Term
| 3 chronic inflamm diseases |
|
Definition
rheumatoid arthritis
osteoarthritis
acute gout |
|
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Term
|
Definition
anti-inflamm
anti-pyretic (fever)
analgesic (pain) |
|
|
Term
|
Definition
| redness, pain, swelling of tissues |
|
|
Term
|
Definition
interfering w/ COX pathway;
specifically block prostaglandin production |
|
|
Term
| 2 lipid mediator products from Arac Acid |
|
Definition
Prostaglandins
Thromboxanes |
|
|
Term
| why are prostaglandins and thromboxanes considered local hormones |
|
Definition
| act in paracrine or autocrine fashion to mediate inflamm. processes and homeostatic fcns |
|
|
Term
COX-1:
constitutive or inducible? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| COX-1 subcellular location |
|
Definition
|
|
Term
|
Definition
Gen. housekeeping;
protection and maintenance fcns |
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|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
COX-2:
Inducible/Constitutive |
|
Definition
|
|
Term
COX-2:
Tissue Location (induced) |
|
Definition
induced by INFLAMM STIMULI
in macrophages, monocytes, synoviocytes, chondrocytes, fibroblasts, osteoblasts, endothelial cells |
|
|
Term
COX-2:
tissue location (constitutive) |
|
Definition
| brain, kidney, bone, ovaries, uterus, sm. intestines (AT LOW LEVELS) |
|
|
Term
COX-2:
subcellular location |
|
Definition
|
|
Term
|
Definition
Proinflamm responses;
signaling and mitogenesis |
|
|
Term
| reason for adverse SE in COX-2 inhibitors |
|
Definition
| low level constitutive expression COX-2 in brain, kidneys, bone, ovaries, uterus, sm int |
|
|
Term
|
Definition
pro-inflamm stimuli:
LPS,TNF-alpha, IL-1,IFN-gamma,EGF,PDGF,FGF, TGF-beta |
|
|
Term
| COX-2 up/down regulated in inflamm cells in response to inflam stim |
|
Definition
|
|
Term
| upreg COX-2 duing inflamm produces production of what lipid mediators |
|
Definition
|
|
Term
| what 2 PGs involved in inflamm |
|
Definition
|
|
Term
|
Definition
|
|
Term
| inflam response to inc PGE2 & PGI2 |
|
Definition
| dilation blood vessels: inc blood flow: contributes to heat and redness |
|
|
Term
| 2 specific inflam fcns PGE2 |
|
Definition
1) enhances migration phag. to inflam. site
2) promotes vascular perm. in response to bradykinin & other agents: contributes to edema and inc. inflamm. |
|
|
Term
| location of PGE2 and PGI2 in arthritic patients |
|
Definition
|
|
Term
|
Definition
| sufficient to induce experimental inflammation |
|
|
Term
|
Definition
|
|
Term
| 4 gen fcns PGs during Inflammatory response |
|
Definition
1) Inflammation
2) Pain
3) Fever
4) increased bone resorption |
|
|
Term
| how do PGs affect pain response? |
|
Definition
1) lowers activation threshold of primary afferent neurons in response to pain stimuli
2) therefore increase responses to pain stimuli |
|
|
Term
| do PGs generate pain responses themselves? |
|
Definition
|
|
Term
| 2 abnormal pain states caused by PGs |
|
Definition
|
|
Term
| normally innocuous stimuli perceived as painful |
|
Definition
|
|
Term
| high intensity pain perceived as MORE painful |
|
Definition
|
|
Term
| fcn of PGs in dorsal horn neurons |
|
Definition
| act as pain-producing neuromodulators in SC: enhance depolar. of secondary sensory neurons |
|
|
Term
| how do PGs cause release of additional inflamm. mediator? |
|
Definition
| increase recruitment of leukocytes to site of inflamm |
|
|
Term
| which tissue location of PGE2 production is involved in causing fever |
|
Definition
|
|
Term
| where does PGE2 act to induce fever? |
|
Definition
| thermoreg cener of hypothalamus |
|
|
Term
| how does PGE2 production increase bone resorption? |
|
Definition
| promotes differentiation of osteoclasts (clasts kill), which contibutes to inflamm. induced bone loss and joint damage |
|
|
Term
| what 2 organ systems are involved in the other fcns of PGs |
|
Definition
1) GI tract
2) Cardiovascular system |
|
|
Term
| what COX isoform is predominantly expressed in stomach? |
|
Definition
| COX-1: PGs constitutively expressed |
|
|
Term
|
Definition
1) inhibit gastric acid secretion
2) inc gastric bicarb production
3) inc gastric mucous production
4) vasodilation: inc gastric blood flow |
|
|
Term
| what is the cause of the significant adverse SE of NSAIDs in the stomach? |
|
Definition
inhibition of COX-1:
1) inc gastric acid secretion
2) dec gastric bicarb production
3) dec gastric mucous production
4) vasoconstriction: dec gastric blood flow |
|
|
Term
| what two cells are involved in AA metabolite effects in CV system? |
|
Definition
1) platelets
2) endothelial cells |
|
|
Term
what COX isotype do plts express?
