T1 L14 Pharmacology of immunology Flashcards
Describe the discovery of aspirin
Rev Edmund Stone (1763) - White willow (Salix alba) - Used bark to treat fever and joint pain Felix Hoffman (Bayer)(1899) - Acetylsalicylic acid ‘aspirin’
Give examples of NSAIDs
Aspirin Paracetamol Propionic acid derivatives Arylalkanoic acids Oxicams Fenamic acids Butazones Coxibs
How are phospholipids converted to arachidonic acid?
Phospholipases
How is arachidonic acid converted to leukotrienes?
Lioxygenases
How is arachidonic acid converted to prostaglandin H2?
Cyclo-oxygenases
What can prostaglandin H2 be converted to?
Thromboxanes
Prostaglandins
Prostacyclins
What is arachidonic acid?
Polyunsaturated 20 carbon lipid which is either metabolised into leukotrienes of prostaglandin H2 depending on tissue and inflammatory stimuli.
What are thromboxanes involved in?
Platelet aggregation and small vessel tone
What are prostacyclines involved in?
Vasodilator properties
What are prostaglandins involved in?
Bronchial tone
Vascular tone
Sensitivity of nerve fibres
What is the NSAID mechanism?
Inhibits cyclo-oxygenase
Prevents conversion of arachidonic acid to prostaglandin H2
What are the 3 isoforms for cyclo-oyxygenase?
COX-1
COX-2
COX-3
What is COX-1 involved in?
Constitutes expression for all tissues
Stomach, kidney, platelets, vascular endothelium
inhibiting has an anti-platelet activity
What is COX-2 involved in?
Induced in inflammation
Injury, infection, neoplasia
Inhibition leads to analgesia and anti-inflammatory actions
What is COX-3 involved in?
CNS
Inhibited specifically by paracetamol leading to antipyretic and analgesic effects
What are the indications for NSAID therapy?
As mild analgesics - mechanical pain - minor trauma - headaches, dental pain, dysmenorrhoea Potent analgesics - peri-operative pain - ureteric colic Anti-inflammatories - gout - inflammatory arthritis
Why is aspirin use for pain and inflammation limited?
GI toxicity
Tinnitus
Reye’s syndrome
What is Reye’s syndrome?
Severe, sudden hepatic failure in children
Describe the metabolism of paracetamol
Phase II conjugation reaction in liver to paracetamol sulphate and glucuronide which is then excreted.
Excess paracetamol is shunted to phase I oxidation reaction to produce NAPQI which causes hepatic necrosis
What does the treatment for paracetamol toxicity rely on?
Provision of substrates which body can use to synthesis glutathione
What do prostaglandins E2 and I2 do in the GI tract?
Decrease acid production
Increase mucus production
Increase blood supply
What is the effect of the inhibition of prostaglandins in the gut?
Irritation
Ulcers
Bleeding
What are the risk factors for an upper GI bleed?
Previous GI bleed
Age
Chronic disease e.g. rheumatoid disease
Steroids
Describe the changes in glomerular blood flow caused by NSAIDs
Decrease in glomerular filtration rate
Sodium retention
Hyperkalaemia
Papillary necrosis
Why do 10% of asthmatics experience bronchoconstriction following NSAID?
Arachidonic acid is shunted down 5-lipoxygenase pathway as COX pathway is inhibited by aspirin
Give examples of non-selective NSAIDs
Ibuprofen
Naproxen
Diclofenac
Indometacin
What is diclofenac widely prescribed for?
Severe, short-term analgesia
How is GI toxicity prevented when using NSAIDs?
Treat with gastroprotective drugs
- misoprostol
Avoid in renal failure and adjust dose if necessary
What are COX-2 inhibitors?
Selective inhibition of COX-2
Anti-inflammatory and analgesic
What are some examples of coxibs?
Celecoxib
Etoricoxib
Foecoxib
Valdecoxib
When are COX-2 inhibitors indicated instead of non-selective NSAIDs?
Patients at high risk of developing gastroduodenal ulceration, perforation or bleeding
After an assessment of cardiovascular risk
What functions does cortisol influence?
Carbohydrate and protein metabolism Fluid and electrolyte balance Lipid metabolism Psychological effects Bone metabolism Profound modulator of immune response
How do steroids reduce immune activation?
Alter gene expression in numerous cell types
Steroid receptors found in cytoplasm complexed with heat-shock protein Hsp90. Steroids cross cell membrane and bind to complex releasing Hsp90.
Steroid receptor complex crosses nuclear membrane.
In nucleus, steroid receptor binds to specific gene regulatory sequences and activates transcription
Describe immunomodulation by steroids
Cell trafficking
- lymphopenia, monocytopeniaa
- neutrophilic and impaired phagocyte migration
Cell function
- T-cell hyporesponsiveness
- inhibited B-cell maturation
- decreased IL-1, IL-6 and TNF alpha production
- widespread inhibition of Th1 and Th2 cytokines
- inhibition of COX
- impaired phagocyte killing
- decrease collagenases, elastases
What is the clinical use of steroids?
Suppress inflammation - asthma, Crohn’s, Eczema, MS, sarcoid, allergy, rheumatoid arthritis, SLE
Suppress specific immunity - graft rejection
Describe the potency, lipid solubility, systemic and topical use of hydrocortisone
Low potency
Good lipid solubility
Systemic use as replacement
Topical use for skin and joints
Describe potency, lipid solubility, systemic and topical use of prednisolone
Medium potency
Good lipid solubility
Systemic use as anti-inflammatory
Topical use for enema
Describe potency, lipid solubility, systemic and topical use of beclomethasone
Medium potency
Poor lipid solubility
No systemic use
Topical use for asthma, Crohn’s
Describe potency, lipid solubility, systemic and topical use of dexamethasone
High potency
Good solubility
Systemic use for cerebral oedema
No topical use
Describe potency, lipid solubility, systemic and topical use of triaminiclone
High potency
Poor lipid solubility
No systemic use
Topical use in skin and joints
What are the early side effects of steroid therapy?
Weight gain
Glucose intolerance
Mood change
Suppression of ACTH release
What are the later effects of chronic steroid use?
Proximal muscle weakness Osteoporosis Skin changes Body shape changes Hypertension Cataracts Adrenal suppression
Describe the increased risk of infection with steroids
Early risk of phagocytic defects
- bacterial infection e.g. S.aureus, enteric bacteria
- fungal infection e.g. candida, aspergillus
Later risks of cell-mediated defects
- intracellular pathogens e.g. TB, varicella, listeria, pneumocystis
