L14 Pharmacological aspects of immunology; NSAID and corticosteroids Flashcards
Examples of NSAIDS
- Aspirin
- Paracetamol
- Propionic acid derivatives - eg. ibuprofen, naproxen
- Arylakanoic acids - eg. indometacin, diclofenac
- Oxicams - eg. piroxicam
- Fenamic acids - eg. mefanamic acid
- Butazones - eg. phenylbutazone
- Coxibs - eg. celecoxib
What do NSAIDS target
- NSAIDS target a cascade of small molecule inflammatory mediators known as eicosanoids
Eicosanoid pathway
- During any form of tissue injury, membrane phospholipids are released and converted by phospholipases to arachidonic acid - a poly unsaturated 20 carbon lipid which can then, depending on tissues and inflammatory stimuli, be metabolised to either leukotrienes
What is the eicosanoid pathway particularly involved in
- Airway responses or prostaglandins
- Including thromboxanes
• Prostacyclines
And prostaglandins – involved in
Or prosaglandins – through the central intermediate prostaglandin H2
Prostaglandins include – depending on tissue specific synthases
• Thromboxanes –which are involved in platelet aggregation and small vessel tone
• Prostacyclines – which have vasodilator properties
• And prostaglandins themselves –
• which are involved in bronchial tone, vascular tone, sensitivity of nerve fibres among other properties
NSAID mechanism of action
- All inhibit cyclo-oxygenase
Isoforms of cox
- COX-1 - Constitutive expression
- COX-2 - Induced in inflammation
- COX-3 - CNS only?
COX-1 location
- Constitutive expression in all tissues
- Stomach, kidney, platelets, vascular endothelium
- Inhibition –> anti-platelet activity, side effects
COX-2 - location
- Induced in inflammation (IL-1)
- Injury, infection, neoplasia
- Inhibition –> analgesia and anti-inflammatory actions
COX-3 - location
- CNS only?
- Inhibited specifically by paracetamol –> antipyretic and analgesic actions
Why is COX 1 important
- Involved in maintenance of vascular supply endothelial junction integrity etc
- Particularly important seem to be the gastric mucosa and the renal tubules - where inhibition is responsible for much of the side-effects
What is COX 2 induced by
- COX2 is induced by the inflammatory response
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
Anti-inflammatory use of NSAIDs
- Gout
- Inflammatory arthritis eg ankylosing spondylitis, rheumatoid arthritis
Limitations of aspirin use for pain and inflammation
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)
Features of paracetamol (acetaminophen)
- Doesn’t bind COX1 or 2
- No significant anti-inflammatory action
- No significant GI toxicity
- Analgesic/anti-pyretic
- Dangerous in overdose
Paracetamol metabolism
- Under normal circumstances, the majority of paracetamol is conjugated in the liver with glucuronide and sulphate but a minority is oxidised by microsomal enzymes to a toxic intermediary which is it self rapidly neutralised by conjugation with glutathione
Paracetamol metabolism - excess amounts
- When excessive amounts of paracetamol is present, both these conjugation reactions are overwhelmed and these toxic intermediates accumulate leading to potentially fatal hepatic necrosis
Treatment of paracetamol toxicity
- Relies on the provision of substrates which the body can use to synthesise glutathione
- The two drugs which are used are NAC and methionine
What is glutathione
- A tripeptide involving cysteine - a non essential amino acid only in that it has to be synthesised from the essential amino acid methionine
- Can be easily converted to glutathione
Effects of prostaglandins E2 and I2 in the GI tract
- Decrease acid production
- Increase mucus production
- Increase blood supply
Effects of NSAID inhibition in stomach and duodenum
- Irritation
- Ulcers (gastric 15-30%, duodenal 10%)
- Bleeding
Similar effect in the colon
- Colitis - esp with local preps eg. rectal diclofenac
How do NSAIDs primarily cause GI toxicity
- Loss of prostaglandins, notably E2 and I2
Upper GI bleeding - NSAID risk
- Relative risk 4.7 all users
- Azapropazone - 23.4
- Piroxicam - 18
- Small differences between others
Biggest risk for GI bleed
Previous GI bleed Also: - Age - Chronic disease(eg. rheumatoid disease) - Steroids
What is NSAID nephrotoxicity associated with
Primarily related to changes in glomerular blood flow
- Decreased glomerular filtration rate
- Sodium retention
- Hyperkalaemia
- Papillary necrosis
Risk of acute renal failure - NSAID
- 5 - 1%
- Avoid or dose adjust in renal failure
- Avoid in patients likely to develop renal failure
What percentage of patients on nsaids experience a bronchospasm
- About 10% of asthmatics experience bronchospasm following NSAID - perhaps because of arachidonic acid is shunted down the 5LPO pathway when COX is inhibited
