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 (
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)
Acetaminophen: antidote to an OD?
mech: regenerates glutathione in the liver
Bisphosphonates (alendronate, -dronates): mech?
inhibit osteoclast activity
pyrophosphate analogs; bind hydroxyapatite in bone, thus inhibiting osteoclasts
Bisphosphonates (alendronate, -dronates): use?
Paget disease of bone
Bisphosphonates (alendronate, -dronates): tox?
-Corrosive esophagitis (ie pill esophagitis; take water w pill and don't lie down for 30 min)
-Osteonecrosis of the jaw
Name 3 preventive gout drugs.
generally what is their mech?
Allopurinol, Febuxostat, Probenecid
A, F: interrupt the process of Purine metabolism -> less uric acid in blood
Allopurinol, Febuxostat: mech?
Inhibit xanthine oxidase
-> less uric acid in blood
Allopurinol: why do we give this to people with leukemia/lymphoma?
1. decreases the destruction of azathioprine and 6-MP (which are normally degraded by xanthine oxidase)
2. prevents urate nephropathy from tumor lysis
what do we NOT give to pts with chronic gout?
they decrease clearance of uric acid
inhibits reabsorption of uric acid in PCT
(also inhibits secretion of PCN)
3 drugs we give for acute gout?
NSAIDs (naproxen, indomethacin)
Glucocorticoids (oral or right into the joint!)
-> inhibits microtubule polymerization
-> decr leukocyte chemotaxis and degranulation
GI side effects
given in escalating doses until the patient can't handle the GI issues
3 TNF-a inhibitors?
what are they for, generally?
-Used for autoimmune diseases (RA, ank spond, IBD etc)
Etanercept, Infliximab, Adalimumab: tox?
-> increased infection since TNF blockers prevents activation of macrophages and destruction of phagocytosed microbes
-> reactivation of latent TB
Infliximab, Adalimumab: mech? use?
anti-TNFa monoclonal antibody
PAIR: Psoriasis, Ank spond, IBD, RA
Etanercept: mech? use?
decoy TNF receptor
fusion protein produced by recombinant DNA: receptor for TNF-a + IgG Fc region)
Use (PAR): Psoriasis, Ank Spond, RA
Antidote for acetaminophen tox?
How does it work (2 mechs)?
1. regenerates glutathione -> allows NAPQI (toxic metabolite) to be cleared
2. donates sulfhydryl groups -> increases amt of acetaminophen that can be metabolized
Normally Acetaminophen is 90% metabolized by sulfation and glucuronide conjugation. 10% turns into NAPQI (via CP450 system, toxic, requires glutathione to be cleared). In overdose, NAPQI increases -> centrilobular necrosis.