what AA metabolite is principally produced by plts? |
|
Definition
|
|
Term
|
Definition
vasoconstrictor
promotes plt aggregation & activation |
|
|
Term
| what COX isoform is expressed in endo cells? |
|
Definition
|
|
Term
| what AA metabolite is primarily produced in endo cells? |
|
Definition
| PGI2 (prostacyclin): fcn in vasodilation and inhibition of plt aggregation |
|
|
Term
| what enzyme do endo cells lack and how does this effect CV fcns of AA metabolites? |
|
Definition
TXA2 synthase
endo cells are responsible for vasodilation and inhibiting plt aggregation (fcns of PGI2) |
|
|
Term
| what is key in regulating systemic blood pressure and thrombogenesis in regards to AA metabolites? |
|
Definition
|
|
Term
|
Definition
vasodilator
inhibits plt aggregation |
|
|
Term
|
Definition
hypertension
ischemia
thrombosis
MI
stroke |
|
|
Term
|
Definition
promote vasodilation
inc renal blood flow
prevent renal ischemia
inc glom filtration rate
inc water & Na excretion |
|
|
Term
| fcns of PGs in angiogenesis |
|
Definition
induces neurovascularization
induces VEGF production
promotes angiogenesis (overexpression COX-2) |
|
|
Term
| what fcn of PGs may be related to anti-tumor effects of NSAIDs |
|
Definition
| promotion of angiogenesis |
|
|
Term
| PG role in female production |
|
Definition
stimulates uterine contractions
may play role in parturition |
|
|
Term
| how do NSAIDs delay labor? |
|
Definition
| blocking PGF2alpha, which normally plays role in parturition |
|
|
Term
| what role do PGs play in fetal blood flow? |
|
Definition
| PG maintain patent ductus arteriosus (shunts blood from PA to aorta to bypass lungs) |
|
|
Term
| how do NSAIDs Tx patent ductus arteriosus? |
|
Definition
| block PG production, which normally maintain patent DA |
|
|
Term
| why can't preg females take NSAIDs in regards to fetal blood flow? |
|
Definition
| NSAIDs can lead to premature closure of ductus arteriosus |
|
|
Term
|
Definition
| PGD2 acts on cerebral ventricles to promote sleep |
|
|
Term
| COX isoforms inhibited by Aspirin and Salicylates |
|
Definition
|
|
Term
| COX isoforms inhibited by Traditional NSAIDs |
|
Definition
|
|
Term
| Aspirin- weak or strong acid? |
|
Definition
|
|
Term
|
Definition
t1/2 = 15-20min
metab by serum esterases
acetylsalicylic acid (aspirin): salicylic acid + acetic acid |
|
|
Term
| what is the unique MOA of aspirin in comparison to other NSAIDs? |
|
Definition
| IRREVERSIBLE inhibitor of COX-1 |
|
|
Term
| how does aspirin irreversibly inhibit COX-1? |
|
Definition
| acetylates Ser 530 to Tyr 350 in active site of COX-1, which inhibits binding of AA substrate |
|
|
Term
| why is aspirin a much less potent inhibitor or COX-2? |
|
Definition
| b/c COX-2 active site is larger and more flexible, so it can still accomodate aa substrate |
|
|
Term
| how does salicylic acid (metabolite of aspirin) differ from aspirin in terms of fcn? |
|
Definition
| salicylic acid CAN'T acetylate COX enzymes, so it only acts as COMPETITIVE ANTAGONIST of AA binding |
|
|
Term
| role of NF-KB in inflammatory process |
|
Definition
| inducible trans. factor involved in upreg. of pro-inflamm. genes for COX-2, TNF-alpha, IL-1, other inflamm cytokines |
|
|
Term
| at high conc (>5mM), aspirin and salicylate inhibit or activate NF-KB? |
|
Definition
|
|
Term
|
Definition
inhibit plt aggregation in Tx for stroke and MI prevention for CAD patients
prevent re-infarction in patients with previous stroke/MI |
|
|
Term
|
Definition
| permanently inhibits COX-1: prevents TXA2 production: anti-thrombotic, prolongs bleeding time |
|
|
Term
|
Definition
|
|
Term