4 common non-selective NSAIDS - in order of increasing potency and increasing side-effects(GI, renal and fluid retention)
Ibuprofen, naproxen, diclofenac and indometacin
What can GI toxicity be treated with
- Gastroprotective drugs (misoprstil - PGE1 analogue, or PPI)
- Avoid in renal failure, dose adjust if necessary
Features of 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
What are the coxibs
- Celecoxib
- Etoricoxib
- Rofecoxib
- Valdecoxib
Coxibs - efficacy
- Numerous clinical trial data
- Comparable efficacy (not superior) to non-selective NSAIDs in
Acute pain
Dysmenorrhoea
Inflammatory joint disease
Do coxibs increase risk of MI
Cox-2 inhibitors - no activity as antithrombotics
two studies published in 2005
- Increase in 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)
Main coxib
- Celecoxib
BNF advice on coxib usage
- Cyclo-oxygenase-2 selective inhibitors should not be used in preference to non-selective NSAIDs except when specifically indicated (ie for patients who are at particularly high risk of developing gastroduodenal ulceration, performation, or bleeding) and after an assessment of cardiovascular risk
Effects of cortisol
- Carbohydrate and protein metabolism
- Fluid and electrolyte balance(mineralocorticoid effects)
- Lipid metabolism
- Psychological effects
- Bone metabolism
- Profound modulator of immune response
Endogenous cortisol from the adrenal cortex
Extensive regulatory functions including the most profound global modulator of the immune response
How do corticosteroids function
- Steroid receptors are found in the cytoplasm complexed with a heat-shock protein
- Steroids cross the cell membrane and bind to the steroid receptor complex, releasing Hsp90
- The steroid:receptor complex can now cross the nuclear membrane
- In the nucleus, the steroid receptor binds to specific gene regulatory sequences and activates transcription
Overall effect of corticosteroids
- 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
Immunomodulation by steroids - cell function
- T cell hyporesponsiveness
- Inhibited B cell maturation
- Decreased IL1, IL6 and TNFalpha production (monocytes)
- Widespread inhibition of Th1 and Th2 cytokines
- Inhibition of COX - prostaglandins
- Impaired phagocyte killing
- Decreas ein collagenases, elastases etc
Don’t affect immunoglobulin levels and complement
Clinical use of steroids
To suppress inflammation - asthma, crohn’s/UC, eczema, MS, sarcoid, allergy, rheumatoid arthritis, systemic lupus erythematosis
To suppress specific immunity - graft injection
Replacement therapy in hypoadrenalism
– Because of these functions, they are widely used to suppress inflammation and specific immunity
How are steroids administered
- Systemic (oral and parenteral)
- Topical (skin, joint injections, inhaled, enteric coated, rectal)
Features of hydrocortisone
- Low potency
- Good lipid solubility
Systemic use - Replacement Rx
Topical use - skin, joints
Features of prednisolone
- Medium potency
- Good lipid solubility
Systemic use - anti-inflammatory
Topical use - enemas
Features of beclomethasone
- Medium potency
- Poor lipid solubility
Topical use - asthma, crohn’s
Features of dexamethasone
- High potency
- Good lipid solubility
Systemic use - cerebral oedema
Features of triaminiclone
- High potency
- Poor lipid solubility
Topical use - skin, joints
Side effects of steroid therapy - early
- Weight gain
- Glucose intolerance
- Mood change
- Suppression of ACTH release
Side effects of steroid therapy - later
- Proximal muscle weakness
- Osteoporosis
- Skin changes
- Body shape changes
- Hypertension
- Cataracts
- Adrenal suppression
Adrenal suppression during corticosteroid therapy
- High-dose exogenous corticosteroids 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
- Abrupt withdrawal below replacement dose reduces ability to deal with physiological stress - eg infection - and may precipitate an adrenal crisis
Steroid use - precautionary measures
- Steroid warning card
- Tail dose slowly
- Increase dose during acute illness and prior to surgery
Link between steroids and infection
Steroids also increase risk of infection:
- 71 placebo controlled trials of prednisolone
- Consistently report increased risk of infection which is related to total accumulative dose
- Eg. for prednisolone > 700 mg (= 10-20 days of a standard dose)
Risk of infection with steroid use - phagocytic defects
Phagocytic defects - risk occurs early
- Bacterial infection - S. aureus, enteric bacteria etc
- Fungal infection - candida, aspergillus
Risk of infection with steroid use - cell mediated defects
Cell mediated defects - risk occurs later Intracellular pathogens - TB - Varicella - Listeria - Pneumocystis
