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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 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 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
QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.
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
AtropineChief 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 blockersSynthetic 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