NSAIDs

Question 1

What are autocoids?

Give some examples of autocoids involved in the inflammatory response

Answer 1

Biological factors “self drugs”- which act like local hormones

They have a brief duration and act near the site of synthesis

e.g. Bradykinins, Histamine, Cytokines, NO, Leukotrines

Question 2

What are eicosanoids?

Give examples of such

Answer 2

A family of oxygenated derivatives of 20-carbon polyunsaturated fatty acids used as signalling molecules

e.g. prostaglandins, thromboxanes

Question 3

What are the key features of inflammatory mediators and signalling agents?

Answer 3

Localised release

Short half lives - fine control

Question 4

Prostaglandins are synthesised from what?

Answer 4

Arachidonic acid

Question 5

Which enzymes are responsible for the synthesis of prostaglandins?

Answer 5

Cyclo-oxygenase (COX) enzymes

Question 6

Cell membrane phospholipids are converted to arachidonic acid by which enzyme?

Answer 6

Phospholipase A₂

Question 7

Arachidonic acid is converted (by COX-1/COX2) into which prostaglandin followed by which other prostaglandin before they are converted by specific prostaglandin enzymes?

Answer 7

1) PG ‘G’
2) PG ‘H’

Question 8

Which is the most important prostaglandin in mediating inflammatory response?

Answer 8

PG ‘E’

Question 9

What kind of responses are elicited by PG ‘E’?

Answer 9

Vasodilatiomnm

Hyperalgesia

Fever

Immunomodulation

Question 10

PG synthesis by COX-1 has a major cytoprotective role, in which tissues is this particularly important? Why?

Answer 10

Gastric mucosa

Myocardium

Renal parenchyma

Because they are very metabolically active tissues

Question 11

What is the approximate half life of PGs?

What does this mean in relation to their production?

Answer 11

10 minutes

They need constant synthesis

Question 12

COX-1 is constitutively expressed.

In what way does this contribute to the enzymes role in certain ADRs?

Answer 12

Most ADRs that are caused by NSAIDs are due to COX-1 inhibition

Question 13

COX-2 expression is induced by what?

Answer 13

Injurious stimuli - inflammatory mediators such as bradykinin

Question 14

Cox-2 appears to be constitutively expressed in which parts of the body?

Answer 14

Brain

Kidney

Question 15

The main therapeutic effects of NSAIDs occurs via which enzyme?

Answer 15

Cox-2

Question 16

What is the structural difference between COX-1 and COX-2 enzymes?

Answer 16

COX-1 is narrow mouthed, has a “tight” opening

COX-2 is wide mouthed, has a “baggy” opening

Question 17

Prostaglandins bind to which receptors?

Answer 17

GPCRs

(G-protein coupled receptors)

Question 18

What effects do prostaglandins have on local blood vessels?

Answer 18

Vasodilation

Allows access by bradykinin and histamine to the site= increased permeability of the site by these and not PGs directly

Question 19

Which specific prostaglandin E receptor is responsible for vasodilation or surrounding blood vessels?

Which type of GPCR is this?

Answer 19

EP2

Gs

Question 20

Which specific Prostaglandin E receptor is responsible for incresed peripheral nociception?

Which kind of GPCR is this?

Where are these receptors found?

Answer 20

EP1

Gq

C fibres

Question 21

Painful stimuli is carried why which fibres of the nervous system?

Answer 21

C fibres

Question 22

Binding of prostaglandin E to EP1 receptors on C fibres results in which downstream effects?

What is the overall effect of these?

Answer 22

Increased neuronal sensitivity to Bradykinin

Inhibition of K+ channels (closer to threshold for AP firing)

Increased Na+ channel sensitivity

Overall effect: increase C fibre activity

Question 23

Explain what is happening at a cellular level when prostaglandin E binds to to EP1 receptors on C fibres

Answer 23

PG E binds EP1 (Gq GPCR)

Increased intracellular calcium

Increased neurotransmitter release

Increased sensitivity via other autocoids

Question 24

What is allodynia?

How does this differ from hyperalgesia?

