Lipoxygenase pathway yields what (generally)?
(remember Lipoxygenase and Cycloxygenases both come from Arachidonic acid)
Name the 4 leukotrienes in FA. What do they do?
LTB4: attracts neutrophils ("neutrophils arrive B4 others"
LTC4, LTD4, LTE4: incr bronchial tone, vasoconstriction, incr vascular permeability
what products come from the Cycloxygenase pathway?
Prostacyclin, Prostaglandins, Thromboxane
-these moderate vascular, bronchial, & uterine tone in different ways.
PGI2: what is it/what does it do?
what cell/tissue releases it?
Prostacyclin from COX pathway
anticoagulation & vascular dilatation
(decreases these: platelet aggregation, vascular tone, bronchial tone, uterine tone)
Released by endothelial cells. Kind of opposes TXA2 from platelets.
PGE2, PGF2a: what do they do?
Increase uterine tone
decrease bronchial tone
TXA2: what does it do?
what cell/tissue releases it?
incr platelet aggregation, incr vasoconstriction, incr bronchial tone
Released by platelets. Kind of opposes PGI2 from endothelial cells.
Irreversibly inhibits COX1 and COX2 via covalent acetylation.
--> decr synthesis of TXA2 and Prostaglandins.
Effect: incr bleeding time until new platelets are synthesized (~7d).
Aspirin: effect on PT? PTT?
only affects bleeding time.
Aspirin: use (3 dose levels)?
Low dose: decr platelet aggregation (<300mg)
Medium dose: anti-fever, analgesic
High dose: anti-inflammatory (>2400mg)
Aspirin: tox (adults)?
Tinnitus (CN VIII)
Chronic use: renal failure, interstitial nephritis, upper GI bleeds.
Stimulates resp centers -> hyperventilation and resp alkalosis.
Aspirin: tox (children)?
Risk of Reye syndrome for kids treated with aspirin for viral infection.
COX 1 preferentially expressed where?
GI tract, platelets
COX 1 blockers: general side effects?
GI ulceration, bleeding
COX 2 receptors preferentially expressed where?
sites of inflammation
advantage to COX 2-specific blockers?
avoid side effects of COX1 (ulceration, bleeding)
ibuprofen, naproxen, aspirin, indomethacin, ketorolac, diclofenac
reversibly inhibit COS1 and COX 2.
Block prostaglandin synthesis
exception: aspirin = IRREVERsible block.
anti-fever, analgesic, anti-inflammatory
Indomethacin: unique use beyond usual NSAIDs use?
interstitial nephritis, gastric ulcer, renal ischemia
how do NSAIDs cause gastric ulcers?
NSAIDs block prostaglandin synth
-->PGs protect gastric mucosa against ulceration
-->PGs vasodilate afferent arteriole
Name a COX-2 specific blocker?
reversibly inhibit COX-2 (found in inflammatory cells and vasc endothelial cells).
Mediates inflammation and pain
does NOT block COX1 -> spares gastric mucosa.
celecoxib: effect on platelet function?
None because TXA2 production is dependent on COX1, not COX 2.
Rheumatoid arthritis, osteoarthritis
(esp patients with gastritis or ulcers)
incr risk of thrombosis
sulfa drug: watch out for allergies
reversibly inhibits COX, mainly in CNS
inactivated in periphery
Acetaminophen: use specific to children?
children with viral illness: don't give aspirin due to possible Reye's (brain swelling -> encephalopathy & liver damage)
use acetaminophen instead
OD -> hepatic necrosis (metabolite from acetaminophen = NAPQ1; depletes glutathione -> causes liver toxicity)