Autonomic Nervous System

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 Autonomic Nervous System
BIMM118
 Autonomic Nervous System

• Ganglia close to the • Ganglia close to the

innervated organs spinal column
• Myelinated axons • Preganglionic axons
are myelinated;
postganglionic axons
are unmyelinated

• Note:
Somatic nervous
system has no
ganglia!
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 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!)
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 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:
– 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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 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
Bethanechol
– Lacks cardiovascular effects
– Treatment of urinary retention
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 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
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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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 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)
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 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)
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 Cholinergic System - Agonists

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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 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)
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 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)
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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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 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
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 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)

Pancuronium
• Atracurium intermediate-lasting action
• Mivacurium short action (<15min)
• etc.
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 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 persistant depolarization (~10min)
– Used for brief procedures (e.g. intubation; shock therapy)
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 Cholinergic System

Parasympathetic Drugs - Summary

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