Answer 24

The feeling of pain in a tissue given a stimulus that would not normally be painful in that tissue

Hyperalgesia is an increased pain stimulus in a tissue that WOULD normally perceive pain

Question 25

Which three changes in nociception might a patient experience following injury?

Answer 25

Spontaneous pain Allodynia Hyperalgesia

Question 26

What does increased sustained nociceptive signalling peripherally result in?

Answer 26

Increased cytokine levels in the dorsal horn cell body Leading to central sensitisation to pain (increased pain perception)

Question 27

What happens at a cellular level to cause increased central sensitisation to pain?

Answer 27

PG E binds to EP2 receptors (Gs GPCR) Increased cAMP Increased PKA Decreases glycine receptor binding affinity Increases the discharge rate

Question 28

In infected/inflammed tissue, bacterial endotoxins stimulte macrophages to release what? What does this then go on to do?

Answer 28

IL-1 IL-1 within hypothalamus stimulates PGE synthesis

Question 29

Prostaglandin E interacts with which receptor to cause pyrexia?

Answer 29

EP3 receptor which is a Gi GPCR It results in increased heat production and reduced heat loss

Question 30

The main therapeutic effects of NSAIDs are achieved via inhibition of which enzyme? What kind of inhibition is this?

Answer 30

COX-2 (and 1) Competitive

Question 31

NSAIDs display _______ pharmacokinetics within the therapeutic dose range

Answer 31

Linear

Question 32

What are some of the main ADRs of NSAIDs?

Answer 32

Stomach and GI tract: nausea, heart burn, gastric bleeding, ulceration Renal ADRs: in HF, renal disease Vascular risk: Increased risk of bleeding, bruising

Question 33

Give an example of a serve hypersensitivity reaction to NSAIDs

Answer 33

Stevens Johnson Syndrome Rash over skin and all mucous membranes within the body Immune-complex mediated hypersensitvity reaction

Question 34

Explain the reason for GI ADRs with NSAIDs

Answer 34

COX-1 inhibition leads to reduced binding to receptors and therefore reducted prostaglandin production The prostaglandins would normally stimulate cytoprotectice mucus secretion through the GI tract, reduce acid secretion and promote mucosal blood flow

Question 35

What drugs can be combined with NSAIDs to extend their therapeutic range for treating pain?

Answer 35

Low dose opiates

Question 36

Are NSAIDs heavily or weakly protein bound?

Answer 36

Heavily bound 90-99%

Question 37

NSAIDs can affect PK and PD of other drugs, give some examples.

Answer 37

Sulphonylurea Warfarin Methotrexate

Question 38

Aspirin is the only NSAID to _________ inhibit COX enzymes by acetylation

Answer 38

Irreversibly

Question 39

When aspirin is taken orally, what is its half life?

Answer 39

Less than 30 minutes

Question 40

Aspirin in hydrolysed in the plasma to what? Which kinetics does this display at varying doses?

Answer 40

Salicylate Lower: first order kinetics Higher: zero order

Question 41

What is the mechanism of action of paracetamol?

Answer 41

Unknown Possibily weak COX-1/2 inhibitor

Question 42

Which order of kinetics does paracetamol show in a **healthy** patient at **normal** doses?

Answer 42

First order (linear) | (Half life 2-4 hours)

Question 43

What pharmacokinetics does paracetamol show at high doses?

Answer 43

Zero order kinetics

Question 44

What is the toxic metabolite produced in the breakdown of paracetamol?

Answer 44

NAPQI

Question 45

Why do doses over 10g (20 tablets) cause a potentially fatal response in the patient?

Answer 45

NAPQI is produced, glutathione which usually mops it up is saturated due to the excess Leading to increased production of NAPQI--\> unconjugated Highly reactive- binds with cellular macromolecules and mitochonrdia Lead to hepatic cell death

Question 46

How can paracetamol iverdose be treated?

Answer 46

Activated charcoal orally within 0-4 hours Acetylcysteine within 0-36 hours or Methionine orally if this cannot be given in this time

Question 47

How do we decide whether to treat a patient following paracetamol overdose?

Answer 47

Use a treatment decision graph Which depends on the time after OD and their current plasma level