14. Pharmacological aspects of immunology

Question 1

NSAIDS examples

Answer 1

Aspirin Paracetamol Propionic acid derivatives - e.g. ibuprofen, naproxen Arylalkanoic acids – e. g indometacin, diclofenac Oxicams - e.g. piroxicam Fenamic acids - e.g. mefanamic acid Butazones - e.g. phenylbutazone Coxibs e.g. celecoxib

Question 2

What do NSAIDS do?

Answer 2

All inhibit cyclo-oxygenase Three isoforms of cyclo-oxygenase COX-1 - Constitutive expression COX-2 – Induced in inflammation COX-3 – CNS only?

Question 3

COX-1

Answer 3

Constitutive expression – all tissues Stomach, Kidney, Platelets, Vascular endothelium Inhibition → anti-platelet activity, side effects

Question 4

COX-2

Answer 4

– Induced in inflammation (IL-1) Injury, infection, neoplasia Inhibition → analgesia and anti-inflammatory actions

Question 5

COX-3

Answer 5

CNS only? Inhibited specifically by paracetamol → antipyretic and analgesic actions

Question 6

Indications for NSAID therapy

Answer 6

Short-term management of pain (and fever) As mild analgesics (orally and topically) - mechanical pain of all types - minor trauma - headaches, dental pain - dysmenorrhoea As potent analgesics (orally, parenterally, rectally) - peri-operative pain - ureteric colic As anti-inflammatories (?) - gout - Inflammatory arthritis eg ankylosing spondylitis, rheumatoid arthritis

Question 7

Aspirin

Answer 7

Use for pain and inflammation limited by: - GI toxicity - Tinnitus – mechanism obscure, usually reversible - Reye’s syndrome (fulminant hepatic failure in children) Anti-platelet effect - Prophylaxis of ischaemic heart disease - Treatment of acute MI

Question 8

Non-NSAID antiplatelet drugs

Answer 8

Clopidogrel and dipyrimidole

Question 9

Paracetamol

Answer 9

Doesn’t bind COX1 or 2. No significant anti-inflammatory action No significant GI toxicity Analgesic/ anti-pyretic Dangerous in overdose

Question 10

Paracetamol metabolism

Answer 10

Question 11

Eicosanoid pathways

Answer 11

Question 12

What is used to treat paracetamol poisoning?

Answer 12

N-acetylcystein / methionine (glutathione precursors) used in paracetamol poisoning

Question 13

NSAID GI toxicity

Answer 13

In the GI tract prostaglandins E2 and I2

• Decrease acid production
• Increase mucus production
• Increase blood supply

NSAID inhibition in stomach and duodenum

• Irritation
• Ulcers (gastric 15-30%, duodenal 10%)
• Bleeding

Similar effect in the colon

• Colitis – esp with local preps e.g. rectal diclofenac

Question 14

Things to ask about when prescribing NSAIDS

Answer 14

Upper GI bleeding

• Relative Risk 4.7 all users
• Azapropazone = 23.4
• Piroxicam = 18.0
• Small differences between others…

Biggest risk factor for GI bleed = previous GI bleed

Also

• Age
• Chronic disease (e.g.rheumatoid disease)
• Steroids

Question 15

NSAID nephrotoxicity

Answer 15

Primarily related to changes in glomerular blood flow

• Decreased glomerular filtration rate
• Sodium retention
• Hyperkalaemia
• Papillary necrosis

Acute renal failure 0.5-1%

Avoid or dose adjust in renal failure

Avoid in patients likely to develop renal failure

Question 16

Asthma and aspirin

Answer 16

About 10% of asthmatics experience bronchospasm following NSAID – perhaps because of arachidonic acid is shunted down the 5LPO pathway when COX is inhibited

Question 17

Which NSAID? - non-selective NSAIDS

Answer 17

Question 18

Preventing NSAID toxicity

Answer 18

Is an NSAID the answer (paracetamol, opioids?)

