14. Pharmacological aspects of immunology Flashcards Preview

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NSAIDS examples

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


What do NSAIDS do?

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



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



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



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


Indications for NSAID therapy

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



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


Non-NSAID antiplatelet drugs

Clopidogrel and dipyrimidole



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


Paracetamol metabolism


Eicosanoid pathways


What is used to treat paracetamol poisoning?

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


NSAID GI toxicity

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


Things to ask about when prescribing NSAIDS

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


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


NSAID nephrotoxicity

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


Asthma and aspirin

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


Which NSAID? - non-selective NSAIDS


Preventing NSAID toxicity

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


Selective COX-2 inhibitors

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


Efficacy of coxibs

Numerous clinical trial data

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

  • Acute pain
  • Dysmenorrhoea
  • Inflammatory joint disease


GI side effects of coxibs

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


Do Coxibs increase risk of MI?

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)


Corticosteroid drugs

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


How do steroids work?

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


Immunomodulation by steroids: cell trafficking

Lymphopenia, monocytopenia (redistribution)

Neutrophilia and impaired phagocyte migration


Immunomodulation by steroids: cell function

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


Steroids inflammatory modulation: things they don't affect

Immunoglobulin levels



Clinical use of steroids

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


Steroid preparations

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)


Corticosteroids as drugs