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