Term
(T/F) Eicosanoids are fatty acid metabolites |
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Definition
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|
Term
What are they derived from? |
|
Definition
Eicosaenoic acid precursors |
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|
Term
What does eicosa mean, related to the structure of the precursors? |
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Definition
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|
Term
What does enoic mean, related to the structure of the precursors? |
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Definition
It contains double bonds (4 double bonds) |
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Term
What is the most important eicosanoid precursor in humans? |
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Definition
Arachidonic Acid (AA, 5,8,11,14-eicosatetraenoic acid) |
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Term
What discovery, related to eicosanoids, was made in 1930? |
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Definition
That semen can contract smooth muscle - prostaglandin discovery |
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Term
What discovery, related to eicosanoids, was made in the 1960s? |
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Definition
That PG activity is due to several compounds |
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Term
What discovery, related to eicosanoids, was made in the 1970s? |
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Definition
The discovery of other AA metabolites (thromboxane, hydroperoxyeicosatetrenoic acids [HPETEs] and hydroxyeicosatetraenoic acids [HETEs]) |
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Term
What discovery, related to eicosanoids, was made in 1978? |
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Definition
That slow acting substance of anaphylaxis (SRS-A) contains leukotrienes |
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Term
What are these leukotrienes conjugated from? |
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Definition
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Term
Describe the process of AA release and metabolism |
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Definition
1. AA exists in an esterified state in membrane phospholipids 2. Phospholipase A2 liberizes the AA from the membrane, in response to a variety of stimuli 3. Undergoes metabolism by two main pathways |
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Term
(T/F) AA normally exists as free, and is present at high levels |
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Definition
False, almost all of it is esterified in lipid bilayers |
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Term
What are the two main enzymes, responsible for each pathway |
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Definition
1. Lipooxygenases (LOX) 2. Cyclooxygenases (COX) |
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Term
Which pathway gives rise to all the prostanoids? |
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Definition
The cyclooxygenase pathway |
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Term
What is the rate limiting step in AA release and metabolism? |
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Definition
Liberization of esterified AA from lipid bilayer by phospholipase AA |
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Term
List/describe the steps to the COX pathway |
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Definition
1. Free AA is acted on by COX enzymes, converting a hydroperoxol to a hydroxyl - PGG2 creation 2. Peroxidases remove a single oxgen from the hydroxyl intermediate - PGH2 creation 3. PGH2 is subject to various metabolic pathways to create various prostaglandins |
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Term
What are the 5 products of the cyclooxygenase pathway |
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Definition
1. Thromboxane (TXA2) 2. PGE2 3. PGFalpha 4. PGD2 5. Prostacyclin (PGI2) |
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Term
What is the intermediate created during the conversion of PGH2 into PGFalpha? |
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Definition
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Term
What is the enzyme responsible for converting PGH2 into TXA2? |
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Definition
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Term
What is the enzyme responsible for converting PGH2 into PGI2 (prostacyclin)? |
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Definition
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Term
List/describe the steps to the LOX pathway |
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Definition
1. AA is converted to 5(s)-HPETE by 5-lox 2. 5(s)-HPETE is converted to LTA4 (an epoxide) by 5-LOX 3. LTA4 undergoes further reactions to create products |
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Term
(T/F) No products of the LOX pathway are derived straight from AA |
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Definition
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Term
What is derived directly from AA? |
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Definition
1. 11, 12 - EET 2. 20 - HETE |
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Term
What are the two final products of the LOX pathway, and their intermediates |
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Definition
1. LTB4 2. LTE3 (via LTC4 and LTD4) |
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Term
What is the enzyme responsible for LTB4 creation? |
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Definition
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Term
What is the function of this enzyme? |
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Definition
To hydrolize the epoxide on LTA4 |
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Term
What is the enzyme responsible for LTC4 creation? |
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Definition
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Term
What is the role of A-glutathione S-transferase? |
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Definition
Conjugates with LTC4 synthase to complete conversion of LTC4 |
