Autonomic Pharmacology - Noradrenalin Synthesis, Release and Degradation Flashcards

1
Q

Autonomic Nervous system organisation

A
The ANS is a part of the peripheral nervous system, conveying all output from the CNS to the rest of the body, except the motor innervation of skeletal muscle. 
Main 3 anatomical divisions:
- Sympathetic
- Parasympathetic
- Enteric
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What does the ANS regulate?

A
Smooth muscle tone, 
All exocrine secretion, 
Some endocrine secretions, 
Heart rate and force,
Certain metabolic processes.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

In the ANS how many neurones are between the CNS and the target organ?

A

2

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the role of the sympathetic NS?

A

Fight and flight.
Causes: Iris dilation, increase salivation, decrease oral/nasal mucus, increase HR and force, dilate bronchial muscle in lungs, reduce GIT motility and increase sphincter tone.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What neurotransmitters are released the in pre and posts ganglion neurones in the parasympathetic NS?

A

Parasympathetic: Pre = ACh;
Post = ACh, NO
Synapse is midway/lower end between the spinal cord and the target organ.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What neurotransmitters are released the in pre and posts ganglion neurones in the sympathetic NS?

A

Sympathetic: Pre = ACh
Post = NAdh (Noradrenaline), ATP
Synapse is very close to the spinal cord.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

In postganglionic sympathetic nerves what are the swellings seen in the terminal branches?

A

These swellings are where the neurotransmitters are stored.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe the synthesis of noradrenaline and adrenaline

A

Tyrosine (aa) -1- Dihydroxyphenylalanine (DOPA) -2-Dopamine -3- Noradrenaline -4- Adrenaline

Enzymes:

  1. Tyrosine hydroxylase
  2. DOPA decarboxylase
  3. Dopamine-B-hydroxylase
  4. Phenylehtanolamine N-methyl transferase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is Tyrosine hydroxylase function in the synthesis of noradrenaline and adrenaline?

A

Converts tyrosine to dihydroxyphenylalanine (DOPA).
Rate-limiting step
Feedback inhibition by NAd
Inhibited by a-methyltryosine (it binds in the same site as the substrate, therefore blocking tyrosine).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is DOPA decarboxylase function in the synthesis of noradrenaline and adrenaline?

A

Converts DOPA into dopamine.

Inhibited by carbidopa (inhibits DOPA in the periphery)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

How does a-methyl tyrosine affect noradrenaline synthesis and what is it used to treat?

A

Inhibits tyrosine hydroxylase, that converts tyrosine into DOPA. It is used to treat Phaeochromocytoma (rare tumour of the adrenal gland tissue. Releases epinephrine and norepinephrine hormones that control HR).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How does Carbidopa affect noradrenaline synthesis and what is it used to treat?

A

Carbidopa is an inhibitor or DOPA-decarboxylase. It works in the periphery, not the CNS. It is used to treat Parkinson’s Disease (with L-DOPA). It decreases unwanted peripheral actions of administered L-DOPA.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

How does Methyldopa affect noradrenaline synthesis and what is it used to treat?

A

Methyldopa is taken up by sympathetic neurones and is converted into a-methylnoradrenaline. It displaces the noradrenaline out of the vesicles and acts as a false transmitter. It is used to treat hypertension in pregnancy.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How is NAd and Ad stored in the adrenal glands?

A

NAd and Ad are not free in the cytoplasm, but are stored in subcellular membrane-limited particles (vesicles) known as chromaffin granules (300nm diameter).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the effects of reserpine drug on vesicular neurotransmitter stores?

A

Reserpine inhibits the vesicular amine transporter. Therefore stores of eg. catecholamine run down slowly as the amine leaks out. Stores fall to about 5% of the normal after 12 hours. Was used to treat hypertension.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

How do vesicles exocytose from sympathetic nerves

A

Arrival of an ap causes depolarisation of the varicosity causing the opening of voltage-gated Ca2+ channels thereby increase the concentration of Ca2+. This activates Ca2+ sensitive proteins that initiates exocytosis. Evidence for this is shown by quantitative release of ATP and soluble proteins with noradrenaline and without the release of lipids.

17
Q

How is the release of neurotransmitters regulated?

A

Sympathetic nerve terminals contains receptors for many different mediators. A variety of substances can act on these prejunctional receptors to regulated release of noradrenaline.
Some facilitate release, other inhibit.

