L11 - NSAIDs Flashcards
Eicosanoids
Prostanoids
Lipoxygenase
Prostanoids
Produced locally on demand with a short half life for fine control
PGE2
Secreted for gastrointestinal mucosal protection
PGI2 - prostacyclin
Inhibits platelet aggregation
Vasodilator
TXA2 - thromboxane A2
Platelet aggregation
Vasoconstrictor
Arachidonic acid
Derived primarily from dietary linoleic acid in vegetable oils and supplements
- converted hepatically into arachidonic acid and incorporated into phospholipids
- found through out the body - muscle, brain and liver
COX -1 homeostatic function
- active across most tissues
- platelets only contain COX 1 therefore platelet aggregation via TXA2
- gastrointestinal mucosal protection - PGE2
- vascular resistance - vasoconstriction- TXA2
COX 1 pathological function
Chronic inflammation
Chronic pain
Raised blood pressure - vasoconstriction THXA2
COX 2 homeostatic function
Inducibke mostly in the brain, kidney and bone
Renal homeostasis
Tissue repair and healing
Reproduction - uterine contractions
Inhibition of platelet aggregation - PGI2 (prostacyclin)
COX 2 pathological functions
Chronic inflammation Chronic pain Fever Blood vessel permeability Tumour cell growth
How do prostanoids exert their effects?
Action is local at GPCRs
Specific action dependent on receptor subtype and location
Imbalance between TXA2 and PGI2
TXA2 and PGI2 antagonise each other Imbalance can cause: - hypertension - MI - Stroke
Diet rich in fish oils (omega FAs)
Omega fatty acids are converted to TXA3 and PGI3
Better prostanoids with lower incidence of CVD
Effects of NSAIDs
Analgesic
Anti- inflammatory
Anti - pyretic
By inhibiting prostaglandins
NSAID mechanism of action
Inhibition of COX - competes with arachidonic acid for the hydrophobic site of COX
Decrease in prostanoids - prostaglandin, prostacyclin and thromboxane synthesis
Analgesic property
- Local peripheral action at site of pain
- works better when inflamed as more prostaglandins present
- blocks PGE2 therefore reduces peripheral pain fibre sensitivity
- less PGE2 synthesis in dorsal horn so less neurotransmitter released
Therefore less excitability of neurones in the pain pathways - full efficacy after several days of dosing
Anti inflammatory effect
NSAIDs reduced the production of prostaglandins released during injury therefore less vasodilation and oedema
- decreases local swelling and permeability
- relieves symptoms but not the cause
Antipyretic properties
Inhibition of hypothalamic COX 2
Therefore less cytokine (IL1 and IL6) induced prostaglandin synthesis, reducing temperature
PGE2 and temperature
PGE2 contributes to the thermoregulatory centre, increasing set point and raising the temperature in the preoptic area of the hypothalamus
Stimulated by pyrogens - IL1 and IL6
COX2 inhibitor selectivity
Are more selective than COX 1 at therapeutic dose
NSAIDs
Aspirin
Ibuprofen
Naproxen
Diclofenac
COX 2 selective: bigger structure binds to the COX2 binding pocket
- celecoxib
- etoricoxib
Gastrointestinal ADRs
- dyspepsia
- nausea
- peptic ulceration
- bleeding and perforation
- exacerbation of IBD
- local irritation and bleeding from rectal administration
Due to:
- decreased mucosal and bicarbonate secretion
- decreased mucosal blood flow - enhanced cytotoxicity and hypoxia
- increased acid secretion
-
Cautions with NSAIDs
- Elderly - often self prescribing or meds not reviewed
- prolonged use
- Glucocorticoid steroids - given PPI as adjunct
- anticoagulants
- smoking
- alcohol
- history of peptic ulceration
- H. pylori
Renal ADRs
- NSAIDs inhibit prostaglandin
- Prostaglandin normally causes vasodilation of the afferent arterioles to increase GFR and inhibit sodium absorption in the collecting duct
- As inhibited, GFR decreases and renal blood flow decreases
- increased sodium and water absorption - increasing BP
Caution in patients with CKD and heart failure as low BP, therefore greater reliance on prostaglandins for vasodilation and renal perfusion
