NSAIDs

Question 1

5 cardinal signs of inflammation

Answer 1

-redness
-heat
-swelling
-pain
-loss of function

***caused by vasodilation, edema, nociceptive stimulation

Question 2

What are NSAIDs used for?

Answer 2

1.prevent and reduce inflammation
2. Reduce fever
3. Analgesic

Question 3

How do NSAIDs prevent inflammation?

Answer 3

-block formation of inflammatory eicosanoids (prostagladins, thromboxane, leukotrienes)

Question 4

How do NSAIDs reduce fever (anti-pyretic)?

Answer 4

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

Question 5

How do NSAIDs reduce analgesic properties?

Answer 5

-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

Question 6

NSAIDs impact on peripheral inflammation pathway

Answer 6

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

Question 7

Tepoxalin

Answer 7

one multi drug that blocked both the cox pathways and lipooxygenase
**not used anymore; never really did well in market

Question 8

Tylenol- NSAID analgesia

Answer 8

-Acetaminophen works more central, and some peripheral

Question 9

Central analgesia effects from NSAIDs

Answer 9

-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

Question 10

NSAID usage

Answer 10

-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!

Question 11

What areas are most effected by NSAIDs?

Answer 11

-GI (dose dependent)
-Renal (dose dependent)
-hepatic (may be dose dependent BUT dose-independent events more common)
-hematologic

Question 12

GI adverse events from NSAIDs (60%)

Answer 12

1. vomiting, diarrhea, ulcers, melena
   -occur because prostaglandins promote gastric mucous and bicarbonate secretion AND increase mucosal blood flow
2. Direct GI irritation (aspirin and emloxicam tablets)

Question 13

Renal adverse events from NSAIDs (20%)

Answer 13

-Prostaglandins help maintain GFR
>NSAIDs believed to decreased GFR and possibly blood flow

-can lead to renal papillary necrosis/idiosyncratic toxicity

Question 14

Hepatic adverse events from NSAIDs (15%)

Answer 14

-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

Question 15

Hematologic adverse events from NSAIDs (1%)

Answer 15

prolonged bleeding times with aspirin and ketoprofen

Question 16

Cox-1

Answer 16

constitutive (produced constantly

Question 17

Cox-1 presence

Answer 17

-platelets and endothelium
-mucosal cells in GI
-renal tubule cells
-neural tissue

Question 18

Cox-2

Answer 18

1.inducible- expressed in response to inflammatory mediators

2.constitutive in some tissues (brain, kidney, spinal cord)

3. expressed near gastric ulcers (accelerates healing)

Question 19

Cox-2 presence

Answer 19

often formed at sites of inflammation

Question 20

Function of Cox-1

Answer 20

produce cytoprotective prostaglandins which play a role in vasodilation and mucous production

Question 21

Cox-2 selective NSAID

Answer 21

drugs that inhibit cox-2 (but not cox-1) at label dose

Question 22

Cox-2 preferential NSAID

Answer 22

drugs that inhibit cox-2 at lower drug concentrations than cox-1, but there is some cox-1 inhibition at label dose

Question 23

Cox-1 sparing and specific NSAID

Answer 23

same thing as cox-2 selective

Question 24

Cox-nonspecific NSAID

Answer 24

-Both cox-1 and cox-2 are inhibited at label doses

Question 25

How to determine cox inhibition category?

Answer 25

-Use IC50: drug concentration at 50% of enzyme activity inhibition
*low IC number=increased drug potency

-High cox-1 IC50= less inhibition by NSAID

Question 26

Cox-1 vs. Cox-2

Answer 26

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.

Question 27

Cox-3

Answer 27

-derivative of cox-1
-found in brain
-unknown function, but inhibited by older NSAIDs that “seem to work”
eg. acetaminophen

Question 28

PK/PD data usage

Answer 28

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)

Question 29

NSAID general PK properties

Answer 29

-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

Question 30

COXIB-specific drug properties

Answer 30

-varying degrees of cox-2 selectivity
-generally very lipophilic
-hepatic metabolism (CYP 450?)
>pharmacogenetic differences
>concurrent drug usage

Question 31

VIOXX (rofecoxib) recall

Answer 31

first CoxIB of its time

Recalled drug because led to increased risk of cardiovascular events

**no evidence found in dogs or cats

Question 32

Intravenous lipid emulsion (ILE) therapy

Answer 32

-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

Question 33

Washout periods

Answer 33

time period when switching between two drugs
*allows 1st drug to be eliminated, increasing the margin of safety when 2nd drug is administered

Question 34

Washout period importance with anti-inflammatory drugs

Answer 34

-Needed when going from steroids/aspirin to NSAIDs or from NSAIDs to NSAIDs

Question 35

How long should your washout period be?

Answer 35

Many theories:
-10 half lives?
-set period of time? 3 days? 7 days?

**warn owner of risks