18
Q

What is autoinhibition of noradrenaline release, how does it work?

A

Noradrenaline, released from sympathetic varicosities, can act locally on presynaptic receptors to inhibitor its own release, and also that of ATP. The presynaptic receptors involved are a2-adrenoceptors, which are negatively coupled to adenylyl cyclase.

19
Q

How does acetylcholine regulate release of noradrenaline?

A

Inhibit the release of NAd via muscarinic receptors. It produces lateral inhibition from parasympathetic nerves.

20
Q

How does adenosine, opioids and angiotensin II affect noradrenaline release?

A

Adenosine = Inhibits release of NAd via A1 receptors
Opioids = Inhibits release of NAd via u-receptors
Angiotensin II = Facilitates release via AT1 receptors

21
Q

What is morphine, its effects and how do these effects come about?

A

Morphine is a alkaloid. Potent analgesic (pain relieving), however autonomic side effects are constipation, pupillary dilation. The autonomic side effects are through the prejunctional inhibition of neurotransmitter release.

22
Q

How is NAd and Ad action terminated?

A

2 stages:

  1. Uptake = Into the sympathetic nerve terminals or into other cells
  2. Degradation = Intracellular enzymes break down the neurotransmitters
23
Q

How are catecholamines taken back up into the presynaptic neurone?

A
  1. Neuronal: Due to the secondary active transporter NAT. Co-transporters Na+, Cl- and catecholamine
  2. Non-neuronal (eg. cardiac, smooth muscle and endothelium): Low affinity for NAd, high maximal rate of uptake.
24
Q

What drugs inhibit neuronal catecholamine re-uptake?

A

Cocaine,
Tricyclic antidepressants (desipramine)
Phenoxybenzamine

25
Q

What inhibits noradrenaline reuptake?

A

NAT inhibitors enhance the effects of sympathetic activity.

  • Desipramine - Tricyclic antidepressant; major action is on the CNS; adverse effects: tachycardia, arrhythmias.
  • Cocaine - euphoria and excitement (CNS excitement); tachycardia and increase BP (peripheral); also a local anaesthetic.
26
Q

What are the autonomic effects of cocaine how do these effects occur?

A

Increased HR, BP, arrhythmias, local vasoconstriction. It inhibits catecholamine transporters, DAT, SERT and NAT

27
Q

What inhibits non-neuronal uptake of catecholamines?

A

Normetanephrine, steroid hormones and phenoxybenzamine.

28
Q

How does monoamine oxidase (MAO) cause metabolic degradation of catecholamines?

A

MAO binds to the membrane of mitochondria and converts catecholamines into aldehydes, which is then metabolised by aldehyde dehydrogenase (Periphery) or aldehyde reductase (CNS).
Several drugs inhibit MAO which are used therapeutically for their effects of the CNS (treatment of depression).

29
Q

How does Mono-amine oxidase inhibitors inhibit the effects of MAO?

A

Most block MAO irreversibly.
Used as an antidepressant as it increases levels of NAd, dopamine and 5-HT in the brain and peripheral tissue.
Adverse effects = weight gain, insomnia, restlessness, postural hypertension.
Examples = Phenelzine, tranylcypromine

30
Q

How does catechol-O-methyl transferase (COMT) cause metabolic degradation of catecholamines?

A

COMT converts catecholamines into methoxy derivatives by transferring a methyl group to one of the catechol -OH groups.
Also acts on other degradative reactions (MAO, ADH, AR).

31
Q

VMA is a metabolite of metabolic degradation of catechoamines what is it?

A

VMA is the main final metabolite of adrenaline and noradrenaline. It is excreted in the urine.

32
Q

How does noradrenergic neurone blocking drugs work?

A

Inhibit noradrenaline release from sympathetic nerve terminals. Enter the nerve terminals through NET and inhibit actions potentials (via ion channels) or excytotic proteins.
No longer used to treat hypertension as severe adverse effects: postural hypotension, diarrhoea, nasal congestion and failure of ejaculation.

33
Q

How does indirectly acting sympathetic amines affect neurotransmitters in vesicles in the presynaptic neurone?

A

Structurally relate to noradrenaline, therefore enters the nerve terminals via NAT and into vesicles, displaces noradrenaline, which leaks out via NAT. Similar effects of dopamine, 5-HT in the CNS.
Long-lasting effects that mimic those of noradrenaline: bronchial dilation, vasoconstriction, positive inotropy, raised BP.