EICOSANOIDS.Katzungdocx

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a are oxygenation products of polyunsaturated long-chain fatty acids are ubiquitous in the animal kingdom and are also found—  together with their precursors—in a variety of plants.

5,8,11,14-eicosatetraenoic acid the most abundant of the eicosanoid precursors is a 20-carbon (C20) fatty acid containing four double bonds (designated C20:4–6). must first be released or mobilized from the sn-2 position of membrane phospholipids by one or more lipases of the phospholipase A2 for eicosanoid synthesis to occur 3 classes of phospholipases mediate arachidonate release from membrane lipids: 1. cytosolic (c) PLA2- dominates the acute release of AA 2. secretory (s) PLA2- contributes under conditions of sustained or intense stimulation of AA production 3. calcium-independent (i) PLA2. ! - can also release AA !

Two unique COX isozymes convert AA into prostaglandin endoperoxides: 1. PGH synthase-1 is expressed constitutively in most cells. 2. PGH synthase-2 is inducible; its expression varies depending on the stimulus.  An immediate early-respo nse gene product produ ct that is markedly upregulated by shear stress, growth factors, tumor promoters, and cytokines. !

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the major source of prostanoids in inflammation and cancer

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 is the primary source of vascular prostacyclin (PGI2)

4 routes that oxygenate the AA 1. the cyclooxygenase (COX) 2. lipoxygenase 3. P450 epoxygenase 4. isoeicosanoid isoeicosanoid pathways

promote the uptake of two molecules of oxygen by cyclization of arachidonic acid to yield a C9–C11 endoperoxide C15 hydroperoxide Meclofenamate and ibuprofen are approximately equipotent on COX-1 and COX-2

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prostanoids are important for normal renal development and maintenance of function

Factors determining the type of eicosanoid synthesized: 1. the substrate lipid species 2. the type of cell 3. the manner in which the cell is stimulated !

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C9–C11 endoperoxide C15 hydroperoxide- rapidly modified by the peroxidase moiety of the COX enzyme to add a 15-hydroxyl group that is essential for biologic activity The , collectively termed the , are generated from  through the action of downstream isomerases and synthases The prostaglandins differ from each other in two ways: 1. in the substituents of the pentane ring (indicated by the last letter, eg, E and F in PGE and PGF) 2. in the number of double bonds in the side chains (indicated by the subscript, eg, PGE1, PGE2). PGH2 is metabolized by synthases (PGIS, TXAS, and PGFS) to !, respectively 1

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9,11-endoperoxide reductase and 9-ketoreductase- 2 additional enzymes that provide for PGF2" synthesis from PGH2 and PGE2, respectively.  At least  have been identified: 1. microsomal (m) PGES-1 2. mPGES-2- the more readily inducible 3. cytosolic PGES- the more readily inducible two distinct PGDS isoforms 1. lipocalin-type PGDS 2. hematopoietic PGDS

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Several products of the arachidonate series with clinical importance: DRUG  Alprostadil

Misoprostol,

PGE2 PGF2 Latanoprost Prostacyclin (PGI2, epoprostenol)

CLINICAL INDICATIONS may be used for its smooth muscle relaxing effects to maintain the ductus arteriosus patent in some neonates awaiting cardiac surgery and in the treatment of impotence. cytoprotective prostaglandin used in preventing peptic ulcer and in combination with mifepristone (RU-486) for terminating early pregnancies. used in obstetrics to induce labor topically active PGF2 " derivatives used in ophthalmology to treat open-angle glaucoma. synthesized mainly by the vascular endothelium and is a powerful vasodilator and inhibitor of platelet aggregation. It is used clinically to treat pulmonary hypertension and portopulmonary hypertension.

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- the primary product of 5-LOX, can be converted with appropriate stimulation via 12-LOX in platelets to the L and  in vitro  is a feature of psoriasis and ichthyosis

Specific isozymes of microsomal cytochrome P450 monooxygenases convert AA to hydroxy- or epoxyeicosatrienoic acids The products are: 20-HETE- generated by the CYP hydroxylases (CYP3A, o 4A, 4F) 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic o acids (EETs) - arise from the CYP epoxygenase (2J, 2C) EETs- have vasodilator effect except on pulmonary vasculature where they cause vasoconstriction.

