Rational use of NSAIDs in clinical practice Flashcards
How do NSAIDs reduce inflammation?
inhibit production of prostaglandins released by damaged tissue through inhibition of cyclo-oxygenase COX enzyme
What are the main clinical indications for NSAIDs?
control of pain and inflammation in non-allergic inflammatory disorders
peri-operative pain managment
decrease platelet aggregation (thromboembolus, heartworm dz)
What is the role of COX1?
physiologic
production of prostaglandins important to physiological modulation of function
- gut mucosal barrier
- intra-renal perfusion when renal blood flow reduced
What is the role of COX-2?
inducible
activated and released when: tissue damage, bact. LPA, cytokines, growth factors, infl. where PGE2 is predominant
inflammation, pain and fever
What are the clinical benefits of inhibiting COX-2?
suppresses inflammation, pain (if due to inflammation), fever
can inhibit certain tumours that produce COX-2 (palliative)
What are the 3 categories of NSAIDs?
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)
What are common non-selective cox inhibitors?
aspirin
phenylbutazone
ketoprofen
tolfenamic acid
What are common preferential inhibitors of COX2?
meloxicam
carprofen (not cats)
mavacoxib
cimicoxib
deracoxib (fully selective in humans but not SA)
What are common selective inhibitors of COX2?
firocoxib
robenocoxib/onsior
What is the mode of action of grapiprant/galliprant?
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
Are selective cox2 inhibitors safer than preferential ones?
no compelling evidence
thought that some drugs work better for certain individuals
How is carprofen different in dogs vs cats vs horses?
dogs: cox2 preferential
cats: cox2 preferential but significantly longer half life than dog = careful with dosing and frequency
horses: non-selective
How is firocoxib different in dogs vs cats vs horses?
dogs: cox2 selective
cats: cox2 preferential
horses: ++selective
Where do NSAIDs distribute in terms of pharmacokinetics?
weak acids = readily penetrate inflammed tissues
highly protein bound = accumulation of drug in protein rich inflammatory exudate
How are NSAIDs metabolised/eliminated?
excreted at varying rayes depending on metab pathway and extent of enterohepatic circulation
main route of elimination is hepatic (metabolised + excreted in bile)
What are potential adverse effects of NSAIDs?
GI
Renal
Haematological
What is the most important fact about species differences with NSAIDs?
toxicity and pharmacokinetics data can NEVER be transposed from one species to another
What is the role of prostaglandin in the GIT?
maintaining the integrity of the protective barrier that prevents gastric mucosa damage by gastric acid
How does PGE and PGI2 protect the gastric mucosa?
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
What are the GIT effects when COX is inhibited?
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
When is it prudent to avoid NSAIDs?
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
What are GIT adverse effects with preferential and highly selective COX 2 inhibitors?
reduced GI toxicity overall
GI ulceration still reported for both
What are other factors that induce GI damage with NSAIDs?
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
What increases the ulcerongenic potential of NSAIDs?
concurrent corticosteroids
dehydration
hypovolaemic shock
disruption to normal blood flow
What is the role of prostaglandins in renal function?
when renal perfusion is reduced, renal prostaglandins maintain renal blood flow: vasodilatory action (COX1 and COX2)
COX2 involved in naturiesis
When can NSAIDs cause severe renal toxicity?
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
Are NSAIDs safe to use in cats with chronic kidney disease?
studies show that cats with CKD on meloxicam for DJD suffered no ill effects and may have longer survival than those not on meloxicam
What NSAIDs are completely renal safe?
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
Is grapiprant/galliprant renal safe?
probably not
EP4 mRNA is expressed in the glomerulus and collecting duct
could regulate glomerular tone and renal renin release
What is thromboxane and how is it affected by NSAIDs?
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
How do NSAIDs affect the liver?
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
With what meds should we take care to also prescribe NSAIDs vs adverse effects or changed effects?
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
When should NSAIDs be avoided?
- 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
What do patients receiving NSAIDs must have?
be well hydrated
good peripheral circulation
good renal function
normal sodium and water balance
ideally no liver disease
no GI pathology/pancreatitis or potential
