Pharmacology of the Sympathetic Nervous System

Question 1

Which adrenergic receptors does adrenaline work on?

Answer 1

Alpha-1 (less so than NA)
Alpha-2 (less so than NA)
Beta-1 (equally with NA)
Beta-2 (predominantly over NA)

(All X4 but some weaker than others)

Question 2

Which adrenergic receptors does noradrenaline work on?

Answer 2

Alpha-1 ( more so than A)
Alpha-2 (more so than A)
Beta-1 (equally with A)
Beta-2 (very weakly)

(Mainly just the first X3 and some weaker than others)

Question 3

What are the only subset of adrenergic receptors found in the heart, alpha or beta?

What does this imply for the actions of adrenaline and noradrenaline in the heart?

Answer 3

Beta only.

This means both adrenaline and noradrenaline must have the same affect on the heart as all beta receptors stimulate increases in cAMP. They work on the same pathway.

Question 4

Which adrenergic receptors cause vasodilation of arterioles in skeletal muscle?

Which hormone will these receptors respond to?

Answer 4

Beta-2

They will respond to adrenaline

(NB: REMEMBER THE AC/BD RULE! - alpha constricts, beta dilates)

Question 5

Which adrenergic receptors cause vasoconstriction of blood vessels?

Which hormone are these receptors most likely to respond to?

Answer 5

Alpha-1

Noradrenaline over adrenaline

(NB: REMEMBER THE AC/BD RULE! - alpha constricts, beta dilates)

Question 6

What is detumescence?

Answer 6

The loss of erection.

Question 7

What is mydrasis?

Answer 7

Pupil dilation.

Question 8

Where abouts in the effector pathway are drugs most likely to target and why?

Answer 8

At the neuroeffector junction, as this allows for more specific targeting and less widespread side effects.

Question 9

What is noradrenaline synthesised from?

Answer 9

Tyrosine

Question 10

What is the first step in noradrenaline synthesis from tyrosine?

Answer 10

Tyrosine ——> DOPA

Via the enzyme tyrosine hydroxylase

Question 11

What is the second step in noradrenaline synthesis from tyrosine?

Answer 11

DOPA ——> Dopamine

Via the enzyme DOPA decarboxylase

Question 12

What is the third step in noradrenaline synthesis from tyrosine?

Answer 12

Dopamine ——> NA

Via the enzyme dopamine beta-hydroxylase

Question 13

Which enzyme converts noradrenaline to adrenaline?

Answer 13

Phenylethanolamine-n-methyltransferase!!!!

Question 14

Which transporters aid in the packaging of NA into vesicles at the axon terminal?

Answer 14

VMAT’s

=vesicular monoamine transporters

Question 15

Which enzyme break down NA?

Answer 15

Monoamine oxidase

Question 16

Which drug can inhibit NA packaging into vesicles?

How does it do this?

Answer 16

RESERPINE

Inhibits the VMAT’s leaving the NA unpackaged and therefore free for MaO’s to degrade it into inactive metabolites.

Question 17

How does NA regulate its own release in a negative feedback loop?

Which receptor is responsible for this?

Answer 17

There are alpha-2 receptors on the pre-synaptic axon terminal from which the NA is released from. This, when triggered by NA, inhibits further release.

Question 18

What are the X2 names of the channel which re-uptakes NA back into the pre-synaptic axon terminal?

Answer 18

Uptake 1 channels or NET’s (Norepinephrine reuptake transporters)

Question 19

Which drug acts on uptake 1 channel reuptake of NA?

Is it an agonist or antagonist?

What does it do to the signal the NA is giving?

Answer 19

Cocaine!

It increases the signalling as it is an antagonist, blocking the channel.

Question 20

Which drug acts on alpha-2 adrenergic receptors for NA on pre-synaptic axon terminals?

Is it an agonist or antagonist?

What does it do to the signal the NA is giving?

Answer 20

Clonadine.

