Adrenergic Transmission (noradrenaline transmission)

Question 1

Where is the best site for drug intervention in sympathetic transmission and why?

Answer 1

At the neuroeffector junction - allows for specific targeting of function.
If CNS or sympathetic ganglia were targeted, the effects would be non-specific and likely widespread.

Question 2

How is noradrenaline synthesised?

Answer 2

From tyrosine.

Tyrosine > DOPA > Dopamine > Noradrenaline >Adrenaline

Question 3

What enzyme converts tyrosine to DOPA?

Answer 3

Tyrosine hydroxylase

Question 4

How can conversion of tyrosine to DOPA be inhibited?

Answer 4

By α-methyl-tyrosine inhibiting tyrosine hydroxylase (competitive inhibition)

Question 5

What enzyme converts DOPA to dopamine?

Answer 5

DOPA decarboxylase

Question 6

What enzyme converts dopamine to noradrenaline?

Answer 6

Dopamine β-hydroxylase

Question 7

What enzyme converts noradrenaline to adrenaline?

Answer 7

Phenylethanol-amine N-methyl transferase

Question 8

What is the effect of α-methyl-tyrosine?

Answer 8

Reduced DOPA production > reduced noradrenaline
Less sympathetic effect > decreases blood pressure.
Side effects: sedation, Parkinsonism, Diarrhoea.

Question 9

How is noradrenaline stored?

Answer 9

In vesicles (transported in via VMAT)
If not in vesicles will be broken down by monoamineoxidase (MAO)

Question 10

What drug inhibits noradrenaline storage? What is the effects of the drug?

Answer 10

Reserpine.
Blocks VMAT - prevents storage in vesicles.
Noradrenaline will be broken down by monoamineoxidase. - Depletes neurons of NA
Used as an antihypertensive.

Question 11

What drug inhibits noradrenaline release? How does it work?

Answer 11

Clonidine.
Normally α2 receptors have a negative feedback mechanism to reduce NA release once activate.
Clonidine in an V2 agonist - stimulates receptor as NA would - prevents further NA release.

Question 12

What drugs promote noradrenaline release and how do they work?

Answer 12

Amphetamines.
Enter the pre-ganglionic neuron via uptake-1 channels and displace NA in vesicles.
Amphetamines also inhibits monoamineoxidase hence less NA is broken down so more is free for release across synapse.

Question 13

What are the 3 types of G-protein and which adrenergic receptors are they associated to?

Answer 13

Gq -α1 receptor
Gi - α2 receptor
Gs - β1,2,3 receptors

Question 14

What is the signalling pathway of an α1 receptor?

Answer 14

Gq protein coupled.
Activates phospholipase C.
PIP3 > IP3 + DAG
IPs increases Ca2+ concentration from sarcoplasmic reticulum.
DAG activate protein kinase C.
Ultimately leads to smooth muscle contraction.

Question 15

What is the signalling pathway of an α2 receptor?

Answer 15

Gi coupled.
Inhibits adenylylcylase.
Decreased cAMP production.
Decreased protein kinase A activation
Decreased exocytosis - inhibits neurotransmitter release.

Question 16

What is the function of α-blockers?

Answer 16

Block sympathetic vasoconstriction - decrease blood pressure.

Question 17

Name two non-selective α-blockers and why they are not in clinical use.

Answer 17

Phenoxybenzamine
Phentolamine
Cause severe reflex tachycardia - shut down negative feedback mechanism.

Question 18

Name two selective α-blockers.

Answer 18

Doxazosin
Tamsulosin
Safer than non-selective α-blockers.

Question 19

Outline the β1 and β2 signalling pathways.

Answer 19

Both Gs coupled.
Activate adenylylcyclase.
Increased cAMP production
Activates protein kinase A.
β1 - increased cardiac myocyte contraction
β2 - phosphorylation of myosin light chain kinase - smooth muscle relaxation.

Question 20

What is salbutamol?

Answer 20

β2 agonist - inhibition causes relaxation of smooth muscle in airways. Bronchodilation.

Question 21

What is the function of β-blockers?

Answer 21

Block sympathetic nervous input to the heart.
Decrease heart rate and stroke force.
Decrease cardiac output and blood pressure.

Question 22

What is a non-selective blocker (a1 and β receptors) drug and what does it do?

Answer 22

Labetolol
Reduces arterial blood pressure - fewer side effects than a-blockers.
Used in stable congestive heart failure.

Question 23

What is a β-selective blocker (β1 and β2) and what is its function?

Answer 23

Propanolol

Treatment in disturbances in cardiac rhythm, myocardial infarction

Question 24

What is a β1 subtype selective blocker? What is its function?

Answer 24

Atenolol

Treatment in disturbances in cardiac rhythm, myocardial infarction

Question 25

Give 5 adverse effects of β-blockers.

Answer 25

Fatigue - reduced cardiac output
Reduced peripheral blood flow
Bronchoconstriction
Increased risk of cardiac failure (sympathetic tone effected)
Risk of hypoglycaemia

Question 26

What does monoamineoxidase catalyse?

Answer 26

Noradrenaline > noradrenaline aldehyde > DOMA

Question 27

Name 3 monoamineoxidase inhibitors?

Answer 27

phenylazine
moclobemide
selegiline

Question 28

What is the significance of tyramine and the ‘cheese effect’?

Answer 28

Tyramine is found in cheese, yogurt and wine. Tyramine is normally degraded by MAO
In patients taking MAO inhibitors, tyramine is not metabolised and can lead to hypertensive crisis.

Question 29

What is salbutamol?

Answer 29

β2 agonist - promotes bronchodilation

Treatment of asthma

Question 30

What is atenolol?

Answer 30

β1 antagonist (beta-blocker)

Treatment of hypertension

Question 31

What is doxasin?

Answer 31

α1 antagonist

Treatment of hypertension

Question 32

What is labetolol?

Answer 32

Non-selective blocker (α1 and beta-blocker)

Treatment for hypertension