see also autacoids, platelet activating factor, physiology main index, pharmacology main index

• Eicosanoids are autacoids derived from membrane phospholipids - mainly formed from polyunsaturated fatty acids (principally arachidonic acid) - 20 carbon essential fatty acids that contain 3-5 double bonds - hence eicosanoids & include prostaglandins, prostacyclin, thromboxane A2 & the leukotrienes.
• They are present in almost every tissue & body fluid & their production increases in response to diverse stimuli & they produce a broad spectrum of biological effects.
• In 1930, observed that human uterus strips relax or contract when exposed to human semen. In ~1940, a lipid-soluble acid was identified & named prostaglandin, but not until 1962 was it realised that there was a family of them when structures of PGE1 & PGF1alpha were elucidated.
• When general structure realised, their kinship with essential fatty acids was recognised & in 1964, the biosynthesis from arachidonic acid was achieved from seminal vesicle homogenates.
• aspirin (acetylsalicylic acid) & related drugs were shown to inhibit PG biosynth. in 1971.
• Thrombaxane A2 was discovered in 1975, prostacyclin in 1976, & leukotrienes in 1983.
• LT receptor antagonists marketed in 1998

• Arachidonic acid is the most abundant precursor & derived from dietary linoleic acid or as a dietary constituent itself;
• Arachidonate then esterified to phospholipids of cell membranes or other complex lipids → free [] very low
  • → eicosanoid synth. dependent on its free [] which is regulated by its regulated release from cellular stores via acyl hydrolases:
    • Plipase A2 → hydrolyses sn-2 ester bond of memb.Plipids → arach. incr.;
    • Plipase C → cleaves phosphodiester bond → 1,2 diglyceride
    • → arach. acid released by sequential di/monglyceride lipases;
      • Once released, a portion of arachidonic acid is rapidly metabolised to oxygenated products by several distinct mechanisms:
        • Cyclooxygenase:
          • inhib. by non-steroidal anti-inflammatory drugs (NSAIDs);
          • → PGG2 → PGH2 (both endoperoxides) → PGI2 (unstable) via prostacyclin synthase
            • → 6-keto-PGF1alpha (stable) non-enz. T1/2 = 3min;
            • → PGF2alpha
            • → PGD2
            • → PGE2
            • → TX A2 (unstable) via thromboxane synthase
              • → TXB2 (stable) via non-enz. T1/2 = 3 min;
        • 5-lipoxygenase:
          • eg. leukocytes but not platelets;
          • → 5-HPETE (unstable) → 5-HETE
            • → lipoxins
            • → LTA4 via LTA synthase
              • → LTB4 via LTA hydrolase
              • → LTC4 via glutathione-S-transferase
                • ↔ LTD4 via -Glutamyl-transpeptidase
                  • → LTE4 via dipeptidase
                    • → LTF4 via -Glutamyl-transpept.
        • 12-lipoxygenase:
          • eg. leukocytes & platelets;
          • → 12-HPETE (unstable) → 12-HETE
            • → hepoxilins
        • Cytochrome P-450 enzymes:
          • → variety including:
            • HETE's, epoxyeicosatrienoic acids,
            • 19- or 20- hydroxyarachidonate;
          • ? physiologic importance.

• Drugs that decr. availability of i/cell. Ca → decr. Plipase A2
  • calpactin an i/cell. protein
    • → binds Plipid substrate in complex with Ca & actin;
• corticosteroids → decr. Plipase A2 via incr. lipocortin;
• non-steroidal anti-inflammatory drugs (NSAIDs) → decr. cyclooxygenase → decr. PG's & TX's but possible incr. LT's & HETE's;
• Dazoxiben → thromboxane synthase inhib. → decr. TX's but no decr. PG's.

• PG's except PGI2: initial rapid metab. by PG 15-OH dehydrogenase (PGDH)
  • esp. lungs, then by reductase & thence beta & omega oxid. in liver.
• LTC4 degrad. to LTE4 in lungs,kidney & liver; LTB4 by omega oxid;

• Although platelet aggreg. occurs without PG's via thrombin, aspirin via inhib. of cyclooxygenase → decr. TXA2 & decr. 2nd phase of platelet aggreg.;
• It appears endothelium released PGI2 is physiol. antag. of TXA2;

• ? role in fertility as high [] in semen & rapid absorption through vagina → actions on Cx, uterine body, tubes, & semen transport;
• ? role in onset of labor - cycloxygenase inhibitors cause:
  • → incr. gestation, incr. labor length, interrupt premature labor;
  • → premature closure of ductus arteriosis;
• PGF's → uterine contraction (esp. prior to menses & in pregnancy);
• PGE's → uterine relax. (esp.mid-cycle) but low [] contracts in preg;
• PGI2 → uterine relaxation in pregnancy;

