Eicosanoids

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Eicosanoids
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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).

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• The eicosanoids include
• the prostaglandins
• thromboxanes
• leukotrienes
• hydroperoxyeicosatetraenoic acids (HPETEs)
• hydroxyeicosatetraenoic acids (HETEs).

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Biosynthesis

• Arachidonic acid, the most common precursor of
  the eicosanoids, is formed by two pathways
• Phospholipase A2-mediated production from
  membrane phospholipids this pathway is inhibited
  by glucocorticoids.
• Phospholipase C.

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Eicosanoids are synthesized by two pathways

• The prostaglandin H synthase
• (COX, cyclooxygenase) pathway produces
• thromboxane
• the primary prostaglandins
• prostaglandin E, or PGE
• prostaglandin F, or PGF
• prostaglandin D, or PGD)
• prostacyclin (PGI2)

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• The lipoxygenase pathway produces
• HPETEs
• HETEs
• leukotrienes

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• The eicosanoids all have short plasma half-lives
  (typically 0.55 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-PGF1a.

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• 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.

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Actions

• Vascular smooth muscle
• PGE2 and PGI2 are potent vasodilators in most
  vascular beds.
• Thromboxane is a potent vasoconstrictor.

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• 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.

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• 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.

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• Uterine smooth muscle.
• PGE2 and PGF2a
• cause contraction of uterine smooth muscle in
  pregnant women.
• The nonpregnant uterus has a more variable
  response to prostaglandins
• PGF2a causes contraction
• PGE2 causes relaxation.

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• 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.

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• 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.

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Therapeutic uses

• Induction of labor at term.
• Induction of labor is produced by
• infusion of PGF2a (carboprost tromethamine)
  Hemabate or
• PGE2 (dinoprostone) Prostin E.

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• Therapeutic abortion
• Inducing abortion in the second trimester
• Infusion of carboprost tromethamine or
• Administration of vaginal suppositories
  containing dinoprostone
• inducing first-trimester abortion
• these prostaglandins are combined with
  mifepristone (RU486)

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• 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.

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• 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.

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• 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
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Adverse effects of eicosanoids

• local pain and irritation
• bronchospasm
• gastrointestinal disturbances nausea, vomiting,
  cramping, and diarrhea.