Terms in this set (30)
What is another name for COX-1 and COX-2?
What is the difference between them?
PGH synthase-1 (COX-1)
PGH synthase-2 (COX-2) -
has a smaller binding site than COX-1
What are the 2 major groups of NSAIDs?
1) cyclooxygenase inhibitors
2) non-cyclooxygenase inhibitors
What COX is involved in homeostatic functions?
Which one is involved more in inflammation?
COX-1 = homeostatic functions
COX-2= mostly inflammation
but also has some homeostatic functions
What are some properties of COX inhibitors?
Are they weak acids or bases?
What are some of the unwanted side effects caused by?
chemically diverse - but function the same way
most are competitive inhibitors of arachonidonic acid binding
most inhibit both COX-1 and COX-2
Some of the unwanted side effects are due to inhibition of COX-1
Do COX inhibitors block tissue damage caused by release of lysosomal enzymes and toxic oxygen radicals (chronic inflammation)?
What are the most common side effects of NSAIDs?
1) ulceration/GI intolerance
2) kidney issues (not super common) - patient is at the most risk for this when dehydrated
What are the 1st generation NSAIDs?
Where are they absorbed/what promotes their absorption?
aspirin and salicylates
Absorbed in stomach and upper small intestine - because they are
Acid medium in stomach promotes absorption
- keeps salicylate in non-ionized form
- Poorly absorbed in horse and cow
Why does higher dose of salicylates --> higher concentration of activity?
because Salicylate binds albumin in serum so under higher doses there is a higher concentration of unbound drug
How does salicylates block COX?
competitive inhibitor- reversible inhibitor
How does aspirin block COX?
covalently irreversible inhibitor
True or false
Most aspirin is converted to salicylic acid by esterases in tissues and blood
True - so most aspirin ends up being a competitive inhibitor instead of covalently binding COX
What is the only irreversible COX inhibitor?
can acetylate COX, which prevents enzyme binding to arachidonic acid
more selective for COX-1 than COX-2
peroxidase activity is not effected
Do non-acetylated salicylates covalently modify/irreversibly inhibit COX?
NO - salicylates competitively inhibit COX (like most NSAIDs)
What are the 3 effects of aspirin?
- reduces pain by reducing inflammation and inhibiting pain stimuli
- blocks pyrogen-induced prostaglandin synthesis (PGEs).
Platelet effects (specific for aspirin)
- inhibits COX-1 (no COX-2 present)
- inhibits thromboxane (TXA2) synthesis in platelets -inhibits platelet aggregation
- irreversible COX-1 inhibition until new platelets are formed
(platelets cannot synthesize new COX1)
Why can't glucocorticoids do this??
Why can aspirin permanently inhibit platelet aggregation?
because they irreversibly bind COX - and platelets produce COX-1
platelets can't synthesize more COX-1 so now it cant make Thromboxane
need new platelets to get back clotting function
Why can't glucocorticoids inhibit platelet aggregation? **Exam
because platelets dont have nuclei - and for GC to work you need gene transcription
What inactivates Aspirin and salicylate?
Inactivated by conjugation to glucuronic acid (glucuronidation)
What is the half life of glucuronidation activity in horses, cats or dogs?
lower glucuronidation activity = longer plasma half-life for aspirin
T1/2 is variable: 1h in horses, 37h in cats, 4-8h dogs
Salicylate conjugates cleared via kidney (excretion more rapid in alkaline urine)
Conjugates to glutathione, when glucuronic acid is absent
How do aspirin and salicylates cause GI disturbances?
COX-1 inhibition of gastric cytoprotection
prostaglandins stimulate bicarbonate and mucous secretions in gastric mucosa
Gastric irritation can be decreased:
- by raising gastric pH to 3.5 or greater
- by administration of misoprostol (a prostaglandin analogue)
What are the symptoms of aslicylism (overdose of aspirin)?
dizziness, deafness, uncoupled oxidative phosphorylation, increased O2 consumption
Dehydration - (from vomiting, sweating or fever)
Convulsions or coma
not seen as much in animals
What is the group of 2nd generation NSAIDs?
What are the 2nd generation NSAID drugs?
Which COX is ibuprofen more selective for?
Can dogs use it?
Moderate COX inhibitor:
more selective for COX-2
less toxic to gastric lining (humans)
toxic to dogs (ulcers, kidney failure)
Which animals can use naproxen?
What is the half life?
Which COX does it have a preferance for?
Naproxen (approved for horses)
horses T1/2 = 5h
dogs T1/2 = 74h -
prolonged enterohepatic recycling
Equipotent on both COX-1 and COX-2
Enhanced ulcerogenic potential in dogs
What generation of NSAIDs is carprofen in?
What type of effect does phenylproprionic acid have on COX?
What drug does it compete with?
Competitive, reversible inhibitors of COX
(interfere w/ arachidonic acid binding)
Compete w/ aspirin for plasma protein binding sites
gastrointestinal toxicities (esp. dogs)
What was the major issue with COX-2 inhibitors (3rd gen NSAIDs) in humans?
What are some vet med 3rd gen NSAIDs? (5)
Robenacoxib (Onsior) -
Why did 3rd generation NSAIDs cause heart attack in humans?
not really known - but thought that COX-2 selective drugs were inhibiting prostacyclin but not disrupting thromboxane (mediated via COX-1)
so now there is not balance between vasodilation and vasoconstriction
What maintains homeostasis of platelet aggregation?
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