular beds including pulmonary and coronary – M3) and hypotension, reduction of the contraction strength (atrial and ventricular cells, IK+ , ICa2+ diastolic depolarization , NO- inhibitable ATP?), negative chronotropic effect (inhibition of adrenergic activation).
  14. 14. - GI - increases in tone, amplitude of contractions, and peristaltic activity of the stomach and intestines, enhances secretory activity of the gastrointestinal tract. - Urinary bladder - increase ureteral peristalsis, contract the detrusor muscle of the urinary bladder, increase the maximal voluntary voiding pressure, and decrease the capacity of the bladder. - Other effects – Increased secretion from all glands that receive parasymphatetic enervation (salivary, lacrimal, tracheobronchial, digestive and exocrine sweat glands) - IMPORTANT - BROCHOCONSTRICTION Side effects
  15. 15. Contraindications ? • Peptic ulcer • Asthma • Ischemic heart • Hyperthyroids
  16. 16. Toxicity/Mycetism • Exaggeration of all symptoms of muscarinic agonism • Significance: Higher consumption of wild mushrooms (culinary) 30-60 minutes, salivation, lacrimation, excessive sweating, nausea, vomiting diarrhea, bronchospasm, headache, visual disturbances, abdominal colic, bradychardia, hypotension, shock ALL SYMPTOMS REVERTED BY ATROPINE 1 - 2 mg intramuscular A. muscaria
  17. 17. Cholinergic System inderct Agonists Acetylcholinesterase Inhibitors => Extend half-life of AcCholine => trigger activation of both M and N receptors
  18. 18. Acetylcholinesterase Inhibitors Reversible Inhibitors: Used to treat Glaucoma (topical) and Myasthenia Gravis (systemic) • Carbamates: – Physostigmine – Neostigmine • Quarternary alcohols: – Edrophonium Used to diagnose Myasthenia Gravis (very short half-life)
  19. 19. Acetylcholinesterase Inhibitors Irreversible Inhibitors: • Organophosphates: – Insecticides • Malathion • Parathion – Nerve gases • Sarin • Tabun • Soman Quick Time™a nd a TIFF( Unco mpre ssed ) dec ompr esso r ar e nee ded to see this pictur e. Antidote PRALIDOXIME
  20. 20. Cholinergic System - Antagonists = Cholinolytics = Parasympatholytics • Muscarinic receptor blockers: – Widespread medical applications: • Inhibition of bronchial and gastric secretion • Relaxation of smooth muscles • Cardioacceleration • CNS-altering effects • Relieving nause • Nicotinic receptor blockers: – Ganglion-specific blockers – Neuromuscular blockers: Muscle relaxants
  21. 21. Muscarinic antagonism Attropa belladona
  22. 22. History/sources • Atropa belladona - used in the renaissance • Deadly nightshade - used in the middle ages for poisoning Jimson plant leaves burned in India to treat Asthma (1800) purification of atropine (1831)
  23. 23. Muscarinic Antagonists ATROPINE SCOPOLAMINE
  24. 24. Muscarinic Antagonists ATROPINE SCOPOLAMINE Attropa belladona - Atropine and Scopolamine are belladona alkaloids (competitive inhibitors) -Drugs differ in their CNS effects, scopolamine permeates the blood-brain barrier -At therapeutic doses atropine has negligible effect upon the CNS, scopolamine even at low doses has prominent CNS effects.
  25. 25. Muscarinic Parasympatholytics Clinical applications: • Atropine: – before anesthesia: prevent hypersecretion of bronchial mucus – Bradycardy – Acetylcholinesterase-inhibitor and mushroom poisoning – Ophtalmology (eye exams) BETTER Tropicamide and Cyclopentolate – Antidote • Scopolamine: – Motion sickness (as patches) • Ipratropium and Thiotropium: – Inhalation for asthma and COPD, rainy nose nasal drops • Pirenzepine: – Peptic ulcers: selectively inhibits M1 =>reduced gastric acid production • Hyoscine butylbromidum: – Spasmolytic (intestinal or menstrual cramps)
  26. 26. Toxidrome • Anticholinergic examples of industrial chemicals and potential chemical warfare/terrorism agents: BZ (3- quinuclidinyl benzilate), and other glycolate anticholinergics (tropane alkaloids) [atropine, hyoscyamine, scopolamine]. • The clinically relevant routes of exposure and types of sources: Inhalation, ingestion, and dermal.
