31.5 Pharmacology of Inflammation

Question 1

What is the mechanism of action for Aspirin and other NSAIDs?

Answer 1

Cyclooxygenase (COX) inhibitors
*suppress prostanoid synthesis (including prostaglandins)
*Aspirin has non-specific action on COX-1 and COX-2

Question 2

How do COX inhibitors work as analgesics?

Answer 2

Decrease prostaglandin synthesis which sensitise nocioceptive fibres to bradykinin

Question 3

How do COX inhibitors work as anti-inflammatories?

Answer 3

Decrease the production of prostaglandin E2 and prostacyclin which reduced vasodilation and indirectly, oedema

Question 4

How are COX inhibitors useful in the treatment of rheumatoid arthritis? What is this condition?

Answer 4

Chronic inflammatory disease characterised by chronic joint swelling and stiffness
COX inhibitors reduce the vasodilation of blood vessels to reduce the delivery of cytokines and chemokines to the joints

Question 5

What are the systemic effects of COX inhibitors?

Answer 5

Analgesic
Skin reactions (rashes)
Renal effects due to less prostaglandins which normally are involved in regulating renal flow
Antiplatelet action
Raise blood pressure
GI disturbances

Question 6

What is the difference in COX1 and COX2?

Answer 6

COX-1 is a constituitive enzyme expressed in most tissues as a ‘housekeeping’ enzyme involved in tissue homeostasis (initiates partuition, platelet aggregation, renal blood flow)
COX-2 is induced in inflammatory cells when they are activated by cytokines (IL-1, TNF alpha)

Question 7

What is the effect of COX-1 inhibitors on the gastrointestinal system?

Answer 7

GASTROINTESTINAL HAEMORRHAGE
Prostaglandins decrease acid secretion and increase mucus secretion so inhibiting this leads to the development of gastric ulcers and bleeds

Question 8

What is the function of prostanoids in the immune response?

Answer 8

Prostacyclin (PGI2) and prostaglandin E2 acts on Gs receptors to vasodilate, cause bronchodilation
Sensitise nocioceptors to inflammatory mediators such as bradykinin
Thromboxane stimulates platelet aggregation

Question 9

What is the mechanism of paracetamol?

Answer 9

Inhibits only a specific COX (localised to the CNS) to produce analgesic and antipyretic effects due to inhibition of prostaglandin synthesis in the CNS
There is an absence of an effect on the inflammatory processes underlying rheumatic disease

Question 10

What is paracetamol used for?

Answer 10

Acts as an analgesic, not an anti-inflammatory.
It inhibits specific COX to produce analgesic and antipyretic effects only. There is an absence of an effect on inflammatory processes underlying rheumatic disease.

Question 11

Why do COX inhibitors have the greatest effect on prostaglandin secretion by platelets?

Answer 11

Platelets have NO nucleus
Cannot resynthesise COX
Becomes irreversibly blocked

Question 12

Which cells produce prostaglandins?

Answer 12

Endothelial cells
Platelets
In degranulation reactions

Question 13

Name a non-steroidal anti-inflammatory drug?

Answer 13

Cyclooxygenase inhibitors (COX)

Question 14

How do NSAIDs and corticosteroids work to treat rheumatoid arthritis?

Answer 14

Both reduce production of prostanoids for inflammatory signalling (weakly by NSAIDs, strongly by corticosteroids)

Question 15

What is the mechanism of action of steroids?

Answer 15

They modulate gene expression and reduce the activity of phospholipase A2 which in turn reduces the production of prostaglandins, leukotrienes and platelet activating factor.

Question 16

What are steroids used for?

Answer 16

Allergic conditions including asthma

Question 17

Give examples of corticosteroids

Answer 17

Dexamethasone, hydrocortisone

Question 18

What are the adverse effects of steroids?

Answer 18

*Immune depression increasing the susceptibility to viral infections
*Hypertension via its effect on fluid and electrolyte balance
*Bone resorption (osteoporosis); diabetes; peptic ulcers; thickening of the skin

Question 19

How can corticosteroids cause bone resorption (osteoporosis)?

