Prostaglandins Flashcards
2013.02.13 prostaglandins • See Slide 11 • See Slide 14 • See Slide 21 • See Slide 44
2013.02.13 prostaglandins • See Slide 11 • See Slide 14 • See Slide 21 • See Slide 44
What are the precursors to Prostaglandins, Leukotrieines, and Thromboxanes?
• unsaturated membrane fatty acids, the 20-carbon eicosaenoic acids aka eicosanoids.
What cells produce eicosanoids?
- Virtually all cells and tissues produce eicosanoids
* the specific types produced vary widely from cell-type to cell-type.
Explain the general cycle of synthesis, release, localization, and degradation of eicosanoids.
- synthesized and released in response to inflammatory, mechanical, neurological, or hormonal stimuli.
- Rapidly degraded by dehydrogenase enzymes, most effectively in the lung.
- Eicosanoids have very short half-lives and thus, eicosanoids are “local” autocrine or paracrine hormones.
NOMENCLATURE & MECHANISM OF ACTION OF EICOSANOIDS
• Letters designate ring structure;
• Numbers denote # of double bonds–important for receptor binding and function;
• Receptors, usually G-protein coupled, are specific for each different eicosanoid;
e.g. DP1 and DP2 are receptors for Prostaglandin D.
EP1, EP2, EP3 and EP4 are four distinct receptors for E prostaglandins.
NOMENCLATURE & MECHANISM OF ACTION OF EICOSANOIDS
• Letters designate ring structure;
• Numbers denote # of double bonds–important for receptor binding and function;
• Receptors, usually G-protein coupled, are specific for each different eicosanoid;
e.g. DP1 and DP2 are receptors for Prostaglandin D.
EP1, EP2, EP3 and EP4 are four distinct receptors for E prostaglandins.
What is the precursors to eicosanoids? What is the primary precursor?
- arachidonic (eicosatetraenoic) acid.
- fatty acids cleaved from membrane phospholipids following activation of phospholipases (e.g. PLA2) are rapidly converted to eicosanoids.
What causes the release of eicosanoids?
- Inflammatory, mechanical, neurological, or hormonal stimuli activate the phospholipase A2 family to release membrane fatty acids (eicosaenoic acids).
- Also…
- —injury (exposed collagen; thrombin; damaged cells)
- —heat (thermal injury)
- —hormones (angiotensin; vasopressin, cytokines …)
- —Ag-Ab complexes, activated complement
- —bacteria, LPS (endotoxin)
What is Cyclooxygenase?
What is Prostaglandin H Synthase I and II?
What eicosanoids are formed by these enzymes?
- Prostaglandins and thromboxanes (prostanoids) are formed via the cyclooxygenase (COX) pathways
- prostaglandin H synthase I (PGHS-1 = COX-1) and PGHS-2 (COX-2).
What eicosanoid is formed via…
5-lipoxygenase?
5-, 12-, 15- lipoxygenase?
- Leukotrienes are produced via the enzyme 5-lipoxygenase.
* Lipoxins are products of 5-, 12-, and 15-lipoxygenases.
Explain the inflammatory pathway with regard to eicosanoid production.
• IL-1, TNF, LPS ==> COX-2 ==> phospholipase A2 (PLA2) ==> eicosanoid production at sites of inflammation.
How do eicosanoids affect pain sensation?
• Eicosanoids are hyperalgesic–do not produce pain directly but increase tissue sensitivity to other stimuli. E-prostaglandins induce hyperalgesia via EP4.
How do eicasanoids affect edema?
• Eicosanoids enhance edema caused by bradykinin, histamine and the C5a anaphylatoxin.
How do eicosanoids affect chemotaxis? Which one is noted?
• Eicosanoids contribute to leukocyte activation and chemotaxis. e.g. LTB4 is chemotactic for both T cells and PMNs.
What is the effect of PGE2 (E-prostaglandin) on inflammation?
• PGE2 induces all cardinal signs of inflammation when injected into an animal or person (rubor, calor, dolor, tumor)
Which eicosanoids are part of asthma?
• Cysteinyl leukotrienes (cysLTs; LTC4, D4, E4) induce many of the abnormalities seen in both acute and chronic asthma.
