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Flashcards in The parasympathetic nervous system Deck (45)
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1

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 

2

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.

3

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 

4

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 

5

What does Carbidopa inhibit?

What is it used to treat?

Dopa decarboxylase (DCC) and is used in the treatment of parkinsons disease

6

What is Carbidopa administered along side of?

L-DOPA 

7

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

8

Carbidopa and L-DOPA 

9

Where is noradrenaline stored?

In vesicles 

10

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

11

What are the drugs that interfere with noradrenaline storage?

What are some side effects?

  • Rauwolfia 
  • Reserpine:

Antihypertensive drug. Has side effects such as depression

12

What drug is represented from this structure?

Guanethidine 

13

Tell me about Guanethidine 

Antihypertensive 

side effects; Orthostatic hypertension

14

The presence of the uptake mechanism for noradrenaline is demonstrated by what?

What is used to prove this?

Iversen

There is the use of radiolabelled Noradrenaline to help prove the mechanism 

15

What is the tissue that recieves sympathetic innervation?

Cardiac tissue 

16

What is the measured amount of noradrenaline accumulated by the tissue?

intact

17

if something is descirbed as being denervated what does this mean?

Its deprived of a nerve supply 

18

Draw the graph of uptake against concentration of nordrenaline

intact= how the system works under normal conditions 

19

The inactivation of NADR following release can be done via two mechanisms. Tell me about each of these mechanisms?

Uptake 1: 

  • High affinity- recognises low concentration of noradrenaline
  • Low capacity 
  • located at the nerve terminal 
  • requires Na+ gradient and ATP 
  • substrate specificity 

Uptake 2:

  • Low affinity- recognises high concentration of noradrenaline 
  • High capacity 
  • Extra neuronal- outside of a neuron
  • inhibited by cortisol 

20

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) 

21

What are some drugs that stimulate noradrenaline release?

Indirect sympathominetics 

Tyramine naturally occurs in foodstuffs 

Ephedrine used in cold remedies 

Amphetamine psychostimulant 

22

What are the two important enzymes in noradrenaline metabolism?

Monoamine oxidase (MAO) 

Catechol-O-methyl transferase (COMT)

23

What are the major metabolites that are generated as a consequence of metabolism of noradrenaline?

3-methoxy-4-hydroxymandleic acid (VMA) 

3-methoxy-4-hydroxyphenylglycol (MHPG)

24

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 

25

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 

26

27

What are some drugs that interfere with noradrenaline metabolism?

Monoamino oxidase inhibitors (MAOIs) 

Iproniazid 

28

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 

29

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 

30

What are some adrenoreceptor subtypes?

Alpha 

  • isoforms 1 and 2
  • all are GPCR

Beta 

  • 1, 2 and 3