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Cholinoceptor activating & cholinesterase-inhibiting drugs


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  • 1. Cholinoceptor-Activating &Cholinesterase-Inhibiting Drugs By M.H.Farjoo M.D. , Ph.D. Shahid Beheshti University of Medical Science
  • 2. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs Introduction Classification Indirect-acting Cholinomimetics Nicotine Dual Effect Organ Effects & Clinical Applications Intoxication Drug pictures
  • 3. Schematic diagram comparing some anatomic andneurotransmitter features of autonomic and somatic motornerves. Only the primary transmitter substances are shown.Parasympathetic ganglia are not shown because most areof vessels Smooth muscle residing in skeletal musclein or near the wall of the organ innervated. Cholinergicnerves are shown in blue; noradrenergic in red; anddopaminergic in green. Note that some sympatheticpostganglionic fibers release acetylcholine or dopaminerather than norepinephrine. The adrenal medulla, amodified sympathetic ganglion, receives sympatheticpreganglionic fibers and releases epinephrine andnorepinephrine into the blood. ACh, acetylcholine; D,dopamine; Epi, epinephrine; M, muscarinic receptors; N,nicotinic receptors; NE, norepinephrine.
  • 4. Introduction  Nicotine stimulates autonomic ganglia and skeletal muscle but not autonomic effector cells.  The ganglion and skeletal muscle receptors were therefore labeled nicotinic.  Muscarine stimulates autonomic effector cells; hence muscarinic.M.H.Farjoo
  • 5. Introduction Cont,d  All muscarinic receptors are of G-protein coupled type.  All nicotinic receptors are ion channels.  The tertiary cholinomimetics are very well absorbed from sites of administration and enter CNS readily.M.H.Farjoo
  • 6. Classification  Direct-acting cholinomimetics:  Esters of choline (acetylcholine, bethanechol)  Alkaloids (muscarine, nicotine)  Indirect-acting cholinomimetic:  Alcohols (edrophonium) Reversible  Esters of carbamic acid (neostigmine)  Organophosphates (echothiophate) IrreversibleM.H.Farjoo
  • 7. indirect-acting cholinomimetic
  • 8. Indirect-acting Cholinomimetics  The indirect-acting cholinomimetics inhibit acetylcholinesterase.  Carbamate insecticides are rapidly absorbed into the insect and distribute to its CNS very rapidly.  Soman is an extremely potent "nerve gas.“  Parathion and malathion (insecticides) are converted to the active derivatives in animals and plants.M.H.Farjoo
  • 9. Indirect-acting Cholinomimetics Cont,d  Physostigmine is well absorbed and is used topically in the eye.  It is distributed into the CNS and is more toxic than the more polar quaternary carbamates.  The organophosphates are well absorbed from all body sites so are dangerous to humans and highly effective as insecticides.M.H.Farjoo
  • 10. Indirect-acting Cholinomimetics Cont,d  Malathion is metabolized in birds and mammals but not in insects.  These agents are safe for sale to the general public.  Fish cannot detoxify malathion, and significant numbers of fish have died from the heavy use of this agent.  All of the organophosphates except echothiophate are distributed to all parts of the body including the CNS.M.H.Farjoo
  • 11. Indirect-acting Cholinomimetics Cont,d  Acetylcholinesterase is extremely active, acting within 150 microseconds.  Edrophonium inhibits the enzyme for 2-10 minutes.  The effect of neostigmine and physostigmine lasts 30 minutes to 6 hours.  Organophosphates bind covalently and hydrolyzes at a rate of hundreds of hours.M.H.Farjoo
  • 12. Nicotine Dual Effect  The nicotine simulates both the sympathetic and the parasympathetic system.  In cardiovascular system, the effects are chiefly sympathetic (hypertension, cardiac arrhythmias).  In GI & urinary tracts, the effects are parasympathetic (vomiting, diarrhea, and urine voiding).M.H.Farjoo
  • 13. Organ Effects & Clinical Applications  Eye  Cardiovascular System  Respiratory System  Gastrointestinal Tract  Genitourinary Tract  Secretory Glands  Central Nervous System  Neuromuscular Junction  Antimuscarinic IntoxicationM.H.Farjoo
  • 14. Eye  Direct acting muscarinic agonists:  Cause miosis and accommodation.  Facilitate aqueous humor outflow into the canal of schlemm.  Indirect acting drugs:  Similar to direct-acting cholinomimetics.M.H.Farjoo
  • 15. Structures of the anterior chamber of theeye. Tissues with significant autonomicfunctions and the associated ANSreceptors are shown in this schematicdiagram. Aqueous humor is secreted bythe epithelium of the ciliary body, flowsinto the space in front of the iris, flowsthrough the trabecular meshwork, andexits via the canal of Schlemm (arrow).Blockade of the adrenoceptors associatedwith the ciliary epithelium causesdecreased secretion of aqueous. Bloodvessels (not shown) in the sclera are alsounder autonomic control and influenceaqueous drainage.
