Autacoids

Eicosanoids

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

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

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

Prostaglandins

Arachidonic acid
PGH2
PGE2
PGA2
TXA2
PGI2
COX
PGF2
PGD2
PGJ2
15-d-PGJ2
V.C.↑PlateletAggreg. V.D.↓plateletAggreg. Inflammation Immunity fertility
V.D., antiviral, antituomr
Contract smooth muscle
V.D.↓plateletAggreg. Anti- inflammatory
Anti-inflammatory
Membrane-bound phospholipid
TX A synthetase
PGI synthetase


PGD synthetase
PGE synthetase
Dehydration (non enzymatic
Dehydration (non enzymatic


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

Hydroperoxy and hydroxy fatty acids (HPETEs and HETEs)

leukotrienesA.B,C.D.E LTC4andLTD4→bronchospasm.

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 laborProstaglandins of the PGE series inhibit gastric acid secretions (synthetic analogs are used to treat gastric ulcers)Regulate platelet aggregation: PGI2 = potent inhibitor of platelet aggregationPGE2 inhibits reabsorption of Na+ and water in the collecting duct. PGI2: vasodilatation and regulation of glomerular filtration rate. Effects of prostaglandins


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

 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. Actions:

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



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.

Arachidonic acid

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


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-2 inhibitors Selective (coxibs) celecoxib, valdecoxib

Selective COX-3 inhibitors Antipyretic analgesics
Nonselective COX-1/COX-2 Inhibitors ibuprufen
NSAIDs
COX INHIBITORS


1.PGF2α(Dinoprost) and PGE2 (Dinoprostone) are used to induce abortion and labour. They are better given intravaginal or intra-amniotic Therapeutic uses of prostaglandins and other eicosanoids:
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.


5. PGE1 (alprostadil) is injected into corpora cavernosa to maintain erection in treatment of impotence. Replaced by PDE-V inhibitors6. 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 prostaglandins and other eicosanoids:



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

Arachidonic acid

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


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