Pharmacological aspects of immunology Flashcards
(30 cards)
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