  • 16. Clinical Application for Eye  In acute angle-closure glaucoma a combination of a direct muscarinic agonist and a cholinesterase inhibitor is used.  Accommodative esotropia is sometimes diagnosed and treated with cholinomimetic agonists.M.H.Farjoo
  • 17. Cardiovascular System  Direct acting muscarinic agonists:  Reduce vascular resistance and change the heart rate.  Decrease the contractility of atrial cells.  Slowing of sinoatrial and atrioventricular rate is opposed by reflex sympathetic discharge.  In the intact organism, muscarinic agonists produce marked vasodilation.M.H.Farjoo
  • 18. Cardiovascular System Cont,d  Direct acting Muscarinic agonists:  Muscarinic agonists release endothelium- derived relaxing factor (EDRF) that relaxes smooth muscle.  EDRF appears to be largely nitric oxide (NO).  Choline esters are resistant to cholinesterase, so have longer duration of actions.M.H.Farjoo
  • 19. Cardiovascular System Cont,d  Indirect acting drugs:  In the heart, the effects on the parasympathetic predominate (mimic the effects of vagus nerve).  The net effects of cholinesterase inhibitors is: bradycardia and modest fall in blood pressure.  Large (toxic) doses of these drugs cause more marked bradycardia and hypotension.M.H.Farjoo
  • 20. Respiratory System  Direct acting drugs:  Muscarinic stimulants contract the smooth muscle of the bronchial tree.  The glands of the tracheobronchial mucosa are stimulated to secrete.  Indirect acting drugs:  Similar to direct-acting cholinomimetics.M.H.Farjoo
  • 21. Gastrointestinal Tract  Direct acting drugs:  The secretory and motor activity of the gut is increased.  Peristaltic activity is increased throughout the gut, and most sphincters are relaxed.  Indirect acting drugs:  Similar to direct-acting cholinomimetics.M.H.Farjoo
  • 22. Genitourinary Tract  Direct acting drugs:  Muscarinic agonists stimulate the detrusor and relax the sphincter of the bladder, thus promoting voiding.  Indirect acting drugs:  Similar to direct-acting cholinomimeticsM.H.Farjoo
  • 23. Clinical Application for GI & GU Tracts  Cholinomimetics are used to increase the tone of the lower esophageal sphincter in reflux esophagitis.  Other applications are:  Postoperative ileus and congenital megacolon.  Urinary retention postoperatively or postpartum or neurogenic bladder.M.H.Farjoo
  • 24. Clinical Application for GI & GU Tracts Cont,d  Of the choline esters, bethanechol is the most widely used for these disorders.  Of the cholinesterase inhibitors, neostigmine is the most widely used for these applications.  The clinician must be certain that there is no mechanical obstruction otherwise, the drug may cause perforation.M.H.Farjoo
  • 25. Secretory Glands  Direct acting drugs:  Muscarinic agonists stimulate secretion by thermoregulatory sweat, lacrimal, and nasopharyngeal glands.M.H.Farjoo
  • 26. Central Nervous System  Direct acting drugs:  The brain is richer in muscarinic sites while the spinal cord has more nicotinic sites.  Nicotine and lobeline cause mild alertness.  In high concentrations, nicotine induces tremor and emesis.M.H.Farjoo
  • 27. Central Nervous System Cont,d  Direct acting drugs:  At higher levels, nicotine causes convulsions, which may terminate in fatal coma.  Indirect acting drugs:  Similar to direct-acting cholinomimetics.M.H.Farjoo
  • 28. Clinical Application For CNS  Tacrine & donepezilhas are cholinomimetics used for Alzheimers disease.  Varenicline is a nicotinic agonist that is approved for smoking cessation treatment.M.H.Farjoo
  • 29. Neuromuscular Junction  Direct acting drugs:  A nicotinic agonist can cause from disorganized fasciculations to a strong contraction.  Prolonged occupancy of the nicotinic receptor abolishes the response of the postjunctional membrane.  The continued presence of the nicotinic agonist prevents electrical recovery of the postjunctional membrane (depolarizing blockade).M.H.Farjoo
