Autonomic drugsII

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 cholinoceptorsType location structure mechanismM1(M1a) nerves STS, G protein IP3, DAGM2(M2b) heart nerve STS, G protein cAMP, K+ channel smooth muscleM3(M2b) glands STS, G protein IP3, DAG smooth muscle endotheliumNN(N1) postganglionic pentamer Na+ channel cell bodyNM(N2) skeletal muscle pentamer Na+ channel neuromuscular junction

STS: seven transmembrane segments

STS: seven trans-membrane segments

M1 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, NN and NM like effects need to be understood action complex, wide, many untoward reactions, short-lived only as research tool

Structures of Ach and carbamylcholineCarbamylcholine

carbamylcholine like Ach, but action lasts longer only used in glaucoma

2, M AchR agonists pilocarpine Pilocarpusjaborandinpilocarpusmicrophylus

Pilocarpine

pilocarpine:actions: through M3 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 inhibitorsneostigmine, 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: 1myasthenia gravis 2postoperative ilius and urinary retention

3, paroxysmal supraventricular tarchycardia

4muscle relaxant intoxication

5, Alzheimers disease (mild-modest)

irriversible cholinesterase inhibitors

irreversible AchE inhibitorsorganophosphatesnerve gas: VX, tabun, soman, sarin

Organophosphates and nerve gas Only of toxicological significance Toxicological mechanism: covalent combination with the enzyme; Ach

MN

Cholinesterase reactivators pralidoxime iodide

attention: early use; large dose