Eicosanoids DS PDF

EICOSANOI DS By Dr. Indalo EICOSANOIDS  PROSTAGLANDINS  THROMBOXANES  LEUKOTRIENES  RELATED COMPOUNDS  Prostaglandins, Leukotrienes and Thromboxanes are derived from membrane phospholipids BIOSYNTHESIS: Formed from 20-carbon essential fatty acids that...

EICOSANOI DS By Dr. Indalo EICOSANOIDS  PROSTAGLANDINS  THROMBOXANES  LEUKOTRIENES  RELATED COMPOUNDS  Prostaglandins, Leukotrienes and Thromboxanes are derived from membrane phospholipids BIOSYNTHESIS: Formed from 20-carbon essential fatty acids that contain 3, 4, or 5 double bonds:  8, 11, 14-eicosatrienoic acid (dihomo-γ-linoleic acid)  5, 8, 11, 14-eicosatetraenoic acid (arachidonic acid)  5, 8, 11, 14,17-eicosapentaneoic acid  Other eicosanoids are derived from modified phospholipids e.g. PAF (platelet-activating factor) Eicosanoids:  Extremely prevalent. Present in almost every tissue & fluid of the body  Function as local hormones ~ synthesized & exert their biological actions in the same tissue  Also found in a variety of plants  Family of highly potent cpds with extraordinary wide spectrum biologic activity  Bind to receptors on target cell plasma membranes in various tissues to stimulate or inhibit the synthesis of other messengers e.g. cAMP  Have physiological and pathological effects on the CV, pulmonary, reproductive and digestive systems  Arachidonate:  is the most abundant precursor & is derived either from dietary linoleic acid (9, 12-octadecadienoic acid) or ingested as a dietary constituent  Esterified to the phospholipids of cell membranes or other complex lipids  Concn low & so the biosynthesis of eicosanoids is mainly from cellular stores of lipids by the action of acyl hydroxylases ******  Eicosanoids biosynthesis closely regulated & occurs in response to widely divergent physical, chemical & hormonal stimuli  Hormones, autacoids & other substances augment the biosynthesis by interfering with plasma membrane- bound receptors that are coupled to G proteins (Guanine Nucleotide-binding Regulatory Proteins)  This results in either direct activation of phospholipases (C and/or A2) or in elevated cytolic [Ca2+] which also activate phospholipases (enzymes)  Physical stimuli may cause an influx of Ca2+ by perturbing the cell membrane thereby activating phospholipase A2  Arachidonic acid:  Rapidly oxygenated by 4 distinct enzyme systems (separate routes):- 1. Cyclooxygenase (COX) pathway to yield Prostaglandins & Thromboxanes 2. Lipoxygenase pathway to yield H(P)ETES (Hydroxy[peroxy]ecosatetraenoic acid), Leukotrienes & Lipoxins 3. Cyt P450 pathway to yield Epoxides 4. Isoprostane pathway to yield Isoprostanes  ****Synthesis of PGs and leukotrienes phospholipid Cell membrane Phospholipase A2 Corticosteroids (-) Bradykinin (+ angiotensin Arachidonic acid 5- cyclooxygenase lipoxygenase NSAIDS (- ) PGG2 hydroperoxidase Leukotrienes PGH2  Eicosanoids have biologic activity  their specific receptor & enzyme inhibitors; their plant & fish oil precursors have therapeutic potential  Eicosanoids have short T halves ~ seconds to minutes  for clinical use need special delivery systems or synthetic stable analogs INHIBITORS OF EICOSANOID BIOSYNTHESIS  Inhibition of Phospholipase A2 decreases the release of the precursor FA & hence the synthesis of all metabolites derived from it  Phospholipase A is activated by 2 Ca2+ & calmodulin & can be inhibited by drugs that reduce the availability of Ca2+  Glucocorticoids indirectly inhibit Phospholipase A2 by inducing the synthesis of the protein lipocortin that inhibits the enzyme  Cellular proteins such as calpactins may also regulate phospholipases  ASA & related anti-inflammatory drugs inhibit COX  PROSTAGLANDINS  Phospholipase A2 hydrolyses the ester bond to mobilise arachidonic acid from membrane phospholipids  Arachidonic acid oxygenated & cyclized by prostaglandin endoperoxide syntheses (COX) to form the cyclic endoperoxide PGG 2 & then coverts it to PGH2  PGH2 transformed enzymatically by synthases to TXA, PGI2, PGEs, PGF and PGD  Interconversion of PGE2 & PGF2α catalysed