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

Most catabolism occurs in the lung. 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. Unlike histamine, eicosanoids are NOT synthesized in advance and stored in granules – when needed, they can be produced very quickly from arachidonate released from membranes

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.

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.

Prostaglandins Stimulus phospholipids Phospholipase A2 Phospholipase C 5-lipoxygenase enzyme (LOX) Arachidonic acid Cyclo-oxygenase enzyme (COX) (HPETEs and HETEs) PGH2 LTB4 LTC2 LTD4 LTE2 PGD2 PGE2 PGF2α PGI2 TXA2

Membrane-bound phospholipid Prostaglandins Membrane-bound phospholipid Arachidonic acid COX V.C. ↑Platelet Aggreg. Contract smooth muscle 2e¯ Reductase TX A synthetase PGH2 TXA2 PGF2 PGD synthetase PGI synthetase synthetase PGE V.D. ↓platelet Aggreg. V.D. ↓platelet Aggreg. PGD2 PGI2 PGE2 Dehydration (non enzymatic Inflammation Immunity fertility Anti- inflammatory PGJ2 Dehydration (non enzymatic Anti-inflammatory 15-d-PGJ2 PGA2 V.D., antiviral, antituomr

Prostaglandins – Structural Features PGA, PGD, PGE, PGF, PGG, PGH, PGI Depending on the functional groups present at X and Y PGF 1, 2 or 3 Depending on the number of double bonds present in the linear hydrocarbon chain

Eicosanoids Hydroperoxy and hydroxy fatty acids (HPETEs and HETEs) leukotrienes A.B,C.D.E LTC4andLTD4 →bronchospasm.

Effects of prostaglandins Mediate inflammation: cause vasodilation  redness, heat (PGE1, PGE2, PGD2, PGI2) increase vascular permeability  swelling (PGE2, PGD2, PGI2) Regulate pain and fever (PGE2) PGE2, PGF2 stimulate uterine muscle contractions during labor Prostaglandins of the PGE series inhibit gastric acid secretions (synthetic analogs are used to treat gastric ulcers) Regulate platelet aggregation: PGI2 = potent inhibitor of platelet aggregation PGE2 inhibits reabsorption of Na+ and water in the collecting duct. PGI2: vasodilatation and regulation of glomerular filtration rate.

Eicosanoids Actions: TXA2 contracts arteries and veins and bronchi, and causes platelet aggregation. PGI2 de-aggregate platelets clumps & reduces myocardial infarct size & ischemic organ damage

Actions: LTB4 is chemotactic for polymorphs, esinophils and monocytes.  PGF2α(contracts uterus), TXA2, LTC4, D4 contract bronchi while PGE1, PGE2 and I2 relax the bronchi.  PGE1, PGE2 induce fever, stimulate renin release,while (PGE2, PGI2) protect stomach against ulcer. LTB4 is chemotactic for polymorphs, esinophils and monocytes.

Inhibitors of eicosanoid biosynthesis: Eicosanoids Inhibitors of eicosanoid biosynthesis: Glucocorticoids Stimulate the synthesis of a protein called lipocortin which inhibit the activity of phospholipase A2 so inhibit synthesis of eicosanoids. Non steroidal anti-inflammatory drugs (NSAIDs) as aspirin, indomethadn, ibuprofern Inhibit cyclo-oxygenase enzyme (aspirin acetylates it).

Anti leukotriene drugs include : Eicosanoids Anti leukotriene drugs include : a)Zileuton : inhibits 5-lipoxygenase enzyme. b)Monteleukast and Zafirleukast: block cysteinyl leukotriene receptors. Dazoxiben is a selective inhibitor of thromboxane A2 synthesis and so inhibits platelet aggregation.

Montelukast, Zafirlukast Arachidonic acid 5-Lipoxygenase Zileuton Leukotrienes (LTs) LTC4- receptor LTD4- receptor LTE4- receptor (-) (-) Montelukast, Zafirlukast

Eicosanoids Steroidal and non-steroidal anti-inflammatory drugs may induce peptic ulcer due to inhibition of PGs generation by gastric mucosa. Drugs inhibiting cyclo-oxygenase enzyme may induce bronchospasm?.

Cyclooxygenase (COX) is found bound to the endoplasmatic reticulum. COX exists in 3 isoforms: COX-1 (constitutive) acts in physiological conditions. COX-2 (inducible) is induced in inflammatory cells by pathological stimulus. COX-3 (in brain)

COX INHIBITORS NSAIDs Nonselective COX-1/COX-2 Inhibitors ibuprufen Antipyretic analgesics COX-2 inhibitors Selective (coxibs) celecoxib, valdecoxib

Therapeutic uses of prostaglandins and other eicosanoids: 1.PGF2α(Dinoprost) and PGE2 (Dinoprostone) are used to induce abortion and labour. They are better given intravaginal or intra-amniotic Therapeutic uses of PGs : Induce abortion & labour. Treatment of Impotance Treatment of glacuma To decrease platelet aggregation Treatment of petic ulcer Treatment of pulmonary hypertension PGE1 analog misoprostol combined with mifepristone or methotoexate( intravaginal or systemic) terminates early pregnancy.

Therapeutic uses of prostaglandins and other eicosanoids: 2. PGE2 induces bronchodilatation but produces irritation. 3.They are tried in peptic ulcer (PGE1 analogs, misoprostol).but their adverse effects , and the presence of more superior drugs in this line limited their use 4. PGE1(Alprostadil)& PGI2 to maintain the patency of ductus arteriosus so used as a presurgical therapy for neonates suffering from transdisposition of great arteries or pulmonary atresia.

Therapeutic uses of prostaglandins and other eicosanoids: 5. PGE1 (alprostadil) is injected into corpora cavernosa to maintain erection in treatment of impotence. Replaced by PDE-V inhibitors 6. Latanoprost, travaprost and bimatoprost are PGF2α derivatives which used topically in treatment of glaucoma. 7 -Epoprostenol (PGI2) to decrease platelet aggregation. Used to prevent platelet aggregation in extracorporal circulation systems

Therapeutic uses of PGs : Induce abortion & labour.e.g PGF2 alpha,PGE2, PGE1 + Treatment of Impotance e.g PGE1 Treatment of glaucoma e.g PGF2 alpha To decrease platelet aggregation e.g PGI2 Treatment of petic ulcer e.g PGE1 Treatment of pulmonary hypertension e.g PGE1, PGI2

Aspirin Cyclooxygenase (Cox) (-) >1 g/24 h Endoperoxides (-) Arachidonic acid Cyclooxygenase (Cox) (-) >1 g/24 h Aspirin Endoperoxides (-) 100 mg/24 h Thromboxane A2 synthase PGs TxA2

Clinical Uses of Eicosanoids Inhibitors: B – uses of eicosanoids blockers: -Corticosteroids Asthma: Leukotrien antagonists (Zafirleukast; Montelukast); or Lipoxegenase inhibitor e.g. Zileuton Anti-inflammatory and RA (NSAIDs) Antiplatelet action (Aspirin), Dazoxiben used as prophylaxis against blood coagulation Dysmenorrhea (NSAIDs)