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Term
What is responsible for cleaving LTC4 into LTD4, and what does it do? |
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Definition
Gamma-GT and gamma-GL' cleaves Glu from the Cys-Glu-Gly peptide |
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Term
What is the enzyme responsible for conversion of LTD4 to LTE4, and how does it accomplish this conversion? |
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Definition
Dipeptidase; removes GLY from Cys-Gly |
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Term
What is the naming convention associated with the LOX pathway? |
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Definition
Leukotrienes are named based on which carbon is oxidated |
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|
Term
What is the function of FLAP? |
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Definition
It is the 5-LOX activating protein |
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|
Term
What is the difference between LTC4 and LTB4? (2_ |
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Definition
1. LTB4 is the CIS version, LTC4 is the trans version 2. LTC4 (and subsequent derivations)are associated with Cys - Glu -Gly chain |
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Term
(T/F) Naturally occuring PG's are slowly degraded |
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Definition
False, they are metabolized regularily |
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Term
What acts as a protective "filter" during PG metabolism, and describe an example |
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Definition
Pulmonary circulation - PGE2 is 95% metabolized in 1 pass through the lung |
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|
Term
What us the purpose of this "filter"? |
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Definition
Keeps effects of PGs localized |
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|
Term
(T/F) Most PGs have a half life of under a minute |
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Definition
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|
Term
(T/F) Most PG metabolites have a half life of over an hour |
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Definition
False, most have a half life of under 8 minutes |
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|
Term
What are the 3 enzymes responsible for PG metabolism? |
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Definition
1. PG 15-dehydroxy dehydrogenase (PGDH) 2. Cytrochrome P450 3. Delta13 reductase |
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|
Term
Describe this metabolic pathway |
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Definition
1. Biologically active PG's are converted to an inactive metabolite by PGDH via carbonyl formation 2. Inactive metabolite is converted to majory urinary metabolite |
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|
Term
What 3 things convert the inactive metabolite to the urinary metabolite? |
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Definition
1. Delta13 reductase 2. Omega (or omega-1) oxidation 3. Beta oxidation |
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|
Term
Which enzyme is responsible for omega oxidation? |
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Definition
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|
Term
(T/F) There is only a single cell surface receptor for eicosanoids |
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Definition
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|
Term
What is the one thing that all eicosanoids are associated with? |
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Definition
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Term
What two things can an eicosanoid receptor be associated with? |
|
Definition
1. Adenyl cyclase 2. Phospholipase C (PIP2 pathway) |
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Term
(T/F) Eicosanoids always signal stimulatory responses |
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Definition
False, sometimes the signal is stimualtory, and sometimes it is inhibitory |
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Term
Name 8 different physiological/pathological processes eicosanoids are involved in |
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Definition
1. Plately aggregation 2. Reproductive physiology 3. Veterinary medicine 4. Afferent nerves/pain 5. Vascular smooth muscle 6. Pulmonary smooth muscle 7. Gastric/Intestinal secretions 8. Inflammatory responses |
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Term
Describe the pathway for platelet aggrgation |
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Definition
1. Stimulus for aggregation 2. Endoperoxide and TXA2 release 3. Platelet aggregation |
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Term
What is the role and the source of PGI2 (prostacylin) in this pathway? |
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Definition
Prevents platelet aggregation; produced by blood vessel walls |
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Term
What does this mean, regarding platelet aggregation? |
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Definition
PGI2 and TXA2 have opposing effects on the formation of hemostatic plugs and thrombi |
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|
Term
Describe the relationship between PG levels and infertility |
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Definition
Some cases of male infertility have been associated with low PG levels in semen |
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|
Term
(T/F) The role of PG in infertility has been confirmed, and is the main target for infertility treatment |
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Definition
False, it is not known whether the trend is causatory or simply coincidence |
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Term
What happens to the levels of eicosanoids in the body during labour? |
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Definition
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Term
What is the role of PGE2 and PGF2alpha with pregnancy? |
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Definition