  • 30. Neuromuscular Junction Cont,d  Indirect acting drugs:  Therapeutic concentrations prolong and intensify the actions of acetylcholine.  This increases strength of contraction in curare- like neuromuscular blocking or in myasthenia gravis.M.H.Farjoo
  • 31. Clinical Application for NMJ  Cholinesterase inhibitors (but not direct-acting agonists) are extremely valuable for myasthenia.  Edrophonium is used to assess the adequacy of treatment in myasthenia gravis.  Edrophonium produces no relief if the patient is receiving excessive cholinesterase inhibitor therapy.M.H.Farjoo
  • 32. Clinical Application for NMJ Cont,d  If the patient improves with edrophonium, an increase in cholinesterase inhibitor dosage is indicated.  Neuromuscular blockade is also produced for surgery.  Following surgery, the paralysis is reversed with cholinesterase inhibitors.M.H.Farjoo
  • 33. Therapeutic uses and durations of action of cholinesterase inhibitors Duration of Uses ActionAlcohols Myasthenia gravis, ileus, Edrophonium - minutes arrhythmiasCarbamates and related agents Neostigmine Myasthenia gravis, ileus - hours Pyridostigmine Myasthenia gravis - hours Physostigmine Glaucoma - hours Ambenonium Myasthenia gravis - hours Demecarium Glaucoma - hoursOrganophosphates Echothiophate Glaucoma hours
  • 34. Antimuscarinic Intoxication  Atropine intoxication is lethal in children. and may cause arrhythmias in adults.  The TCA overdosage causes severe muscarinic blockade.  The above agents are competitive antagonists and can be overcome by increasing acetylcholine.M.H.Farjoo
  • 35. Antimuscarinic Intoxication Cont,d  Physostigmine is used for treatment, because it reverses both the central and the peripheral signs.  Physostigmine itself can be dangerous on CNS.  It is only used in dangerous hyperthermia or very rapid supraventricular tachycardia.M.H.Farjoo
  • 36. Intoxication  Muscarinic  Nicotinic  AChE InhibitorsM.H.Farjoo
  • 37. Muscarinic Intoxication  The effects include: nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, and bronchial constriction.  Certain mushrooms, contain muscarinic alkaloids. If ingested they cause signs of muscarinic excess.  Treatment is with atropine.M.H.Farjoo
  • 38. Nicotinic Intoxication  The fatal dose of nicotine is 40 mg. This is the nicotine present in two cigarettes.  Ingestion of nicotine insecticides or of tobacco is usually followed by vomiting, limiting the amount absorbed.  The signs include: convulsion, coma and respiratory arrest, respiratory paralysis and arrhythmias.M.H.Farjoo
  • 39. Nicotinic Intoxication Cont,d  Muscarinic excess resulting from parasympathetic ganglion stimulation can be controlled with atropine.  Central stimulation is treated with diazepam.  Neuromuscular blockade is not responsive to drugs and may require mechanical respiration.  Nicotine is metabolized rapidly. Patients who survive the first 4 hours recover completely if brain damage have not occurred.M.H.Farjoo
  • 40. Nicotinic Intoxication Cont,d  The addictive power of cigarettes is directly related to their nicotine content.  Smoking increases vascular disease, sudden coronary death and ulcer recurrences in peptic ulcer.M.H.Farjoo
  • 41. AChE Inhibitor Intoxication  The initial signs are of muscarinic excess.  Therapy always includes:  Maintenance of vital signs especially respiration.  Decontamination by removal of all clothing and washing of the skin.M.H.Farjoo
  • 42. AChE Inhibitor Intoxication  Therapy Cont,d :  Atropine parenterally in large doses as often as required.  Pralidoxime is able to regenerate cholinesterase to reverse insecticide poisoning.M.H.Farjoo
  • 43. bethanechol
  • 44. Summary In English
  • 45. Thank you Any question?