| why is low dose aspirin's anti-thrombotic effects long lasting in plts? |
|
Definition
| b/c plts lack ability to re-synthesize COX-1 in presence of aspirin |
|
|
Term
| why doesn't low level aspirin significantly affect production of PGI2? |
|
Definition
| b/c endothelial cells are able to re-synthesize COX-1, thus low level aspirin blocks pro-thrombotic TXA2 w/o blocking anti-thrombotic PGI2 |
|
|
Term
| why does a high anti-inflamm dose of aspirin offset the anti-platelet effect of inhibiting pro-thrombotic TXA2? |
|
Definition
| at high doses, PGI2 production is increasingly inhibited in endo cells |
|
|
Term
| what is the anti-platelet/anti-thrombotic dose of aspirin? |
|
Definition
|
|
Term
| what is the analgesic dose of aspirin? |
|
Definition
|
|
Term
| what is the anti-inflamm dose of aspirin? |
|
Definition
high: 4-6000mg/day
(at this dose, anti-thrombotic fcn is offset) |
|
|
Term
| more potent anti-inflamm agent than aspirin |
|
Definition
|
|
Term
| why doesn't Diflunisal have anti-pyretic (fever) effects? |
|
Definition
| poor CNS penetration (doesn't cross BBB) |
|
|
Term
| why are other salicylates (diflunisal, salsalate) preferable in patients with increased risk of GI complications or bleeding tendencies (hemophiliacs)? |
|
Definition
| they are non-acetylated and do NOT irreversibly inhibit COX-1 |
|
|
Term
| anti-inflamm Rx for pts with GI complications, bleeding tendencies |
|
Definition
| other salicylates (Diflunisal, Salsalate) |
|
|
Term
| do salicylates cross the BBB? |
|
Definition
yes, except for Diflunisal
therefore they have anti-pyretic effects |
|
|
Term
|
Definition
| converted to water soluble conj. in lover, rapidly cleared by kidney |
|
|
Term
| low dose aspirin pharmacokinetics |
|
Definition
elim w/ first order kinetics
serum t1/2 = 3.5hrs |
|
|
Term
| high/anti-inflamm. dose aspirin pharmocokinetics |
|
Definition
hepatic enzymes saturate: zero order kinetics
serum t1/2 = 15+hrs |
|
|
Term
low dose aspirin:
inc/dec uric acid secretion? |
|
Definition
dec
therefore increases uric acid conc in blood, which can lead to gout |
|
|
Term
high dose aspirin:
inc/dec uric acid secretion? |
|
Definition
|
|
Term
| why don't pts with gout use low doses aspirin? |
|
Definition
| decreases uric acid secretion, which leads to inc uric acid conc in blood, and therefore potential inc precip uric acid crystals |
|
|
Term
|
Definition
alkalinize urine
(increases rate of salicylate excretion) |
|
|
Term
| what are the most common adverse SE of all NSAIDs? |
|
Definition
GI
(>100,000 hospitalizations/yr) |
|
|
Term
|
Definition
| epigastric distress, nausea, vomiting, GI bleeding, gastric/duodenal ulcers |
|
|
Term
| causes of aspirin induced GI damage (2) |
|
Definition
1) direct damage to gastric epithelium by ion-trapping
2) inhibition of PGs (which are cytoprotective) |
|
|
Term
| how do you ameliorate GI SE of aspirin |
|
Definition
co-administration of:
1) Misprosotol (PGE analog)
2) proton pump blockers |
|
|
Term
| Misprostol use with aspirin |
|
Definition
| ameliorates GI SE of aspirin b/c it is PGE analog |
|
|
Term
|
Definition
| dec renal blood flow, inc Na & H2O retention, impaired renal fcn: HTN |
|
|
Term
|
Definition
| prolongs bleeding time (blocks TXA2 pro-thrombotic agent) |
|
|
Term
| contraindications aspirin |
|
Definition
| hemophiliacs, pts going in for surgery |
|
|
Term
| can aspirin cause respiratory depression? |
|
Definition
|
|
Term
| why do 15% patients taking aspirin have hypersensitivity rxns |
|
Definition
| inc production leukotrienes, due to AA build-up |
|
|
Term
| symptoms of hypersensitivity aspirin SE |
|
Definition