They contract the uterus throughout pregnancy |
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Term
What 3 things do cyclooxygenase inhibitors do, regarding pregnancy? |
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Definition
1. Increase gestation 2. Prolong labour 3. Interrupt premature labour |
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|
Term
(T/F) There are toxic effects on the fetus when using COX inhibitors during pregnancy |
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Definition
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Term
What 3 ways is PGE2/PGF2alpha administered, and which is the preferred method? |
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Definition
1. IV 2. IM (intramusculat) 3. Intravaginal - preferred |
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|
Term
Why are intravaginal injections preferred? |
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Definition
Because the effects of the PG's will be localized |
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|
Term
What is the purpose of injecting these PG inhibitors? |
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Definition
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|
Term
(T/F) These PGs are effective as post-implantaiton contraceptives |
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Definition
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Term
Why are they inneffective? |
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Definition
High doses of PGE2/PGF2alpha are required, and this brings many undesired side effects |
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Term
How are PGs involved with pain, and what is the result? |
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Definition
PGs sensitize afferent nerve endings' PG release during inflammation "amplifies" pain |
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|
Term
Which PG is the main PG involved in this? |
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Definition
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Term
What is used to alleviate the pain, and how does it work? |
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Definition
Aspirin; inhibits COX, therefore decreased PG creation and reduced pain |
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|
Term
Which two PGs are potent vasodilators? |
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Definition
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|
Term
(T/F) They can be used to treat peripheral vascular disease |
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Definition
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Term
Why is this treatment effective? |
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Definition
Infusion of PGE1/PGI2 causes vasodilation of peripheral vasculature, increasing perfusion to the areas affected |
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Term
What is the role of PGE2 and PGI2 in the development of fetal vasculature? |
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Definition
Presence of PGE2/PGI2 prevent closing of the ductus arteriousus |
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Term
What is the function of indomethacin, and how does it help treat patency of the ductus arteriosus? |
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Definition
It is a COX inhibitor - prevents PG production, allowing closure of the ductus arteriosus |
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|
Term
What two vessels does the ductus arteriosus connect? |
|
Definition
Pulmonary artery and aorta |
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|
Term
Which eicosanoids act as bronchodilators? |
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Definition
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|
Term
Which eicosanoids act as bronchoconstrictors? |
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Definition
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Term
Which response dominates in bronchoconstriction, the response to leukotrienes or prostanoids? |
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Definition
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Term
(T/F) Leukotrienes causes acute bronchoconstriction |
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Definition
False, it causes prolonged bronchoconstriction |
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|
Term
How are PGs used in veterinary medicinem relating to pregnancy? |
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Definition
PGF2alpha causes regression of the corpus luteum (luteolytic effect) |
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Term
What is seen in cattle a few days after treatment? |
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Definition
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|
Term
What is the purpose of PGs for veterinary applications? |
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Definition
Control of the estrous cycle: - Allows control of when calves are born - Mitigates insemination |
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|
Term
(T/F) These effects are also seen on PG treatment with humans during pregnancy |
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Definition
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|
Term
|
Definition
An artificial PGF2alpha analog |
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|
Term
What is the role of PGEs and PGI2, regarding GI secretions? |
|
Definition
Inhibits gastric acid secretions |
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|
Term
What is seen, as a result of this? (3) |
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Definition
1. Decreased volume 2. Decreased acidity 3. Decreased pepsin content |
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|
Term
(T/F) Orally ingested PGs have anti-ulcer activity |
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Definition
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|
Term
(T/F) Misoprostol is a PGF2alpha analog |
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Definition
False, it is a PGE analog |
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|
Term
(T/F) Misoprostol is often used to mimic PGE actions |
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Definition
