L14. Pharmacological aspects of immunology (Theme 1) Flashcards
examples of NSAIDS
Large, chemically diverse family of drugs:
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 is the Eicosanoid pathway
Study slide 6
what do nSAIDS all do
They antagonise cyclooxygenase stopping the conversion of arachidonics and Prostaglandins H2 to thromboxanes
what are the 3 isoforms of cyclo-oxygenases
COX-1 - Constitutive expression
COX-2 – Induced in inflammation
COX-3 – CNS only?
what are the 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
what are NSAID used for
for gout
inflammatory arthritis e.g- ankylosing spondylitis, rheumatoid arthritis
what is Aspirin used for
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
Clopidogrel and dipyrimidole
-Non-NSAID antiplatelet drugs
action of paracetamol/acetaminophen
Doesn’t bind COX1 or 2.
No significant anti-inflammatory action
No significant GI toxicity
Analgesic/ anti-pyretic
Dangerous in overdose (see later slides)
how is paracetamol metabolised
see slide 17
describe 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
describe 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
study slide
21
describe NSAIDs in increasing toxicity
Ibuprofen- naproxen- dielofenae - indomethacin
how can you prevent 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
describe 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
what is the 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
lower than for NSAIDs
do coxibs increase the risk of MIs
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)
which coxib do we need to know
Celecoxib:cyclo-oxygenase-2 selective inhibitors should not be used in preference to non-selective NSAIDs except when specifically indicated (i.e. for patients who are at a particularly high risk of developing gastroduodenal ulceration, perforation, or bleeding) and after an assessment of cardiovascular risk’
give an example of a corticosteroid
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
mechanism of action of corticosteroids
- steroid receptors are found in the cytoplasm complexed with a heat-shock protein HSp90
- steroids cross the cell membrane and bind to the steroid receptor complex releasing Hsp90
the steroid-receptor complex can now cross the nuclear membrane
Steroids reduce immune activation by 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
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
Don’t effect
- Immunoglobulin levels
- Complement
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
routes of admin-steroids
Systemic (oral and parenteral)
Topical (skin, joint injections, inhaled, enteric coated, rectal)
