antiinflamm 1 Flashcards
(36 cards)
non-pharmalogical therapeutic options for inflammation
Non-Pharmacological
* Rest
* Heat / Cold
* Weight reduction
* Surgery
pharmalogical therapeutic options for inflammation
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- Glucocorticoids
- misc others
what is the mechanism of action of aspirin?
inhibition of prostaglandin synthesis
main benefits of NSAIDs
NSAIDs are a family of chemically dissimilar drugs that produce three main benefits:
* Anti-inflammatory effects
* Antipyretic effects
* Analgesic effects
prostoglandins are in this categoy
eicosanoids
normal physiological roles of Eicosanoids (mainly prostaglandins)
Prostaglandins (PGs) are required for normal homeostasis in all tissues
how are prostoglandins synthesized? What enzymes help with this?
They are synthesized from arachidonic acid by cyclo- oxygenase (COX) enzymes
There are two main COX enzymes, COX1 & COX2
what is COX1? what does it do?
COX1 is a normal housekeeping enzyme present at low levels in most tissues
-helps synthesize prostoglandins which help maintain tissue blood flow
-helps synthesize thromboxane in platelets > promotion of platelet aggregation
-helps synthsize prostacyclin > inhibition of platelet aggregation, vasodilation
-PGE2 and PGI2 also involved in gastric mucosa protection
what does thromboxane do and how is it made?
Synthesized by COX1 in platelets
Promotion of platelet aggregation
what does prostacyclin do and what enzymes are important for making it?
Inhibition of platelet aggregation
Vasodilation
Other protective functions
-COX1 and 2
why is COX2 important? how do levels compare to COX1, generally?
COX2 is normally present at much lower levels than COX1 in most tissues, but is important for homeostasis in a few tissues (e.g., renal medulla, gastric mucosa)
Involved in healing of gastric ulcers
roles of eicosanoids (mainly prostaglandins) in inflammation? what is the importance of the COX enzymes?
-COX2 is up-regulated in response to plasma membrane damage or inflammatory mediator release
-COX2 induction is a local response that occurs at the site of cell damage or mediator release
> marked vasodilation occurs, promoting inflammation:
* Redness
* Swelling
* Heat
* Pain
* Loss of function
> COX2 stimulates production of various PGs and prostacyclin
Increased blood flow at site of injury or mediator release
Mechanism of action of NSAIDs and general effects
NSAIDs inhibit ( -) cyclooxygenase enzymes
Most NSAIDs inhibit both COX1 & COX2
Reduces synthesis of PGs, including those that promote vasodilation
Reduces blood flow to site
Reduces sensitization of nociceptors
Alleviates inflammation
mechanism of adverse effects of NSAIDs in gastric mucosa
The normal protective effects of PGs in the stomach are inhibited, resulting in:
* Decreased blood flow, bicarb secretion, & mucus secretion
* Increased acid secretion
> gastric bleeding +/- ulceration (the most common adverse effect associated with NSAIDs)
what are the important gastric effects of PGE2 & PGI2?
↓ acid secretion by gastric parietal cells, ↑ bicarb & mucus secretion, ↑ vasodilation
Mechanism of adverse effects of NSAIDs on platelets
Only COX1 is present in platelets
NSAIDs inhibit the conversion of AA to thromboxane in platelets
> result is a slightly increased general tendency to bleed
Mechanism of adverse effects of NSAIDs on the kidney
COX enzymes produce PGs that maintain adequate blood flow to many tissues, including the renal medulla
-Excessive COX inhibition can lead to
renal medullary hypoxia & papillary necrosis
what are coxibs? what is a problem that can get worse with coxid administration and why?
What are advantages and disadvantages to this type of drug, and when do we want to use it?
Some drugs are highly selective for COX2 (called ‘coxibs’), but pre-existing gastric epithelium lesions can become exacerbated by coxib administration, since products of COX2 are involved in healing of ulcers
The take-home message is that NSAIDs that selectively target COX2 produce fewer adverse GI events as long as GI lesions are not present initially
Coxibs also cause less bleeding, since platelet aggregation is not inhibited
shared pharmacokinetic properties of NSAIDs
- Weak acids
- Highly protein bound
- Hepatic metabolism (Phase 2 conjugation)
- Variable elimination
shared adverse effects of NSAIDs
- GI ulceration*
- Inhibition of platelet aggregation > bleeding*
- Inhibition of uterine motility
- Inhibition of PG-mediated renal perfusion
- Renal papillary necrosis in dehydrated animals (a problem with many NSAIDs)
Shared contraindications for NSAIDs
“As with all non-steroidal anti-inflammatory drugs (NSAIDs), administration of this drug is advised against in the following circumstances:
* Animals with gastro-intestinal ulcers, renal disease, hepatic disorders, hypoproteinemia, dehydration, or cardiac disease;
* A known hypersensitivity to the drug;
* Concurrent use of other NSAIDs or corticosteroids.”
shared clinical uses of NSAIDs
For the relief of musculoskeletal & inflammatory pain, including post-operative pain
what does aspirin do? what specied is it approved for? what is tis mechanism and what are its effects?
Aspirin (acetylsalicylic acid; ASA) The only NSAID that blocks COX enzymes irreversibly
Approved for use in cattle & horses
In vitro it is a non-selective inhibitor of COX 1 & 2, but in vivo it acts mainly to inhibit COX 1
Anti-inflammatory, antipyretic, analgesic
* Effective for musculoskeletal / cutaneous pain, but poor for visceral pain
* T1⁄2: horse and cow ~1 h, pig 6 h (much longer in dogs [10 h] and cats [38 h]), but irreversible binding to COX enzymes produces prolonged effects in many species, even with low doses
* Narrow therapeutic margin
* Metabolized to salicylic acid (active form)
* Only available in oral formulations
adverse effects and contraindications of aspirin
Adverse effects:
* *Bleeding; inhibits platelet function
-bovine platelets not affected
* Dose-dependent *gastric ulceration (subclinical at low doses)
- Renal damage in dehydrated animals
- Avoid in cats (deficient in glucuronide conjugation)
Contraindications:
* Cats (though it has been used)
* Animals with bleeding disorders
* Animals prone to GI ulcers
(e.g., those receiving glucocorticoids)
