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57 Cards in this Set
- Front
- Back
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general properties of NSAIDs
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-anti-inflamm (PGs effect)
-anti-pyertic (IL1-->PGs-->fever) -analgesic (PGs lower pain threshold by increasing sensitivity of receptors to bradykinin and histamine) |
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how do NSAIDs work
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-inhibit cox so arach acid can't become PGs
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acetylsalicylic acid mech
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-irreversible inhibitor of cox
-acetylates serine group on cox |
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therapeutic implications of irreversible inhibition of cox (seen only with aspirin)
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-platelets have no nucleus and no protein synthesis --> can't regenerate cox, have to wait for platelet turnover
-endothelial cells-- have nuclei and can do protein synthesis --> can regenerate cox |
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absorption of aspirin
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-limited by dissolution rate (chewing helps)
-buffered covering neutralizes acid -enteric-coated means it isn't absorbed til intestines |
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distribution of aspirin
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-plasma protein binding
-crosses BBB -crosses placenta |
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metabolism of aspirin
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-acetylsalicylic acid hydrolyzed to salicylic acid --> a number of less polar metabolites
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uric acid excretion and aspirin
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-low doses: competes for organic acid transport into renal tubules --> causes an inc in serum uric acid
-high doses: competes for both absorption and secretion --> dec serum uric acid (uricosuic agent) (not related to inhib cox) |
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CNS and aspirin (esp with high doses)
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-crosses BBB
-delirium and psychoses -nausea and vomiting -characteristics of aspirin toxicity (not related to inhib cox) |
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respiration and aspirin
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-direct stim of resp centers to inc resp rate --> resp alkalosis --> renal compensation via bicarb excretion
-indirect effects by inc oxygen consumption and CO production in skel m -->compensation results in stim of respiration (not related to inhibition of cox) |
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NSAID GI effects
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-gastric irritation --> ulcers and bleeding
-inhibition of cox1 prevents production of cytoprotective PGs |
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NSAID blood effects
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-increased bleeding time
-inhib of cox1 in platelets blocks TXA2 production and decreases platelet aggregation (dec PGI2 production in endothelial cells) -1 dose causes 7-10 days of inc bleeding time as platelets regen |
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NSAIDs and hypersensitvity effects
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-bronchoconstriction, edema
-may be dt action of LTs because of shunting of arach acid pathway from COX to lipoxygenase -more common in pts with asthma and nasal polyps -NOT igE mediated |
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NSAID renal effects
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-dec renal blood flow and GFR
-salt and water retention -inhibit cox 1 (and 2?)--> dec vasodilatory PGs -more important of an effect in pts with CHF, chronic renal failure, elderly, liver disease (renal perfusion is more dep on vasodilatory PGs) |
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NSAID use in pregnancy
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-decreases uterine contractions, may prolong labor
-normally, PGF2a and PGE2 cause contraction and PGI2 causes dilation in early pregnancy |
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salicylism
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-aspirin overdose
-initial: slight resp stim, nausea, vomiting, tinnitus, deafness -confusion with inc doses, fever, dehydration, electrolyte imbalance, metabolic acidosis -bc of saturation of enzymes that convert salicylic acid to inactive metabolites (build up of salicylic acid) |
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treatment of salicylism
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-gastric lavage
-activated charcoal to prevent absorption -replacement fluid and electrolytes -alkalization of urine via IV bicarb (ionizing increases excretion) |
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Reye's syndrome
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-following viral epidemics
-can result in liver failure and death -possibly dt mitchochondrial damage |
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drug interactions with aspirin/NSAIDs
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-alcohol (inc GI bleeding)
-antacids (dec absorption) -prednisone (GI toxicity) -methotrexate (impair renal fx) |
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therapeutic uses of aspirin
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-fever (325 mg/day)
-low intensity pain (325 mg) -inflamm disorders (5-8g/day) -cancer -CV prevention (80mg/day) |
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ibuprofen/naproxen mech of action
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-reversible inhibitors of cox1 and 2
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ibuprofen/naproxen pharmokinetics
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-ibu t1/2: 2 hrs
-naprox t1/2: 14 hours -both highly bound to plasma proteins |
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therapeutic applications of ibuprofen
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-inflamm disease like juvenile rheumatoid arthritis, mild-mod pain, fever, dysmenorrhea, osteoarthritis
-with lysine injection --> close PDAs in premies |
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therapeutic applications of naproxen
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-ankylosing spondylitis, osteoarthritis, rheumatoid disorders
-acute gout -mild-mod pain, tendonitis, bursitis, dysmenorrhea, fever |
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indomethacin applications
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-not routinely used for fever/pain
-acute gouty arthritis, rheumatoid -close PDAs freq adverse rxns including CNS effects: severe frontal headache |
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what is a drug that is used as an alternative to opioids post-op?
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ketorolac
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what NSAIDs are acetic acid derivatives
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indomethacin
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what NSAIDs are oxicam derivatives
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piroxicam
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what drug may offer an advantage in treating osteoarthritis because of its long t1/2?
