What is the synthesis pathway for tyrosine turning into adrenaline.
Draw the structures of the intermediates
What is added at each stage to form the intermediates
for instance on the diagram tyrosine hydroxylase is added to tyrosine to form L-DOPA
dopadecarboxylase is added to L-DOPA to form dopamine
Tell me about the 'false' transmitters in the catecholamine pathway
The catecholamines that act as neurotransmitters include dopamine and norepinephrine. Epinephrine is not produced in the central nervous system, but in the peripheral nervous system (adrenals). The catecholamines share a common synthetic pathway. The rate limiting step is tyrosine hydroxylase. The activity of tyrosine hydroxylase can be modified by phosphorylation. This provides a point of regulation for the neuron. Clinically there are no agents capable of modulating tyrosine hydroxylase. However, treatment with agents such as methyldopa can compete with dopa for further processing. The result is a formation of false neurotransmitters. The false neurotransmitters are packaged in the synapse as though they were the catecholamine but when released into the synapse they are ineffective at the receptor. False neurotransmitters such as octopamine are also thought to be increased in hepatic encephalopathy. The packaging of false transmitters in the periphery is thought to be increased by inhibiting MAO. This is thought to explain the orthostatic blood pressure effects caused by therapeutic doses of MAO inhibitors.
Whats a competitive inhibitor of tyrosine hydroxylase and what is it used to treat?
alpha methyl- tyrosine is a competitive inhibitor of tyrosine hydroxylase
It is used in the treatment of phaeochromocytoma
alpha methyl-DOPA is a drug that can be used for what?
How does this work?
It can be used to interfere with noradrenaline transmission as it leads to the synthesis of the false transmitter alpha methyl-noradrenaline
What does Carbidopa inhibit?
What is it used to treat?
Dopa decarboxylase (DCC) and is used in the treatment of parkinsons disease
What is Carbidopa administered along side of?
What does Carbidopa stop the metabolism of?
What doesn't it cross?
Stops the peripheral metabolism of L-DOPA
It doesn't cross the blood brain barrier
It inhibits DDC but doesnt cross the BBB
Carbidopa and L-DOPA
Where is noradrenaline stored?
How does noradrenaline move and what is it stored with?
Its transported via an active mechanism which is drived by a proton gradient
It is stored with ATP and Chromogranin
What are the drugs that interfere with noradrenaline storage?
What are some side effects?
Antihypertensive drug. Has side effects such as depression
What drug is represented from this structure?
Tell me about Guanethidine
side effects; Orthostatic hypertension
The presence of the uptake mechanism for noradrenaline is demonstrated by what?
What is used to prove this?
There is the use of radiolabelled Noradrenaline to help prove the mechanism
What is the tissue that recieves sympathetic innervation?
What is the measured amount of noradrenaline accumulated by the tissue?
if something is descirbed as being denervated what does this mean?
Its deprived of a nerve supply
Draw the graph of uptake against concentration of nordrenaline
intact= how the system works under normal conditions
The inactivation of NADR following release can be done via two mechanisms. Tell me about each of these mechanisms?
- High affinity- recognises low concentration of noradrenaline
- Low capacity
- located at the nerve terminal
- requires Na+ gradient and ATP
- substrate specificity
- Low affinity- recognises high concentration of noradrenaline
- High capacity
- Extra neuronal- outside of a neuron
- inhibited by cortisol
What are some drugs that will block the uptake 1 of noradrenaline?
- will potentiate (increase the effect) of the action of noradrenaline
- most clinically used as antidepressants e.g.
cocaine, Imipramine (first tricyclic antidepressant being prescribed), desipramine , amitriptyline, guanethidine (weakly blocks uptake 1)
What are some drugs that stimulate noradrenaline release?
Tyramine naturally occurs in foodstuffs
Ephedrine used in cold remedies
What are the two important enzymes in noradrenaline metabolism?
Monoamine oxidase (MAO)
Catechol-O-methyl transferase (COMT)
What are the major metabolites that are generated as a consequence of metabolism of noradrenaline?
3-methoxy-4-hydroxymandleic acid (VMA)
When the major metabolites are produced due to metabolism of noradrenaline, what can these plasma levels of the metabolites be useful for?
They can be useful biomarkers of disease
What is the metabolic pathway for noradrenaline metabolism?
How does the route vary dependent on what enzyme is used?
What is the overall product?
Shorter or longer metabolic pathways producing VMA depending on whether MAO or COMT is used
What are some drugs that interfere with noradrenaline metabolism?
Monoamino oxidase inhibitors (MAOIs)
What did Alqhuist describe in 1948 try to hypothesise?
He described the main receptor subtypes and looked at the effects of noradrenaline on smooth muscle
When noradrenaline is present
Vascular smooth muscles contracts
Bronchial smooth muscle relaxes
Why does the response of smooth muscle vary?
Theres different responses to noradrenaline depending on what organ the smooth muscle was extracted from
Different receptors caused these different responses in the same muscle using the same drug
What are some adrenoreceptor subtypes?
- isoforms 1 and 2
- all are GPCR
- 1, 2 and 3