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(TXA2)- has undesirable properties (aggregation of platelets, vasoconstriction ).  All the naturally occurring COX products undergo rapid metabolism to inactive products either by:  A. (for PGI2 and TXA2) B.  of the key 15-hydroxyl group to the corresponding ketone by prostaglandin 15-hydroxy prostaglandin dehydrogenase (15-PGDH) after cellular uptake via an organic anion transporter polypeptide (OATP 2A1). Further metabolism is by ,! , and "

are family of eicosanoid isomers, are formed nonenzymatically by  on AA and related lipid substrates.  are prostaglandin stereoisomers have potent vasoconstrictor effects when infused into renal and other vascular beds and may activate prostanoid receptors may modulate other aspects of vascular function, including leukocyte and platelet adhesive interactions and angiogenesis

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 for the formation of the isoprostanes, and its inhibition with aspirin or other NSAIDs should not affect the isoprostane pathway Peroxidation of arachidonate by free radicals- primary epimerization mechanism in the production of isoeicosanoids

eicosanoids act mainly in an fashion PGI2 (IP), PGF2" (FP), and TXA2 (TP) receptors- has a single gene product PGE2- have 4 receptors PGD2 – have 2 receptors LTB4 (BLT1 and BLT2) and the cysteinyl leukotrienes- both have 2 receptors !

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 AA (metabolized by hydroperoxyeicosatetraenoic acids (HPETEs) " hydroxy derivatives (HETEs) and leukotrienes and are potent bronchoconstrictors and are recognized as the primary components of the that is secreted in asthma and anaphylaxis. There are four current approaches to antileukotriene drug development: 1. 5-LOX enzyme inhibitors 2. leukotriene-receptor antagonists 3. inhibitors of FLAP 4. phospholipase A2 inhibitors.

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 All of these receptors are G protein-coupled

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have major effects on smooth muscle in the vasculature, airways, and gastrointestinal and reproductive tracts. 2

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 of smooth muscle is mediated by the release of , while relaxing effects are mediated by the generation of cAMP.

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SMOOTH MUSCLE

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- are also bronchodilators act principally on smooth muscle in peripheral airways and are a thousand times more potent than histamine, both in vitro and in vivo also stimulate bronchial mucus secretion and cause mucosal edema

PROSTAGLANDINS !

PLATELET

potent vasoconstrictor smooth muscle cell * and is the  that has convincingly been shown to have this effect.

Low concentrations of PGE2 enhance platelet aggregation (via EP3), whereas higher concentrations inhibit (via IP) Both  inhibit aggregation TXA2 is the major product of COX-1, the only COX isoform expressed in mature platelets. Itself a platelet aggregator, TXA2 amplifies the effects of other, more potent, platelet agonists such as thrombin. Platelet COX-1-derived TXA2 biosynthesis is increased during platelet activation and aggregation and is irreversibly inhibited by chronic administration of aspirin at low doses !

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PGE2 

KIDNEY

PGI2 

medulla and the cortex of the kidney synthesize prostaglandins, the medulla substantially more than the cortex COX-1 is expressed mainly in cortical and medullary collecting ducts and mesangial cells, arteriolar endothelium, and epithelial cells of Bowman’s capsule. COX-2 is restricted to the renal medullary interstitial cells, the macula densa, and the cortical thick ascending limb. major renal eicosanoid products are , followed by PGF2" and TXA2 also synthesizes several hydroxyeicosatetraenoic acids, leukotrienes, cytochrome P450 products, and epoxides   play important roles in maintaining blood pressure and regulating renal function, particularly in marginally functioning kidneys and volume-contracted states. renal cortical COX-2-derived PGE2 and PGI2 maintain renal blood flow and glomerular filtration rate through their local vasodilating effects   increase medullary blood flow and inhibit tubular sodium reabsorption, while products promote salt excretion in the collecting ducts. Loop diuretics, eg, furosemide, produce some of their effect by stimulating COX activity. patient response to a loop diuretic is diminished if a COX o inhibitor is administered concurrently TXA2 causes intrarenal vasoconstriction (and perhaps an ADHlike effect), resulting in a decline in renal function. Hypertension is associated with increased TXA2 and decreased PGE2 and PGI2 synthesis increased TXA2 formation has been reported in o -induced nephrotoxicity !

