Rational use of NSAIDs in clinical practice

Question 1

How do NSAIDs reduce inflammation?

Answer 1

inhibit production of prostaglandins released by damaged tissue through inhibition of cyclo-oxygenase COX enzyme

Question 2

What are the main clinical indications for NSAIDs?

Answer 2

control of pain and inflammation in non-allergic inflammatory disorders
peri-operative pain managment
decrease platelet aggregation (thromboembolus, heartworm dz)

Question 3

What is the role of COX1?

Answer 3

physiologic
production of prostaglandins important to physiological modulation of function
- gut mucosal barrier
- intra-renal perfusion when renal blood flow reduced

Question 4

What is the role of COX-2?

Answer 4

inducible
activated and released when: tissue damage, bact. LPA, cytokines, growth factors, infl. where PGE2 is predominant

inflammation, pain and fever

Question 5

What are the clinical benefits of inhibiting COX-2?

Answer 5

suppresses inflammation, pain (if due to inflammation), fever

can inhibit certain tumours that produce COX-2 (palliative)

Question 6

What are the 3 categories of NSAIDs?

Answer 6

non-selective/specific
preferential (at least 2x greater inhibition of COX2 usually 10-40x, analgesic and anti-infl. at doses that inhibit cox2 but not 1)
selective (>100x for cox2)

Question 7

What are common non-selective cox inhibitors?

Answer 7

aspirin
phenylbutazone
ketoprofen
tolfenamic acid

Question 8

What are common preferential inhibitors of COX2?

Answer 8

meloxicam
carprofen (not cats)
mavacoxib
cimicoxib
deracoxib (fully selective in humans but not SA)

Question 9

What are common selective inhibitors of COX2?

Answer 9

firocoxib
robenocoxib/onsior

Question 10

What is the mode of action of grapiprant/galliprant?

Answer 10

EP4 receptor antagonist
one of the 4 receptors that PGE2 binds to, primarily responsible for pain and infl. associated with OA

ideally inhibits infl. without impacting on homeostatic PG2 functions

Question 11

Are selective cox2 inhibitors safer than preferential ones?

Answer 11

no compelling evidence
thought that some drugs work better for certain individuals

Question 12

How is carprofen different in dogs vs cats vs horses?

Answer 12

dogs: cox2 preferential
cats: cox2 preferential but significantly longer half life than dog = careful with dosing and frequency
horses: non-selective

Question 13

How is firocoxib different in dogs vs cats vs horses?

Answer 13

dogs: cox2 selective
cats: cox2 preferential
horses: ++selective

Question 14

Where do NSAIDs distribute in terms of pharmacokinetics?

Answer 14

weak acids = readily penetrate inflammed tissues
highly protein bound = accumulation of drug in protein rich inflammatory exudate

Question 15

How are NSAIDs metabolised/eliminated?

Answer 15

excreted at varying rayes depending on metab pathway and extent of enterohepatic circulation
main route of elimination is hepatic (metabolised + excreted in bile)

Question 16

What are potential adverse effects of NSAIDs?

Answer 16

GI
Renal
Haematological

Question 17

What is the most important fact about species differences with NSAIDs?

Answer 17

toxicity and pharmacokinetics data can NEVER be transposed from one species to another

Question 18

What is the role of prostaglandin in the GIT?

Answer 18

maintaining the integrity of the protective barrier that prevents gastric mucosa damage by gastric acid

Question 19

How does PGE and PGI2 protect the gastric mucosa?

Answer 19

inhibiting gastric acid secretion
maintaining mucosal blood flow
being involved in secretion and composition of healthy mucous
may also act as intercellular messengers for the stimulus of mucosal cell turnover and migration

Question 20

What are the GIT effects when COX is inhibited?

Answer 20

COX1= main source of “good” PGs
inhibiting COX1 = main mechanism by which GI ulceration occurs
both COX1 and COX2 need to be inhibited to generate muscosal injury in the absence of pre existing injury
COX2 rapidly expressed in response to GI injury and contributes ++ to mucosal defense/repair

nsaids disrupt mucosal gel layer of GI tract, letting in acid = ulceration

Question 21

When is it prudent to avoid NSAIDs?

Answer 21

in ptx w/ confirmed/presumed/potential GI inflammation
includes pancreatitis

patients with hypovolaemic shock secondary to trauma: no rational basis and clinically insupportable especially if with corticosteroids

avoid if possible with hepatic dz

Question 22

What are GIT adverse effects with preferential and highly selective COX 2 inhibitors?

Answer 22

reduced GI toxicity overall
GI ulceration still reported for both

Question 23

What are other factors that induce GI damage with NSAIDs?

Answer 23

relative rate of gastric absorption
systemic availability of the drug via circulation to the mucosa
direct damage to gastric mucosa
degree of eneterohepatic re-cycling

Question 24

What increases the ulcerongenic potential of NSAIDs?

Answer 24

concurrent corticosteroids
dehydration
hypovolaemic shock
disruption to normal blood flow

Question 25

What is the role of prostaglandins in renal function?

Answer 25

when renal perfusion is reduced, renal prostaglandins maintain renal blood flow: vasodilatory action (COX1 and COX2)
COX2 involved in naturiesis

Question 26

When can NSAIDs cause severe renal toxicity?

Answer 26

reduced renal prostaglandin of little consequence in healthy well hydrated animals

volume depleted/ poorly perfused (dehydration, blood loss, shock)
avidly retaining sodium (CHF, hepatic cirrhosis, etc)
pre-existing renal insufficiency

Question 27

Are NSAIDs safe to use in cats with chronic kidney disease?

Answer 27

studies show that cats with CKD on meloxicam for DJD suffered no ill effects and may have longer survival than those not on meloxicam

Question 28

What NSAIDs are completely renal safe?

Answer 28

NONE, esp. when kidney is stressed/ renal perfusion is or may be reduced
could also include grapiprant/galliprant

preferential and +/- selective cox2 inhibitors have less risk of renal toxicity when renal perfusion is reduced than non-selective nsaids

Question 29

Is grapiprant/galliprant renal safe?

Answer 29

probably not
EP4 mRNA is expressed in the glomerulus and collecting duct
could regulate glomerular tone and renal renin release

Question 30

What is thromboxane and how is it affected by NSAIDs?

Answer 30

a potent vasoconstrictor and activator of platelet aggregation

produced by COX1, only significant with older NSAIDs or in breeds with high prevalence of vonWillibrands dz

inhibition of thromboxane can lead to increased risk of bleeding

Question 31

How do NSAIDs affect the liver?

Answer 31

they undergo extensive hepatic metabolism

critical review of id NSAIDs are really needed: avoid if possible
if essential, increase dosage interval instead of decreasing dose

Question 32

With what meds should we take care to also prescribe NSAIDs vs adverse effects or changed effects?

Answer 32

Ace inhibitors (if renal perfusion is reduced)
alpha2 agonists as premeds
avoid high dose ACP as premed
diuretics: COX2 inhib may attenuate effect of diuretic

Question 33

When should NSAIDs be avoided?

Answer 33

• evidence/suspicion of GIT infl.
• gut and renal blood flow is/may be reduced (shock, dehydration, blood loss, reduced cardiac output)
• pathological sodium retention is present (nephrotic syndrome, cardiac failure, cirrhotic heptatic disease)
• renal dysfunction is present? unless benefit in old cats

Question 34

What do patients receiving NSAIDs must have?

Answer 34

be well hydrated
good peripheral circulation
good renal function
normal sodium and water balance
ideally no liver disease
no GI pathology/pancreatitis or potential