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47 Cards in this Set

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