BIMM 118 Autonomic Nervous System BIMM 118 Autonomic

BIMM 118 Autonomic Nervous System

BIMM 118 Autonomic Nervous System

Autonomic Nervous System • Ganglia close to the innervated organs • Ganglia close to the spinal column • Myelinated axons • Preganglionic axons are myelinated; postganglionic axons are unmyelinated BIMM 118 • Note: Somatic nervous system has no ganglia!

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): BIMM 118 – Adrenal medulla upon sympathetic impulses (no ganglion!)

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: BIMM 118 – a, b - receptors

Cholinergic System Cholinergic receptors: • Muscarinic receptors: Hetrotrimeric G protein-coupled – CNS, gastric mucosa: M 1 – Cardiac: M 2 – Glandular/Smooth muscle: M 3 • Nicotinic receptors: Ion channel-coupled – Muscle type (motor endplate) – Ganglion type – CNS type BIMM 118 Acetylcholine is rapidly hydrolyzed by a membrane-associated Acetylcholinesterase in the synaptic cleft

Cholinergic System - Agonists = Cholinomimetics = Parasympathomimetics Two main classes: • Direct Parasympathomimetics: – Have affinity for M (and/or N receptors) => mimic Ac. Choline – Act mostly on the M type receptors (not subtype selective) Exception: Nicotine, (Muscle N type only: Tubocurarine, Succinylcholine) • Indirect Parasympathomimetics : BIMM 118 – Inhibit the activity of Acetylcholinesterase => [Ac. Choline] increased

Cholinergic System - Agonists Muscarinic Parasympathomimetics The extremely short half-life of Ac. Choline makes it therapeutically useless => • Carbachol: – Not hydrolyzed by Ac. Cholinesterase – Also activates N receptors • Bethanechol: BIMM 118 – – Not hydrolyzed by Ac. Cholinesterase Does not activate N receptors Lacks cardiovascular effects Treatment of urinary retention Bethanechol

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 BIMM 118 • Muscarine: – Chief alkaloid in Amanita muscaria – No therapeutic application

Cholinergic System - Agonists Acetylcholinesterase Inhibitors BIMM 118 => Extend half-life of Ac. Choline => trigger activation of both M and N receptors

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 BIMM 118 Used to diagnose Myasthenia Gravis (very short half-life)

Cholinergic System - Agonists Acetylcholinesterase Inhibitors • “Horny goat weed” BIMM 118 – Epimedium sagittatum – Acts as Ac. Ch-esterase inhibitor (active ingredient unknown) – Indirect stimulation of vascular M 3 receptors triggers NO production => vasodilation (action similar to Sildenafil (Viagra®), which potentiates NO effects)

Cholinergic System - Agonists Acetylcholinesterase Inhibitors Irreversible Inhibitors: No medical application! • Organophosphates: – Insecticides • Malathion • Parathion – Nerve gases BIMM 118 • Sarin • Tabun • Soman

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 BIMM 118 – Neuromuscular blockers: Muscle relaxants

Cholinergic System - Antagonists Muscarinic Parasympatholytics Atropine Chief alkaloid in Atropa belladonna: CNS-stimulant (leaves were used as “asthma cigarettes”) Hyoscine (=Scopolamine) BIMM 118 Chief alkaloid in Datura stramonium: CNS-depressant => antiemetic (motion sickness)

Cholinergic System - Antagonists Muscarinic Parasympatholytics Clinical applications: • Atropine: – – • Scopolamine: – • Peptic ulcers: selectively inhibits M 1 receptors (gastric mucosa) => reduced gastric acid production N-Butyl-scopolamine: – BIMM 118 Inhalation for asthma and bronchitis Pirenzepine: – • Motion sickness (as patches) Ipratropium: – • before anesthesia: prevent hypersecretion of bronchial mucus Bradycardy Acetylcholinesterase-inhibitor and mushroom poisoning Ophtalmology (eye exams) Spasmolytic (intestinal or menstrual cramps)

Cholinergic System - Antagonists Nicotinic Parasympatholytics Two classes (both act as neuromuscular blockers => muscle relaxants): • Competitive antagonists = Nondepolarizing blockers – Act by competing with Ac. Ch for binding to the N receptors – Prevent depolarization of the endplate – Action can be reversed by increasing Ac. Ch concentrations (e. g. via Ac. Ch-esterase inhibitors) • Agonists = Depolarizing blockers – Ac. Ch mimetics that are not hydrolyzed by Ac. Ch-esterase (but hydrolyzed by plasma esterases) – Act by triggering a sustained depolarization of the neuromuscular endplate – No new action potential can be generated BIMM 118 – Can NOT be reversed increasing Ac. Ch concentrations (would cause further depolarization)

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 BIMM 118 but: Tubocurarine triggers histamine release => blood pressure drops

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 -2 h) Used in lethal injection (together with barbiturate + BIMM 118 KCl) • Vecuronium intermediate-lasting action (<30 min) • Atracurium intermediate-lasting action • Mivacurium short action (<15 min) • etc. Pancuronium

Cholinergic System - Antagonists Nicotinic Parasympatholytics Depolarizing blockers • Succinylcholine = Suxamethonium BIMM 118 – “dimeric” Acetylcholine – Acts agonistic like Ac. Ch – NOT hydrolyzed by Ac. Ch-esterase (only by plasmaesterases) – Initial depolarization triggers muscle twitching – Followed by persistent depolarization (~10 min) – Used for brief procedures (e. g. intubation; shock therapy)

Cholinergic System BIMM 118 Parasympathetic Drugs - Summary