Lecture 16- Pharmacological aspects of Immunology

Question 1

NSAIDS:

Answer 1

Large chemically diverse family of drugs

• Aspirin
• propionic acid derivates- ibuprofen, naproxen
• Arylalkanoic acid- piroxicam
• Oxicams- piroxicams
• Fenemic acid- mefanamic acid
• Butazones- phenylbutazones

Question 2

which pathways does the NSAIDs work on?

Answer 2

Eicosanoid pathways

Question 3

Describe the mechanism of action of NSAIDs?

Answer 3

arcachidonic acid—->prostaglandins H2 via Cox enzyme

• NSAID block this enzyme
• Preventing the building up of:
• thromboxanes
• Prostaglandins
• Prostacyclins

Question 4

Explain the function of Thromboxanes, prostaglandins, and prostacyclins?

Answer 4

Thromboxanes: -Platelet aggregation and vasoconstriction
-Prostaglandins: 
Bronchial tone
vascular tone and hyperalgesia
-Prostacyclins:
Vasodilation

Question 5

Which COX enzymes does the NSAID block and what is the normal function?

Answer 5

COX-1: all tissues express it- stomach, kidney, platelets, vascular endothelium
Inhibition: antiplatelet activity
-COX-2: Induced inflammation (IL-1)
caused by:
injury, infection and neoplasia
Inhibition: Analgesia and anti-inflammatory actions
COX-3: CNS only?
May be relevant to paracetamol only

Question 6

what are the indication for NSAID therapy?

Answer 6

Short-term management of pain (and fever) and anti-inflammation

1) As mild analgesics (orally and topically):
- mechanical pain of all types
- minor trauma
- headaches, dental pain
- dysmenorrhoea
2) As potent analgesics (orally, parenterally, rectally)
- peri-operative pain
- ureteric colic

Question 7

Why has aspirin is no longer used for pain-relief and inflmmation?

Answer 7

Use for pain and inflammation limited by

• GI toxicity
• Tinnitus – mechanism obscure, usually reversible
• Reye’s syndrome (fulminant hepatic failure in children)

Question 8

What are the current uses of aspirin?

Answer 8

Anti-platelet effect:

• Primary and secondary prevention eg stroke and MI
• Treatment of acute MI and stroke

Question 9

How is GI toxicity caused by NSAIDS?

Answer 9

In the GI tract prostaglandins E2 and I2:
-Decrease acid production
-Increase mucus production
-Increase blood supply
NSAIDS block the production of prostaglandins

Question 10

what is the consequences of NSAID use on the stomach and dueodenum and colon?

Answer 10

• Irritation
• Ulcers (gastric 15-30%, duodenal 10%)
• Bleeding
• Colitis: esp with local preps

Question 11

Which NSAIDs have the highest risk for upper GI bleeds?

Answer 11

1) Azapropazone = 23.4
2) Piroxicam = 18.0
Small differences between others…

Question 12

what is the biggest risk factor for the GI bleeds and what are the other risk factors?

Answer 12

1) Biggest risk factor for GI bleed = previous GI bleed
Other risk factors:
-Age
-Chronic disease (e.g.rheumatoid disease)
-Steroids

Question 13

How does the NSAIDS cause the nephrotoxicity?

Answer 13

Primarily related to changes in glomerular blood flow causing:

1) Decreased glomerular filtration rate
2) Sodium retention
3) Hyperkalaemia
4) Papillary necrosis

Question 14

How does aspirin cause bronchospasm?

Answer 14

-Due to increased production of leukotrienes

Question 15

How can the NSAID toxicity be prevented?

Answer 15

• Use of NSAID esstential? alternatives?
• Consider other risk factors
• Give with a PPI (gastroprotection)

Question 16

Which NSAIDS to use?

Answer 16

From least to Most risk of SE:

Ibuprofen>Naproxen>Diclofenac>Indometacin

Question 17

Describe paracetamol use and mechanism of action?

Answer 17

-Not NSAID
-Minimal anti-inflammatory
-Good analgesic/antipyretic
-very well tolerated
-Mechanism of action not well understood:
does not bind to CoX-1 or 2- weak inhibitor
-May Inhibit COX-3
-Dangerous in overuse

Question 18

Describe the metabolism of paracetamol?

Answer 18

Normal metabolism:

Paracetamol………….>Paracetamol sulphate and glucuronide via phase II conjugation reaction and excreted

Question 19

Describe the metabolism of paracetamol in an overdose?

Answer 19

Paracetamol converted to N-acetyl–p-benzoquinoneimine
(NAPQI) via phase I oxidation reaction causes hepatic necrosis
NAPQI goes through phase II conjugation reaction to form: NAPQI - glutathione
which is then excreted

Question 20

What is the treatment option in paracetamol poisoning?

Answer 20

-N-acetylcysteine (glutathione precursor) used in paracetamol poisoning

Question 21

Describe the use of selective COX-2 inhibitors?

Answer 21

• Selective inhibition of COX-2 in vitro and in vivo
• Anti-inflammatory and analgesic in humans
• Objective evidence of selectivity (GI, platelets) at > anti-inflammatory doses

Question 22

Are the selective COX-2 inhibitors better than NSAIDs?

