1. BIMM118 Autonomic Nervous System

2. BIMM118 Autonomic Nervous System

3. BIMM118 Autonomic Nervous System Ganglia close to the innervated organs Myelinated axons Ganglia close to the spinal column Preganglionic axons are myelinated; postganglionic axons are unmyelinated Note: Somatic nervous system has no ganglia!

4. BIMM118 Autonomic Nervous System Transmitters : Acetylcholine: –ALL preganglionic neurons –ALL parasympathetic postganglionic neurons Norepinephrine (= Noradrenalin): –MOST sympathetic postganglionic neurons –Exceptions: Sweat glands (Acetylcholine); Renal arteries (Dopamine) Epinephrine (= Adrenalin): –Adrenal medulla upon sympathetic impulses (no ganglion!)

5. BIMM118 Autonomic Nervous System Receptors: Cholinergic Receptors: –Muscarinic (M): at the target organ named after activation by Muscarine (poison of Amanita muscaria) –Nicotinic (N): ganglia, motor endplate, medulla named after activation by Nicotine Adrenergic Receptors: –  receptors

6. BIMM118 Cholinergic System Cholinergic receptors : Muscarinic receptors: Hetrotrimeric G protein-coupled –CNS, gastric mucosa: M1 –Cardiac: M2 –Glandular/Smooth muscle: M3 Nicotinic receptors: Ion channel-coupled –Muscle type (motor endplate) –Ganglion type –CNS type Acetylcholine is rapidly hydrolyzed by a membrane-associated Acetylcholinesterase in the synaptic cleft

7. BIMM118 Cholinergic System - Agonists = Cholinomimetics = Parasympathomimetics Two main classes: Direct Parasympathomimetics: –Have affinity for M (and/or N receptors) => mimic AcCholine –Act mostly on the M type receptors (not subtype selective) Exception: Nicotine, (Muscle N type only: Tubocurarine, Succinylcholine) Indirect Parasympathomimetics : –Inhibit the activity of Acetylcholinesterase => [AcCholine] increased

8. BIMM118 Cholinergic System - Agonists Muscarinic Parasympathomimetics The extremely short half-life of AcCholine makes it therapeutically useless => Carbachol: –Not hydrolyzed by AcCholinesterase –Also activates N receptors Bethanechol: –Not hydrolyzed by AcCholinesterase –Does not activate N receptors –Lacks cardiovascular effects –Treatment of urinary retention Bethanechol

9. BIMM118 Cholinergic System - Agonists Muscarinic Parasympathomimetics Pilocarpine: –Chief alkaloid in Pilocarpus jaborandi –Does not activate N receptors –Used to treat glaucoma Ciliary muscle contraction=>increased outflow of aqueous humor => reduction in intraocular pressure Muscarine: –Chief alkaloid in Amanita muscaria –No therapeutic application

10. BIMM118 Cholinergic System - Agonists Acetylcholinesterase Inhibitors => Extend half-life of AcCholine => trigger activation of both M and N receptors

11. BIMM118 Cholinergic System - Agonists Acetylcholinesterase Inhibitors Reversible Inhibitors: Used to treat Glaucoma (topical) and Myasthenia Gravis (systemic) Carbamates: –Physostigmine (only topical) from Physostigma venenosum (= Calabar bean; West Africa) –Neostigmine Quarternary alcohols: –Edrophonium Used to diagnose Myasthenia Gravis (very short half-life)

12. BIMM118 Cholinergic System - Agonists Acetylcholinesterase Inhibitors “Horny goat weed” –Epimedium sagittatum –Acts as AcCh-esterase inhibitor (active ingredient unknown) –Indirect stimulation of vascular M3 receptors triggers NO production => vasodilation (action similar to Sildenafil (Viagra®), which potentiates NO effects)

13. BIMM118 Cholinergic System - Agonists Acetylcholinesterase Inhibitors Irreversible Inhibitors: No medical application! Organophosphates: –Insecticides Malathion Parathion –Nerve gases Sarin Tabun Soman

14. BIMM118 Cholinergic System - Antagonists = Cholinolytics = Parasympatholytics Muscarinic receptor blockers: –Competitive antagonists –Widespread medical applications: Inhibition of bronchial and gastric secretion Relaxation of smooth muscles (Bronchii, pupillary sphincter…) Cardioacceleration CNS-altering effects Nicotinic receptor blockers: –Ganglion-specific blockers: no clinical applications –Neuromuscular blockers: Muscle relaxants

15. BIMM118 Cholinergic System - Antagonists Muscarinic Parasympatholytics Atropine Chief alkaloid in Atropa belladonna: CNS-stimulant (leaves were used as “asthma cigarettes”) Hyoscine (=Scopolamine) Chief alkaloid in Datura stramonium: CNS-depressant => antiemetic (motion sickness)

16. BIMM118 Cholinergic System - Antagonists Muscarinic Parasympatholytics Clinical applications: Atropine: –before anesthesia: prevent hypersecretion of bronchial mucus –Bradycardy –Acetylcholinesterase-inhibitor and mushroom poisoning –Ophtalmology (eye exams) Scopolamine: –Motion sickness (as patches) Ipratropium: –Inhalation for asthma and bronchitis Pirenzepine: –Peptic ulcers: selectively inhibits M1 receptors (gastric mucosa) => reduced gastric acid production N-Butyl-scopolamine: –Spasmolytic (intestinal or menstrual cramps)

17. BIMM118 Cholinergic System - Antagonists Nicotinic Parasympatholytics Two classes (both act as neuromuscular blockers => muscle relaxants): Competitive antagonists = Nondepolarizing blockers –Act by competing with AcCh for binding to the N receptors –Prevent depolarization of the endplate –Action can be reversed by increasing AcCh concentrations (e.g. via AcCh-esterase inhibitors) Agonists = Depolarizing blockers –AcCh mimetics that are not hydrolyzed by AcCh-esterase (but hydrolyzed by plasma esterases) –Act by triggering a sustained depolarization of the neuromuscular endplate –No new action potential can be generated –Can NOT be reversed increasing AcCh concentrations (would cause further depolarization)

18. BIMM118 Cholinergic System - Antagonists Nicotinic Parasympatholytics Nondepolarizing blockers Curare: –Plant derived arrow poison in S-America –Active ingredient is d-Tubocurarine –Death occurs through respiratory paralysis –Tubocurarine is not absorbed orally => no risk eating the prey –Tubocurarine was used clinically as muscle relaxant during surgery but: Tubocurarine triggers histamine release => blood pressure drops

19. BIMM118 Cholinergic System - Antagonists Nicotinic Parasympatholytics Nondepolarizing blockers Synthetic quarternary ammonium compounds –Replaced tubocurarine as muscle relaxants –No or little histamine release Pancuronium long-lasting action (1-2h) Used in lethal injection (together with barbiturate + KCl) Vecuronium intermediate-lasting action (<30min) Atracurium intermediate-lasting action Mivacurium short action (<15min) etc. Pancuronium

20. BIMM118 Cholinergic System - Antagonists Nicotinic Parasympatholytics Depolarizing blockers Succinylcholine = Suxamethonium –“dimeric” Acetylcholine –Acts agonistic like AcCh –NOT hydrolyzed by AcCh-esterase (only by plasma- esterases) –Initial depolarization triggers muscle twitching –Followed by persistent depolarization (~10min) –Used for brief procedures (e.g. intubation; shock therapy)

21. BIMM118 Cholinergic System Parasympathetic Drugs - Summary