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Autonomic Nervous System

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Eugene Lai

on 7 September 2012

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Transcript of Autonomic Nervous System

Autonomic Nervous System Receptors and Drugs :) Neurotransmitters:
NANC system - Non Adrenergic Non Cholinergic system Overview Removal:
ACh - inactivated by cholinergic esterases
NA - reabsorbed Effects of ANS? Receptors of the ANS Nicotinic - boring (pharmacologically similar in terms of ganglia)
Muscarinic - 5 subtypes
Adrenogenic - 5 subtypes Muscarinic Adrenogenic M1, M4 and M5 - CNS
M2 and M3 - CNS/Periphery Sweat glands - probably M3. Ref: http://www.ncbi.nlm.nih.gov/pubmed/2068048 Further sub-division of alpha adrenoceptors? - Don't bother: only good to know we may have more specific drugs in the future Synthesis Acetylcholine Storage Release Activation (recptor) Inactivation Synthesis CAT - choline acetyl transferase

Choline + acetyl CoA = ACh + CoA Hemicholinium - blocks the reuptake of choline so that acetyl choline cannot be recycled Hemicholinium has no real clinical use - purely research Storage Acetylcholine is stored in vesciles in the presynaptic terminal Vesamicol - inhibits choline uptake and inhibits transport protein which moves ACh into vesicles Still experimental Release Exocytotic mechanism of release:
Vesicle fuses with presynaptic terminal membrane
Releases ACh into synaptic cleft Botulinum - toxin and drug (botox)

Prevents the fusing of and therefore release of ACh vesicles Symptoms:
Nausea and vomiting*
Abdominal cramps*
Dry mouth*
Double vision*
Difficulty swallowing and speaking
Progressive weakness and paralysis
Breathing difficulty
* = parasympathetic interference

Therapeutic uses? Inactivation Acetyl cholinesterase is an endogenous cholinesterase which breaks down the neurotransmitter-receptor complex

Floating around the synaptic clefts Anticholinesterase or acetylcholinesterase inhibitor: pyridostigmine

Acts by inhibiting the cholinesterase and increasing duration that ACh is in the receptors Therpeutic uses:
Myasthenia gravis

Side effects:
Nausea and vomiting
Abdominal cramps Ganglion stimulants:
Nicotine and epibadtidine
Normally causes stimulation then a block
They act at ganglia --> both PNS and SNS effects
No clinical use
Ganglion blocking drugs
Nicotine (causes stimulation then block)
Trimethapha - competative antagonist
Hexamethonium - non-competative antagonist Receptor Mediating Drugs Sources:
Agricultural insecticides
Nerve gas - sarin
ACh overactivity - causes?
Ventilation - if required
Blocks muscarinic actions of ACh (atropine)
Reactivate cholinesterases - pralidoxime Anticholinesterase
Poisoning 2 types of agonists:
ACh itself
Synthetic equivalents
Basically the same in every way except for their:
Duration of action
Selectivity for muscarinic or nicotinic receptors - some selectivity between different muscarinic receptors ACh Agonists Opthalmological:
Causes constriction of pupils - useful for Tx of glaucoma
Stimulates GI motility
Stimulates bladder emptying
Clinical trials into using ACh agonists - anticholinesterases are now additional early Tx for Alzheimers Muscarinic Agonist Uses Opthalmological:
Dilates pupils - exam and surgery
Suppress gastric acid secretion
Prevent motion sickness
Movement disorder treatments Muscainic Antagonist Uses Atropine and hyoscine - both nightshade derivatives
There are other semi and fully synthetic derivatives - they vary in:
Duration of action
Distribution throughout body
Selectivity for different muscarinic receptor subtypes (some) Muscarinic Antagonists Sympathetic Nervous System Drugs NA Synthesis Where can they affect the SNS?
At the ganglia:
Neuroeffector Junction Parkinson's Neurological disorder - imapaired voluntary movement
Association: decrease in dopamine levels in the brain and thus a decrease in dopamine receptors
Drug therapy: increase dopamine activity in these regions We try to flood the brain with dopamine at the early stages of Parkinson's
Since Levodopa is systemic and dopamine eventually become adrenaline it can activate the SNS inappropriately
We add a peripheral DOPA decaroxylase inhibitor to keep peripheral levels of adrenaline in check (drug doesn't cross the BBB) Drug: reserpine
Blocks the transportation of the NA vesicle
NA stores depleat
Substrates are broken down in the cytoplasm
Can have effects on 5HT and dopamine
Rarely used - we have better drugs now NA Storage Main methods:
Modify stores of NA - reserpine
Interact via receptors to inhibit/enhance release
Directly block release
Artificially cause release of NA NA Release Autoinhibitory (negative) feedback
Presynaptic alpha-2 adrenoceptors
Facilitatory (positive) feedback
Presynaptic beta-adrenoceptors Presynaptic Receptors Examples: guanethidine, bretylium, bethanidine
Mechanism of action (not completely known):
Compete with NA uptake
Block stimulation
Replace Na in storage vesicles
Prevent vesicle docking Direct Blocking of NA Release Examples: amphetamine, ephedrine/pseudophedrine
Mechanism of action:
Enters presynaptic nerve terminal via the same uptake as NA (uptake 1)
Taken up into NA vesicles in exchange for NA
Causes NA to release by preventing it from being reabsorbed and secreting it from the vesicles Drugs Causing NA Release Inhibitors of uptake 1:
Tricyclic antidepressants, cocaine, amphetamines
Enhances sympathetic transmission --> increase in HR, BP and causes eurphoria
Inhibitors of uptake 2:
Some corticosteroids
Not too much clinical significance NA Uptake We can use MAO inhibitors to increase the available stores of NA. They're mainly used for CNS related issues (anxiety, depression etc).

Cheese Reaction:
In the body MAO also breaks down tyramine, a tyrosine derivative
Tyramine is found in large quantities in: moderealty decayed meats (e.g. fermented or aged), chocolate, alcohol and most cheese
If a patient is on MAO inhibitors and eats a large quantity of these foods then the circuluating tyramine increases
This can result in increased systemic NA as the tyramine has the ability to displace NA from its vesicles --> SNS overstimulation MAO Inhibitors and the Cheese Reaction Andreoceptor Agonists and Antagonists Alpha adrenoceptors:
noradrenaline > adrenaline > isoprenalin
Beta adrenoceptors:
isoprenaline > adrenaline > noradrenalin
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