Block C Lecture 2 - Autocoids Flashcards
What are autocoids?
They are substances which are produced on demand and act locally (autocrine or paracrine) and have very short half lives
(Slide 3)
What are 3 major classes of autocoids?
Polypeptides
Biogenic amines
Phospholipid-derived
(Slide 3)
What are kinins?
Potent biological peptides which are formed following cleavage of kininogens by the enzyme kallikrein
(Slide 5)
What are 2 examples of kinins an their properties?
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
(Slide 5)
What can Kallidin (Lys-Bradykinin) be converted into and what enzymes do this?
It can be converted into bradykinin (BK) by aminopeptidase enzymes
(Slide 5)
What happens once kinins are released into circulation?
They are rapidly (within 15 secs) inactivated by kininases
(Slide 5)
When is bradykinin produced and how is it regulated?
It is produced during inflammation and it is regulated as it has sites in which ACE can degrade it
(Slide 7)
What is the rank of potency of B1 and B2 receptors?
B1: Lys-BK (KD) > des-Arg9 > BK
B2: Lys-BK (KD) > des-Arg9
(Slide 7)
What does inflammation activate that produces more bradykinin?
Kallikreins
(Slide 9)
What are kallikreins?
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
(Slide 9)
What does bradykinin promote the release of?
Inflammatory PG mediators
(Slide 9)
What 2 things happen in inflammation in reference to the B1 receptor?
It is upregulated and B1 receptor agonists are released
(Slide 9)
What 3 things do B1 agonists cause?
Vasodilation
Oedema
Increased vascular leakage
(Slide 9)
What is 1 example of a B1 agonist and 1 example of a B2 agonist?
B1: R-838
B2: Labradimil
(Slide 11)
What is an example of a non-peptide antagonist for B1 and 1 for B2 receptors and what are they used to treat?
B1: Safotibant - use to treat inflammatory pain
B2: Firazyr (a peptidomimetic) - used to treat hereditary angioedema (HAE)
(Slide 11)
What is angioedema?
The localized swelling of deeper layers of the skin and mucous membranes
(Slide 11)
What is histamine formed by?
The decarboxylation of L-histidine by histidine decarboxylase
(Slide 18)
What 2 enzymes is histamine metabolised by?
Histamine N-methyltransferase (HNMT/HMT) and diamine oxidase (DAO)
(Slide 18)
What tissues can synthesise histamine and in what tissues is the rate of synthesis increased?
All tissues can synthesise histamine, but the rate of synthesis is increase in inflamed tissues
(Slide 18)
What are 4 examples of triggers for histamine release?
Answers Include:
Allergens binding to mast-cell bound IgE antibodies
Release from mast cells
Anaphylatoxins
Tissue damage
Heat mechanical injury
(Slide 19)
What are anaphylatoxins?
Small peptide fragments that are generated during the activation of the complement system
(Slide 19)
Where is histamine generated and stored?
In the granules of mast cells and WBCs
(Slide 19)
What G proteins are H1,2,3 and 4 receptors coupled to?
H1: Gq
H2: Gs
H3 and 4: Gi
(Slide 20)
Other than mepyramine, what is an example of a histamine H1 antagonist and what is it used for?
Promethazine - used for allergic conditions, skin reactions and hay fever
(Slide 21)
What is an example of a H2 antagonist and what are they used for?
Ranitidine and Cimetidine - Used in the treatment of peptic ulcer/stomach acid productions
(Slide 21)
How is serotonin synthesised?
- L-tryptophan is hydroxylated to 5-hydroxytryptophan (HTP) by tryptophan hydroxylase
- HTP is then decarboxylated to 5-HT (serotonin) by DOPA decarboxylase
(Slide 25)
What are 3 examples of places serotonin is stored?
Intestines - enterochromaffin cells
Platelets
Neurons
(Slide 25)
When is serotonin released from enterochromaffin cells, platelets and neurons?
Enterochromaffin cells - Released during stimulation of the gut
Platelets - released during clotting (platelet activation)
Neurons - released during nerve stimulation
(Slide 25)
What is the function of serotonin in the brain?
Regulation of mood and sleep patterns
(Slide 26)
What is the function of serotonin in blood vessels?
Causes vasoconstriction, preventing blood loss
(Slide 26)
What is the function of serotonin in the intestine?
It mediates motility by activating enteric neurones which in turn regulates contraction and relaxation
(Slide 26)
What does SSRI stand for?
Selective serotonin reuptake inhibitor
(Slide 28)
What is an example of an SSRI?
Fluoxetine (PROZAC)
(Slide 28)
How do SSRIs work?
They inhibit serotonin reuptake via the serotonin transporter (SERT) meaning there are higher levels of serotonin in the synaptic cleft to activate the receptor
(Slide 28)
