Autonomic drugs II Chapter 6 Cholinoceptor agonists and drugs affecting cholinesterase activity pay attention to action types and representative drugs, instead of all drugs cholinoceptor agonists nonselective M, N receptor agonists M receptor agonists N receptor agonists cholinesterase inhibitors reversible cholinesterase inhibitors irreversible cholinesterase inhibitors cholinesterase reactivators Subtypes and characteristics of cholinoceptors Type location structure mechanism M 1 (M 1a ) nerves STS, G protein IP3, DAG M 2 (M 2b ) heart nerve STS, G protein cAMP, K + channel smooth muscle M 3 (M 2b ) glands STS, G protein IP3, DAG smooth muscle endothelium N N (N 1 ) postganglionic pentamer Na + channel cell body N M (N 2 ) skeletal muscle pentamer Na + channel neuromuscular junction STS: seven transmembrane segments STS: seven trans- membrane segments M 1 receptor Intramolecular interactions proposed to stabilize the ground state of the M1 muscarinic acetylcholine receptor. Interacting groups of amino acids are shown in the same colour. (a) View from the extracellular surface; side-chains participating in the hydrophobic latch structure are shown in space-filling format. (b) Lateral view. 1, nonselective M, N AchR agonists acetylcholine M, N N and N M like effects need to be understood action complex, wide, many untoward reactions, short-lived only as research tool Structures of Ach and carbamylcholine Carbamylcholine carbamylcholine like Ach, but action lasts longer only used in glaucoma 2, M AchR agonists pilocarpine Pilocarpusjaborandin pilocarpusmicrophylus Pilocarpine pilocarpine: actions: through M 3 receptor (1) eye: miosis reduction of intraocular pressure cyclospasm 2, glands: secretion of sweat, salivary, lacrimal gland, etc 3, smooth muscle: excitation in GI, respiratory, Clinical uses: 1, Glaucoma normal pressure: 11~21 mmHg > 24 mmHg 2, Iritis prevention of adherence of iris and lens when alternatively used with atropine 3,3, N AchR agonists nicotine not used clinically because of complex actions and toxicity lobeline : seldom used as respiratory stimulant Cholinesterase inhibitors acetylcholinesterase: RBC butyrocholinesterase: 1, reversible AchE inhibitors neostigmine , huperzine A , galanthamine , donepezil , reverstigmine Neostigmine Weak Ach like actions with more potent effects on gastrointestinal tract and bladder and even more on skeletal muscle Clinical uses: 1 myasthenia gravis 2 postoperative ilius and urinary retention 3, paroxysmal supraventricular tarchycardia 4 muscle relaxant intoxication 5, Alzheimers disease (mild-modest) irriversible cholinesterase inhibitors irreversible AchE inhibitors organophosphates nerve gas: VX, tabun, soman, sarin Organophosphates and nerve gas Only of toxicological significance Toxicological mechanism: covalent combination with the enzyme; Ach M N Cholinesterase reactivators pralidoxime iodide attention: early use; large dose