13 – NSAIDs Flashcards
Leaves and bark of willow tree
- Anti-inflammatory properties
- *contains SALICYCLIC ACID: pre-cursor to aspirin
5 cardinal signs of inflammation
- Redness
- Heat
- Swelling
- Pain
- Loss of function
- **caused by vasodilation, edema, nociceptive stimulation
If wanting to prevent peripheral inflammation, NSAIDs or steroids?
- Can use either or
NSAID uses
- Prevent or reduce inflammation
- Reduce fever (anti-pyretic)
- *Analgesic (central and/or peripheral effects)
NSAID: prevent or reduce inflammation
- Block formation of inflammatory EICOSANOIDS
o Ex. prostaglandins, thromboxane, leukotrienes
NSAID: reduce fever (anti-pyretic)
- PGE2 (prostaglandin) is an endogenous pyrogen
o Increase body T by re-setting the ‘set-point’ in hypothalamus - *if more prostaglandin expressed=increase T
- *if decrease prostaglandin=decrease T
NSAID inflammation pathway: peripheral
- Prevent AA from going to prostaglandins
o Block COX1 and COX2 - Do NOT get PGE2 or PGF2
- *Immune-mediated products (ex. leukotrienes) are STILL PRODUCED!
NSAID analgesia
- Reducing PERIPHERAL may decrease pain sensation
o If due to swelling/pressure (same mechanism as with corticosteroids) - Prostaglandin ‘synergy’ with bradykinin and histamine
PG ‘synergy’ with bradykinin(BK) and histamine(HT)
- PG can increase afferent neurone firing due to BK&HT-mediated stimulation of peripheral nociceptors
o Hyperalgesia (increase effect of painful stimuli)
o Allodynia (normally non-painful stimuli become painful)
What about Tylenol (ex. acetaminophen)?
- Has lots of CENTRAL analgesia effect
o Still lots of PGs being produced in CNS - Poor PERIPHERAL analgesia effect
- Not much anti-inflammatory activity
‘central’ analgesia
- Both cyclo-oxygenase isoforms (COX-1 and COX-2) are present in brain and spinal tissue
o Produce PGs in neural tissues
What is the result of ‘central’ PGE formation?
- Sensitizes central nociceptors (‘wind-up”)
- Lowers spinal depolarization threshold
NSAIDs is one of most commonly classes of vet drugs
- Efficacious
- Relatively safe
- Potential for profit (giving multiple times a day)
NSAIDs and reported adverse effects (‘pharmovigilance’)
- Typically 10% of total adverse effects
- Used a lot, so will see more adverse effects
- Tend to use them in animals that are less healthy
o Geriatric, perioperative, etc.
NSAIDs: GI adverse drug events
*60%
- Vomiting
- Diarrhea
- Ulcers
- Melena
- *PG usually protect
- *direct GI irritation (aspirin, meloxicam tablets)
NSAIDS: renal adverse events
*20%
- PG help maintain GFR
o NSAIDs: decrease GFR
- Renal papillary necrosis
NSAIDs GI and renal adverse events
- *DOSE-DEPENDENT in most cases
o Use lowest dose that is still effective
NSAIDs hepatic adverse events
15%
- Idiosyncratic hepatic necrosis/toxicity
- Increase liver enzymes: change in bile acids?
- *cats most susceptible, but can’t predict individual toxicity
- **probably dose-dependent, but dose-independent is (‘less) common’
o If see independent=liver
NSAIDS hematologic adverse events
1%
- Prolonged bleeding time with aspirin and ketoprofen
COX1
- Constitutive (produced constantly)
- Present under normal conditions in many cells
- Produce ‘cytoprotective’ PGs (vasodilation, mucous)
o *positive
COX1 present under normal conditions in many cells
- Platelets and endothelium
- Mucosal cells (GI)
- Renal tubule cells
- Neural tissues
COX2
- Inducible (expressed in response to inflammatory mediators)
- Often formed at sites of inflammation
o *what we want to target - Constitutive in some tissues
COX2 selective
- Drugs that inhibit COX2 (but not COX1) at label dose
COX2 preferential
- Drugs that inhibit COX2 at lower drug concentrations than COX1
o Some COX1 inhibition at label dose