| ocular & nasal congestion, urticaria & skin rashes, angioneurotic edema, airway obstruction |
|
|
Term
| unique aspirin SE in children |
|
Definition
|
|
Term
|
Definition
| liver degenarative disease w/ assoc encephalitis; similar to fulminating hepatitis |
|
|
Term
| 2 reasons why aspirin is never given to children |
|
Definition
1) Reye's syndrome
2) very prone to salicylate intoxication |
|
|
Term
| high doses aspirin (50-110mg/day) may result in what toxicity? |
|
Definition
|
|
Term
| very high dose aspirin (>110mg.day) may result in what toxicity? |
|
Definition
|
|
Term
|
Definition
| vomiting, hypervent, headache, tinnitus, dec hearing, vertigo, confusion |
|
|
Term
| Sx salicylate intoxication |
|
Definition
| restlessness, delirium, hallucinations, convulsions, coma, renal failure, resp/metab acidosis, resp failure/death |
|
|
Term
| what dose can cause salicylate intox in children? |
|
Definition
|
|
Term
| effects of traditional NSAIDs |
|
Definition
anti-inflamm
anti-pyretic
analgesic |
|
|
Term
|
Definition
REVERSIBLY inhibit COX
prevent PG production |
|
|
Term
| Traditional NSAIDs: Proprionic Acid Derivatives |
|
Definition
KOIN
Ketoprofen, Oxaprozin, Ibuprofen, Naproxen |
|
|
Term
| advantage of Proprionic acid derivatives over aspirin |
|
Definition
|
|
Term
|
Definition
| analgesic for arthritis and dysmenorrhea |
|
|
Term
| advantage of Ibuprofen over aspirin |
|
Definition
less GI bleeding
OTC analgesia |
|
|
Term
|
Definition
analgesia
NO anti-inflamm effects |
|
|
Term
| advantages Naproxen over aspirin |
|
Definition
20x more potent
long serum t1/2 (14hrs0 |
|
|
Term
| disadvantage naproxen vs ibuprofen |
|
Definition
| 2x risk GI bleed at OTC doses |
|
|
Term
|
Definition
Oxaprozin
long t1/2 (50-60hrs) |
|
|
Term
|
Definition
| major adverse SE in GI and nervous system |
|
|
Term
| Traditional NSAIDs: acetic acid derivatives |
|
Definition
ST KID
Sulindac, Tolmetin, Ketorolac, Indomethacin, Diclofenac |
|
|
Term
| Advantages of Indomethacin (3) |
|
Definition
1) more potent anti-inflamm than aspirin
2) most effective NSAID fever reducer
3) promotes closure ductus arteriosus
4) delay labor (suppresses uterine contractions) |
|
|
Term
| Rx patent ductus arteriosus |
|
Definition
|
|
Term
| disadvantages - Indomethacin |
|
Definition
1) 50% users experience SE
2) toxicity limits use |
|
|
Term
|
Definition
1) CNS (dizziness, anxiety, confusion)
2) hematologic (thrombocytopenia, aplastic anemia) |
|
|
Term
|
Definition
|
|
Term
|
Definition
| liver damage more common than other NSAIDs |
|
|
Term
|
Definition
| more potent anti-inflamm than indomethacin & naproxen |
|
|
Term
|
Definition
|
|
Term
| IV analgesic for post-surgical pain |
|
Definition
|
|
Term
| NSAID that can be used as a replacement for opioids |
|
Definition
|
|
Term
|
Definition
| renal toxicity w/ chronic use |
|
|
Term
| why is Tolmetin seldom used? |
|
Definition
|
|
Term
| Tolmetin is ineffective in what condition? |
|
Definition
|
|
Term
|
Definition
| Piroxicam, Meloxicam, Fenamates, Ketones (Nabumetone) |
|
|
Term
| non-selective COX inhibitor w/ long t1/2 (57hrs) that modulates neutrophil fcn |
|
Definition
|
|
Term
|
Definition
| peptic ulcers and bleeding |
|
|
Term
| Meloxicam preferentially inhibits what AA enzyme? |
|
Definition
|
|
Term
|
Definition
| fewer GI SE and complications |
|
|
Term
|
Definition
|
|
Term
| disadvantages of Fenamates |
|
Definition
less anti-inflamm than aspirin
more toxic
little advantage to use |
|
|
Term
|
Definition
| analgesia in primary dysmenorrhea |
|
|
Term
| specific drug name of ketone NSAID oxicam? |
|
Definition
|
|
Term
