11.26 arachidonic acid cascade Flashcards
Substrates are formed from:
polyunstaurated fatty acids (PUFA
NSAIDs act
locally and on demand, they do not have distant sites of action
PUFA can be metabolized by:
cyclooxygenase
lipoxygenase enzymes or
P450 “epoxygenase” (we aren’t really going to talk about epoxygenases)
phospholipases release PUFA precursors from
phospholipsds, and arachiadonic acid comes from PUFA
arachidonic acid structure
20 carbon molecules with 4 double bonds
kind of looks like a hair pin
first arachiodonic pathway
cycloxygenase pathway, produces the prostaglandins
types of cycloxygenase
COX 1 and COX-2
COX-1 is
constitutive (always on/always making PGs)
COX-2 is constitutive or inducible?
inducible (so when you injure yourself it will be present)
selective COX-2 inhibitors
Celecoxib (celebrex) blocks COX-2 therefore less GI and platelet effects
what is the only irreversible NSAID?
aspirin
selective COX-2 inhibitors
Celecoxib (celebrex) blocks COX-2 therefore less GI and platelet effects
-blocks production of COX-2 at the site of injury
good things that PGE2, PGF2a, and PGD2 do
decrease gastric acid, increase gastric mucous (protection), Ca2+ mobilization, sodium and water excretion
-so when you take NSAIDS you don’t get these benefits, and can get ulcers, water retention and swelling
cycloxygenase makes…
prostaglandins (PGE2, PGF2a, PGD2, PGI2, and Thromboxance A2
PGI2 (the two means it has two double bonds) does…
- t 1/2=5 minutes
- inhibits platelet aggregation
- vasodilation
- less sensitive to low doses of aspirin than thromboxane
bad things that PGE2, PGF2a, and PGD2 do
-vasodilation vasc permeability sensitize to pain increases body temperature uterine contraction (cramps)
what is the major Lipoxygenase in our body?
5-lipoxygenase
lipoxygenase pathway leads to production of
-leukotrienes (C, D, and E)
Thromboxane A2
- from the cyclo-oxygenase pathway
- t 1/2=30 seconds
- induces platelet aggregation
- smooth muscle contraction
- thus in smaller doses of aspirin it mostly affects thrombaoxane and not PGI2
- inhibited by NSAIDs and aspirin
Leukotriene actions (C, D, and E)
bronchial smooth muscle contraction, thus they are major players in asthma
Zileuton
5-lipoxygenase inhibitor, will block both of the lipoxygenase pathways, it blocks the enzyme, whereas Zafirlukast and Montelukast block the receptors
what class of drugs will inhibit all the pathways of AA?
antiinflammatory steroids, in inhibits phospholipase, thus these drugs have a lot of side effects
if you wanted to inhibit just the production of the leukotrienes C, D, and E, what drug would you use?
Zafirlukast, Montelukast, the leukotrienes are still made, but these drugs block the receptors so they can’t bind
leukotriene B4
the second pathway in the lipoxygenase pathway It increases the following: -chemmotaxis -WBC stickiness -vascular permeability -neutrophil secretion