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-prioxicam
-t1/2=50 hours (99% bound to plasma protein) |
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what is the proposed mech for sulfasalazine
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-NOT cox inhibitor
-inhibits production of IL1 and TNFa, inhibits lox pathway, scavenges free radicals and oxidants, inhibits NFkB |
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what are the main uses of sulfasalazine
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-mile or moderately active ulcerative colitis (not active til colonic bacteria cleave the azo linkage)
-rheumatoid arthritis and ankylosing spondylitis |
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celecoxib mech and metabolism
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-inhibits cox2 by binding tightly to a distinctive hydrophilic side pocket region (not present in cox1)
-metabolized cia CYP2C9 to inactive metabolites |
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contraindications of celecoxib use
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-pts with sulfonamide toxicity
-prior NSAID hypersensitivity -pre-existing CV risk -hx of GI disease -coronary artery bypass graft (more prone to clots) -deficiency of CYP2C9 |
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mech of acetaminophen
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-not understood
-no affinity for cox1/2 -inhibits reduction of cox to its peroxide form (prevents PG formation) -not anti-inflamm |
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excessive use of acetaminophen
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-usually 95% metab via glucuronidation/sulfation to nontoxic metabolits; 5% CYP to toxic metabolites then glutathione conjug to nontoxic
-accum NAPQI with xs use -hepatic toxicity -nausea, vomiting, abdominal pain |
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treatment of acetaminophen poisoning
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-n-acetylcysteine
-works as a glutathione substitute to allow NAPQI to be conjugated into a nontoxic metabolite |
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gout
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-inflamm rxn to sodium urate crystals that are deposited in joint
-assoc with hyperuricemia (not the sole determinant) |
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therapeutic goals of treating gout
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-inc uric acid excretion
-inhibit inflamm cells -inhibit uric acid biosynthesis -provide symptomatic relief |
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NSAID use with gout
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-provide symptomatic relief
-indomethacin often -aspirin is NOT used becuase it inhibits urate excretion at low doses and inc risk of renal calculi at higher doses |
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contraindications to NSAID use for gout
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-active peptic ulcer disease
-impaired kidney fx -hx of allergic (hypersensitivity) to NSAIDs |
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why is aspirin not used for treating gout?
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-at low doses it inhibits urate excretion by competing for transporters
-at high doses, acts as a uricosuric agent, but increases risk of renal calculi -can also inhibit other uricosuric agents |
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corticosteroids in treating gout
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-dramatic symptomatic releif in acute episodes
-most useful in pts with contraindications to NSAID use |
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colchicine use in gout
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-prevent and treat acute flares
-treats IF given within first few hours -antimitotic effects: interferes with microtubule/spindle formation -decreases the crystal-induced secretion of chemotactic factors and superoxide anions by activated neutrophils |
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what drug sees a latent period before onset of toxic symptoms
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colchicine
(GI effects, diarrhea-- severe) |
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allopurinol use in gout
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-lowers uric acid concentration below its solubility
-prevents attacks of gouty arthritis |
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allopurinol mechanism
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-competitive inhib of xanthine oxidase (blocks hypoxanthine-->xanthine and xanthine-->uric acid)
-converted by xanthine oxidase to oxypurinol --> even better inhibitor -increases conc of hypoxanthine and xanthine (higher solubilities, dont crystallize) -conc of uric acid in plasma dec and excretion inc |
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what are the main adverse effects of allopurinol
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-may cause acute gouty attacks by causing a mobilization of tissue stores of uric acid (give with colchicine or NSAIDs to prevent this)
-hypersensitivity (even after months/years) |
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what else is allopurinol used for?
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-tx of secondary hyperuricemia (during tumor/leukemia treatment)
-prevention of recurrent calcium oxalate calculi |
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drug interactions of allopurinol
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-increases t1/2 or probenecid
-dec metab of mercaptopurine and azathioprine -inc risk of hypersensitivity if taken with ACE inhibitors, amoxicillin, thiazide diuretics -interfere with hepatic inactiv of warfarin |
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what gout drug inhibits organic acid transport in renal tubule?
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-probenecid (dec reabsoprtion of uric acid)
-for chronic gout -NOT for pts with nephrolithiasis (kidney stones) |
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rheumatoid arthritis
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-unknown mech
-autoimmune -activated Tcells--> IL1 and TNFa -primary target: synovium |
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therapeutic goals of treating rheumatoid arthritis
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-relieve pain
-reduce inflamm -slow or stop joint damage |
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NSAID use with RA
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-produce anti-inflamm changes if given in large doses for long periods of time
-no evidence they have any effect on progression of disease --> mostly symptomatic relief |
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what drug is used for RA by binding soluble and membrane-bound TNF to inhibit it?
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-etanercept
-IV or SC administration -must monitor closely for infection |
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what RA drug is an IgG monoclonal antibody that binds to TNFa and inhibits its binding to its receptor
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-infliximab
-IV -also used for Crohn's and ulcerative colitis -monitor closely for infection |
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what RA drug is an antagonist of IL1
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-anakinra
-subcutaneous daily injection -should not be used with TNF antags, but can be used with DMARDs |
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disease-modifying anti-rheumatic drugs (DMARDs)
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-immunosuppressive agents
-glucocorticoids -methotrexate -cyclosporine -azathiopurine -penicillamine -hydroxychloroquine -leflunomide |
