Fatty Acid Derivatives (Eicosanoids) PDF

█ Fattty acid derivative d es (eicos sanoids) They are group ofo fatty acid derivativves derived d from ara achidonic aacid (20 ca...

█ Fattty acid derivative d es (eicos sanoids) They are group ofo fatty acid derivativves derived d from ara achidonic aacid (20 ca arbons). The fam mily of eico osanoids in ncludes: Prosta aglandins s (PGs) PGs arre memberrs of fatty acid deriva atives. All are derive ed from araachidonic acid by the action of cycllooxygenase (COX) eenzyme wh hich has 3 isoforms:  COX X-1 (physiiological; constitutiv c ve): is invoolved in sy ynthesis o of protective PGs (e.g g. PGE2, PGI2) respo onsible for protection n of stomaach from H HCl, regulaation of RBF F, inhibition of platele et aggregaation, etc.  COX X-2 (pathhological; induciblle): is invoolved in synthesis of undessirable PGss (e.g. PGF2α, PGD2) involvved in infla ammatory reacctions, bronchoconsttriction, etc c.  COX X-3 (centrral): it is a variant off COX- 2 th hat found only o in the e brain an d may be included in syntthesis of PGs respponsible for fev ver and pain sensation. It is selectiv vely inhibitted by anaalgesic/antipyretic drugs e.g. aceetaminoph hen (para acetamol)) and dipyyrone. Throm mboxanes s (TXs)  The ey are also products of cyclooxxygenase enzyme. e  The ey are synthesized in high conccentration in platelets s.  The ey are of 2 forms: TX XA2 (the acttive form) and a TXB2 (the ( inactivve form).  A2 is the most TXA m potentt endogenoous stimulator of platelet aggreegation. Leuko otrienes (L LTs)  The ey are derivved from arachidonic a c acid by the action of o lipooxyg genase enzzyme.  The ey are of 4 main types: LTB4, LT TC4, LTD4, and LTE4.  A m mixture off LTC4, LTDL 4, LTE E4 is terme ed (the slow-reactinng substa ance of ana aphylaxis = SRS-A) th hat is relea ased during g inflammaatory respo onse.  B4 is powerful bronchoconstri ctor and chemotact LTB c tic for leukkocytes. 119  Pharmacological actions of eicosanoids PGs and other eicosanoids act on cell surface G-protein coupled receptors. These receptors are termed DP1-2, EP1-4, FP, etc. The following table summarizes the important effects of different eicosanoids: PGE1, PGE2 PGI2 PGF2α TXA2 LTB4 BV VD VC VD Edema + – +++ Severe Bronchi Relaxation Constriction constriction Pregnant: contraction Uterus Contraction Contraction Non-pregnant: relaxation Kidney ↑ RBF ↓ RBF ? Platelets ↓aggregation ↑aggregation - ↓ gastric HCl and Other ↑ mucus secretion Chemotaxis effects - Hyperpyrexia Therapeutic uses of prostaglandins PGE1: – PGE1 (Alprostadil) is still available as urethral inserts for treatment of erectile dysfunction in men: it produces VD of the vascular smooth muscle of the corpus cavernosum and improves erection. – To maintain patency of the ductus arteriosus in infants with congenital cyanotic heart diseases until surgical correction is undertaken. The ductus arteriosus in neonates and infants is highly sensitive to VD by PGE1. Patency of the ductus is necessary in those patients to ensure additional oxygenation of the blood until surgical correction of the problem is undertaken. – Treatment of peptic ulcer: Mesoprostol is approved for use in patients taking high doses of NSAIDs to prevent gastric ulceration. PGE2: – Induction of labor near full term (Dinoprostone). – Treatment of peripheral vascular disease. PGI2 (Prostacycline): – To inhibit platelet aggregation and prevent thrombosis during cardiopulmonary bypass surgery, hemodialysis, and retinal artery occlusion. – Treatment of pulmonary hypertension and peripheral vascular disease. 120  PGF F2α: – Induction of o labor ne ear full terrm (Enzaprost). – T Therapeutic abortion: as va aginal supppositories. It may b be combine ed with PGE2 and d mifepristo one (anti-p progesterone) to prod duce moree powerful uterine c contraction. – T Treatment of open n-angle g glaucoma: to dilate e uveoscleeral vesseels and e enhance uveoscleral u l outflow (↑ drainage)) of aqueou us humor ((Latanopro ost). Thrromboxanes and leu s: they hav ukotrienes ve NO currrent clinicaal uses. █ INHIBITORS OF O EICOSA ANOIDS Corrticosteroids: they inhibit pphos- phoolipase A2 enzyme and co onse- queently inhibit synthesis of ALL L the osanoids family (s eico see endoc crine phaarmacologyy). Nonn-steroida al anti--inflamma atory drugs (NSA AIDs): they inhibit cy- cloo oxygenasee enzyme: – Cla assical N pirin) NSAIDs (e.g. asp inhiibit all COX enzyme e non- sele ectively. – Newwer NSAIIDs (e.g. celecoxib)) in- hibit COX-2 selectively. s Leu ukotriene inhibitors: i : Zaffirlukast an nd Montelukast: – They blocck leukotrie ene recepto ors. – They are absorbed a orally. o Zafiirlukast it is given tw wice daily b but Montelukast is given once daily. – Uses: LTss receptor antagonissts are new w drugs to be used inn the treatment of bronchiall asthma and a other i nflammato ory conditio ons. Zile euton: – It inhibits 5-lipooxyg genase enzzyme leading to decrrease LTs ssynthesis. – Uses: treaatment of bronchial b asthma and other in nflammato ry conditioons. 121