Adrenergic transmission - sympathetic nervous system

Question 1

If you stimulate the adrenergic system what effects do you mediate and if you inhibit it what effects do you inhibit?

Answer 1

If you stimulate the adrenergic system you mimic the effects of the sympathetic nervous system, and if you inhibit the adrenergic system you inhibit the effects of the sympathetic nervous system.

Question 2

Give an overview of the sympathetic nervous system

Answer 2

• The pre-ganglionic fibres lie in the thoracic and lumbar regions of the spinal cord. These send out pre-ganglionic axons to the ganglia or the adrenal medulla.
• The ganglia release acetylcholine acting at nicotinic acetylcholine receptors stimulating post ganglionic fibres which causes the release of noradrenaline from sympathetic nerves.
• The adrenal medulla releases acetylcholine which interact with nicotinic acetylcholine receptors causes the release of adrenaline (a hormone)/ and or noradrenaline, which enters the blood stream effecting lots of receptors.
• Adrenergic transmission mediates the effects of sympathetic nervous system

Question 3

Describe the mechanism of action at a adrenergic synapse e.g between a post-ganglionic fibre and the heart

Answer 3

1. Noradrenaline is made.
2. It is packaged into vesicles, so it can be stored, so it is primed ready for its release so it can be released into the synaptic cleft.
3. The vesicles translocate to the membrane which causes the release of neurotransmitter into the synaptic cleft.
4. This then bonds to a receptor (adrenoreceptor) which induces a biological response.
5. If too much noradrenaline is released it can bind to an alpha 2 receptor on the presynaptic terminal – a negative feedback mechanism so less noradrenaline is released.
6. It can also be taken up by the presynaptic terminal – recycled for further use (taken into vesicles or broken down by enzymes – monoamine oxidase).

Question 4

Describe direct and indirect regulation of adrenergic transmission

Answer 4

• At which points can these systems be modulated:
Synthesis of noradrenaline
Modulate release of noradrenaline (increase or decrease it).
Modulate the receptors that it is acting on (activate or inhibit).
Change uptake transport (block of facilitate this).
Regulate breakdown – if more is broken down there is less in the vesicles
• Direct – Drugs that act at adrenoceptors – mimics the noradrenaline.
• Indirect – Drugs that act at altering release/termination of transmission – modulate/inhibit the system.

Question 5

How are noradrenaline and adrenaline synthesised and?

Answer 5

1. Tyrosine is converted into DOPA (this is the rate limiting step – how fast this happens determines how fast you produce noradrenaline) by tyrosine hydroxylase.
2. DOPA is converted to dopamine

Question 6

Describe how noradrenaline can be stored and broken down (MOA and Reserpine)

Answer 6

• Prevent storage of NA in vesicles – NA in cytosol broken down by MAO
• Reduces NA release
• Less sympathetic actions, e.g. Less 1-mediated vasoconstriction
• Early treatment for hypertension
• Set principle for future treatments – reduce sympathetic nerves reduce BP

Question 7

Describe the facilitation of release in the adrenergic system

Answer 7

• Tyramine
Dietary constituent (meats, cheeses, chocolate)
Enter terminal, displaces NA into synaptic cleft – sympathetic, BP
Normally tyramine broken down by MAO in GI tract – so it has little effect
But causes marked hypertension in patients treated with MAO inhibitors for depression – called the ‘cheese effect’
• Amphetamine / Ephedrine
Reverses uptake transporters causing release of NA into cleft
Ephedrine (decongestant) – vasoconstriction of nasal blood vessels

Question 8

Describe inhibition of adrenergic transmission

Answer 8

• Guanethidine
Compete with NA for inclusion into vesicles, reduces NA release – broken down by MAO.
• Clonidine / -methyl-DOPA
Stimulate pre-synaptic 2 receptors, reduces NA release. This drugs has affinity for alpha 2.

Question 9

Describe termination of adrenergic transmission

Answer 9

• NA is terminated by re-uptake unchanged into pre-synaptic terminal
• NA is then, recycled back into vesicles
• Metabolised by monoamine oxidase (MAO) in neurones or catechol-O–methyltransferase (COMT) in non-neuronal sites (e.g. adrenal medulla)
• Cocaine / tricyclic anti-depressants (imipramine)
Inhibit Uptake, increase adrenergic transmission
• MAO inhibitor e.g. Moclobemide
Anti-depressant, increase adrenergic transmission in brain

Question 10

Give an overview of adrenergic receptor pharmacology

Answer 10

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