• local generation of PGE2 & PGI2 modulate vascular tone:
  • appear to fn by countering the effects of circulating vasoconstrictor autacoids & to maintain flow to vital organs;
  • maintenance of patency of ductus arteriosis;
  • maintenance of placental blood flow?;
• bronchoconstriction via PGF2alpha, PGD2, TXA2 , LTD4 & LTC4:
  • as LT are relatively slowly metab. in lung cf PG's & the fact that LT antagonists inhib. Ag-induced asthma but not aspirin, makes it likely that the prime bronchoconstrictor is LTC4;
• bronchodilatation via PGE2;

• decr. RBF → incr. PGE2 & PGI2 → incr. water, Na & K excretion but little change in GFR;
• PGE2
  • → decr. ADH reabsorption of water;
  • → decr. Cl reabsorption in thich asc.limb in rabbits;
• PGI2, PGE2, PGD2 → incr. renin secretion via direct effect on JG cells;
• TXA2 → decr. RBF & decr. GFR;
• Barrter's synd. → XS PG's;

• most types of injury → incr. eicosanoids:
  • LT's → incr. vasc.permeability & LTB4 is powerful PMNL chemoattractant;
  • PGE2 & PGI2
    • → incr. oedema & WBC infiltration via vasodil.
    • → potentiate pain-producing activity of bradykinin, etc;
    • → decr. lymphocytes in delayed HS reactions;
    • → decr. PMNL release of hydrolases & lysosomal enzymes;

• PGE's & PGF's
  • → contract longitudinal muscle stomach → colon;
  • → incr. water & electrolytes into GIT lumen;
• PGE's → relax circular muscle but PGF's contract it;
• PG endoperoxides, TXA2 & PGI2 all contract but are less active;
• LT's have potent contractile effects;
• THUS, → decr. transit time, diarrhoea (not PGI2), cramps, N & V;
• PGE's & PGI2
  • → decr. gastric acid secretion stim. by food, hist/gastrin;
  • → incr. gastric mucosal blood flow & mucus secretion;
  • → decr. gastric damage caused by ulcerogenic agents;

• Both stimulant & depressant effects noted;
• ? PGE2 in hypothalamus → pyrogen-induced fever;

• PGE's cause prolonged pain on i/derm. injection;
• PGE2 & PGI2 sensitise nerve endings to effects of chemo/mech. stimuli;
• LTB4 also causes hyperalgesia;

• PGE2
  • → incr. ACTH, incr. GH, incr. PRL, incr. gonadotrophins;
  • → incr. steroid prod. by adrenals;
  • → incr. insulin release;
  • → thyrotropin-like activity on thyroid;
  • → LH-like effects on isolated ovarian tissue → incr. progest.
• PGF2alpha → luteolytic effect but not in pregnant women;

• PGE's
  • → decr. basal rate of lipolysis from adipose tissue;
  • → decr. lipolysis stimulated by catecholamines;
  • → insulin-like effects on CHO metabolism;
  • → parathyroid-like effects → incr. Ca mobilisation from bone;

• PGE2 & PGF2alpha: → use in midtrimester abortion & for ripening Cx in labor;
• PGE1 & PGI2:
  • → IV/IA use in severe PVD → prolonged vasodilatation;
  • → incr. pulm. blood flow & blood oxygenation in infants with CHD that decr. pulm.flow thus dilating duct.art. beneficial;
• PGE1: → i/cavernous use to Rx impotence → erection for 1-3hrs;
• PGI2:
  • → use in extracorporeal circulation to decr. plat.aggreg.;
  • → ? use in AMI as ? decr. ischaemic damage but may dilate certain cor. vessels & divert blood from ischaemic areas!

• misoprostol:
  • PGE1 analog used as antiulcerant but → diarrhoea;
  • see under anti-ulcer drugs;
  • also used in medical mx of miscarriage and for termination of pregnancy following Mx with mifepristone / RU486
• Alprostadil:
  • PGE1 agonist used to maintain patency of ductus arteriosis until surgery can be performed
• Latanaprost:
  • PG F2 alpha agonist used topically for reducing intraocular pressure as it increases outflow of aqueous humor
  • introduced in Aust. 1997.
• Other expt. analogs:
  • rioprostil - PGE1 analog;
  • enprostil, arbaprostil & trimoprostil - PGE2 analogs;
  • carbacyclin & ilioprost - PGI2 analogs;

• cysteine leukotriene (C4, D4 & E4) receptor antagonists:
  • developed mainly as a non-steroidal anti-asthma Rx (see Asthma for more details of use in asthma) but also of use in allergic rhinitis
• onset of action within hours (cw inhaled steroids weeks)
• has bronchodilator activity as well by decreasing LT-mediated bronchoconstriction, thus may have better compliance than inhaled steroids
• fewer responders than with inhaled steroids
• examples:
  • zafirlukast (1998 USA)
  • montelukast (1998 USA, 2000 Aust)
  • pranlukast (1998 Japan)