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  1. 1. Cholinergic Agonists ‘Cholinomimetic agents’ Lecture 2 Dr. Hiwa K. Saaed Department of Pharmacology & Toxicology 1
  2. 2. 2 Cholinergic Agonists
  3. 3. Classification A. Pharmacologically: by their spectrum of action. 1. Muscarinic agonists:  Bethanechol  Methacholine  Pilocarpine 2. Nicotinic agonists:  nicotine 3
  4. 4. B. mode of action 1. Direct-acting: bind directly to and activate muscarinic or nicotinic receptors, Also subdivided chemically: A. Esters of choline (including acetylcholine, bethanechol, methacholine and carbachol) B. Alkaloids (such as muscarine, pilocarpine and nicotine). 4 Classification
  5. 5. 2. Indirect-acting: by inhibiting the hydrolysis of endogenous acetylcholine. also subdivided to A. Reversible: neostigmine, physostigmine, pyridostigmine, ambenomium, edrophonium, donepezil, galantamine, rivastigmine, tacrine. B. Irreversible echothiophate, isoflurophate 5 Classification
  6. 6. Indirect and direct Some quaternary cholinesterase inhibitors also have a modest DIRECT action as well, example, neostigmine, which activates neuromuscular nicotinic cholinoceptors directly in addition to blocking cholinesterase. 6
  7. 7. Basic Pharmacology of Direct-acting  Muscarinic and Nicotinic agents Acetylcholine & Carbachol: have effects on both receptors.  muscarinic agents; ‘Pilocarpine and Bethanechol’ preferentially bind to muscarinic receptors. 7
  8. 8. Pharmacokinetics  All the direct-acting cholinergic drugs have longer durations of action than Ach.  Choline esters are poorly absorbed and poorly distributed into the CNS because they are hydrophilic.  The tertiary cholinomimetic alkaloids (pilocarpine, nicotine, lobeline) are well absorbed from most sites of administration. 8
  9. 9. Pharmacokinetics  Although all are hydrolyzed in the gastrointestinal tract (and less active by the oral route).  they differ markedly in their susceptibility to hydrolysis by cholinesterase. 1. Acetylcholine is very rapidly hydrolyzed. 2. Methacholine 3 times more resistant to hydrolysis 3. Carbachol & Bethanechol are extremely resistant to hydrolysis. 9
  10. 10. 10  Pharmacology of Ach-like agonist
  11. 11.  Although, it affects almost every system within the body. it is therapeutically of no importance!!!! because of 1. its multiplicity of actions, 2. and its rapid inactivation by the cholinesterases. A. Acetylcholine (Ach) 11
  12. 12. Acetylcholine (Ach)  CVS: it ↓s heart rate, contractility, and blood pressure.  GIT: it ↑s motility of the GIT and bladder.  Pulmonary system: it ↑s secretions of the bronchioles  Eye: miosis and accommodation.  PNS: contraction of skeletal muscle  CNS: it affects neurotransmission  Endocrine system: it causes release of epinephrine from the adrenal medulla (via Nn receptors).  And it stimulates sweat gland secretions. 12
  13. 13. Response mediated by Muscarinic receptors 13
  14. 14. Response mediated by Nicotinic receptors 14
  15. 15. Adverse effects: excessive generalized cholinergic stimulation DUMBLES: • Diarrhea and decreased BP, • Urination, • Miosis, • Bronchoconstriction, • Lacrimation, • Excitation of skeletal muscle, • Salivation and Sweating 15
  16. 16. B. Bethanechol  It has duration of action of about one hour.  Its major action on the smooth musculature of the bladder and GIT, causing increased intestinal motility and tone.  (BBB- Bethanechol stimulates the Bladder and Bowel) Therapeutic Uses:  to stimulate the atonic bladder in postoperative, non- obstructive urinary retention. 16
  17. 17. C. Carbachol actions:  Systemically: Carbachol has profound effects on both the CVS and the GIT  because of its ganglion (Nn receptor) stimulating activity, and it may first stimulate and then depress these systems.  It can cause release of epinephrine from the adrenal medulla by its nicotinic action.  Locally instilled into the eye, it mimics the effects of Ach, causing miosis and a spasm of accommodation.  is rarely used therapeutically except in the eye to treat glaucoma. Because of its high potency, and relatively long duration of action. 17
  18. 18.  Act on muscarinic receptors  Used in diagnosis of asthma and bronchial hyperreactivity D. Methacholine 18
  19. 19. E. Pilocarpine (an alkaloid)  is a tertiary amine, and is stable not hydrolyzed by AchE.  It is far less potent compared with Ach and its derivatives.  Pilocarpine exhibits muscarinic activity  is used primarily in ophthalmology, topically produces a rapid miosis and contraction of the ciliary muscle; a spasm of accommodation; the vision is fixed at some particular distance, making it impossible to focus. 19
  20. 20. 20 E. Pilocarpine action
  21. 21.  Pilocarpine is one of the most potent stimulators of secretions such as sweat, tears, and saliva,  but its lack of selectivity (adverse effects) limited its use: 1. can enter the brain and causes CNS disturbances. 2. It stimulates profuse sweating and salivation. Pilocarpine actions: 21