by a 9-keto reductase in some tissues  Synthesis of PGs and leukotrienes phospholipid Cell membrane Phospholipase A2 Corticosteroids (-) Bradykinin (+ angiotensin Arachidonic acid 5- cyclooxygenase lipoxygenase NSAIDS (- ) PGG2 hydroperoxidase Leukotrienes PGH2 Prostacylin PGH2 PGD2 (PGI2) (- Dypyridomol ) e PGE2 Thromboxane PGF2α Structural features of PGs  Letter after PG such as A, B, G, H, F refers to the substituents on the cyclopentane ring  Most common conformations are E & F  Subscript shows the number of double bonds in the side chain  PROSTAGLANDINS: O OH E and F OH OH O 7 4 2 8 6 3 1 9 5 COOH 10 20 14 16 18 11 12 15 OH 13 PGE 17 19 O H PGE and D series are hydroxy ketones Fα are 1, 3 – diols 2 PGA, B and C unsaturated ketones  PGs are analogs of prostanoic acid  Unsaturated fatty acid derivatives containing 20 carbons & cyclic ring structure  Prostacycline (PGI2) has a double ring structure ~ in addition to a cyclopropane , a 2nd ring is formed by an oxygen bridge between C 6 & 9  Thromboxanes (TX) contain a 6 member oxane ring instead of the cyclopentane ring CYCLO-OXYGENASES (PG ENDOPEROXIDE SYNTHESES)  2 isozymes – COX-1 & COX-2  COX important ~ NSAIDS exert their therapeutic effect at this step  COX-1  widely distributed & has such functions as gastric cytoprotection  COX-2  inducible & its expression varies markedly depending on the stimulus; immediate early response gene product in inflammation & immune cells; involved in normal renal development & prostacycline production CHARACTERISTICS OF PROSTAGLANDIN (PG) RECEPTORS PG Platel Smoot Nutur G 2nd recept et h al protei messe or aggre muscl agonis n nger type gator e tone t DP - +/- PGD2 Gs cAMP( ↑) EP1 + PGE2 Gq? Ca2+; IP3/DAG (?) EP2 - PGE2 Gs cAMP( ↑) EP3 + PGE2 Gi, Gs, cAMP( Gq ↑/↓); IP3/DAG /Ca2+ EP4 - PGE2 Gs cAMP( ↑) FP + PGF2α Gq IP3/ DAG/ Ca2+ ROLES OF PGS ON REPRODUCTIVE PROCESSES Effect on smooth muscle:  PGF strongly contracts uterine 2α smooth muscle  PGEs effect depends on spp & hormonal state  Mense:  Dysmenorrhoea attributable to increased endometrial synthesis of PGE2 & PGF2α during mense ~ causes contraction of the uterus leading to ischaemic pain Parturition:  Initiating factor is probably the release of PGs from foetal & maternal placenta  PGF2α inhibits progesterone synthesis & stimulates oestrogen synthesis which further stimulates PGF2α synthesis  Uterine contraction induced by PGF2α & reinforced by oxytocin from maternal pituitary, resulting in expulsion of the foetus  PGE is 5x more potent than PGF for 2 2α induction of labour at term  Abortion:-  PGE2, PGF2α & their analogs have potent oxytoxic effects and are used clinically (i/v or vaginal tabs):- - to promote uterine contraction at any stage i.e. after 12 wk of pregnancy (surgical techniques have serious disadvantages); & for ripening the cervix before abortion; & as post coital contraceptives  Dinoprostone, a synthetic analogue of PGE2 adm vaginally; carboprost tromethamine (15-methyl derivative of PGF2α) intraamnionitic injn for 2nd trimester abortion ~ may cause CV collapse. Can give i/m  NB: 15-methyl analogues of PGF2α & PGE2 more potent than parent cpds (not substrates of PG-15- dehydrogenase)  Main side effects of PGs used therapeutically:- - diarrhoea, nausea & vomiting and are more severe with PGE2 & PGF2α - Irritation of the vein at the site of  PGs in semen:-  May play a role in the transport of sperm in the female & male genital tracts during & after coitus  May assist in the nutrition of sperm by producing vasodilatation in genital mucous membranes  Absorbed thr’ the genital mucosa to affect motility of the fallopian tubes ~ facilitate transport of spermatozoa to ovum  NB: PGE content of seminal fluid of infertile males is low PGE1  May be used in the Tx of importence  Intracarvenous injn or urethral suppository of PGE1 (alprostadil) causes complete or partial erection in importent patients ~ erection lasts 1-3 hours  Adverse effects:- - Penile pain ~ may be related to algesic effect of PGE derivatives - Prolonged erection & priapism (