Answer 19

They decrease the function of osteoblasts directly, plus indirectly via inhibiting insulin-like growth factor I expression
–> inhibition of bone formation, osteoporosis

Question 20

How can corticosteroids cause hypertension?

Answer 20

They can overstimulate the mineralocorticoid receptor –> leading to sodium and thus water retention in the kidney
–> volume expansion, increase in BP

Question 21

How can corticosteroids cause immune depression?

Answer 21

Following reduction of PLA2 there can be further systematic anti-inflammatory responses that make the individual immunosuppressed
*also upregulate production of TGF-β and IL-1β for further, systemic anti-inflammatory responses

Question 22

How do corticosteroids treat asthma?

Answer 22

Block negative IL-4/5 signalling to relax inflamed lung tissue and reduce bronchoconstriction, reduce mucus secretion

Question 24

For histamine, summarise:

• Where it is released from
• How it is stored
• Receptors it acts on
• Actions

Answer 24

• Released from mast cells
• Stored in granules with heparin
• Acts via histamine receptors -> H1-H4
• Actions:
  
  • Increased vascular permeability (H1)
  • Smooth muscle cell contraction (H1)
  • Vasodilatation (H1)
  • Cardiac stimulation (H2)
  • Stimulation of gastric secretion (H2)

Question 25

What is chlorpheniramine?

Answer 25

Anti-histamine

Question 26

What are the limitations of chlorpheniramine?

Answer 26

Poorly selective for H1
- can affect CNS histamine neurotransmitter, –> drowsiness
- can affect gastric H1 –> decreased stomach acid

Also not useful for non-allergic inflammatory responses

Question 27

What is chlorpheniramine used to treat?

Answer 27

Allergies, anaphylaxis

Question 28

What is the mechanism of chlorpheniramine?

Answer 28

H1 antagonist
Reduces histamine inflammatory effects from mast cells

Question 29

What are two main drugs used to treat anaphylaxis?

Answer 29

Antihistamines - address root cause
Adrenaline - oppose hypotensive shock

Question 30

What is anaphylaxis?

Answer 30

A severe allergic reaction due to mass mast cell degranulation

Question 31

What does mass mast cell degranulation lead to in anaphylaxis?

Answer 31

Hypersensitivity reactions:
- Bronchiolar constriction
- Vascular leak
- Blood pressure drop, shock

Question 32

Which four main therapies are used to treat rheumatoid arthritis?

Answer 32

• Aspirin (/other NSAIDs)
• Corticosteroids
• DMARDs: disease-modifying anti-rheumatic drugs
• Therapeutic antibodies

Question 33

What are DMARDS?

Answer 33

Disease modifying anti-rheumatic drugs. They are immunosuppressants that depress the production of immune cells. (e.g. methotrexate)

Question 34

What is the mechanism of DMARDS action?

Answer 34

Diff DMARDs interfere with diff critical pathways in inflammatory cascade
Over time depress immune response - relieve joint inflammation

Question 35

How long does the full effect of DMARDs take to build up?

Answer 35

Several months

Question 36

How do NSAIDs and corticosteroids work to treat rheumatoid arthritis?

Answer 36

Both reduce production of prostanoids for inflammatory signalling (weakly by NSAIDs, strongly by corticosteroids)

Question 37

How do therapeutic antibodies treat rheumatoid arthritis?

Answer 37

They more specifically target the cytokines involved and reduce the persistent joint inflammation

Question 38

Which cytokines might RA therapeutic antibodies target?

Answer 38

IL-6, TNF, IL-1

Question 39

What is rheumatoid arthritis?

Answer 39

An autoinflammatory disorder affecting joints

Question 40

What is Rituximab?

Answer 40

anti-lymphocyte monoclonal antibody causing B lymphocyte lysis used to treat rheumatoid arthritis.

Question 41

What is abatacept?

Answer 41

An Ig-CTLA-4 fusion protein that interferes with the immune activity of T-cells. Used in the treatment of rheumatoid arthritis.