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PGD2 

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 is potentiated by exposure of smooth muscle cells to testosterone, which up-regulates smooth muscle cell TP expression !

 Another vasoconstrictor is the

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PGF2 !

PGF2 !

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PROSTAGLANDINS

PGE2 ( 

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PGI2- 

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PGE2  PGE2 or PGF2 !

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PROSTAGLANDINS Contraction by TXA2 !

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REPRODUCTIVE ORGANS (FEMALE) !

Uterine muscle is

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BONE METABOLISM !

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 cause . PGF2", together with oxytocin, is essential for the onset of parturition.

REPRODUCTIVE ORGANS (MALE) !

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 A major source of these prostaglandins is the seminal vesicle; the prostate, despite the name “prostaglandin,” and the testes synthesize only small amounts. Smooth muscle-relaxing prostaglandins such as PGE1 enhance penile erection by relaxing the smooth muscle of the corpora cavernosa

CNS and PNS 1.

FEVER PGE2 increases body temperature, predominantly via EP3 , whereas # PGD2 and TXA2 do not Endogenous pyrogens release interleukin-1, which in turn promotes the synthesis and release of PGE2 ! synthesis is blocked by aspirin and other antipyretic compounds. SLEEP  induces natural sleep    infusion into the posterior hypothalamus causes . NEUROTRANSMISSION PGE compounds inhibit the release of norepinephrine from postganglionic sympathetic nerve endings Both COX-1 and COX-2 are expressed in the spinal cord and release prostaglandins in response to peripheral pain stimuli

also induces chemotaxis and migration of TH2 lymphocytes

  are abundant in skeletal tissue and are produced by osteoblasts and adjacent hematopoietic cells increase bone turnover o

EYE !

PGE and PGF derivatives lower intraocular pressure

CANCER !

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In familial polyposis coli, COX inhibitors significantly decrease polyp formation , which is considered the principal oncogenic prostanoid, facilitates tumor initiation, progression, and metastasis through multiple biologic effects, increasing proliferation and angiogenesis, inhibiting apoptosis, augmenting cellular invasiveness, and modulating immunosuppression

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Blood Cells and Inflammation

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LTB4 chemoattractant 

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cysteinyl leukotrienes 

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Heart and Smooth Muscle

INFLAMMATORY AND IMMUNITY !

PGE2 and PGI2 are the predominant prostanoids associated with inflammation enhance edema formation and leukocyte infiltration PGE2 and PGI2, through activation of EP2 and IP, respectively, increase vascular permeability and leukocyte infiltration. TXA2 can also increase platelet-leukocyte interactions. PGE2 suppresses the immunologic response by inhibiting differentiation of B lymphocytes into antibody-secreting plasma cells PGD2, a major product of mast cells, is a potent chemoattractant for eosinophils

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 promotes vascular smooth muscle cell proliferation and migration at low concentrations  reduce myocardial contractility and coronary blood flow, leading to cardiac depression. Human colonic epithelial cells synthesize , a chemoattractant for neutrophils. The , are potent bronchoconstrictors and cause increased micro- vascular permeability, plasma exudation, and mucus secretion in the airways 20-HETE, which potently blocks the smooth muscle cell Ca2+-activated K+ channel and leads to vasoconstriction of the renal arteries " HPN !

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lipoxin A and lipoxin B 

Renal System

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diseases because, unlike oxytocin, they have no antidiuretic effect. !

