Autonomic Nervous SystemSlide 2Slide 3Slide 4Slide 5Cholinergic SystemCholinergic System - AgonistsSlide 8Slide 9Slide 10Slide 11Slide 12Slide 13Cholinergic System - AntagonistsSlide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21BIMM118Autonomic Nervous SystemBIMM118Autonomic Nervous SystemBIMM118Autonomic 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!BIMM118Autonomic Nervous SystemTransmitters:•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!)BIMM118Autonomic Nervous SystemReceptors:•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:– receptorsBIMM118Cholinergic SystemCholinergic 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 typeAcetylcholine is rapidly hydrolyzed by a membrane-associated Acetylcholinesterase in the synaptic cleftBIMM118Cholinergic System - Agonists= Cholinomimetics = ParasympathomimeticsTwo 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] increasedBIMM118Cholinergic System - AgonistsMuscarinic ParasympathomimeticsThe 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 retentionBethanecholBIMM118Cholinergic System - AgonistsMuscarinic ParasympathomimeticsPilocarpine:–Chief alkaloid in Pilocarpus jaborandi–Does not activate N receptors–Used to treat glaucomaCiliary muscle contraction=>increased outflow of aqueous humor => reduction in intraocular pressure•Muscarine:–Chief alkaloid in Amanita muscaria–No therapeutic applicationBIMM118Cholinergic System - AgonistsAcetylcholinesterase Inhibitors=> Extend half-life of AcCholine => trigger activation of both M and N receptorsBIMM118Cholinergic System - AgonistsAcetylcholinesterase InhibitorsReversible Inhibitors:Used to treat Glaucoma (topical) and Myasthenia Gravis (systemic)•Carbamates:–Physostigmine (only topical)from Physostigma venenosum(= Calabar bean; West Africa)–Neostigmine•Quarternary alcohols:–EdrophoniumUsed to diagnose Myasthenia Gravis (very short half-life)BIMM118Cholinergic System - AgonistsAcetylcholinesterase 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)BIMM118Cholinergic System - AgonistsAcetylcholinesterase InhibitorsIrreversible Inhibitors:No medical application!•Organophosphates:–Insecticides•Malathion•Parathion–Nerve gases•Sarin•Tabun•SomanQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.BIMM118Cholinergic 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 relaxantsBIMM118Cholinergic System - AntagonistsMuscarinic ParasympatholyticsAtropineChief alkaloid in Atropa belladonna: CNS-stimulant (leaves were used as “asthma cigarettes”)Hyoscine (=Scopolamine)Chief alkaloid in Datura stramonium: CNS-depressant => antiemetic (motion sickness)BIMM118Cholinergic System - AntagonistsMuscarinic ParasympatholyticsClinical 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)BIMM118Cholinergic System - AntagonistsNicotinic ParasympatholyticsTwo 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)BIMM118Cholinergic System - AntagonistsNicotinic ParasympatholyticsNondepolarizing 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 surgerybut: Tubocurarine triggers histamine release => blood pressure dropsBIMM118Cholinergic System - AntagonistsNicotinic ParasympatholyticsNondepolarizing blockersSynthetic quarternary ammonium compounds–Replaced tubocurarine
View Full Document
Unlocking...