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|
Term
What is the downside to treatment with misoprostol? |
|
Definition
1. Multiple, repeated doses needed daily 2. Induces diarrhea |
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|
Term
(T/F) Inflammatory responses are associated with the release of eicosanoids |
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Definition
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|
Term
What is seen during inflamm responses? |
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Definition
1. Leaking of plasma into interstitial space 2. Migration of leukocytes to site of inflamm 3. Hyperalgesia (increased sensitivity to pain) |
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|
Term
What is the role of LTB4 in inflammation? |
|
Definition
Is the chemotactic factor for polymorphonuclear leukocytes (ie neutrophils and eosinophils) |
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|
Term
What role does PGE2/PGI2 play in inflammation? |
|
Definition
Increases local blood flow, therefore increased edema is seen |
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|
Term
Name the 5 potential mechanisms of drug interaction with eicosanoids |
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Definition
1. Stimulation of biosynthesis 2. Inhibition of biosynthesis 3. Direct stimulation of receptors 4. Blockade or receptors 5. Inhibition of degredation |
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|
Term
What is the rate limiting step of eicosanoid production, and what is the effect of stimulating phospholipase? |
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Definition
Release of AA by phospholipase; stimulation increases eicosanoid formation |
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|
Term
What is the problem with stimulation of phospholipase? |
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Definition
The stimulation is non-specific, and thus many different eicosanoids are formed |
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|
Term
|
Definition
- Undesired effects - Formed eicosanoids can oppose the effects of each other |
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|
Term
Name the 3 substances involved in the inhibition of eicosanoid biosynthesis |
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Definition
1. Glucocorticoids 2. Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) 3. Lipoxygenase inhibitors |
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|
Term
How do glucocorticoids inhibit eicosanoid biosynthesis? |
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Definition
They stimulate the synthesis of lipocortin, which inhibits phospholipases |
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|
Term
What is the result of this? |
|
Definition
- Decreased AA release - Decreased eicosanoids |
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|
Term
What is the effect of decreased eicosanoids? |
|
Definition
- Decreased chemotaxis - Decreased inflammation |
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|
Term
What is the problem with glucocorticoids? |
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Definition
They can be toxic to the patient |
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Term
(T/F) The inhibitory effects evoked by NSAIDs are more selective than glucocorticoid effects |
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Definition
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|
Term
How do NSAIDs operate, and how does this account for the increased selectivity of NSAIDs |
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Definition
They inhibit COX enzymes, therefore are more specific because they only prevent PG formation, and not formation of leukotrienes |
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|
Term
How does ASA inhibit COX enzymes? |
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Definition
It acetylates the serine at the COX active site |
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|
Term
What type of inhibition is this? |
|
Definition
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|
Term
Describe what occurs when ASA is administered in vivo |
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Definition
ASA is rapidly converted to salicylic acid in vivo |
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|
Term
What is the role of salicylic acid in vivo? |
|
Definition
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|
Term
(T/F) ASA effects that are observed in vivo are soley due to ASA |
|
Definition
False, the effects are a combination of ASA and salicylic acid actions |
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|
Term
How do other NSAIDs inhibit COX? |
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Definition
Both reversible and irreversible |
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|
Term
(T/F) The efficacy of the drug will parallel the COX inhibition seen |
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Definition
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|
Term
When was the presence of COX1/2 discovered? |
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Definition
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|
Term
What type of cells is COX-1 found in? |
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Definition
Primarily non-inflammatory cells |
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|
Term
What type of cells is COX-2 found in? |
|
Definition
Primarily inflammatory cells |
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|
Term
(T/F) Most conventional NSAIDs are selective for COX-2 |
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Definition
False, most are unselective |
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|
Term
What was the result of this? |
|
Definition
GI toxicity due to COX-1 inhibition |
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|
Term
How did this toxicity manifest? |
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Definition
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|
Term
(T/F) Celecoxib and rofecoxib are both COX-2 selective |
|
Definition
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|
Term
What was the problem with these COX-2 selective drugs? |
|
Definition
Use was associated with an increased incidence of myocardial infarction |
