NSAIDs Flashcards
what are the clinical uses of NSAIDs (5)
- management of inflammatory disorders (osteoarthritis, opthalmological disorders, keratitis, uveitis)
- management of pain (acute pain –> traumatic or surgical, chronic pain –> osteoarthritis, cancer pain, dental pain)
- management of endotoxaemia in large animals (equine colic, bovine toxic mastitis)
- management of prothrombotic states (feline hypertrophic cardiomyopathy)
- management of tumours (some tumours are dependent on COX-2 activity, piroxicam used to treat transitional cell carcinoma of the urinary bladder)
what are arachnidonic acid metabolites (eicosanoids)
COX1 and COX2 –> inhibited by aspirin, NSAIDs, selective COX-2 inhibitors
what are the mechanism of action of NSAIDs
inhibit cyclooxygenase (COX)
COX is the enzyme which is responsible for the production of prostaglandins and thromboxanes
inhibiting COX therefore decreases the production of these mediators
what do endogenous prostanoids have a role in
- immune system
- GI tract
- cardiovascular system
- kidney
- lungs
- reproduction
- brain and spinal cord
what are prostanoids
collective term for the cyclooxygenase metabolites of arachidonic acid and include prostaglandin (PG) D2, PGE2, PGF2alpha, PGI2 and thromboxane A2
what is cyclooxygenase (COX)
COX is the enzyme which converts arachidonic acid to the prostaglandin precursor PGH2
A: arachidonic acid enters the COX enzyme channel and is converted first to prostaglandin G2 then to prostaglandin H2 (these steps not shown) then into a prostaglandin, the example shown is prostaglandin E2
what is COX-1
constitutively expressed in most tissues
involved in normal homeostasis
many physiological functions - especially maintaining GI tract mucosa
up-regulated under stress conditions (nerve injury)
what is COX-2
constitutively expressed in many tissues, including kidney, testicular ovarian cells and in the CNS
physiological functions: maintaining renal blood flow, nerve function, bone metabolism
induced in response to inflammatory stimuli
how do NSAIDs block COX-1
bind to non-selective binding site to block arachnidonic acid from enetering the channel and converted to PG
what is a COX continuum
two distinct genes for COX-1 and 2 may give rise to a number of constitutive and inducible COX proteins with overlapping functions
how can NSAIDs be categorized
- non-selective COX inhibitors (most commonly used ex. flunixin, ketoprofen)
- preferential COX-2 inhibitors (carprofen, meloxicam)
- specific COX-2 inhibitors (firocoxib, robenacoxib)
what are the useful effects of NSAIDs
- analgesic (central/peripheral)
- anti-pyretic
- anti-inflammatory
- anti-thrombotic
- anti-endotoxic
- other uses –> cancer treatment
what are the adverse effects of NSAIDs
- GI –> dyspepsia, nausea and vomiting, ulceration
- renal toxicity
- hepatotoxicity
- injury to articular cartilage
- precipitate asthma
what are the analgesic effects
- peripheral action –> NSAIDs decrease PG production at site of inflammation –> reduced sensitization of nociceptive nerve endings to inflammatory mediators
- central action –> NSAIDs block PG release and neuronal excitation –> reduced central sensitization
reduces hyperalgesia and pain
how do NSAIDs reduce fever
the hypothalamus regulates normal body temperature –> ensures balance between heat loss and heat production
inflammation –> endogenous pyrogen (interleukin-1) –> COX –> PGE2 synthesis –> act on thermoregulatory centre in hypothalamus –> increase body temperature –> fever
what are the anti-pyretic effects of NSAIDs
high concentration of PGE2 are found in CSF during infection
NSAIDs decrease production of PGE2 thus prevent increase temperature associated with fever
no effect on normal body temperature
what are the anti-inflammatory effects
NSAIDs inhibit COX induction and release of prostanoids at site of inflammation to
- decrease vasodilator prostaglandins (reduces edema)
- reduces the inflammatory response (prevent peripheral sensitization)
how do NSAIDS cause anti-thrombotic action
NSAIDs inhibit synthesis of thromboxanes (TXA2) –> inhibits platelet aggregation
more effective as anti-thrombotic agents at low doses
what pathways do NSAIDs inhibit to cause anti-thrombotic action
what are the anti-endotoxic action
endotoxins are lipopolysaccharides generated by gram -ve bacteria
endotoxins damage white blood cells and vascular endothelium thus releasing vasoactive mediators
triggers cascade of events which can result in endotoxemia
NSAIDs can prevent the generation of vasoactive mediators during endotoxemia
what are the adverse effects on the GIT
PGs in the GIT
PGI2 and PGE2 in the gut protect the gastric mucosa by inhibiting gastric secretion, inducing vasodilation and increasing blood flow through gastric mucosa
COX-1 is primary isoform responsible for gastric mucosal PG production
COX-2 absent in normal gastric mucosa but induced rapidly in response to injury/gastric erosions
what are the effects of NSAIDs in the GIT
inhibition of COX-1 –> reduction in PGs –> ulceration
mucosal ischemia
impairment of protective mucus barrier
exposing mucosa to damaging effects of acid
NSAIDs should be given with food to protect gastric mucosa –> contact area of the tablet results in high localized concentration of the drug increasing the potential for ulcer formation
what are the roles of PGs in the kidney
PGE2 and PGI2 synthesized in renal medulla and glomerulus
involved in renal blood flow and excretion of salt and H2O via their vasodilatoru actions
modulate renal hemodynamics and excretion
PGE2 and PGI2 compensatory vasodilation
what are the effects of NSAIDs in the kidney
- inhibition of PGs impairs renal blood flow
- in healthy well-hydrated animals, reduced renal PGs is of little consequence
- can cause acute renal failure in conditions which depend on protective PGs
- significant renal toxicity can occur in dogs and cats if they are volume depleted
what are the pharmacokinetics
- admin: most well absorbed following oral administration, with food, parenteral formuations also available
- distribution: relatively small Vd (extracellular), highly plasma protein bound (>99%), good penetration into acute inflammatory exudate
- metabolism/excretion: generally by conjuction and renal elimination of metabolites (some biliary elimination), marked interspecies variability
how do NSAIDs bind to COX-2 selectively
COX-2 channel is wider –> NSAID will bind at 2 points and block it