  27. 27. Toxidrome • Blind as a bat • dry as a bone • full as a flask • hot as hell • red as a beet • mad as a hatter • tacky (tachycardic) as a leisure suit (pink flamingo); phantom behaviors
  28. 28. Nicotinic Parasympatholytics Two classes (both act as neuromuscular blockers => muscle relaxants): • Competitive antagonists = Nondepolarizing blockers – Act by competing with AcCh for binding to the N receptors – Prevent depolarization of the endplate – Action can be reversed by increasing AcCh concentrations (e.g. via AcCh-esterase inhibitors) • Agonists = Depolarizing blockers – AcCh mimetics that are not hydrolyzed by AcCh-esterase (but hydrolyzed by plasma esterases) – Act by triggering a sustained depolarization of the neuromuscular endplate – No new action potential can be generated – Can NOT be reversed increasing AcCh concentrations (would cause further depolarization)
  29. 29. Cholinergic System - Antagonists Nicotinic Parasympatholytics Nondepolarizing blockers • Curare: – Plant derived arrow poison in S-America – Active ingredient is d-Tubocurarine – Death occurs through respiratory paralysis – Tubocurarine is not absorbed orally => no risk eating the prey – Tubocurarine was used clinically as muscle relaxant during surgery but: Tubocurarine triggers histamine release => blood pressure drops
  30. 30. Cholinergic System - Antagonists Nicotinic Parasympatholytics Nondepolarizing blockers Synthetic quarternary ammonium compounds – Replaced tubocurarine as muscle relaxants – No or little histamine release • Pancuronium long-lasting action (1-2h) Used in lethal injection (together with barbiturate + KCl) • Vecuronium intermediate-lasting action (<30min) • Atracurium intermediate-lasting action • Mivacurium short action (<15min) • etc. Pancuroniu m
  31. 31. Cholinergic System - Antagonists Nicotinic Parasympatholytics Depolarizing blockers • Succinylcholine = Suxamethonium – “dimeric” Acetylcholine – Acts agonistic like AcCh – NOT hydrolyzed by AcCh- esterase (only by plasma- esterases) – Initial depolarization triggers muscle twitching – Followed by persistent depolarization (~10min)
  32. 32. Cholinergic System Parasympathetic Drugs - Summary
  33. 33. At home • Describe Ganglion-specific blockers • Recall the sympathetic nervous system compounds and its effects on the organs functioning • Describe the following pharmacological classes • Alpha – blockers (1 student) • Drugs affecting the entire sympathetic nervous system
  34. 34. How to describe? • The name of the pharmacological group • Available classification • Mechanism of action • Pharmacological effects • Indications • Side effects • Contraindications • Antidotes
  35. 35. Questions 1. What anticholinesterase drug should not be used in ophthalmology? 2. What antidotes can be used for treatment of different poisoning. 3. Complete the table: poison Antidotes Irreversible AcHe-inhibitors Atropine Pilocarpine Physostigmine Tubocurarine chloride Succinylcholine
  36. 36. Questions 4. How does atropine influence on eyes? 5. How does ganglionic blocker influence on blood pressure? 6. How to manage shrooms intoxication with muscarine?
  37. 37. Questions 7. Dilated pupils, sensitivity to light, blurred vision, tachycardia, loss of balance, headache, rash, flushing, severely dry mouth and throat, slurred speech, urinary retention, constipation, confusion, hallucinations, delirium, and convulsions… what plant is able to cause these symptoms? 8. The Indigenous Polynesians use curare for hunting (they apply this poison on their arrows) and eat the prey. Why does not poisoning occur?