1.06 - Chronic Inflammation & Pain

Question 1

Define: Chronic Inflammation

Answer 1

Inflammation of prolonged duration in which active inflammation, tissue destruction and attempts at repair are proceeding simultaneously

Question 2

Provide examples of conditions where Chronic Inflammation may occur

Answer 2

Persistent infection (tuberculosis)
Prolonged exposure to toxic agents (endogenous - lipids, exogenous - silicosis, miner's lung)
Autoimmune diseases (rheumatoid arthritis)

Question 3

What are the three characteristic histological features of Chronic Inflammation

Answer 3

1. Collection of Chronic Inflammatory cells (lymphocytes)
2. Destruction of parenchyma (e.g. normal alveoli replaced by spaces lined with cuboidal epithelium)
3. Replacement by connective tissue (fibrosis)

Question 4

Describe the origin of pain and suffering

Answer 4

Visceral and Somatic stimuli lead to nociception and subsequently pain.
Psychological processes and neuropathic mechanisms also lead directly to pain.
Pain –> suffering
Psychological processes can also lead directly to suffering.

Question 5

Describe agents that are used to prevent pain and suffering and where they act in the process

Answer 5

NSAIDs: act to prevent nociception
Opioids: Block the signalling of nociception to the pain centres in the brain. They also block neuropathic mechanisms leading to pain
Anticonvulsants: Block europathic mechanisms leading to pain
Anti-depressants: Reduce the psychological processes that cause pain and also the associated suffering

Question 6

What two broad mechanisms of action can anti-inflammatory drugs have?

Answer 6

Decrease the production of inflammatory compounds

Decrease response to product of inflammation

Question 7

Describe how anti-inflammatories can decrease the production of inflammatory compounds

Answer 7

They can:

• Decrease number of cell producing cytokines (immunosuppressants: azathioprine; glucocorticosteroids: prednisolone)
• Decrease production of inflammatory cytokines (NSAIDs: aspirin)
• Decrease immunoglobulin synthesis (Penicillamine)

Question 8

Describe how anti-inflammatories can decrease the response to products of inflammation

Answer 8

Antibodies to defined cytokines (Anti-TNFalpha: Infliximab)

Decrease cellular response to cytokines by modification of nuclear response (e.g. pathway utilising NF-kb: mesalazine)

Question 9

How do NSAIDs work?

Answer 9

They decrease the production of prostanoids, which are some of the mediators of the inflammatory response

Question 10

What are some examples of prostanoids?

Answer 10

PGE2
PGF2alpha
PGD2
PGI2* (Prostacyclin)
TXA2* (Thromboxane A2)

*Remember these ones

Question 11

List some examples of NSAIDs

Answer 11

Aspirin
Ibuprofen
Naproxen
Paracetamol
Celecoxib (Celebrex)
Ketoprofen
Diclofenac

Question 12

Describe Cyclooxygensase

Answer 12

Two isoforms: COX-1 & COX-2
Produce Prostaglandins from Arachidonic Acid
Platlets, smooth muscles (vascular and bronchial), vascular endothelium, GIT mucose
COX is unregulated in inflammation

Question 13

Describe the associated between COX and pain

Answer 13

Some prostanoids (produce by COX) potentiate pain caused by bradykinin and serotonin
E.g. PGE2 & PGD2

Question 14

Describe the association between COX and temperature

Answer 14

PGE2 (produced by COX) raises temperature in the hypothalamus

Question 15

Describe the mechanism of action of NSAIDs

Answer 15

NSAIDs are inhibitors of COX –> decreased production of Prostaglandins –> pain signalling and anti-pyretic

Question 16

What are the adverse consequences of NSAIDs?

Answer 16

NSAIDs inhibit COX but not lipoxygenase –> increased production of leukotrienes (can cause bronchoconstriction)
Most NSAIDs are non-selective inhibitors of COX. COX-1 believed to be protective in the GIT –> GIT disturbances with aspirin use. Paracetamol only works in the CNS.

Question 17

Is aspirin a reversible or irreversible inhibitor of COX?

Answer 17

Irreversible non-competivie
Aspirin donates its acetyl group and acetylates COX –> permanent deactivation of the enzyme.
New COX must be synthesised to restore enzyme activity

Question 18

Q. Why do you think osetomyelitis can progress to become chronic?

Answer 18

A nidus of bone becomes devascularised and the cells necrose. The extra-cellular matrix is highly mineralised, which makes it difficult to breakdown. Depending upon size of piece of bone, if it is not broken down, its presence acts as a “foreign body”. Alternative scenario may be external fistula or sinus to skin surface with constant re-infection (remember clinical photo from lecture).

Question 19

Q. Considering flow diagram of arachadonic acid metabolism, identify three (3) potential significant side effects associated with NSAID use?

Answer 19

Gastric mucosal ulceration (decreased PGE2 - mucosal protection), haemorrhage (decreased PGF2a & PGD2 - inhibit platelet aggregation), bronchoconstriction/ asthma (increased Leukotrienes - bronchoconstrictors), decreased renal function (PGI2 & TXA2 - kidney protection)

Question 20

Q. Which of the drug groups listed is/are likely to be disease-modifying rather than “simple” symptom control?

Answer 20

Drugs which act by immunosuppression or immunomodulation. In general everything apart from NSAIDs.