1、Zhi-guo Song,Department of Pharmacology,Parasympathomimetics,cholinergic agonists anticholinesterases,Parasympathomimetics,cholinergic agonists,complete cholinergic drugs acetylcholine ( ACh ) carbachol M-cholinoceptor agonist pilocarpine N-cholinoceptor agonist nicotine,Acetylcholine (ACh),M effect
2、s:1. Cardiovascular systemvasodilationdecrease heart ratenegative dromotropic effect negative inotropic effectshorten atrial refractory period,ACh has both M-R and N-R activity,2. stimulate visceral smooth muscle3. increase intestinal secretions and salivary ， bronchiolar4. miosis5. contract skeleta
3、l muscle,Acetylcholine (ACh),Pilocarpine(毛果芸香碱, 匹鲁卡品),Origin of the Drug-South American- Pilocarpus jaborandi-Isolated in 1875,Chemical Structure,Parasympathomimetic （Cholinergic agonist),ActionsM-receptor agonist1. Eye:miosis: constrict the pupillae sphincter muscle, causing miosis (marked constric
4、tion of the pupil).lower intraocular pressureaccommodate spasm,Eye Fluid Production and Pressure,Types of Glaucoma,Open-Angle Glaucoma,Closed-Angle Glaucoma,Anterior Chamberangle closure,Blocked drainage of aqueous,Blockage at trabecular meshwork,Anterior chamber open,Blocked drainage of aqueous,acc
5、ommodate spasm,Actions:2.Gland: increase gland secretion , especially sweat gland and salivary gland .3.Smooth muscle: stimulate intestinal and airway smooth muscle4.Cardiovascular: decrease heart rate,Therapeutic use,glaucoma (main closed-angle glaucoma)iritis: contracts the pupils to prevent the a
6、dhesion of iris and lensXerostomiaNotice: presses inner canthus, prevents absorption of drugs from nasolacrimal canal, otherwise, it can enter the brain and cause CNS symptoms, sweating and salivation.,muscarine (毒蕈碱),Anticholinesterase agents,ACh在AChE作用下水解过程,Anticholinesterase agents can inhibit or
7、 inactivate AChE, causing the accumulation of ACh at the cholinergic receptors. These drugs can thus provoke M and N receptors resulting in M and N effects. Anticholinesterases are classified as reversible and irreversible inhibitors.,Neostigmine (新斯的明),myasthenia gravis(重症肌无力): an autoimmune diseas
8、e caused by antibodies to the nicotine receptor that bind to the ACh-R of neuromuscular junctions.Neostigmine has a direct and indirect actions on NM-R (end-plate).,It can reversibly inhibit AChE,flatulence and uroschesis after operationantidotes to poisoning from skeletal muscle relaxant such as tu
9、bocurarineparoxysmalventriculartachycardiaglaucomaAdverse effects: include the actions of generalized cholinergic stimulation, such as salivation, nausea, vomitting, diarrhea.,Physostigmine (毒扁豆碱, eserin),Eye: 1) miosis 2) lowers intraocular pressure 3) accommodates spasm mainly used in glaucoma,Pha
10、rmacological action and uses:,What is the difference between physostigmine and pilocarpine?,Organophosphates intoxication and rescue,Types: Agricultural insectcides: Dipterex （敌百虫） DDVP （敌敌畏） Malathion （马拉硫磷） Parathion （对硫磷，1605） Systox （内吸磷，1059） Rogor （乐果） War gas: Sarin （沙林） Soman （梭曼） Tabun （塔崩）
11、,It can irreversibly inhibits AChE,Mechanism of intoxication,Organophosphates are “ irre-versible ” anticholinesterase drugs . Their phosphor atom combines with AChE by covalent bond and forms phosphated AChE that is uneasy to be hydrolyzed.The activity of AChE diminishes markedly and the concentrat
12、ion of ACh increases.Administering as soon as possible in order to prevent enzyme from “aging”.,The way of intoxication: skin; respiratory tract; gastrointestinal tract,Symptoms of poisoning1)M-R: Glands, Eye, Bronchial, GI tract N1-R: both Sympthetic and Para.2)N-R N2-R: Skeletal muscle tremor3)CNS
13、 exciting inhibition,1) Removal any ingested poison (lavage) Dipterex - dont gastric lavage with alkaline solution DDVP Parathion（1605） - dont gastric lavage with KMnO4 solution Mintacol（1600）,2) Rescuing with drugs Atropine anti muscarinc effects Cholinesterase reactivator,Emergency treatment,PAM (
14、pralidoxime iodide) Cholinesterase reactivator,Action and uses: reactivating the cholinesterase : effective groups: quaternary nitrogen combines with phosphated AChE oxime combines with phosphoryl phosphated-PAM decomposes AChE dissociates,It directly combines with free- organophosphates prevents th
15、em further combine with AChE It has marked action on neuromuscular junctions and promptly inhibits fasciculation. Improves CNS symptoms It cant directly antagonize the accumulated ACh, therefore, it should be used with atropine,PAM-CLObidoxime (双复磷) administered by iv. and im. power and longer than PAM,Question: What are the different results between using atropine and PAM for organophosphate poisoning? Why?,
