BIMM118 Autonomic Nervous System

BIMM118 Autonomic Nervous System

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!

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!)

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

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

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

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

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

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

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)

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)

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

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

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)

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)

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)

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

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

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)

BIMM118 Cholinergic System Parasympathetic Drugs - Summary