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  2. 2. 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. 2
  3. 3. Chemistry (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 venenosum3
  4. 4. 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) 4 Cholinesterase inhibitors
  5. 5. 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. 5
  6. 6. In most cases, no.  however, if Pralidoxime “2-PAM” (a cholinesterase reactivator) is given before a process called aging;  Aging: the organophosphate binds to ChE and loses one of its alkyl groups, then it may be possible to remove the organophosphate from ChE. 6 Q. Is it at all possible to reverse the effects of organophosphates?
  7. 7.  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: 7 Absorption, Distribution, and Metabolism of 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
  8. 8. Thiohosphate (parathion, malathion, and related compounds) The thiohosphate insecticides (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. 8
  9. 9.  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 9 Thiohosphate (parathion, malathion, and related compounds)
  10. 10. 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 10
  11. 11. 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. 11
  12. 12. 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 12
  13. 13. Treatment of AChE Poisoning AChE Adverse effects:  Excessive cholinergic stimulation 1. Atropine: Reverses muscarinic but not nicotinic 2. Pralidoxime (2-PAM): 13