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76 Cards in this Set

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In in vitro measurements of NSAIDS, what inhibition is measured?
inhibition of prostaglandins, (except for sunindac, which is a prodrug and will not be activated in vitro)
What is the site of action of NSAIDS?
inhibition of prostaglandins: where the primary site of action is the cyclooxygenase enzyme, which catalyzes the conversion of arachidonic acid to the PGG2.
What do PGE and PGF produce?
cardinal signs of inflammation, including vasodilation and hyperemia, swelling and pain, and increased leukocyte migration
Do COX inhibitors effect the production of leukotrienes?
Do COX inhibitors effect prostacyclins and TXA2?
what liberates arachidonic acid from cell membrane during pain and fever?
Phospholipase A
Where is the site of action for corticosteroids in PG synthesis?
liberation of arachidonic acid from the cell membrane
would corticosteroids inhibit leukotrienes?
Where is aspirin-like NSAIDS site of action?
at the cyclooxygenase
Between COX1 and COX2, which is constituitively produced?
What causes the production of COX2 ?
What do COXIBs inhibit?
What are the 5 toxic side effects of NSAIDS?
GI (extensive), Renal (papillary necrosis), fetal (cardio & increased gestation), increase bleed time, displace other drugs from plasma proteins.
How are salicylates absorbed?
upper small intestine via passive diffusion of undissociated molecule >> stomach
What is the optimum pH range for salicylates in the stomach?
pH 2.5 to 4
What is aspirin metabolized by and what is the metabolite? What is the half life of aspirin?
aspirin --esterases --> salicylic acid… t1/2=15 min
At what point are (time) the peak concentration of salicylates found ?
2 hrs
Given the two fates of aspirin, what causes the short term effects and what causes the long term effects?
Short term = aspirin… long term = liberated salicylates
which of the following amino acids metabolizes slicylates? tyrosine, leucine, methionine, glycine, proline
which of the following amino acids metabolizes slicylates? GLYCINE
In terms of serum concentration, what happens once the glycine pathway for salicylates is saturated? What happens to the half life of salicylate when it is saturated?
small increments of the drug cause large increases in serum concentration… thus the half-life of salicylates becomes longer with increased dosage and serum concentration becomes disproportionally larger as drug dose is increased
Are plasma protein bound salicylates pharmacologically active?
How are salicylate excreted?
mainly via the kidney
What pH increases excretion of salicylates and its metabolites?
increase of pH from 5 --> 8 increases salicylate excretion from a few percent to 80% at pH 8
What are the toxicities of aspirin?
GI, platelet aggregation, tinitis, hepatotoxicity, hypersensitivity (uticaria, asthma, rhinitis)
Which affect platelet aggregation reversibly, aspirin or non acetylated salicylates?
non acetylated salicylate… aspirin affects platelet aggregation for up to 72 hours
which has fewer GI problems, acetysalicate (asprin) or Na-salicylate?
Name the 3 carbo- and heterocyclic acetic acids
indomethacin, tolmetin, and sulindac
Besides inhibiting PPG biosynthesis, what 2 things does indomethacin do?
it inhibits motility of polymorphonuclear leukocytes and uncouples oxidative phosphorylation in hepatic mitochondria
Is indomethacin an effect NSAID?
it's the most effective NSAID
T/F indomethacin has few GI side effects, it's absorbed poorly, and excreted as active unconjugated metabolites.
False, false, false
What effect does indomethacin on have on the CNS.
major: headaches, depersonalization, depression and lightheadedness
What is indomethacin used for?
gout, ankylosing spondylitis, tendonitis, bursitis, and rheumatoid arthritis... can close a patent ductus arteriosis
Does Tolmetin have CNS side effects?
no… not like indomethacin
What is the pharmacokinetics of sulindac?
it's a prodrug, which has no anti inflammatory effects until it's absorbed and metabolized to its sulfide form
T/F sulindac must be administer often.
false, it has a half-life of 16 hours (once or twice a day, an improvement over aspirin).
Name the two propionic acids and what are they approved for?
ibuprofen and naproxen… over the counter analgesic, antipyretic
How is ibuprofen different from aspirin?
dosing is 4 times daily, and it's very well tolerated
What are the SE of ibuprofen?
epigasatric discomfort, nausea, indigestion and blurred vision
What is advantage of naproxen over aspirin?
half-life of 14 hours requires 2xdaily admin, virtually from SE
name the two oxicams (benzothiazines), what is their main benefit?
sudoxicam and piroxicam… superior antiinflammatory properties to date
What is the half-life of piroxicam?
about 48 hrs
What has piroxicam been effective in treating?
rheumatoid arthritis
Why were the oxicams pulled from clinical trials?
liver toxicity
why have COXIBs been pulled from the market?
increase in the incidence of serious thromboembolic adverse events… it has since been returned with a warning of risk of CV disease and GI bleed
What are the 3 reasons that valdecoxib was pulled from the market?