Answer 22

• COX-2 Comparable efficacy (not superior) to non-selective NSAIDs in
• Acute pain
• Dysmenorrhoea
• Inflammatory joint disease
• Controversy due to apparent increased risk of MI – but may have been a result of absence of anti-platelet effect

Question 23

Why is the COX-2 superior than NSAIDS?

Answer 23

-Rates of GI SE and peptic ulceration low

Question 24

Describe the functions of cortisol?

Answer 24

-Cortisol (hydrocortisone) – predominant endogenous glucocorticoid:
Carbohydrate and protein metabolism
Fluid and electrolyte balance (mineralocorticoid effects)
Lipid metabolism
Psychological effects
Bone metabolism
Profound modulator of immune response

Question 25

Describe the mechanism of action for cortiscosteriods?

Answer 25

- Steroid receptors are bound to heat shock protein HSP90 - Steroid crosses the cell membrane and bind to the steroid receptor releasing HSP90 - The steroid receptor complex can now leave the cross the nuclear membrane - In the nucleus, steroid receptor binds to specific gene regulatory sequence and activates transcription

Question 26

Describe immunomodulation caused by steroids?

Answer 26

1) Cell trafficking -Lymphopenia, monocytopenia (redistribution) -Neutrophilia and impaired phagocyte migration 2) Cell function -T cell hyporesponsiveness -Inhibited B cell maturation -Decreased IL1, IL6 and TNFa production (monocytes) -Widespread inhibition of Th1 and Th2 cytokines I-nhibition of COX - prostaglandins -Impaired phagocyte killing -↓collagenases, elastases etc

Question 27

What does the steroid not affect?

Answer 27

- Immunoglobulin levels | - Complement

Question 28

what are the clinical uses for the steroid use?

Answer 28

-To suppress inflammation of all kinds, particularly in acute disease but also in maintenance therapy Asthma, Crohn’s / UC, Eczema, Multiple sclerosis, Sarcoid, allergy, rheumatoid arthritis, systemic lupus erythematosis etc etc -Replacement therapy in hypoadrenalism

Question 29

Describe the preparation and routes for the steroid use?

Answer 29

- Systemic (oral and parenteral) | - Topical (skin, joint injections, inhaled, enteric coated, rectal)

Question 30

What are the early SE of steroid therapy?

Answer 30

Early: - Weight gain - Glucose intolerance - Mood change - Suppression of ACTH release

Question 31

What are the late SE of steroid use?

Answer 31

Later: - Proximal muscle weakness - Osteoporosis - Skin changes - Body shape changes - Hypertension - Cataracts - Adrenal suppression

Question 32

Describe the adrenal suppression during corticosteroid therapy?

Answer 32

- High dose exogenous steroids suppress endogenous production within 1 week - After prolonged therapy, the adrenal cortex begins to atrophy and endogenous production takes some time to recover upon cessation

Question 33

What are the consequences of abrupt withdrawal of steroids after prolonged use?

Answer 33

-Abrupt withdrawal below replacement dose reduces ability to deal with physiological stress – eg infection – and may precipitate an adrenal crisis

Question 34

How can the adrenal crisis be prevented?

Answer 34

-Steroid warning card Tail dose slowly Increase dose during acute illness and prior to surgery

Question 35

Explain the risk of infection due to steroid use?

Answer 35

-Risk is related to cumulative dose -Phagocytic defects Bacterial infection – S. aureus, enteric bacteria etc Fungal infection – candida, aspergillus These are risk factors in early use of steroids

Question 36

Explain the infection risk of prolonged use steroid which occurs later?

Answer 36

``` -Cell mediated defects Intracellular pathogens TB Varicella Listeria Pneumocystis ```

Question 37

Explain what DMARDs are?

Answer 37

- A diverse group of drugs that target the immune system - Derive name from use in rheumatoid arthritis, - Also used in transplantation and other autoimmune and inflammatory disorders; - for cancer chemotherapy (higher doses)

Question 38

Describe the mechanism of action of methotrexate?

Answer 38

- Competitive inhibitor of dihydrofolate reductase (DHR), therefore anti-folate action - Folate needed for purine synthesis in DNA - This reduces T cell activity, and also (in higher doses) tumour synthesis

Question 39

What are the main indications for the methotrexate use?

Answer 39

- Rheumatoid arthritis - Psoriasis - Crohns disease

Question 40

Describe main toxicities caused by methotrexate?

Answer 40

- Hepatotoxicity - Leucopenia - Pulmonary fibrosis - Teratogenic

Question 41

Describe the mechanism of action of azathioprine and uses?

Answer 41

- Inhibits thiopurine S methyltransferase (TPMT): inhibits purine synthesis - Similar indications to methotrexate; - more widely used in transplantation compared to methotrexate

Question 42

Describe the toxicities caused by azathioprine use?

Answer 42

Toxicities similar to methotrexate; GI upset very common when starting

Question 43

Describe the mechanism of ciclosporin and its uses?

Answer 43

- Inhibits calcineurin, which in turn reduces T lymphocyte activity - Similar indications to aza/ metho, but used more in Dermatology and transplantation

Question 44

What are the main toxicities of ciclosporin?

Answer 44

- Nephrotoxic - Hepatotoxic - Gum hyperplasia - Hirsuitism