overview eicosanoids are a large group of autocoids with potent effects on virtually every tissue...
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Overview
Eicosanoids are a large group of autocoids with potent effects on virtually every tissue in the body
these agents are derived from metabolism of 20-carbon, unsaturated fatty acids (eicosanoic acids).
The eicosanoids include: 1. the prostaglandins 2. thromboxanes 3. leukotrienes 4. hydroperoxyeicosatetraenoic
acids (HPETEs)5. hydroxyeicosatetraenoic acids
(HETEs).
Biosynthesis
Arachidonic acid, the most common precursor of the eicosanoids, is formed by two pathways:1. Phospholipase A2-mediated
production from membrane phospholipids; this pathway is inhibited by glucocorticoids.
2. Phospholipase C.
Eicosanoids are synthesized by two pathways:
1. The prostaglandin H synthase (COX, cyclooxygenase) pathway
produces: A. thromboxane B. the primary prostaglandins
prostaglandin E, or PGE prostaglandin F, or PGF prostaglandin D, or PGD)
C. prostacyclin (PGI2)
2. The lipoxygenase pathway produces:
HPETEs HETEs leukotrienes
The eicosanoids all have short plasma half-lives (typically 0.5—5 min).
Most catabolism occurs in the lung. Metabolites are excreted in the
urine. Thromboxane A2 (TXA2) is rapidly
hydrated to the less active TXB2. PGI2 is hydrolyzed to 6-keto-PGF1α.
Various eicosanoids are synthesized throughout the body
synthesis can be very tissue specific: PGI2 is synthesized in endothelial and
vascular smooth muscle cells. Thromboxane synthesis occurs
primarily in platelets. HPETEs, HETEs, and the leukotrienes
are synthesized predominantly in mast cells, white blood cells, airway epithelium, and platelets.
Actions:
Vascular smooth muscle PGE2 and PGI2 are potent
vasodilators in most vascular beds. Thromboxane is a potent
vasoconstrictor.
Inflammation PGE2 and PGI2 cause an increase in
blood flow and promote, but do not cause, edema.
HETEs (5-HETE, 12-HETE, 15-HETE) and leukotrienes cause chemotaxis of neutrophils and eosinophils.
Bronchial smooth muscle PGFs cause smooth muscle
contraction. PGEs cause smooth muscle
relaxation. Leukotrienes and thromboxane
are potent bronchoconstrictors and are the most likely candidates for mediating allergic bronchospasm.
Uterine smooth muscle. PGE2 and PGF2a
cause contraction of uterine smooth muscle in pregnant women.
The nonpregnant uterusnonpregnant uterus has a more variable response to prostaglandins PGF2a causes contraction
PGE2 causes relaxation.
Gastrointestinal tract PGE2 and PGF2a
increase the rate of longitudinal contraction in the gut and decrease transit time.
The leukotrienes are potent stimulators of gastrointestinal smooth
muscle.
PGE2 and PGI2 inhibit acid and pepsinogen secretion in the
stomach.
Prostaglandins increase mucus, water, and electrolyte secretion in
the stomach and the intestine.
Blood TXA2
is a potent inducer of platelet aggregation.
PGI2 and PGE2 inhibit platelet aggregation.
PGEs induce erythropoiesis by stimulating the renal
release of erythropoietin.
5-HPETE stimulates release of histamine
PGI2 and PGD inhibit histamine release.
Therapeutic uses
Induction of labor at term. Induction of labor is produced by:
infusion of PGF2 (carboprost tromethamine) [Hemabate] or
PGE2 (dinoprostone) [Prostin E].
Therapeutic abortion:A.Inducing abortion in the second
trimester: Infusion of carboprost tromethamine
or Administration of vaginal suppositories
containing dinoprostone
B.inducing first-trimester abortion: these prostaglandins are combined with
mifepristone (RU486)
Maintenance of ductus arteriosus
is produced by PGE1 [Prostin VR] infusion
PGE1 will maintain patency of the ductus arteriosus, which may be desirable before surgery.
Treatment of peptic ulcer.
Misoprostol [Cytotec] a methylated derivative of PGE1
is approved for use in patients taking high doses of nonsteroidal antiinflammatory drugs (NSAIDs) to reduce gastric ulceration.
Erectile dysfunction: Alprostadil (PGE1) can be injected directly
into the corpus cavernosum or administered as a transurethral suppository to cause vasodilation and enhance tumescence.
injected directly into the corpus cavernosum
transurethral suppository
Adverse effects of eicosanoids
local pain and irritation bronchospasm gastrointestinal disturbances:
nausea, vomiting, cramping, and diarrhea.