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BIM
M11
8
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!
BIM
M11
8
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!)
BIM
M11
8
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, medullanamed after activation by Nicotine
• Adrenergic Receptors:– α, β − receptors
BIM
M11
8
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
BIM
M11
8
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
BIM
M11
8
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
BIM
M11
8
Cholinergic System - Agonists
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
BIM
M11
8
Cholinergic System - Agonists
Acetylcholinesterase Inhibitors=> Extend half-life of AcCholine => trigger activation of both M and N receptors
BIM
M11
8
Cholinergic System - Agonists
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)
BIM
M11
8
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)
BIM
M11
8
Cholinergic System - Agonists
Acetylcholinesterase Inhibitors
Irreversible Inhibitors:No medical application!
• Organophosphates:– Insecticides
• Malathion• Parathion
– Nerve gases• Sarin• Tabun• Soman
BIM
M11
8
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
BIM
M11
8
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)
BIM
M11
8
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)
BIM
M11
8
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)
BIM
M11
8
Cholinergic System - Antagonists
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
BIM
M11
8
Cholinergic System - Antagonists
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
BIM
M11
8
Cholinergic System - Antagonists
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)