BIMM118. Autonomic Nervous System
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1 Autonomic Nervous System
2 Autonomic Nervous System
3 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 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 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: α, β receptors
6 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 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 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 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 Cholinergic System - Agonists Acetylcholinesterase Inhibitors => Extend half-life of AcCholine => trigger activation of both M and N receptors
11 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 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 Cholinergic System - Agonists Acetylcholinesterase Inhibitors Irreversible Inhibitors: No medical application! Organophosphates: Insecticides Malathion Parathion Nerve gases Sarin Tabun Soman
14 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 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 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 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 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 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 Pancuronium Mivacurium short action (<15min) etc.
20 Cholinergic System - Antagonists Nicotinic Parasympatholytics Depolarizing blockers Succinylcholine = Suxamethonium dimeric Acetylcholine Acts agonistic like AcCh NOT hydrolyzed by AcCh-esterase (only by plasmaesterases) Initial depolarization triggers muscle twitching Followed by persistant depolarization (~10min) Used for brief procedures (e.g. intubation; shock therapy)
21 Cholinergic System Parasympathetic Drugs - Summary
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