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Cholinesterase-lnhibiting Drugs Department of pharmacology Zhu ling (朱玲) 2010.3 1 The indirect-acting agents produce their primary effects by inhibiting the action of acetylcholinesterase (AchE), which hydrolyzes acetylcholine to choline and acetic acid. 2 3 Cholinesterase-lnhibiting Drugs Anticholinesterases are drugs that inhibit or inactivate acectylcholinesterase, causing the accumulation of acetylcholine at the cholinergic receptors. This produces effects similar to prolonged stimulation of cholinergic fibers. Classified by the stability of the enzyme-drug complex (marked differences in duration of action) Reversible Cholinesterase-lnhibiting Drugs neostigimine physostigimine Irrevesible Cholinesterase-lnhibiting Drugs 7 organophosphates Neostigmine 新斯的明 1 Pharmacokinetics Quaternary ammonium agent Oral absorption is predictable poor much larger doses (at least 10 multiple) are required for oral administration than for parenteral injection Distribution into the CNS is negligible (difficult penetrate blood-brain barrier) 8 Neostigmine 新斯的明 2 Mechanism of action inhibit acectylcholinesterase, causing the accumulation of acetylcholine at the cholinergic receptors. muscarinic and nicotinic action 9 ‘-’ anionic site (process 150ms) ‘ser-o’ hydrolyzable covalent bond at the eseratic site 10 ‘-’ anionic site (process hours) ‘ser-o’ hydrolyzable covalent bond at the eseratic site 11 Neostigmine 新斯的明 3.Effects and clinical uses 1) skeletal muscle :contraction inhibit AchE, accumulation of Ach at the cholinergic receptors; activate neuromuscular nicotinic cholinoceptors directly in addition to blocking cholinesterase; promote motor nerve to release Ach * therapy of myasthenia gravis 12 Neostigmine 新斯的明 Myasthenia gravis A disease affecting skeletal muscle neuromuscular junction. An autoimmune process causes production of antibodies that decrease the number of functional nicotinic receptor on the postjunctional endplates. Symptoms: weakness and fatigability (remit with rest and worsen with exercise); affect skeletal muscle (small muscle: ptosis all muscle:dyspnea) therapy: usually oral administration,severe or emergency subcutaneously or i.m. 13 Neostigmine 新斯的明 2) gastrointestinal and bladder smooth muscle exciting (muscrinic effect) * therapy: postoperative abdominal distention (postoperative ileus,atony or paralysis of the stomach or bowel following surgical manipulation) and urinary retention (atony of the urinary bladder) 3) * therapy: treatment of overdose of the nondepolarizing neuromuscular relaxants; reverses the peripheral signs of antimuscarinic drug intoxication (eg. atropine) (central signs use Physostigimine) 4) modest bradycardia * treatment of paroxysmal supraventricular tachycardia (in the past) 14 Neostigmine 新斯的明 4.toxicity Therapeutic dosage : few side effects Excessive drug therapy :cholinergic crisis ( worsen myasthenic signs ) small dose of edrophonium used to distinguish, emergency and support systems avilable contraindication:asthma, atrioventricular block, mechanical obstruction 15 Cholinesterase-lnhibiting Drugs Physostigimine (eserine) clinic- glaucoma al uses refresh after anesthetics (analeptic) action tertiary nitrogens Lipid-solubility Pyridostig- Edrophon- ambenoniu mine ium(tensil m on) myastheni myastheni myasthenia a gravis a gravis gravis diagnose and Distinguish long rapid and similar to duration short effect neostigmine poor selectivity weak effect weak effect long Local 16 duration medication Irreversible Cholinesterase-lnhibiting Drugs organophosphates Organophosphates inhibitor poisoning and treatment 1. Insecticides and chemical warfare pesticides: isoflurophate (DFP), parathion, malathion, DDVP(dichlorvos) , dipterex, rogor “nerve (war) gas” soman, sarin, tabun et al. 2. Mechanism of organophosphates inhibitor poisoning ‘-’ anionic site (process hundreds of hours) 19 ‘ser-o’ covalent bond at the eseratic site (stable and slow hydrolyze) 3 signs of organophosphates inhibitor poisoning Muscarinic signs :eye, gland, smooth muscle Nicotinic signs : N1 ganglia excite (all of autonomic nerve excite) N2 neuromuscular junction (skeletal muscle contraction muscle tremble) CNS effects:stimulate (tremor, emesis, mania, stimulant respiratory center et al) inhibit (convulsion coma) 20 1) Muscarinic effect cardiovascular system↓ miosis glands secretion ↑ smooth muscle↑ 2) nicotinic effect to excite ganglia adrenal medulla secrete Adr cardiovascular system: ↑ smooth muscle ↑ glands secretion ↑ skeletal muscle ↑ 21 4. Treatment of organophosphates inhibitor poisoning Maintenance of vital signs—respiration in particular may be impaired Decontamination to prevent further absorption removal of all clothing, washing of the skin and stomach, conducting of rushing down ,et al Therapy includes treatment with atropine and cholinesterase reactivators Others sedation et al 22 cholinesterase reactivators cholinesterase reactivators a class of oxime compounds, capable of regenerating active enzyme (AchE) from the organophosphorus-cholinesterase complex, available for the treatment of organophosphates poisoning inhibit. These oxime agents include Pralidoxime PAM-Cl(氯解磷定) Pralidoxime iodide PAM(碘解磷定) iacetylmonoxime DAM and others 23 cholinesterase reactivators 24 cholinesterase reactivators 1 treatment Obviously reverse nicotinic effects, rapidly inhibit skeletal muscle tremble Poorly control muscarinic effects relieve part of CNS effects 2 principle of application Early, large dose (enough dose), repeat administration 25 cholinesterase reactivators 3. Mechanism 1) reactivating active enzyme (AChE) by splitting off the phosphorus from the organophosphoruscholinesterase complex 26 2) binding of free organophosphates cholinesterase reactivators 3. Mechanism 1) organophosphates+ AchE Phosphorylated AchE Phosphorylated PAM regenerating active AchE PAM 2) PAM +organophosphates Phosphorylated PAM 27 cholinesterase reactivators 4. adverse reaction Local prickle (ache) Instead inhibit AchE when overdosage 28