  22. 22. Sjogren syndrome  Sjogren syndrome, immunologic disorder with destruction of the exocrine glands leading to the mucosal dryness (dry mouth and lack of tears)  is usually treated with cevimeline, a cholinergic drug that also has the drawback of being nonspecific.  Recent studies have shown that mouth sprays of Pilocarpine are beneficial in promoting salivation in patients with Xerostomia (dryness of the mouth). 22
  23. 23. is the DOC in the emergency lowering of IOP of both narrow-angle and a wide-angle glaucoma. Therapeutic use in glaucoma: 23 is extremely effective in opening the trabecular meshwork around Schlemm canal result in an increased drainage of aqueous humor
  24. 24. Organ system effects of cholinergic agonists 24
  25. 25. INDIRECT-ACTING CHOLINOMIMETICS (ANTICHOLINESTERASE) Dr. Hiwa K. Saaed Department of Pharmacology & Toxicology
  26. 26. Basic Pharmacology of the Indirect-Acting Cholinomimetics Q. How do they work?  By inhibiting ChE, protect Ach from hydrolysis.  Their pharmacodynamic properties are almost identical.  The chief differences between members of the group are chemical and pharmacokinetic. 26
  27. 27. Chemistry of the Indirect-Acting Cholinomimetics 1. Simple alcohols bearing a quaternary ammonium group, e.g., edrophonium 2. Carbamic acid esters of alcohols bearing  Quaternary ammonium groups (e.g., neostigmine)  Tertiary ammonium groups (e.g., physostigmine). 3. Organic derivatives of phosphoric acid (organophosphates, e.g., echothiophate). Physostigma venenosum27
  28. 28. Reversible Irreversible bind covalently to ChE. Carbamates Acridine organophosphates Physostigmine Neostigmine Pyridostigmine Edrophonium Rivastigmie Donepezil tacrine Dyflos (DFP) , Echothiophate Drug Parathion, Malathion (insecticide) Diazinon, Tabun, sarin, soman (nerve gases for chemical warfare) 28 Cholinesterase inhibitors
  29. 29. Irreversible cholinesterase inhibitors  Irreversible: Only the organophosphate inhibitors,  because they bind covalently to ChE, and can permanently inactivate the enzyme.  The effects of organophosphates can last as long as a week, which is approximately the time, needed to synthesize a new molecule of ChE. Q. Is it at all possible to reverse the effects of organophosphates? In most cases, no. However, if Pralidoxime “2-PAM” (a cholinesterase reactivator) is given before a process called aging. 29
  30. 30.  Aging: the organophosphate binds to ChE and loses one of its alkyl groups, then it may be possible to remove the organophosphate from ChE. 30 Aging:
  31. 31.  Edrophonium, Neostigmine, Pyridostigmine:  Absorption from the conjunctiva, skin, and lungs is predictably poor.  Distribution into the CNS is negligible.  Physostigmine (lipid soluble):  is well absorbed from all sites and can be used topically in the eye.  It is distributed into the CNS and is more toxic Synthetic quaternary ammonium agents Naturally occurring tertiary amine: 31 Absorption, Distribution, and Metabolism All are well absorbed from the skin, lung, gut, and conjunctiva except for echothiophate; Therefore, dangerous to humans and highly effective as insecticides. The organophosphate cholinesterase inhibitors
  32. 32. are also rapidly metabolized (detoxify) by other pathways to inactive products in birds and mammals but not in insects and Unfortunately, fish ; these agents are therefore considered safe enough for sale to the general public. is not detoxified effectively in vertebrates; thus, it is considerably more dangerous than malathion to humans and livestock and is not available for general public use. Malathion and a few other organophosphate insecticides Parathion 32 Thiohosphate (parathion, malathion, and related compounds) • Are quite lipid-soluble rapidly; absorbed by all routes. • They must be activated in the body by conversion to the oxygen analogs, a process that occurs rapidly in both insects and vertebrates.
  33. 33. Treatment of AChE Poisoning AChE Adverse effects:  Excessive cholinergic stimulation 1. Atropine: Reverses muscarinic but not nicotinic 2. Pralidoxime (2-PAM): 33
  34. 34. Actions of AChE Inhibitors 1. CNS: • Low doses: CNS activation • High: coma and respiratory arrest 2. Eye, respiratory tract, GI & urinary tract: The same as muscarinic agonists 3. Cardiovascular: • Heart: Bradycardia, ↓contraction, ↓COP • Blood vessels? No effect 4. Neuromuscular junction: • low dose ↑ force of contraction • high dose Muscle fasciculation and depolarizing blockade 34
  35. 35. The major therapeutic uses of the cholinomimetics: 1. Eye:  glaucoma,  accommodative esotropia 2. Gastrointestinal & Urinary tracts:  postoperative atony,  neurogenic bladder 3. Neuromuscular junction:  myasthenia gravis,  curare-induced neuromuscular paralysis NB. Cholinesterase inhibitors, but not direct-acting acetylcholine receptor agonists; are extremely valuable as therapy for myasthenia.?? 35
  36. 36. Drugs Used in Myasthenia Gravis Drug Duration of Action Diagnosis: Edrophonium I.V (improvement) 5-15 min Treatment: Neostigmine (do not cross BBB) 0.5-2 hours Pyridostigmine 3-6 hours Ambenonium 4-8 hours 36