14. pharmacological aspects and immunology Flashcards
discovery of aspirin
white willow, bark used to treat fever and joint pain
hoffman: acetylsalicylic acid (aspirin)
NSAID examples
aspirin paracetamol propionic acid derivative, eg ibuprofen, naproxen arylakanoic acid derivatives, eg indometacin, diclofenac oxicams fanatic acid derivatives betazones coxibs, eg celecoxib
eicosanoid pathway
during tissue injury
phospholipids converted by phospholipase to arachidonic acid
converted to leukotrienes (lipoxygenases) or prostaglandin H2 (cyclo-oxygenases)
tissue specific syntheses convert prostaglandin H2 into: thromboxane, prostaglandins or prostacyclins
NSAID mechanism of action
all inhibit cycle-oxygenase enzymes
3 isoforms of cycle oxygenase exist
precent prostaglandin H2 formation and thus thromboxanes, prostaglandins and prostacyclins
COX-1
constitutive expression
in stomach, kidney, platelets, vascular epithelium
inhibition leads to anti platelet activity
side effects
COX-2
induced in inflammation (by IL-1)
injury, infection, neoplasia
inhibition leads to analgesia and anti-inflammatory actions
COX-3
in CNS only (?)
specifically inhibited by paracetamol
antipyretic and analgesic actions
indications for NSAID therapy
mild analgesics
potent analgesics
anti-inflammatories
NSAIDs as mild analgesics
orally and topically mechanical pain of all types minor trauma headaches, dental pain dysmenorrhoea
NSAIDs as potent analgesics
orally, parentally, rectally
peri-operative pain
ureteric colic
NSAIDs as anti-inflammatories
not great anti inflammatory action, most of the time
gout
inflammatory arthritis, eg ankylosing spondylitis, rheumatoid arthritis
aspirin
used for pain and inflammation
anti platelet effect: prophylaxis for ischaemic heart disease, treatment of acute MI
aspirin is limited by
GI toxicity
tinnitus (mechanism obscure, usually reversible)
Reye’s syndrome (fulminant hepatic failure in children)
non-NSAID anti-platelet drugs
clopidogrel
dipyrimidole
paracetamol
only binds COX3 no significant anti-inflammatory action no significant GI toxicity analgesic/anti-pyretic dangerous in overdose
paracetamol metabolism under normal circumstances
paracetamol conjugated in the liver with glucoronide and sulphate
minority is oxidised by microsomal enzymes to toxic intermediary - rapidly self-neutralised by conjugation with glutathione
paracetamol metabolism when present in excess
conjugation reactions overwhelmed
toxic intermediaries accumulate
can cause potentially fatal hepatic necrosis
NSAID GI toxicity - prostaglandins
prostaglandins E2 and I2 lost
decreases acid production
increases mucus production
increases blood supply
NSAIDs - effect on stomach and duodenum (and colon)
irritation
ulcers (gastric 15-30%, duodenal 10%)
bleeding
similar effect in colon - colitis
risk factors for NSAIDs and GI
relative risk 4.7 for all - higher for some NSAIDs (piroxicam = 18) previous GI bleed age chronic disease steroid use
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%
asthma and aspirin
about 10% asthmatics experience bronchospasm following NSAIDs
perhaps because arachidonic acid is shunted down 5-lipoxygenase pathway to form leukotrienes
non selective NSAIDs - least to most potent
ibuprofen
naproxen
diclofenac (voltarol)
indometacin - reserved fro specialist diseases
preventing NSAID toxicity
use sparingly - paracetamol or opioids
GI toxicity - use gastroprotective drugs (PPIs, misoprostil - PGE1 analogue)
selective COX-2 inhibitors
anti-inflammatory and analgesic in humans
objective evidence of selectivity - less side effects than non-selective NSAIDs
coxibs - celecoxib, rofecoxib, etoricoxib
coxibs efficacy
numerous clinical trials - data
comparable efficacy to non-selective NSAIDs - for acute pain, dysmenorrhoea, inflammatory joint disease etc
less side effects
celecoxib
only current coxib prescribed
indicated for patients at risk for GI bleed
corticosteroids
cortisol (hydrocortisone)
have many effects on:
carb, protein and lipid metabolism, fluid and electrolyte balance, bone metabolism, psychological
modulates immune respnose
how do steroids modulate the immune responses?
reduce immune activation
alter gene expression by binding to steroid receptor which activates transcription
onset of action is delayed
effects T and B cells and cells of the innate immune system
immunomodulation by steroids
cell trafficking
cell function
steroids and cell trafficking
lymphopenia, monocytopenia
neutrophilic and impaired phagocyte migration
steroids and cell function
T cell hyper-responsiveness
inhibited B cell maturation
decreased IL1, IL6 and TNF alpha production
inhibits COS
widespread inhibition of Th1 and Th2cytokines
impaired phagocyte killing
clinical uses of steroids
suppress inflammation
asthma, Crohn’s, UC, eczema, MS, sarcoid, allergy, rheumatoid arthritis, SLE
suppress specific immunity - graft refection
replacement therapy in hypoadrenalism
steroid preparation
different routes of administration-systemic or topical
different drugs - potencies, pharmacokinetics
early side effects of steroid therapy
weight gain
glucose intolerance
mood change
suppression fo ACTH release
later side effects of steroid therapy
proximal muscle weakness osteoporosis skin changes (striae) body shape changes (buffalo hump, central obesity) hypertension cataracts adrenal suppression
adrenal suppression during corticosteroid therapy
high dose corticosteroids suppress endogenous production within 1 week
adrenal cortex atrophies afternoon prolonged therapy - endogenous production takes time to recover upon cessation
abrupt withdrawal reduces ability to deal with physiological stress - may precipitate adrenal crisis
steroids and risk of infection
phagocytic defects
bacterial - S. aureus, enteric bacteria
fungal - candida, aspergillus
cell mediated
intracellular pathogens - TB, varicella, listeria, pneumocystis
