BIMM118 Autonomic Nervous System. BIMM118 Autonomic Nervous System.

BIMM118

Autonomic Nervous System

BIMM118


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• 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!

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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!)

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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

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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

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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

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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

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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

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Acetylcholinesterase Inhibitors=> Extend half-life of AcCholine => trigger activation of both M

and N receptors

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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)

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• “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)

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Irreversible Inhibitors:No medical application!

• Organophosphates:– Insecticides

• Malathion• Parathion

– Nerve gases• Sarin• Tabun• Soman

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

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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

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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)

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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)

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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)

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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

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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

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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)

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Cholinergic System

Parasympathetic Drugs - Summary

BIMM118 Autonomic Nervous System. BIMM118 Autonomic Nervous System.

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