What effects do cysteinyl leukotrienes have on asthma?
- -Induce smooth muscle contraction and protracted bronchoconstriction;
- -Promote of microvascular permeability, bronchovascular leakage & mucous secretion;
- -Promote leukocyte infiltration and production of pro-inflammatory cytokines.
What inhibits eicosanoid production? (long list)
- anti-inflammatory NSAIDs, coxibs (COX-2 inhibitors) and glucocorticoids.
- 5-lipoxygenase inhibitors and leukotriene receptor antagonists (anti-asthma drugs).
- Lipoxins, resolvins & protectins counter the inflammatory effects of leukotrienes.
How do glucocorticoids affect eicosaniods?
- induce synthesis of annexin-1 which blocks cPLA2
- inhibit synthesis of COX-2 (but not COX-1)
- induce MAPK phosphatase 1
- inhibiting production of inflammatory cytokines that stimulate PG production.
- Thus, GCs can inhibit production of prostaglandins, thromboxanes and leukotrienes.
How do NSAIDs affect eicosanoids?
- block cyclooxygenases 1 and 2 (COX-1 and COX-2);
* But do not inhibit and may lead to enhanced leukotriene production.
How do 5-lipoxygenase inhibitors affect eicosanoids?
• block production of leukotrienes.
How do Coxibs (new COX-2 selective inhibitors) affect eicosaniods? Why are they special?
- block the inflammation-
- induced cyclooxygenase (COX-2) enzyme with little effect on COX-1.
- selectively inhibit COX-2 at inflammatory sites.
- do not inhibit cytoprotective E-prostaglandins that are produced by gut epithelial cells via COX-1 (ie. You can block inflammation without causing ulcers)
What inhibits eicosanoid production in asthma?
• 5-lipoxygenase inhibitors and leukotriene receptor antagonists (anti-asthma drugs).
How are eicosanoids part of lung inflammation?
• lung inflammation–mast cells produce PGD2 and slow reacting substance of anaphylaxis (LTC4 and LTD4) causing bronchoconstiction, bronchovascular leakage, microvascular permeability & mucous secretion.
What is the effect of Thromboxane on platelet and blood vessel function?
• platelets (via COX-1) ==> Thromboxane A2 ==> platelet aggregation and vasoconstriction.
What is the effect of prostaglandin I2/ prostacyclin (PGI2) on platelet and blood vessel function?
• vascular endothelial cells (via COX-1 and COX-2) ==> Prostacyclin (PGI2) ==> inhibits platelet aggregation and causes vasodilation.
Recap: Compare Thromboxane and Prostacyclin with regard to platelet and blood vessel function.
- platelets (via COX-1) ==> Thromboxane A2 ==> platelet aggregation and vasoconstriction.
- vascular endothelial cells (via COX-1 and COX-2) ==> Prostacyclin (PGI2) ==> inhibits platelet aggregation and causes vasodilation.
How does aspirin affect platelet and blood vessel function?
What about other NSAIDs?
When and How are the affects of aspirin reversed?
- Aspirin, unlike other NSAIDs, irreversibly inhibits COX-1 and COX-2.
- anucleate platelets cannot synthesize new COX-1, thromboxane production is markedly impaired.
- Endothelial cells, via synthesis of new COX-1 and 2, can produce prostacyclin once aspirin levels decline.
- Details: Aspirin donates its acetyl group to a Serine near the PGH2 synthase active site, blocking arachidonate binding, and causing irreversible inhibition of the PG synthase enzyme.
- Details: The anti-clotting effect of aspirin is due to irreversible inhibition of COX-1, needed to form thromboxanes in blood platelets. The effect is long-lived since platelets (as anucleate progeny of megakaryocytes) can not make new enzyme. Endothelial cells can regenerate COX and thus continue to produce Prostacyclin (PGI2).
What is Patent Ductus Arteriosus (PDA)?
• a congenital disorder in the heart wherein a neonate’s ductus arteriosus fails to close after birth.
Which eicosanoids contribute to Ductus Arteriosus Patency?
• maintained in the fetus by locally produced and circulating I and E prostaglandins.
What is a pharmacological treatment for Ductus Arteriosus Patency early after birth?
