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47 Cards in this Set
- Front
- Back
What are the 4 main classes of eicosanoids?
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1) prostaglandins, 2) thromboxanes, 3) prostacyclins, & 4) leukotrienes
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What two eicosanoids are biosynthesized from PGH2?
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Thromboxanes & Prostacyclin
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Eicosanoid structure
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derived from w-3 or w-6 C20 unsaturated fatty acids
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Eicosanoid properties
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found in every component of the body; involved in all signs of inflammation, redness, swelling, pain and heat
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Prostaglandin structure
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15-alpha -OH and a trans double bond at C13; naturally occurring 20C cyclopentano-fatty acid derivatives
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Thromboxanes
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facilitate platelet aggregation and are vasoconstrictors
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Prostacyclin
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primarily prevents platelet aggregation and is a vasodilator
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Leukotrienes
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biosynthesized from arachidonic acid by lipoxygenase and are involved in inflammation and asthma
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cyclooxygenase reaction
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arachidonic acid to PGG2
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Arachidonic acid
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a w-6 C20 unsaturated fatty acid
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NSAIDs mechanism of action
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inhibit PG (prostaglandin) biosynthesis at the cyclooxygenase step
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Aspirin properties (3)
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antipyretic, analgesic, and anti-inflammatory properties
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By what mechanism does aspirin modify COX?
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Covalently- the only NSAID that does this
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Does aspirin modify or inhibit COX1?
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inhibit (irreversibly)
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Does aspirin modify or inhibit COX2?
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modify
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Does aspirin irreversibly or reversibly inhibit COX1?
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irreversibly
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Is aspirin more potent at COX1 or COX2?
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COX1
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What two things is aspirin synthesized from?
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1) salicylic acid & 2) acetic anhydride
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Side effects of aspirin?
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GI effects (bleeding and ulceration) - related to COX1 inhibition
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Where is the -OH in salicylic acid derivatives?
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In the ortho position. NOT meta or para because that would abolish its activity.
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SAR of salicylic acid derivatives (3)
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1) conversion of carboxylate group to amide maintains analgesic activity but NOT anti-inflammatory action, 2) removing -OH or placing in meta or para position abolishes activity, & 3) substitution of aromatic rings at the 5 position enhances anti-inflammatory activity
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What is the major metabolite of salicylic acid?
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Salicyluric acid (75%)
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What is salicyluric acid composed of?
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salicylic acid and glycine (via amide bond)
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What are the arylalkanoic acids?
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nonselective COX inhibitors that mimic arachidonic acid
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Similarities between arylalkanoic acids and arachidonic acid? (5)
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1) acidic group mimics the -CO2H. any other acid group sub decreases activity, 2) the acidic group is located 1 C away from a flat ring (mimics the 5- and 8- double bonds), 3) the second lipophilic group mimics the 11- double bond and enhance the activity, 4) the 5 position of the indole ring are substituted in most cases, & 5) the presence of an indole nitrogen is NOT essential for activity
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Is the N in the indole ring of indomethacin necessary for activity?
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NO
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What class of drug is indomethacin?
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arylalkanoic acid
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Is indomethacin more or less potent (analgesic or antipyretic) than aspirin?
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MORE
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What is the main structural features of the aryl- or heteroarylpropionic acids?
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an aromatic ring, 1 carbon, a methyl and a carboxylic acid of that 1 carbon.
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How to enhance the activity and reduce side effects of the aryl- and heteroarylpropionic acids?
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Add an alpha methyl group on the alkanoic acid portion
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What class does ibuprofen belong to?
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arylpropionic acid
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Which form of ibuprofen is active?
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S(+) isomer but the the R(-) enantiomer was inverted to the S(+) in vivo
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Is ibuprofen more or less potent than aspirin?
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MORE
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Is ibuprofen more or less potent than indomethacin?
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LESS
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Are the metabolites of ibuprofen active or inactive?
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INACTIVE
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Which COX form has a larger binding pocket?
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COX-2
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Which COX contains Ile?
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COX-1
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Which COX is specific to inflamed tissue?
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COX-2
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Which COX is associated with less gastric irritation?
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COX-2
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Which COX contains Val?
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COX-2
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Is acetaminophen anti-inflammatory?
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NOPE. but it can treat inflammatory "pain"
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What is acetaminophen a metabolite of?
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acetanilide and phenacetin (also antipyretic analgesics)
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What side effect are the COX-2 selective inhibitors associated with?
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Cardiovascular problems (Vioxx)
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How is the reactive metabolite of acetaminophen normally detoxified?
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Hepatic glutathione (GSH)
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What are the two hepatotoxic metabolites of acetaminophen?
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N-hydroxyamideand N-acetylimidoquinone
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What happens in an APAP OD or with alcohol?
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the glutathione stores are depleted the quinone reacts with -SH groups on cysteine on hepatic proteins
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What AA reacts with the quinone in APAP OD or with alcohol?
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Cys in hepatic proteins
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