NSAIDS Flashcards
what are 5 cardinal signs of inflammation?
- redness
- heat
- swelling
- pain
- loss of fxn
What causes the 5 cardinal signs of inflammation?
vasodilation, edema, & nociceptive stimulation
What are the uses of NSAIDS?
- prevent or reduce inflammation: block formation of inflammatory EICOSANOIDS (prostaglandins, thromboxane, leukotrienes)
- reduce fever (anti-pyretic): PGE”2” (prostaglandin E2) is an endogenous pyrogen (increases body temp by resetting set pt in hypothalamus)
- analgesic (central &/or peripheral effects)
Why do steroids cause immunosuppression while NSAIDS do not?
Glucocorticoids inhibit arachidonic acid production which in turn reduces leukotrienes (leading to immune suppression), but NSAIDs block PGH”2” synthase (cyclooxygenase - COX-1 or COX-2) which converts the arachidonic acid into prostaglandin
How do NSAIDS act as analgesics?
-they reduce PERIPHERAL inflammation which may lead to decreased pain sensation if the peripheral pain was due to swelling/press (same as corticosteroids)
- reduce prostaglandins
How do prostaglandins contribute to pain?
prostaglandin synergy w/ bradykinin (BK) & histamine (HT): PG can increase afferent neuron firing due to BK & HT-mediated stimulation of peripheral nociceptors
- hyperalgesia (increase effect of painful stimuli)
- allodynia (normally non-painful stimuli become painful)
How do NSAIDS contribute to central analgesia (like acetaminophen (Tylenol))?
- both cyclo-oxygenase isoforms (COX-1 & -2) are present in brain & spinal tissue (produce prostaglandins in neural tissues)
- result of central PGE formation:
> sensitizes central nociceptors (“wind-up”)
> lowers spinal depolarization threshold
(so not a lot of analgesic activity on its own but lowers pain perceived by animal)
why are NSAIDS one of the most commonly used classes of vet drugs?
efficacious, relatively safe, potential for profit
Why are there lots of adverse effects of NSAIDS reported to regulatory authorities?
- 10% of total adverse drug events reported
- lots of usage & used in riskier situations (geriatrics, perioperative, etc.)
What kinds of adverse drug events (ADE) are reported for NSAIDS?
- GI (~60% of ADE): vomiting, diarrhea, ulcers, melena
- prostaglandins promote gastric mucus & bicarbonate (HCO3) secretion, increase mucosal blood flow
- direct GI irritation (aspirin, meloxicam tablets) - renal (~20% of ADE)
- prostaglandins help maintain glomerular filtration
- NSAIDS potentially decrease glomerular filtration rate (or just in hypovolemic animals?)
- renal papillary necrosis/idiosyncratic toxicity?
GI & RENAL ADEs ARE DOSE-DEPENDENT IN MOST CASES - hepatic (~15% of ADE)
- idiosyncratic hepatic necrosis/ toxicity (carprofen/bute)
- increased liver enzymes - change to bile acids?
- Fe most susceptible, but cant predict individual toxicity!
HEPATIC ADE ARE STILL PROBABLY DOSE-DEPENDENT BUT DOSE-INDEPENDENT DO OCCUR - hematologic (~1%)
- prolonged bleeding times w/ aspirin & ketoprofen
what is the difference btwn COX-1 & COX2?
COX-1
- constitutive (produced constantly)
- present under normal conditions in many cells (platelets & endothelium, mucosal cells (GI), renal tubule cells, neural tissue)
- produce “cytoprotective” prostaglandins (vasodilation, mucous, etc.)
COX-2
- inducible (expressed in response to inflammatory mediators)
- often formed @ sites of inflammation
What does COX-2 SELECTIVE mean?
drugs that inhibit COX-2 (but not COX-1) AT LABEL DOSE
aka COX-1 SPARING & COX-2 SPECIFIC
What does COX-2 PREFERENTIAL mean?
drugs that inhibit COX-2 @ lower drug concentrations than COX-1, but there is some COX-1 inhibition @ label dose
What does COX-NONSPECIFIC mean?
both COX-1 & COX-2 are inhibited @ label doses
How is the category of COX inhibition determined?
IC ratios
- IC”50”: the drug concentration @ which 50% of enzyme activity is inhibited
- LOWER IC # means INCREASED drug potency
- so, high COX-1 IC”50” # means LESS inhibition by NSAID (COX-1 is “spared”
