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Sympathetic nervous system
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Neurotransmitter in SNS
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Autonomic NS

Physiology and Pharmacology

QuestionAnswer
Sympathetic nervous system Leaves spinal cord and synapse onto ganglion cells in paravertebral chain ganglia Originate in lateral grey matter Myelinated - preganglionic - white ramus Unmyelinated - postganglionic - grey ramus
Neurotransmitter in SNS Preganglionic - Ach Postganglionic - NA except sweat glands
Varicosities Bulbous structures on nerves contain storage granules Sequentially depolarises varicosities to release NA
Production of NA Tyrosine - LDOPA by tyrosine hydroxylase LDOPA - dopamine by dopamine decarboxylase Dopamine - noradrenaline by dopamine beta hydroxylase Noradrenaline - adrenaline by Phenylethanolamin n-methyltransferase
Tyrosine hydroxylase Tyrosine moved actively into the nerve varicosity by Na dependent aromatic L amino acid transporter A cytoplasmic enzyme that forms LDOPA Loosely associated with ER Fe and biopterin are cofactors
Regulation of tyrosine hydroxylase Acute regulation; noradrenaline competes for biopterin binding site to reduce activity Longer term up regulation by de novo synthesis Can also be inhibited by phosphorylation
Dopamine beta hydroxylase Located in storage vesicles Specificity not hight so will convert many phenylethylamine derivatives e.g. octopamine from tyramine Ascorbate is a cofactor
PNMT Located in chromaffin cells of the adrenal medulla Also converts other hydroxylated phenylethylamines e.g. synephrine from octopamine
Alpha methyltyrosine inhibits tyrosine hydroxylase A competitive inhibitor Higher affinity that tyrosine Reduces amount of transmitter
Carbidopa Inhibits dopa decarboxylase A peripheral inhibitor of dopa decarboxylase Reduces peripheral side effects and effective dose in LDOPA therapy
Disulfiram Inhibits dopamine beta hydroxylase Reduces noradrenalin synthesis Clinical use as an inhibitor of aldehyde dehydrogenase - used in alcoholism
LDOPA Bypass tyrosine hydroxylase Increases dopamine/noradrenaline/adrenaline synthesis Increases brain dopamine in parkinsons
False transmitters Alpha methyl dopa is converted to alpha methyldopamine and aplha methylnoradrenaline by normal enzymes Stored and released as a false transmitter Binds to alpha 2 receptors and down regulated secretion of noradrenaline - decreases vasoconstriction
Storage of noradrenaline Hight conc of noradrenaline in cytoplasmic vesicles Bound along with ATP and chromogranin A Transported into vesicle by VMAT2 Driven by proton gradient set up by ATP dependent H pump
Reserpine Binds to amine binding site to block uptake and deplete stored NA due to leak from vesicle Acts in periphery and brain Previously used as an antihypertensive Leads to depression due to activity on CNS 5-HT
Adrenergic neuron blocking drugs Carried into nerve by uptake 1 - may potentiate exogenous NA Low doses - block release of NA by APs, mechanism may involve hyperpolarisation of nerve ending High doses - indirectly acting sympathomimetic effect
Presynaptic auto receptors All sympathetic nerve ending express alpha2 adrenoreceptors NA activates and reduces release Can also have other receptors e.g. Beta 2. opioid and M2
Indirectly acting sympathomimetics Increase NA release e.g. tyramine and amphetamines
Termination of NA effects Uptake 1 - norepinephrine transporter - on presynaptic nerve terminals to recycle NA Uptake 2 - extra neural monoamine transporter - on postsynaptic cells for uptake and metabolism Diffusion - transmitter carried to liver for metabolism
NA uptake into cells Uptake 1 - 12 transmembrane domain NET, Na dependent and blocked by cocaine and tricyclic antidepressants Uptake 2 - ENT, not Na dependent and can also carry dopamine and other amines, blocked by corticosteroids
Monoamine oxidase Found in outer mitochondrial membrane and extracellularly Metabolise catecholamines, 5-HT, DA, histamine etc Neuronal MAO maintains low cytoplasmic NA MAO-A - NA, Adr, DA, 5-HT MAO-B - %-HT, DA and trace amines
Monoamine oxidase inhibitors MAO-A - Clorgiline used in depression MAO-B - Selegiline in parkinsons Both - tranylcypromine in depression
Catechol O-methyl transferase Cytoplasmic enzyme found in liver, kidney and other tissues Most NA and Adr in circulation is metabolised by COMT Often associated with uptake 2 Inhibited by entacapone (used in parkinsons)
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