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|
Term
What is the limitation of NSAIDs? |
|
Definition
They offer no inhibition of lipoxygenase |
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|
Term
What often accompanies COX inhibition, and why? |
|
Definition
Increased LT formation because of increased AA available to lipoxygenase |
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|
Term
What do LT's often participate in, and how does this explain ASA hypersensitivity? |
|
Definition
- LT's play a role in inflammation - Most people can handle having increased LT's, but those with hypersensitivies cannot handle increased LT count |
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|
Term
ASA hypersensitivity occurs primarily in patients with ____________. |
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Definition
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|
Term
What is the difference between eicosatetraynoic acid (ETYA) and AA? |
|
Definition
Similar structure, but has triple bonds where AA has double bonds |
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|
Term
Describe the in vitro and in vivo responses to ETYA |
|
Definition
In vitro: prevents LT formation In vivo: not effective |
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|
Term
What enzyme is ETYA designed to block? |
|
Definition
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|
Term
What is Zileuton (Zyflo) used for, and what is it prescribed to treat? |
|
Definition
5-LOX inhibition; treats asthma |
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|
Term
(T/F) This treatment is equally as effective as steroid treatments for asthma |
|
Definition
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|
Term
Why is it likely that Zyflo will likely never reach the Canadian market? |
|
Definition
Because it is hepatotoxic to certain individuals, and there are other drugs that are just as effective, if not more, without hepatotoxicity |
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|
Term
(T/F) FLAP is a target of lipoxygenase inhibition |
|
Definition
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|
Term
(T/F) FLAP inhibitors are readily available on the market today |
|
Definition
False, they are still in clinical trial |
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|
Term
Why would FLAP inhibitors work? |
|
Definition
Because FLAP is necessary for 5-LOX activity |
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|
Term
What is the goal of inhibition of thromboxane synthesis? |
|
Definition
To inhibit TXA2 formation, without inhibiting PGI2 inhibition |
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|
Term
What is the source of TXA2? |
|
Definition
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|
Term
What is the source of PGI2? |
|
Definition
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|
Term
During a heart attack/stroke, what do we want to avoid? |
|
Definition
- Avoid thrombus formation - Avoid vasoconstriction |
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|
Term
During a heart attack/stroke, does PGI2 produce the desired, or undesired responses? TXA2? |
|
Definition
PGI2: Desired responses - vasodilation and platelet aggregation inhibition TXA2: Undesired responses - vasoconstriction and stimulation of platelet aggregation |
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|
Term
What is the problem when attempting to minimize TX synthesis without affecting PGI2 synthesis |
|
Definition
- Cannot block PGH2 formation, because it is a precursor for both PGI2 and TXA2 - TXA2 and PGH2 have very similar structure, and can act on the same receptors |
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|
Term
What are the 2 methods used to try and inhibit TX formation? |
|
Definition
1. Thromboxane inhibitors 2. Aspirin - irev COX inhibition |
|
|
Term
What is the problem with using thromboxane inhibitors? |
|
Definition
PGH2 mimicks TXA2 activity, so there is limited success with this method |
|
|
Term
What is the difference between platelets and vascular endothelium, regarding COX? |
|
Definition
Platelets cannot resynthesize COX, but vascular endothelium can |
|
|
Term
How is this taken advantage of when reducing TX production? |
|
Definition
ASA can prevent TXA2 synthesis for the life of the platelet (by inhibiting COX), but PGI2 synthesis recovers within hours |
|
|
Term
How does PGI2 synthesis recover in hours? |
|
Definition
Because PGI2 is synthesized in vascular endothelium, which also can reproduce COX enzymes. Because of this, COX enzymes reform within hours, and thus, PGI2 production resumes |
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|
Term
(T/F) The antithrombic effects of aspirin lasts for days |
|
Definition
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|
Term
Provide an apparent explanation for cardiovascular toxicity related to COX-2 inhibitors |
|
Definition
- TXA2 formation is not affected, because platelets only have COX-1 - PGI2 formation is affected, because endothelial cells have COX-2 (in inflammatory cells) - Result: imbalance of PGI2 to TXA2, resulting in increased risk of thrombus formation |
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|
Term
Name the 2 eicosanoid receptors that have potential for drug interactions |
|
Definition
1. TXA2/PGH2 receptors 2. LTD4/LTE4 receptors |
|
|
Term
What is the target of TXA2/PGH2 receptors used for? |
|
Definition
The treatment of asthma/heart disease/etc |
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|
Term
(T/F) Drugs meant for the blockade of these receptors are still in development |
|
Definition
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|
Term
What do receptors for LTD4/LTE4 play a role in? |
|
Definition
Asthma - binding causes bronchoconstriction |
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|
Term
How does zafirlukast help treat asthma? |
|
Definition
It is an LTD4/LTE4 antagonist, therefore prevents bronchoconstriction |
|
|
Term
What is the molecular change that results in PG metabolism inhibited? |
|
Definition
Modificaiton of the 15-OH group by a drug |
|
|
Term
What does this accomplish, and what is the result of this? |
|
Definition
Alters PG structure, therefore its breakdown is slowed, and the effects of the PG are prolonged |
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|