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INDIRECT-ACTING CHOLINOMIMETICS (ANTICHOLINESTERASE) Pharmacology I Lecture 3 Dr. Hiwa K. Saaed HD, MSc. PhD Department of Pharmacology & Toxicology Basic Pharmacology of the Indirect-Acting Cholinomimetics 2 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. Chemistry (1) Simple alcohols bearing a quaternary ammonium group, eg, edrophonium (2) Carbamic acid esters of alcohols bearing Quaternary ammonium groups (eg, neostigmine) Tertiary ammonium groups (eg, physostigmine). (3) Organic derivatives of phosphoric acid (organophosphates, eg, echothiophate). Physostigma 3venenosum Irreversible cholinesterase inhibitors 4 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. Cholinesterase inhibitors Reversible Irreversible bind covalently to ChE. Carbamates Acridine organophosphates Physostigmine tacrine Dyflos (DFP) , Echothiophate Drug Neostigmine Parathion, Malathion (insecticide) Pyridostigmine Diazinon, Tabun, sarin, soman (nerve Edrophonium gases for chemical warfare) Rivastigmie Donepezil 5 Q. Is it at all possible to reverse the effects of organophosphates? 6 In most cases, no. however, if Pralidoxime (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. Absorption, Distribution, and Metabolism of 7 Synthetic quaternary ammonium agents Edrophonium, Neostigmine, Pyridostigmine: Absorption from the conjunctiva, skin, and lungs is predictably poor. Distribution into the CNS is negligible. Absorption, Distribution, and Metabolism of 8 Naturally occurring tertiary amine: 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 than the more polar quaternary carbamates. Absorption, Distribution, and Metabolism of 9 The organophosphate cholinesterase inhibitors All are well absorbed from the skin, lung, gut, and conjunctiva except for echothiophate; Therefore, dangerous to humans and highly effective as insecticides. Absorption, Distribution, and Metabolism of 10 The thiohosphate insecticides (parathion, malathion, and related compounds) are quite lipid-soluble and are 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. Malathion 11 Malathion and a few other organophosphate insecticides are also rapidly metabolized by other pathways to inactive products in birds and mammals but not in insects; these agents are therefore considered safe enough for sale to the general public. Unfortunately, fish cannot detoxify malathion, Parathion 12 Parathion 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. Actions of AChE Inhibitors 13 1. CNS: • Low doses: CNS activation • High: coma and respiratory arrest 2. Eye, respiratory tract, GI & urinary tract: The same as muscarinic agonists Actions of AchEI 14 3. Cardiovascular: • Heart: Bradycardia, decrease contraction, COP • Blood vessels? No effect 4. Neuromuscular junction: • low dose Increase force of contraction • high dose Muscle fasciculations and depolarizing blockade The major therapeutic uses of the cholinomimetics: 15 1. Eye: glaucoma, accommodative esotropia 2. Gastrointestinal & Urinary tracts: postoperative atony, neurogenic bladder 3. Neuromuscular junction: myasthenia gravis, curare-induced neuromuscular paralysis Myasthenia gravis 16 Cholinesterase inhibitors—but not direct-acting acetylcholine receptor agonists—are extremely valuable as therapy for myasthenia. Drugs Used in Myasthenia Gravis 17 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 Treatment of AChE Poisoning 18 Adverse effects: Excessive cholinergic stimulation 1. Atropine: Reverses muscarinic but not nicotinic 2. Pralidoxime (2-PAM):
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