Test 2: lecture 27 NSAIDs Flashcards
what is a common side effect of COX inhibitors
GI intolerance- ulcers
what are some negative side effects of COX2 inhibition in humans
COX2 blocks prostacyclin, but not thromboxane
causes strokes from increased clot formation and vasoconstriction in humans
Does not happen in dogs
COX inhibition in the GI will cause
COX1
peptid ulcers
GI bleed
NSAIDs will do what to the kidneys
COX 1 and 2 make PGE2 and PGI1: vasodilation and increased NA and water excretion
Blocking
will cause Na/water retention
hypertension
hemodynamic AKI
NSAIDs and aspirin will do what to the cardiovascular system
can cause stroke and MI in humans by inhibiting PGI2 which causes inhibits platelet aggregation → form clots
and not inhibiting thromboxane in platelets
—is an irreversible covalent COX inhibitor
aspirin
aspirin is absorbed in the — and binds to — in the serum
stomach
albumin
will irreversibly inhibit COX1>COX2
therapeutic effect of aspirin
antiinflammatory cause it irreversibly inhibits COX 1+2 → inhibits PG synthesis (reduces pain and fever)
irrevesible COX1 inhibition in the platelets will also block thromboxane synthesis → inhibits platelet aggregation (thins the blood)
body needs to make new platelets to clot
why cant glucocorticoids inhibit platelet thromboxane synthesis?
platetes dont have nuclei
steroids need to get into nucleus and cause gene expression
salicylates — inhibit COX
competitively
reversible COX inhibitor
Some aspirin is converted to salicylic acid by esterases in tissues and blood
how is aspirin and salicylate metabolized
glucuronidation
Salicylate conjugates cleared via kidney
cats do not have UDP-glucuronosyltransferase (UGT) enzymes- therefore half life of aspirin is much higher 37 hr
why is half life of aspirin in cats so high
Cats do not have UDP-glucuronosyltransferase (UGT) enzymes
can not metabolize aspirin and salicylate acid
adverse effects of aspirin and salicylates
GI issues= ulcers
aspirin is a COX-1 inhibitor → decrease bicarb and mucous secretion in the stomach
can try to counteract this effect by giving buffered aspirin with pH 3.5 or greater
ibuprofen is a — inhibitor and is toxic to —
COX- slightly more selective for COX 2 in humans
Dogs (ulcers, kidney failure)
NSAID: Phenylproprionic acid- competitive reversible inhibitor of COX, compete with aspirin for plasma protein binding sites
naproxen is an inhibitor of —
COX 1 = COX2
can cause enhanced ulcerogenic potential in dogs
-prolonged enterohepatic recycling: dog half life 74 hrs, horse half life 5 hrs
NSAID: Phenylproprionic acid- competitive reversible inhibitor of COX, compete with aspirin for plasma protein binding sites
what are some NSAID: Phenylproprionic acids
naproxen
iburprofen
carprofen (rimadyl)
Etodalac
adverse reactions of NSAID: Phenylproprionic acids
- gastrointestinal toxicities (esp. dogs)
- possible nephrotoxicity
- nausea
- peripheral edema
Ibuprofen, naproxen, carprofen- competitive, reversible inhibitors of COX
how does carprofen (rimadyl) work
NSAID: Phenylproprionic acid
selective for COX-2 in dogs
inhibits COX-1 slightly
metabolized in the liver
used for Pain relief, joint pain, post- surgical inflammation
adverse effects of carprofen (rimadyl)
GI intolerance / ulceration
Nausea, appetite loss, vomiting, diarrhea (0.1% dogs)
Hepatopathy (1 in 5000 dogs)- in first 3 weeks
should not be given to patients with pre-existing liver, kidney disease or GI
ulcerations
— is similar to carprofen(rimadyl) and is used for managment of chronic OA
etodolac (etogesic)
Metabolized in liver
Side effects: GI ulceration
cox2 selective inhibitors in human medicine can cause
stroke and heart attack- from clot formation
NO COX2 receptors in platelets: Can not block Thromboxane in platelets → vasoconstiction and platelate formation
blocking COX2→ blocks PGI2 which prevents clot formation
both actions increase clot formations in different ways
Valdecoxib (Bextra)
Rofecoxib (Vioxx)
— are slightly COX2 selective inhibitors in vet medicine
Carprofen (Rimadyl)
Etodolac (Etogesic)
— are strongly COX 2 selective inhibitors in vet medicine
– Deracoxib (Deramaxx) -dog
– Firocoxib (Previcox) -horse
– Robenacoxib (Onsior) –cats
Coxibs are larger than non-selective COX inhibitors and bind to —
COX2
Slightly COX2-selective
– Carprofen (Rimadyl)
– Etodolac (Etogesic)
Strongly COX2 selective (coxibs)
– Deracoxib (Deramaxx) -dog
– Firocoxib (Previcox) -horse
