Pharmacological aspects of immunology Flashcards
NSAIDS
Large, chemically diverse family of drugs
- aspirin
- paracetamol
- propionic acid derivatives
- arylalkanoic acids
- axicams
- fenamic acids
- butazones
- coxibs
NSAID mechanism of action
All inhibit cyclo-oxygenase
Three isoforms of cyclo-oxygenase
- COX-1 constitutive expression
- COX-2 induced in inflammation
- COX-3 CNS only
COX-1
Constitutive expression- all tissues
Stomach, kidney, plateletse, vascular endothelium
Inhibition -> anti-platelet activity, side effects
COX-2
Induced in inflammation (IL-1)
Injury, infection, neoplasia
Inhibition -> analgesia and anti-inflammatory actions
COX-3
CNS only?
Inhibited specifically by paracetamol -> antipyretic and analgesic actions
Indications for NSAID therapy
Short term management of pain (and fever)
As mild analgesics
- 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 e.g. ankylosing spondylitis, rheumatoid arthritis
Aspirin
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
Paracetamol
Doesn’t bind COX1 or 2
No significant anti-inflammatory action
No significant GI toxicity
Analgesic/ anti-pyretic
Dangerous in overdose
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
- bleeding
Similar effect in the colon
- colitis- esp with local preps
Upper GI bleeding
- relative risk 4.7 all users
Biggest risk factor for GI bleed is previous GI bleeds
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
Preventing NSAID 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 COX2 in vitro and in vivo
Anti-inflammatory and analgesic in humans
Objective evidence of selectively (GI, platelets) at > anti-inflammatory doses
The ‘coxibs’
Coxibs efficacy
Numerous clinical trial data
Comparable efficacy to non-selective NSAIDs in
- acute pain
- dysmenorrhoea
- inflammatory joint disease
Coxibs increase risk of MI
Cox-2 inhibitors- no activity as antithrombotics
Increased rates of MI in clinical trials of celecoxib and reofecoxib
Corticosteroids
Cortisol (hydrocortisone)- predominant endogenous glucocorticoid
- carbohydrate and protein metabolism
- fluid and electrolyte balance
- lipid metabolism
- psychological effects
- bone metabolism
- profound modulator of immune response
Immunomodulation by steroids
Cell trafficking
Cell function
Don’t effect
- immunoglobulin levels
- complement
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
Decrease collagenases, elastases etc
Clinical use of corticosteroids
To suppress inflammation
- asthma, Crohn’s/ UC, eczema, multiple sclerosis, sarcoid, allergy, RA, SLE
To suppress specific immunity
- graft rejection
Replacement therapy in hypoadrenalism
Steroid preparation
Different routes of administration
- systemic (oral and parenteral)
- topical (skin, joint injections, inhaled, enteric coated, rectal)
Different drugs
- different potencies
- different pharmacokinetics
Hydrocortisone
Potency: low
Lipid solubility: good
Systemic use: replacement Rx
Topical use: skin, joints
Prenisolone
Potency: medium
Lipid solubility: good
Systemic use: anti-inflammatory
Topical use: enemas
Beclomethasone
Potency: medium
Lipid solubility: poor
Topical use: asthma, crohn’s
Dexamethasone
Potency: high
Lipid solubility: good
Systemic use: cerebral oedema
Triaminiclone
Potency: high
Lipid solubility: poor
Topical use: skin, joints
Early side effects of steroid therapy
Weight gain
Glucose intolerance
Mood change
Suppression of ACTH release
Later side effects of steroid therapy
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 e.g. infection and may precipitate an adrenal crisis
Steroids and infection risk
Phagocytic defects
- bacterial infection: S. aureus, enteric bacteria
- fungal infection: candida, aspergillus
Cell mediated defects
- intracellular pathogens: TB, varicella, listeria, pneumocystis