• Indomethacin and ibuprofen (eicasonoid inhibitors) can dramatically reduce blood flow through the ductus within 24 hours and eliminate the need for surgery in many premature infants.
What are the mechanisms through which E and I prostaglandins affect blood vessels?
- reduce arterial blood pressure
- direct vasodilator action on resistance vessels
- modulation of norepinephrine release
- modulation of renal hormones.
What is the role of eicosanoids in artherogenesis?
- 5-lipoxygenase gene polymorphisms are linked to coronary occlusion
- Omega-3 fatty acid rich diet decreases cardiovascular disease
- Thromboxane B3 inactive, PGI3 active
- Low dose aspirin reduces arterial thrombosis.
What is the mechanism of Coxibs (Cox-2 inhibitors) for increasing thrombosis?
• increase thrombosis by selectively inhibiting prostocyclin but not thromboxane.
In general, how do E- and F- Prostaglandins affect reproduction?
— production stimulated by LH
— induce follicular rupture, release of ovum
— stimulate cervical ripening/dilation
— stimulate uterine smooth muscle contraction
— induce penile erection
Explain the effects of PGE2 and PGF2 in ovulation and parturition.
- PGE2 and PGF2 ==> follicular rupture and release of the ovum.
- PGE2 & PGF2 ==> cervical softening/dilation & uterine contractions.
What is the drug Misoprostol, a PGE1 analogue, is effective for?
cervical ripening and induction of labor
• Reducing postpartum hemorrhage
• Medical abortion (combined with RU486)
Explain the effects of PGE2 in the penis.
• PGE2 induces penile erection.
How do NSAIDs affect gestation time?
• NSAIDs can prolong gestation and are sometimes effective in arresting premature labor.
Which prostaglandin is used for termination of pregnancy? At what time during pregnancy is it effective?
• E-prostaglandins can be used for termination of both early and late pregnancies.
In general what are the effects of eicosanoids in the kidneys?
- PGI2 and PGE2 normally low, but increased by angiotensin II, norepinephrine and vasopressin
- Maintain renal blood flow through direct renal vasodilatory action, thus ameliorating renal vasoconstriction by angiotensin II and norepinehrine.
- Antagonize both hydroosmotic and vascular effects of ADH.
- PGI2 (and PGE2) play a positive role in baroreceptor-induced renin release.
What is the effect of RAAS on PGI2 and PGE2?
• PGI2 and PGE2 normally low, but increased by angiotensin II, norepinephrine and vasopressin (ADH)
What is the effect of PGI2 and PGE2 on renal blood flow?
• PGI2 and PGE2 maintain renal blood flow through direct renal vasodilatory action.
What is the effect of prostaglandins on ADH?
• Prostaglandins antagonize both hydroosmotic and vascular effects of ADH
What is the role (+ or -) of PGI2 and PGE2 on rennin release?
• PGI2 (and PGE2) play a positive role in baroreceptor-induced renin release.
Recap: What is the effect of PGI2 and PGE2 on…
on renal blood flow?
on ADH?
on rennin release?
- PGI2 and PGE2 maintain renal blood flow through direct renal vasodilatory action.
- Prostaglandins antagonize both hydroosmotic and vascular effects of ADH
- PGI2 (and PGE2) play a positive role in baroreceptor-induced renin release.
What is the effect of eicosanoids int the gut?
- PGE»PGA>PGI decrease acidity
- ↑ bicarbonate secretion by epithelial cells
- ↑ mucous secretion by epithelial cells
- protect the gastric mucosa.
What is the effect of NSAIDs on the gut?
- Increase acidity and gastric ulcers
- ↓ bicarbonate secretion by epithelial cells
- ↓ mucous secretion by epithelial cells
For patients who must receive NSAID therapy, is there an treatment that can help protect their gut?
• Misoprostol, an E prostaglandin analog, is useful for protection against gastric ulcers in high-risk groups, such as patients receiving NSAID therapy for arthritis and other inflammatory diseases.
What is the effect of NSAIDs and COX-2 inhibitors on GI tumors?
- NSAIDs and COX-2 inhibitors decrease the frequency of colorectal polyps.
- Low dose aspirin reduces the occurrence of familial adenomas.
Don’t forget the diagrams…
Don’t forget the diagrams…