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  block all the known pathways of eicosanoid synthesis. - They inhibit phospholipase A2 activity, probably by interfering with phospholipid binding, thus preventing the release of arachidonic acid. NSAIDs (eg, - block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity.  is an irreversible COX inhibitor. 5-LOX inhibitor ( ) and selective antagonists of the CysLT1 receptor for leukotrienes ( and used clinically in mild to moderate asthma.

Dysmenorrhea ! !

 successfully inhibit the formation of these prostaglandins in patients with primary dysmenorrhea  is also effective in dysmenorrhea, but because it has low potency and is quickly hydrolyzed,

MALE REPRODUCTIVE ORGANS !

(PGE1) is a second-line treatment for erectile dysfunction o

 is a frequent side effect, which may be related to the algesic effects of PGE derivatives

RENAL SYSTEM FEMALE REPRODUCTIVE ORGANS

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PGE2 and PGF2" have potent oxytocic actions. ! by promoting uterine contractions ! a synthetic preparation of PGE2, is administered vaginally for oxytocic use. ! it is approved for , for , and   of the cervix for induction of labor in patients at or near term. !  A stimulates the contraction of the uterus through- out pregnancy. ! also directly affects the collagenase of the cervix, resulting in softening. Excreted in urine T " is 2.5- 5 mins. 20-mg dinoprostone vaginal suppository repeated at 3to 5-hour intervals – recommended dose for abortifacient purposes mean time to abortion is 17 hours, !  Antiprogestins (eg, ) have been combined with an oral oxytocic synthetic analog of PGE1 ( ) to produce early abortion. ! analog of PGF2" ! used to induce second-trimester abortions and to control postpartum hemorrhage that is not responding to conventional methods of management. SIDE EFFECTS: Prostaglandins have moderate AE, with a slightly higher incidence of nausea, vomiting, and diarrhea than that produced by oxytocin PGF2" has more gastrointestinal toxicity than PGE2 PGF2" is a bronchoconstrictor and should be used with caution in women with asthma both PGE2 and PGF2" pass the fetoplacental barrier, fetal toxicity is uncommon

Bartter’s syndrome – results when synthesis of prostaglandins is increased. ! characterized by low-to-normal blood pressure, decreased sensitivity to angiotensin, hyperreninemia, hyperaldosteronism, and excessive loss of K+

CARDIOVASCULAR SYSTEM ! !

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  lowers peripheral, pulmonary, and coronary vascular resistance PGI2 ( ) side effects include flushing, headache, hypotension, nausea, and diarrhea. prostacyclin analogs used also for pHPN may be delivered by subcutaneous or intravenous infusion.

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use of PGE1 and PGI2 compounds in Raynaud’s phenomenon and peripheral arterial disease

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COX inhibitors are often used to inhibit synthesis of PGE2 and so close the ductus.

BLOOD !

Chronic administration of low-dose aspirin " selectively and irreversibly inhibits platelet COX-1 without modifying the activity of systemic COX-1 or COX-2

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be superior to oxytocin for inducing labor in women with preeclampsia-eclampsia or cardiac and renal

RESPIRATORY SYSTEM ! ! ! !

  is a powerful bronchodilator when given in aerosol form " promotes  are both strong bronchoconstrictors and ! were once thought to be primary mediators in . leukotriene-receptor inhibitors (eg, are effective in asthma. Corticosteroids and cromolyn are also useful in asthma

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GASTROINTESTINAL SYSTEM !

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orally active synthetic analog of PGE1 approved indication is for prevention of NSAID-induced peptic ulcers

IMMUNE SYSTEM !

  to renal transplant patients has reversed the rejection process TXA2 increases during acute rejection - the first- line drugs used for treatment of acute rejection because of their lymphotoxic effects, inhibit both phospholipase and COX-2 activity. Inflammation  Aspirin has been used to treat arthritis Rheumatoid Arthritis Eicosanoids- amplify the inflammatory response

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GLAUCOMA !

a stable long-acting PGF2" derivative, was the first prostanoid used for glaucoma Other drugs are: , and o o

 Adverse effects include irreversible brown pigmentation of the iris and eyelashes, drying of the eyes, and conjunctivitis

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