This is an alpha-2 adrenergic agonist, therefore it increases the reduction of NA release and decreases the signal strength of the NA.

Question 21

What happens to NA that does NOT:

1) Diffuse across the synapse and come into contact with post-synaptic receptors
2) Get reuptaken by uptake 1 channels (NET’s)

Answer 21

It can diffuse across the synapse and get taken up by uptake 2 channels found on extra-neuronal cells.

Question 22

What enzyme breaks down NA that has been taken up by uptake 2 channels on extra-neuronal cells?

Answer 22

COMT = catechol-o-methyl transferase

Question 23

How do monoamine oxidises work on catecholamines?

Explain the steps for the example of NA.

Answer 23

They convert catecholamines into their corresponding aldehyde and then using aldehyde dehydrogenases (ADH’s) they covert them to carboxylic acids.

E.g. NA —(MoA)—> NA Aldehyde —(ADH)—> DOMA (dihydroxymandelic acid)

Question 24

What are the X2 isoforms if MaO?

Where are each found?

Answer 24

MaO A - CNS, liver, pulmonary vascular endothelium, GI tract.

MoA B - CNS, blood platelets.

Question 25

Name X3 MaO inhibitors.

Answer 25

1) Phenylzine
2) Moclobemide
3) Selegiline

Question 26

What does Phenylzine do?

Answer 26

It is an irreversible non-selective inhibitor of both MaO isoforms.

Question 27

What does Moclobemide do?

Answer 27

It is a short acting MaO A inhibitor.

Question 28

What does Selegiline do?

Answer 28

It is an irreversible MaO B inhibitor.

Question 29

Where is tyramine found?

What are it’s implications for patients taking MaO inhibitors?

Answer 29

Tyramine is found in cheese, yoghurt and wine. It is usually degraded by MaO’s but in patients taking MaO inhibitors this can accumulate and lead to a hypertensive crisis.

Question 30

Explain a side effect of non-selective alpha adrenergic receptor antagonists (alpha-blockers) and why they are no longer used.

What is the mechanism of actions that cause this side effect?

Answer 30

Reflex tachycardia.

This is because the non-selective alpha antagonist will block alpha-1 receptors which are located post-synaptically. This will inhibit constriction if the blood vessels, lowering blood pressure (the desired effect).

It will, however, also block alpha-2 receptors which are located pre-synaptically and through negative feedback block further NA release and therefore mediate its release. If these are blocked there will be no control of NA release, allowing more neurotransmitter release which will stimulate beta-1 receptors post-synaptically and therefore increase chronotropy and inotropy. This causes a reflex tachycardia and will increase BP.

Question 31

Name X2 non-selective alpha adrenergic receptor antagonists.

Answer 31

Phentolamine
Phenoxybenzamine

(Both have ‘..amine’ in their name)

Question 32

What is phenylephrine?

Answer 32

An alpha-selective adrenergic agonist.

Question 33

Name X2 alpha-1 selective adrenergic receptor antagonist (alpha-1 blocker).

Answer 33

1) Prazosin

2) Doxazosin

Question 34

What is the aim of giving beta-blockers?

Answer 34

They are antihypertensives and work to try and decrease inotropy and chronotropy (and also vascular tone although the mechanism of action is unknown).

Question 35

Name X2 non-selective blockers of alpha-1 and both beta receptors.

Answer 35

1) labetalol

2) carvediol

Question 36

Name X2 beta-selective antagonists which block both beta-1 and 2 receptors.

Answer 36

1) propranolol

2) timalol

Question 37

Name X2 beta-1 subtype selective blockers.

Answer 37

1) atenalol

2) metoprolol

Question 38

Why do asthmatics have to be careful if taking beta-selective antagonists?

Answer 38

They will block their beta-2 receptors, which means they can not be stimulated to dilate their airways.

Question 39

What is reynaud’s phenomenon? (can be due to beta-blockers)

Answer 39

Having cold fingers and toes.