– Robenacoxib (Onsior) –cats
which coxibs is used in dogs
Deracoxib (Deramaxx)
coxibs= cox 2 selective inhibitor
which coxibs is approved for horses
Firocoxib (Previcox)
coxibs= cox 2 selective inhibitor
how does COX selectivity assays work
if ratio greater than 1= cox 2 selective
if less than 1 = cox 1 selective
two NSAIDs for cats
Robenacoxib (Onsior)- cox 2 selective inhibitor
Meloxicam (Metacam)
Cats lack the major UDP-glucuronosyltransferase (UGT) enzymes so they can’t metabolize most NSAIDs
repeated usage of — NSAID in cats can cause renal failure and death
meloxicam (metacam)
two NSAIDS approved for cats:
Robenacoxib (Onsior)- cox 2 selective inhibitor
Meloxicam (Metacam)
meloxicam is moderately — selective
COX 2 at low doses
Repeated usage is associated with renal failure and death
approved as NSAID for cat
why can meloxicam be given to cats
metabolized in the liver (not glucuronidated)
moderately COX-2 selective at low doses
Repeated usage is associated with renal failure and death
Flunixin meglumine (Banamine) is a — inhibitor
Irreversible, non-covalent COX
NSAID for large animal
Powerful analgesic (on par w/ opiods in horses)
advantages of Flunixin meglumine (Banamine)
Powerful analgesic (on par w/ opiods in horses)
rapid action (2 hrs) and long duration (24-36hrs)
Useful for relieving pain associated w/ muscoskeletal disorders, surgery, GI spasm (colic) and endotoxic shock.
large animal NSAID
adverse effect of Flunixin meglumine (Banamine)
Ulceration of tongue, lips, gums, palate, stomach
Anorexia
CNS depression
May cause acute renal failure in dogs via unknown mechanism
– ensure adequate hydration; avoid reductions in blood pressure/volume
large animal NSAID with high pain relief (rapid action and long duration)
— is a large animal NSAID that is toxic to humans and can not be used in food animals
Phenylbutazone
Irreversibly binds COX (non-covalent)
adverse reactions of Phenylbutazone
Oral and GI tract erosions, diarrhea, depression
Death - if enteropathy leads to decreased blood volume, hypovolemic shock, circulatory collapse
Do not use if patient has hematocytologic disorders or cardiac, renal or hepatic dysfunction (idiosyncratic bone marrow toxicity in humans)
Can cause permanent kidney damage if animal is dehydrated
large animal NSAID that is toxic to humans= Irreversibly binds COX (non-covalent)
grapiprant (galliprant) works as
EP4 receptor antagonist (inhibits PGE2 receptor)
– does not inhibit production of homeostatic
Analgesic for canine osteoarthritis
MOA: blocks PGE2-elicited pain via EP4
side effects of galliprant
Vomiting, diarrhea, decreased appetite
EP4 receptor antagonist
inhibitors prostaglandin receptor → decreases pain
— is the primary mediator of the PGE2-elicited sensitization of sensory neurons (inflammation-associated pain)
EP4
prostaglandin receptors that sit on nociceptors and trigger pain
galliprant blocks this receptor
— are non-cyclooxygenase inhibitors
Dimethyl Sulfoxide (DMSO)
Galliprant
what does DMSO do
anti-inflammatory
analgesic
anti-microbial, anti-fungal, anti-diuretic
anti-cholinesterase
Non-cyclooxygenase inhibitor
DMSO is metabolized by
expelled through breath - garlic/oyster smell
some is excreted via kidney
adverse effects of DMSO
dissolves through skin can introduce external toxins into body (wear appropriate gloves)
Irreversible, covalent COX inhibitor (“gold standard” NSAID)
aspirin
Poor anti-inflammatory; analgesic, fever; contraindicated for cats, dogs
acetaminophen (tylenol)
Enhanced ulcerogenic potential in dogs; contraindicated for dogs
ibuprofen
Enhanced ulcerogenic potential in dogs; approved for horses
naproxen
Moderately COX-2 selective; approved for dogs
carprofen
Weakly COX-2 selective; approved for dogs
etodolac(similar to carprofen)
Strongly COX-2-selective; approved for dogs
Deracoxib
Strongly COX-2-selective; approved for dogs and horses
Firocoxib
Strongly COX-2-selective; only coxib approved for cats
Robenacoxib
1 of 2 NSAIDs approved for cats- not glucuronidated; single injection to relieve post-operative pain; ok for horses, cattle etc
Meloxicam
Most common NSAID for horses; non-food animals only; idiosyncratic bone marrow toxicity
Phenylbutazone
Potent analgesic for horses, cattle (on par w/ opiods)
Flunixin
EP4 receptor antagonist; Analgesic for dogs
galliprant
Solvent; penetrates skin; MOA not well understood –prob ROS scavenger
DMSO
Non-cyclooxygenase inhibitor
