PHARM - Anti-Inflammatory Drugs I: The Arachidonic Acid Pathway and NSAIDS - Week 5

Question 1

Describe two means of chemical signalling between cells and give examples for each (5).

Answer 1

Release of molecules by other cells
-neurotransmitters
-hormones
-local mediators
-exosomes
Membrane-bound molecules
-immune system

Question 2

What are exosomes?

Answer 2

Extracellular vesicles

Question 3

Name 5 kinds of important local mediators and their composition.

Answer 3

Histamines - small amine
Prostaglandins - lipid-derived
Leukotrienes - lipid-derived
Bradykinin - a peptide
Nitric oxide - a gas

Question 4

In what two cells are histamines largely stored in and released from? Where are these cells found?

Answer 4

Mast cells
-found in tissue, particularly mucosal surfaces/skin
Basophils
-blood

Question 5

What relation do enterochromaffin-like cells have with histamines?

Answer 5

They regulate stomach acid secretion using histamine

Question 6

Describe the triple response of Lewis and what each one occurs due to.

Answer 6

Occurs due to the release of histamine
Reddening - due to capillary dilation
Flare - redness in the surrounding area due to arteriolar dilation
Wheal - due to exudation of fluid from capillaries and venules

Question 7

List 7 biological effects of histamine.

Answer 7

Vasodilation - hypotension
Increased vascular leak - hypovolaemia
Bronchospasm
Pain/itch - sensory nerve activation
Mucus secretion
Increased wakefulness
Gastric acid secretion

Question 8

How does histamine induce pain/itch?

Answer 8

Sensory nerve activation

Question 9

List the four major histamine receptors.

Answer 9

H1, H2, H3, H4

Question 10

What is the major histamine receptor for allergic inflammation? What drug class targets this receptor and in what way?

Answer 10

H1 receptor

Anti-histamines are antagonists to this receptor.

Question 11

Name four conditions that anti-histamines are useful in treating.

Answer 11

Hayfever - allergic rhinitis
Urticaria
Anaphylaxis
Angioedema

Question 12

Can anti-histamines be useful in treating colds or athsma?

Answer 12

No

Question 13

Are H1 receptor antagonists reversible or irreversible?

List the three classes of this drug.

Answer 13

Sedative
Non-sedative
Newer non-sedative

Question 14

Which class of anti-histamines lacks anti-muscarinic activity and what is a consequence of this?

Answer 14

Non-sedative - lacks GIT effects but can cause sudden ventricular arrhythmia (rare)

Question 15

What can be said of the newer non-sedative class of anti-histamines?

Answer 15

Reduced risk of unwanted cardiac effects

Question 16

What is the active constituent of aspirin? What is it derived from?

Answer 16

Salicylate - derived from willow bark.

Question 17

Name three effects of salicylate.

Answer 17

Anti-pyretic (fever)
Analgaesic
Anti-inflammatory

Question 18

How did prostaglandins get their name?

Answer 18

The active components were thought to be from the prostate gland and was first derived and isolated from semen ( ͡° ͜ʖ ͡°)

Question 19

What do prostaglandins have structural similarity to?

Answer 19

Arachidonic acid

Question 20

What defines an eicosanoid?

Answer 20

20 carbon containing compounds

Question 21

What umbrella term do prostaglandins and thromboxanes fall under?

Answer 21

Prostanoids

Question 22

Are eicosanoids stored? Explain.

Answer 22

No, they are produced on demand

Question 23

Which cells produce prostaglandins?

Answer 23

Most of them

Question 24

Briefly describe the generation of eicosanoids and name two stimuli that can induce this process.

Answer 24

A cytokine/inflammatory mediator acts on its receptor to begin the process. Mechanical trauma may also induce it.
This increases Ca2+ levels, which activates phospholipase A2, which liberates arachidonic acid from the cellular membrane.

Question 25

Where is arachidonic acid liberated from, and what is the rate-limiting step?

Answer 25

From the cell membrane - the action of phospholipase A2 is the rate-limiting step.

Question 26

Are levels of free phospholipase A2 high or low in resting cells?

Answer 26

Very low

Question 27

How does phospholipase A2 act?

Answer 27

It cleaves a phospholipid at its second carbon atom to result in the release of arachidonic acid

Question 28

Name three derivatives of arachidonic acid (4) and two enzymes responsible for its conversion.

Answer 28

Cyclo-oxygenase to form prostanoids -prostaglandins -thromboxanes Lipoxygenase to form leukotrienes

Question 29

How many major cyclo-oxygenase enzymes are there and which of the two do most cells have? Which one do inflammatory cells have?

Answer 29

2 enzymes, COX1 and COX2 Most cells have COX1 Inflammatory cells have COX2

Question 30

Which cells mainly use lipoxygenase?

Answer 30

Inflammatory cells

Question 31

How do eicosanoids produce their effects?

Answer 31

Selective G-protein coupled receptors and subsequent second messengers.

Question 32

What effect do prostaglandins have on vascular smooth muscle?

Answer 32

Vasodilation

Question 33

What effect do thromboxanes have on vascular smooth muscle?

Answer 33

Vasoconstriction

Question 34

What effect do leukotrienes have on bronchial smooth muscle?

Answer 34

Constriction

Question 35

What effect do prostaglandins have on uterine smooth muscle?

Answer 35

Contraction

Question 36

What effect do prostaglandins have on gastrointestinal smooth muscle?

Answer 36

Contraction

Question 37

What effect do prostaglandins and thromboxanes have on platelet aggregation?

Answer 37

Prostaglandins - anti-aggregatory | Thromboxanes - pro-aggregatory

Question 38

What effect do leukotrienes have on leukocytes?

Answer 38

Chemoattractant

Question 39

Haemostasis is the balance between what two hormones?

Answer 39

PGI2 (prostaglandin) and TXA2 (thromboxane) PGI2 is a vasodilator and anti-thrombotic TXA2 is a vasoconstrictor and pro-thrombotic

Question 40

What effect do prostaglandins have on gastric secretion?

Answer 40

Inhibits gastric acid secretion

Question 41

What effect do prostaglandins have on the kidney (3)?

Answer 41

Increases renal blood flow and increases excretion of water and sodium.

Question 42

List three therapeutic uses for eicosanoids.

Answer 42

Glaucoma (latanoprost) Gastric ulceration Uterine contraction

Question 43

Do leukotrienes induce vasodilation?

Answer 43

No

Question 44

``` Which of the following induce chemotaxis (2): Histamine Bradykinin Prostanoid Leukotriene ```

Answer 44

Histamine | Bradykinin

Question 45

``` Which of the following induce pain: Histamine Bradykinin Prostanoid Leukotriene ```

Answer 45

Bradykinin

Question 46

``` Which of the following most induce vascular permeability (2): Histamine Bradykinin Prostanoid Leukotriene ```

Answer 46

Histamine | Leukotriene

Question 47

``` Which of the following acts synergistically with other mediators: Histamine Bradykinin Prostanoid Leukotriene ```

Answer 47

Prostanoid

Question 48

Describe what is meant by hyperalgaesic and give two hormones that fall under this term.

Answer 48

Increases sensitivity of receptors to painful stimuli | PGE2 and PGI2 (prostaglandins)

Question 49

Briefly describe how fever occurs in 5 steps.

Answer 49

``` Inflammation Neutrophil activation Cytokine release PGE2 release in the hypothalamus Temperature raised ```

Question 50

What do NSAIDs target?

Answer 50

COX enzyme

Question 51

What three effects do NSAIDs have?

Answer 51

Anti-pyretic Analgaesic Anti-inflammatory