Adrenergic Transmission (noradrenaline transmission) Flashcards

1
Q

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

A

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.

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2
Q

How is noradrenaline synthesised?

A

From tyrosine.

Tyrosine > DOPA > Dopamine > Noradrenaline >Adrenaline

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3
Q

What enzyme converts tyrosine to DOPA?

A

Tyrosine hydroxylase

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4
Q

How can conversion of tyrosine to DOPA be inhibited?

A

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

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5
Q

What enzyme converts DOPA to dopamine?

A

DOPA decarboxylase

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6
Q

What enzyme converts dopamine to noradrenaline?

A

Dopamine β-hydroxylase

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7
Q

What enzyme converts noradrenaline to adrenaline?

A

Phenylethanol-amine N-methyl transferase

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8
Q

What is the effect of α-methyl-tyrosine?

A

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

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9
Q

How is noradrenaline stored?

A
In vesicles (transported in via VMAT)
If not in vesicles will be broken down by monoamineoxidase (MAO)
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10
Q

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

A

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

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11
Q

What drug inhibits noradrenaline release? How does it work?

A

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.

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12
Q

What drugs promote noradrenaline release and how do they work?

A

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.

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13
Q

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

A

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

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14
Q

What is the signalling pathway of an α1 receptor?

A

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.

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15
Q

What is the signalling pathway of an α2 receptor?

A
Gi coupled.
Inhibits adenylylcylase.
Decreased cAMP production.
Decreased protein kinase A activation
Decreased exocytosis - inhibits neurotransmitter release.
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16
Q

What is the function of α-blockers?

A

Block sympathetic vasoconstriction - decrease blood pressure.

17
Q

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

A

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

18
Q

Name two selective α-blockers.

A

Doxazosin
Tamsulosin
Safer than non-selective α-blockers.

19
Q

Outline the β1 and β2 signalling pathways.

A

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.

20
Q

What is salbutamol?

A

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

21
Q

What is the function of β-blockers?

A

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

22
Q

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

A

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

23
Q

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

A

Propanolol

Treatment in disturbances in cardiac rhythm, myocardial infarction

24
Q

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

A

Atenolol

Treatment in disturbances in cardiac rhythm, myocardial infarction

25
Q

Give 5 adverse effects of β-blockers.

A
Fatigue - reduced cardiac output
Reduced peripheral blood flow
Bronchoconstriction
Increased risk of cardiac failure (sympathetic tone effected)
Risk of hypoglycaemia
26
Q

What does monoamineoxidase catalyse?

A

Noradrenaline > noradrenaline aldehyde > DOMA

27
Q

Name 3 monoamineoxidase inhibitors?

A

phenylazine
moclobemide
selegiline

28
Q

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

A

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.

29
Q

What is salbutamol?

A

β2 agonist - promotes bronchodilation

Treatment of asthma

30
Q

What is atenolol?

A

β1 antagonist (beta-blocker)

Treatment of hypertension

31
Q

What is doxasin?

A

α1 antagonist

Treatment of hypertension

32
Q

What is labetolol?

A

Non-selective blocker (α1 and beta-blocker)

Treatment for hypertension