NSAIDs Flashcards
5 cardinal signs of inflammation
-redness
-heat
-swelling
-pain
-loss of function
***caused by vasodilation, edema, nociceptive stimulation
What are NSAIDs used for?
1.prevent and reduce inflammation
2. Reduce fever
3. Analgesic
How do NSAIDs prevent inflammation?
-block formation of inflammatory eicosanoids (prostagladins, thromboxane, leukotrienes)
How do NSAIDs reduce fever (anti-pyretic)?
PGE2 is an endogenous pyrogen (increase body temperature by re-setting the set point in hypothalamus)= fever
**NSAIDs block the central prostaglandin production and therefore are able to reduce fever
How do NSAIDs reduce analgesic properties?
-They play a role in the peripheral effects when peripheral pain due to swelling and pressure
**prostaglandin synergy with bradykinin and histamine. An increase in PG can increase afferent neuron firing to BK and HT mediated stimulation of peripheral nociceptors resulting in hyperalgesia and allodynia
NSAIDs impact on peripheral inflammation pathway
NSAIDs block Cox-1 and cox2 pathways
-blocks PGD2 and PGE2
-blocks prostacyclin and therefore vasodilation
-blocks thromboxane and therefore vasoconstriction and platelet aggregation
No impact on leukotriene production and therefore less impact on immune function
Tepoxalin
one multi drug that blocked both the cox pathways and lipooxygenase
**not used anymore; never really did well in market
Tylenol- NSAID analgesia
-Acetaminophen works more central, and some peripheral
Central analgesia effects from NSAIDs
-Both Cox-1 and cox-2 isoforms are present in the brain and spinal cord. They produce prostaglandins in neural tissues
-Prostaglandins result in sensitization of central nociceptors (wind up pain), and lower spinal depolarization threshold
NSAIDs inhibit cox pathways to reduce this pain
NSAID usage
-commonly used because efficacious, relatively safe, potential for profit
-lots of adverse effects reported (~10% total adverse events). Seems high, but linked with fact that they are used with already sicker animals, and used lots!
What areas are most effected by NSAIDs?
-GI (dose dependent)
-Renal (dose dependent)
-hepatic (may be dose dependent BUT dose-independent events more common)
-hematologic
GI adverse events from NSAIDs (60%)
- vomiting, diarrhea, ulcers, melena
-occur because prostaglandins promote gastric mucous and bicarbonate secretion AND increase mucosal blood flow - Direct GI irritation (aspirin and emloxicam tablets)
Renal adverse events from NSAIDs (20%)
-Prostaglandins help maintain GFR
>NSAIDs believed to decreased GFR and possibly blood flow
-can lead to renal papillary necrosis/idiosyncratic toxicity
Hepatic adverse events from NSAIDs (15%)
-idiosyncratic hepatic necrosis/toxicity
-NSAIDs may increase liver enzymes. May affect livers ability to make bile acids.
**cats most susceptible but cannot predict individual toxicity
Hematologic adverse events from NSAIDs (1%)
prolonged bleeding times with aspirin and ketoprofen
Cox-1
constitutive (produced constantly
Cox-1 presence
-platelets and endothelium
-mucosal cells in GI
-renal tubule cells
-neural tissue
Cox-2
1.inducible- expressed in response to inflammatory mediators
2.constitutive in some tissues (brain, kidney, spinal cord)
- expressed near gastric ulcers (accelerates healing)
Cox-2 presence
often formed at sites of inflammation
Function of Cox-1
produce cytoprotective prostaglandins which play a role in vasodilation and mucous production
Cox-2 selective NSAID
drugs that inhibit cox-2 (but not cox-1) at label dose
Cox-2 preferential NSAID
drugs that inhibit cox-2 at lower drug concentrations than cox-1, but there is some cox-1 inhibition at label dose
Cox-1 sparing and specific NSAID
same thing as cox-2 selective
Cox-nonspecific NSAID
-Both cox-1 and cox-2 are inhibited at label doses
How to determine cox inhibition category?
-Use IC50: drug concentration at 50% of enzyme activity inhibition
*low IC number=increased drug potency
-High cox-1 IC50= less inhibition by NSAID
Cox-1 vs. Cox-2
Originally thought to keep Cox-1, inhibit cox-2. Thought higher cox1:cox 2 ratio was better.
**this is not necessarily true, because cox-2 is not a “bad” enzyme.
Cox-3
-derivative of cox-1
-found in brain
-unknown function, but inhibited by older NSAIDs that “seem to work”
eg. acetaminophen
PK/PD data usage
Cannot make direct comparisons of NSAID safety or efficacy based on PK/PD
**safety and efficacy only come from clinical trials (not in vitro data)
NSAID general PK properties
-good oral bioavailability
-hepatic metabolism
-some are highly protein bound (low VD; present at sites of inflammation)
-usually weak acids, can be ion trapped in cells
**variable between species
Note: cats poor glucuronidation
COXIB-specific drug properties
-varying degrees of cox-2 selectivity
-generally very lipophilic
-hepatic metabolism (CYP 450?)
>pharmacogenetic differences
>concurrent drug usage
VIOXX (rofecoxib) recall
first CoxIB of its time
Recalled drug because led to increased risk of cardiovascular events
**no evidence found in dogs or cats
Intravenous lipid emulsion (ILE) therapy
-give IV lipid into animal which can “grab” lipophilic drugs; helpful in cases of lipophilic NSAID toxicosis
-Lipophilic drug distributes from CNS into lipid emulsion in vasculature, facilitating clearance
**can be risky
Washout periods
time period when switching between two drugs
*allows 1st drug to be eliminated, increasing the margin of safety when 2nd drug is administered
Washout period importance with anti-inflammatory drugs
-Needed when going from steroids/aspirin to NSAIDs or from NSAIDs to NSAIDs
How long should your washout period be?
Many theories:
-10 half lives?
-set period of time? 3 days? 7 days?
**warn owner of risks