In terms of GI toxicity

Treatment with

• Gastroprotective drugs (misoprostil – PGE1 analogue, or proton pump inhibitor)

Avoid in renal failure, dose adjust if necessary

Question 19

Selective COX-2 inhibitors

Answer 19

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

The ‘coxibs’

• celecoxib
• etoricoxib
• rofecoxib
• valdecoxib
• etc

Question 20

Efficacy of coxibs

Answer 20

Numerous clinical trial data

Comparable efficacy (not superior) to non-selective NSAIDs in

• Acute pain
• Dysmenorrhoea
• Inflammatory joint disease

Question 21

GI side effects of coxibs

Answer 21

that rates of peptic ulceration and GI symptoms much lower with coxibs than NSAIDS but not lower than control

Question 22

Do Coxibs increase risk of MI?

Answer 22

Cox-2 inhibitors – no activity as antithrombotics

Two studies published in 2005

↑ rates of MI in clinical trials of celecoxib and rofecoxib

Data not fully disclosed by companies?

Relative risk

• small (1.56 for celecoxib higher for others)
• acute (first three months)

Question 23

Corticosteroid drugs

Answer 23

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 24

How do steroids work?

Answer 24

Steroids reduce immune activation by crossing cell membrane

binding their receptors intracellularly

then entering nucleus altering gene expression in numerous cell types

including T cells, B cells and cells of the innate immune system.

Their onset of action is delayed and they must be taken regularly

Question 25

Immunomodulation by steroids: cell trafficking

Answer 25

Lymphopenia, monocytopenia (redistribution) Neutrophilia and impaired phagocyte migration

Question 26

Immunomodulation by steroids: cell function

Answer 26

T cell hyporesponsiveness Inhibited B cell maturation Decreased IL1, IL6 and TNFa production (monocytes) Widespread inhibition of Th1 and Th2 cytokines Inhibition of COX - prostaglandins Impaired phagocyte killing ↓collagenases, elastases etc

Question 27

Steroids inflammatory modulation: things they don't affect

Answer 27

Immunoglobulin levels Complement

Question 28

Clinical use of steroids

Answer 28

To suppress inflammation * Asthma, Crohn’s / UC, Eczema, Multiple sclerosis, Sarcoid, allergy, rheumatoid arthritis, systemic lupus erythematosis etc etc To suppress specific immunity * Graft rejection Replacement therapy in hypoadrenalism

Question 29

Steroid preparations

Answer 29

Different routes of administration * Systemic (oral and parenteral) * Topical (skin, joint injections, inhaled, enteric coated, rectal) Different drugs * Different potencies * Different pharmacokinetics (esp lipid solubility and half-life)

Question 30

Corticosteroids as drugs

Answer 30

Question 31

Side-effects of steroid therapy

Answer 31

Predictable from steroid actions Early * Weight gain * Glucose intolerance * Mood change * Suppression of ACTH release Later * Proximal muscle weakness * Osteoporosis * Skin changes * Body shape changes * Hypertension * Cataracts * Adrenal suppression

Question 32

Adrenal suppression during corticosteroid therapy

Answer 32

High-dose exogenous corticosteroids suppress endogenous production within 1 week After prolonged therapy, adrenal cortex starts to atrophy and endogenous production takes some time to recover upon cessation Abrupt withdrawal below replacement dose reduces ability to deal with physiological stress – eg infection – and may precipitate an adrenal crisis * Steroid warning card * Tail dose slowly * Increase dose during acute illness and prior to surgery

Question 33

Steroids increase the risk of infection

Answer 33

71 Placebo controlled trials of prednisolone Consistently report increased risk of infection which is related to total cummulative dose E.g for prednisolone \> ~700mg (= 10 – 20 days of a standard dose)

Question 34

Risk of infection

Answer 34

Phagocytic defects - risk occurs early * Bacterial infection – S. aureus, enteric bacteria etc * Fungal infection – candida, aspergillus Cell mediated defects * Intracellular pathogens * TB * Varicella * Listeria * Pneumocystis