Block C Lecture 2 - Autocoids

Question 1

What are autocoids?

Answer 1

They are substances which are produced on demand and act locally (autocrine or paracrine) and have very short half lives

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Question 2

What are 3 major classes of autocoids?

Answer 2

Polypeptides
Biogenic amines
Phospholipid-derived

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Question 3

What are kinins?

Answer 3

Potent biological peptides which are formed following cleavage of kininogens by the enzyme kallikrein

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Question 4

What are 2 examples of kinins an their properties?

Answer 4

Bradykinin (BK) is an important inflammatory mediator and is a 9 amino acid peptide chain

Kallidin(KD) aka Lys-Bradykinin (Lys-BK) is the same 9 acid amino chain as bradykinin but with a Lysine added on the end

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Question 5

What can Kallidin (Lys-Bradykinin) be converted into and what enzymes do this?

Answer 5

It can be converted into bradykinin (BK) by aminopeptidase enzymes

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Question 6

What happens once kinins are released into circulation?

Answer 6

They are rapidly (within 15 secs) inactivated by kininases

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Question 7

When is bradykinin produced and how is it regulated?

Answer 7

It is produced during inflammation and it is regulated as it has sites in which ACE can degrade it
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Question 8

What is the rank of potency of B1 and B2 receptors?

Answer 8

B1: Lys-BK (KD)&raquo_space; des-Arg9&raquo_space; BK

B2: Lys-BK (KD)&raquo_space; des-Arg9

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Question 9

What does inflammation activate that produces more bradykinin?

Answer 9

Kallikreins
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Question 10

What are kallikreins?

Answer 10

Kallikreins are a group of serine proteases involved in a variety of physiological and pathological processes, including the regulation of blood pressure, inflammation, and tissue remodelling

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Question 11

What does bradykinin promote the release of?

Answer 11

Inflammatory PG mediators

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Question 12

What 2 things happen in inflammation in reference to the B1 receptor?

Answer 12

It is upregulated and B1 receptor agonists are released

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Question 13

What 3 things do B1 agonists cause?

Answer 13

Vasodilation
Oedema
Increased vascular leakage

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Question 14

What is 1 example of a B1 agonist and 1 example of a B2 agonist?

Answer 14

B1: R-838
B2: Labradimil

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Question 15

What is an example of a non-peptide antagonist for B1 and 1 for B2 receptors and what are they used to treat?

Answer 15

B1: Safotibant - use to treat inflammatory pain
B2: Firazyr (a peptidomimetic) - used to treat hereditary angioedema (HAE)

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Question 16

What is angioedema?

Answer 16

The localized swelling of deeper layers of the skin and mucous membranes

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Question 17

What is histamine formed by?

Answer 17

The decarboxylation of L-histidine by histidine decarboxylase

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Question 18

What 2 enzymes is histamine metabolised by?

Answer 18

Histamine N-methyltransferase (HNMT/HMT) and diamine oxidase (DAO)

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Question 19

What tissues can synthesise histamine and in what tissues is the rate of synthesis increased?

Answer 19

All tissues can synthesise histamine, but the rate of synthesis is increase in inflamed tissues

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Question 20

What are 4 examples of triggers for histamine release?

Answer 20

Answers Include:

Allergens binding to mast-cell bound IgE antibodies
Release from mast cells
Anaphylatoxins
Tissue damage
Heat mechanical injury

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Question 21

What are anaphylatoxins?

Answer 21

Small peptide fragments that are generated during the activation of the complement system

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Question 22

Where is histamine generated and stored?

Answer 22

In the granules of mast cells an WBCs
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Question 23

What G proteins are H1,2,3 and 4 receptors coupled to?

Answer 23

H1: Gq
H2: Gs
H3 and 4: Gi

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Question 24

Other than mepyramine, what is an example of a histamine H1 antagonist and what is it used for?

Answer 24

Promethazine - used for allergic conditions, skin reactions and hay fever

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Question 25

What is an example of a H2 antagonist and what are they used for?

Answer 25

Ranitidine and Cimetidine - Used in the treatment of peptic ulcer/stomach acid productions

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Question 26

How is serotonin synthesised?

Answer 26

1. L-tryptophan is hydroxylated to 5-hydroxytryptophan (HTP) by tryptophan hydroxylase
2. HTP is then decarboxylated to 5-HT (serotonin) by DOPA decarboxylase

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Question 27

What are 3 examples of places serotonin is stored?

Answer 27

Intestines - enterochromaffin cells

Platelets

Neurons

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Question 28

When is serotonin released from enterochromaffin cells, platelets and neurons?

Answer 28

Enterochromaffin cells - Released during stimulation of the gut

Platelets - released during clotting (platelet activation)

Neurons - released during nerve stimulation

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Question 29

What is the function of serotonin in the brain?

Answer 29

Regulation of mood and sleep patterns

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Question 30

What is the function of serotonin in blood vessels?

Answer 30

Causes vasoconstriction, preventing blood loss

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Question 31

What is the function of serotonin in the intestine?

Answer 31

It mediates motility by activating enteric neurones which in turn regulates contraction and relaxation

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Question 32

What does SSRI stand for?

Answer 32

Selective serotonin reuptake inhibitor

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Question 33

What is an example of an SSRI?

Answer 33

Fluoxetine (PROZAC)

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Question 34

How do SSRIs work?

Answer 34

They inhibit serotonin reuptake via the serotonin transporter (SERT) meaning there are higher levels of serotonin in the synaptic cleft to activate the receptor

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