1. Long term CV and short term adverse events after CV artery bypass surgery trial… 2. Serious and potential life threatening skin rxns… 3. Failure to show an advantage over other NSAIDs.
What are the therapeutic effects of acetaminophen?
analgesic/antipyretic… NOOOO anti-inflammatory
What is the major metabolite of acetaminophen?
When is the maximal level of acetaminophen achieved? What is its half-life?
peak = 30-60 min… half-life = 1-3 hours
Which metabolite of acetaminophen causes liver damage?
N-acetylimidoquinone, which is deactivated by glutathione
What are the major non toxic metabolites of acetaminophen?
glucuronide (60%) and sulfate (35%)
At low dose (2 g/day) what is the major action of aspirin?
analgesic (antiinflammatory at high doses… generally toxic at high doses)
T/F: COXIBs inhibit TXA2
false… they do not inhibit platelet aggregation
What is the mechanism by which COX inhibitors cause GI side effects? (5 things)
PGs turn off cytoprotection: 1. Stimulation of Glycoprotein (mucin) secretion… 2. Stimulation of HCO3… 3. Stimulation of phospholipid secretion… 4. Enhancement of mucosal blood flow and oxygen delivery to cells via local vasodilation…. 5. Enhanced epithelial cell proliferation
What is warfarin's action
what are the 8 renal toxicities of NSAIDs?
Afferent arteriole constriction --> decreased GFR… 2. Sodium retention… 3. Increased ADH action, hypnatremia… 4. Hyperkalemia… 5. Acute interstitial nephritis… 6. Minimal change GN… 7. Papilary necrosis… 8. Analgesic nephrophathy… 9 transitional cell carcinoma
When is COX2 naturally expressed?
Volume depletion --> in response to reduced GFR --> JG apparatus releases COX --> afferent arteriole dilation
With respecdt to COX2 expression, what are the events that occurs during [low salt] interpreted by the JG macula densa?
low salt delivery to JG macula densa --> induction of COX2 --> release of PG1/PG2 at afferent arterioles --> afferent arteriole dilation--> increase in GFR
With respect to hepatotoxicity, when should NSAIDs be stopped? (3 reasons)
1. when aminotransferases reach 3x the upper limits of normal… 2. Fall in serum albumin… 3. Increased prothrombin time… (note: liver failure is rare)
T/F aspirin and its metabolites are irreversible inhibitors of COX1 and COX2?
False, only aspirin (acetyl-salicylic acid) is irreversible… salicylates are reversible inhibitors
What causes the anagesic effects of aspirin?
inhibition of COX3 in the CNS
T/F aspirin can cause an acid base disturbance?
What has aspirin been use for?
low to moderate pain, osteoarthritis, Rx of rheumatoid arthritis
What is the duration of the analgesic and antiinflammatory effects of naproxen?
analgesic t1/2= 7h… antiinflammatory = 12 h
in normal renal function, what is the t1/2?
12-17 hrs
What is naproxen used for?
gout, migraine, osteoarthritis, pain, acute tendonitis, bursitis, rheumatoid arthritis --> improved Rx of these complaints by indomethacin
What can be used to close the ductus arteriosis in neonates?
Indomethacin, by blocking PGE
What is the main advantage of COXIBs?
no GI problems
COX2 --> PGE2 has what effect?
mediates pain and inflammation
What is the effect of COX2 expressed in gastric ulcers?
it promotes gastric ulcers…
what are the 4 beneficial effects of COX-2?
cause pain/inflammation, GI ulcer healing, renal health, vascular health
What effect do COX2 --> prostacyclins have on blood vessels?
dilation and decreased
What can be given with non-selective NSAIDs to decrease the risk of a gastric ulcer?
proton-pump inhibitor
if patient requires low dose aspirin, what can be given to decrease the risk of a gastric ulcer?
a) naproxen + proton-pump inhibitor… b) if no inflammation ==> acetaminophen
what is acetaminophen's mechanism of action?
inhibition of COX-3 (found in CNS), with weak inhibition of COX1&2
What are the toxicities of acetaminophen?
hepatic necrosis, renal tubular necrosis, methemoglobinemia, hemolytic anemia
how do you treat toxically high levels of acetaminohen (w/alcohol) to avoid hepatic necrosis?
acetylcysteine, which increases glutathione stores