Autonomic Nervous System - Class Websitesclasses.biology.ucsd.edu/bimm118.WI16/PPT Lecture... ·...

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BIMM118 Autonomic Nervous System

Transcript of Autonomic Nervous System - Class Websitesclasses.biology.ucsd.edu/bimm118.WI16/PPT Lecture... ·...

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Autonomic Nervous System

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Autonomic Nervous System

• Ganglia close to theinnervated organs

• Myelinated axons

• Ganglia close to thespinal column

• Preganglionic axonsare myelinated;postganglionic axonsare unmyelinated

• Note:Somatic nervoussystem has noganglia!

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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, medullanamed after activation by Nicotine

• Adrenergic Receptors:– α, β − 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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MuscarinicParasympathomimetics

Pilocarpine:– Chief alkaloid in Pilocarpus jaborandi– Does not activate N receptors– Used to treat glaucoma

Ciliary muscle contraction=>increased outflowof aqueous humor => reduction in intraocularpressure

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

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Cholinergic System - Agonists

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) andMyasthenia 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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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)

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Acetylcholinesterase Inhibitors

Irreversible Inhibitors:No medical application!

• Organophosphates:– Insecticides

• Malathion• Parathion

– Nerve gases• Sarin• Tabun• Soman

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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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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)

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Nicotinic 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 surgery

but: Tubocurarine triggers histamine release => blood pressure drops

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Nicotinic ParasympatholyticsNondepolarizing 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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Nicotinic ParasympatholyticsDepolarizing 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 persistant depolarization (~10min)– Used for brief procedures (e.g. intubation; shock therapy)

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Parasympathetic Drugs - Summary