| Nabumetone preferentially inhibits? |
|
Definition
|
|
Term
| pro-drug NSAID that is oxidized to active form |
|
Definition
|
|
Term
| 3 major adverse SE of NSAIDs |
|
Definition
1) GI problems (nausea, dyspepsia, ulcers, diarrhea)
2) Renal problems (dec renal blood flow, inc salt & fluid retention, HTN)
3) Allergic rxns (fever, rash, urticaria, angioedema, pulm infiltrate, asthma) |
|
|
Term
| cause of GI SE from NSAIDs |
|
Definition
1) inhibition COX-1
2) reduction PGs |
|
|
Term
| 2 NSAIDs w/ highest incidence GI SE |
|
Definition
|
|
Term
|
Definition
|
|
Term
| cause of Renal SE for NSAIDs |
|
Definition
|
|
Term
| where is COX-2 constitutively expressed? |
|
Definition
|
|
Term
| contraindication NSAIDs in regards to renal SE |
|
Definition
ACE inhibitors
diuretics
both inc risk of renal failure |
|
|
Term
|
Definition
1)CNS (headache, tinnitus, anxiety, drowsiness, confusion)
2)Photosensitivity
3)Liver (raised liver enzymes) |
|
|
Term
| 2 NSAIDs that raise liver enzymes |
|
Definition
|
|
Term
|
Definition
| heart failure, hyperkalemia, hemolytic anemia, aplastic anemia |
|
|
Term
| cause of non-selective NSAID adverse SE |
|
Definition
|
|
Term
| cause of therapeutic effects, non-selective NSAIDs |
|
Definition
|
|
Term
| 3 selective COX-2 inhibitors |
|
Definition
CRV
Celecoxib (Celebrex)
Rofecoxib (Vioxx)
Valdecoxib (Bextra) |
|
|
Term
why were COX-2 inhibitors withdrawn?
which 2 were withdrawn? |
|
Definition
increased incidence CV events (MI and stroke)
Rofecoxib, Valdecoxib |
|
|
Term
| why is Celecoxib still on market? |
|
Definition
less selective for COX-2 than R&V
benefits outweigh risks |
|
|
Term
| why are there fewer GI SE w/ COX-2 inhibitors? |
|
Definition
| they don't inhibit COX-1 in stomach |
|
|
Term
| why are there renal toxicities with COX-2 inhibitors? |
|
Definition
| constitutive COX-2 expression in kidney |
|
|
Term
| any effect on plt aggregation with COX-2 inhibitors? |
|
Definition
|
|
Term
|
Definition
rheumatoid arthritis
osteoarthritis
familial adenomatous polyposis (FAP) |
|
|
Term
| pt group indicated for Celecoxib use |
|
Definition
| pts w/ inc risk of GI complications |
|
|
Term
| evidence that Celecoxib more efficacious than traditional NSAIDs |
|
Definition
|
|
Term
| cause of inc CV risks with COX-2 inhibitors |
|
Definition
selective inhibitory effect on endothelial cells:
inhibition of PGI2 (prostacyclin)- which is normally pro-thrombotic |
|
|
Term
| FDA recommendations for Celecoxib |
|
Definition
|
|
Term
| FDA recommendations for strong warnings of CV and GI SE added to what drugs? |
|
Definition
| all prescription & OTC NSAIDs |
|
|
Term
| contraindications for NSAIDs |
|
Definition
1) Hx ulcers
2) bleeding disorders
3) anti-coagulant use
4) renal disorders
5) hypersensitivity to aspirin
6) pregnancy (delays onset labor, premature DA closure)
7) elderly |
|
|
Term
| how do all NSAIDs inhibit activity of COX enzymes? |
|
Definition
| prevent binding of AA substrate |
|
|
Term
3 exceptions to the rule:
"the choice of NSAIDs does not usually make a substantial difference in the clinical outcome |
|
Definition
1) Tolmetin ineffective for gout
2) aspirin less effective for ankylosing spondylitis
3) diflusinal has no anti-pyretic activity |
|
|
Term
|
Definition
| pts at highest risk of GI bleeds |
|
|
Term
|
Definition
oral anti-coagulants (except COX2 inh)
anti-HTN
diuretics (only salicylates)
uricostrics (only salicylates)
oral hypoglycemics
Li
Methotrexate
Aminoglycosides |
|
|
Term
| 3 drugs that have dec clearance and inc toxicity b/c of NSAIDs |
|
Definition
(LAM)
Li
Aminoglycosides (gentamycin)
Methotrexate |
|
|
