Prostaglandins and Leukotrienes

Prostaglandins and Leukotrienes  


     The eicosanoids are a group of substances derived from phospholipids. These substances are found in animals and plants where they display a wide variety of biological activities. In humans, they are available in all tissues of the body and are often formed de novo. The student should reflect on the pathogenesis and pharmacotherapy of many diseases – pain and inflammation, spontaneous abortion, asthma, peptic ulcer, thrombosis etc. Indeed knowledge of the eicosanoids has revolutionized the pharmacotherapy of pain and inflammation. The mechanisms of action of NSAIDs and glucocorticoids cannot be fully discussed without mention of their effects on eicosanoid biosynthesis.  The term eicosanoids as used in this lecture refers to prostagladins, thromboxanes, leukotrienes and lipoxins all of which are derived from arachidonic acid (eicosatetraenoic acid). The term, prostanoids encompasses both prostaglandins and thromboxanes both of which have the same synthetic origin. 


     The precursor of the eicosanoids is arachidonic acid (5,8,11,14-eicosatetraenoic acid), a 20-carbon unsaturated fatty acid that is found in esterified form in phospholipids and glycerides of cell membranes. Phospholipids exist as: phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine and diacylglycerol. Liberation of arachidonic acid (AA) from phospholipids may involve one or two steps. One-step process involves phospholipase A2 (PLA2) but the two-step process involves first phospholipase C (PLC) and diacylglycerol (DAG) lipase (or phospholipase D), and then finally PLA2. There are at least two forms of PLA2 – cytosolic and extracellular but the former is by far more important from the point of view of inflammation and is Ca2+-dependent. Certain factors which include antigen-antibody reactions, cell damage as well as thrombin in platelets, C5a in neutrophils and bradykinin in fibroblasts all trigger the release of AA. Arachidonic acid is metabolized through the cyclooxygenase pathway to form prostaglandins and thromboxanes or through the lipoxygenase pathways to form leukotrienes, the lipoxins and other compounds (Fig 2, page 6). 

      The Prostanoids These are formed by the action of cyclooxygenase [(COX) which may also be referred to as prostaglandin endoperoxide synthase] on AA. There are two forms of COX: COX-1 which is constitutive and is found in most cells. The action of COX-1 may involve normal homeostasis (e.g. actions on vascular responses as well as gastric cytoprotection). COX-2 is more pertinent to inflammation and is induced following an inflammatory stimulus. The enzyme converts AA to unstable PGG2 first and then PGH2 both of which are called cyclic endoperoxides. PGH2 is the immediate precursor of other prostanoids and the eventual product depends on the cell: TXA2 in platelets, PGE2 in macrophages, PGD2 in mast cells, PGI2 in vascular endothelium and the GIT. The term “prostaglandin” (PG) was coined from the observation by early workers that extracts of semen contracted the isolated uterus. While PGE was partitioned into ether, PGF was partitioned into phosphate (Fosfat in Swedish) buffer. PGA and PGB were artifacts stable in acidic and basic media respectively. Other PGs were named to fill the gaps. The subscript refers to the number of double bonds in the molecule. α – refers to the orientation of the hydroxy group above or below the plane of the ring. Action of COX on eicosatrienoic acid results in only a single bond as in PGE1. 

    Pharmacokinetics They are metabolized by several intracellular PG-specific enzymes which are very abundant in the lungs and then slowly by general fatty acid oxidizing enzymes at β-, ω-, 15-hydroxyl positions to the corresponding ketones. The products are excreted in the urine. The t½ of most PGs in circulation is less than 1 minute. PGI2 (t½ = 5 mins) is metabolized to 6-ketoPGF1α.  


    Pharmacological Actions The receptors for the prostanoids have been named one each for the natural prostanoids, PGD2, PGF2α, PGI2, TXA2, and PGE2 as DP, FP, IP, TP, and EP-receptors respectively. EP receptors may further be sub-divided into EP1, EP2, EP3-receptors. The effects of the various PGs vary with tissues and animal species. Therefore, their actions may be confusing in many cases. 


    1. PGD2 acting on DP receptors causes vasodilatation, inhibition of platelet aggregation, relaxation of GIT smooth muscle, and uterine relaxation. Signal transduction involves adenylate cyclase and an increase in cAMP. 

    2. PGF2α acts on FP receptors causing myometrial contractions in humans, luteolysis in some species (e.g cattle) bronchoconstriction in others (cats and dogs). It is said to mediate release of gonadotrophins and prolactin. Signal transduction involves IP3 generation and increased intracellular Ca2+. 

    3. PGI2 (prostacyclin) acts on IP receptors and causes vasodilatation, inhibition of platelet aggregation, renin release, and natriuresis. Signal transduction involves increased generation of cAMP. 

    4. TXA2 acting on TP-receptors causes vasoconstriction, platelet aggregation and possibly bronchoconstriction. Signal transduction involves IP3.

     5. PGE2 has many actions: - Acting on EP1 receptors, it causes contraction of the bronchial and GI smooth muscles. This involves IP3 - Acting on EP2 receptors causes bronchodilatation, vasodilatation, stimulation of intestinal fluid secretion and relaxation of GI smooth muscles. It involves cAMP generation. - EP3 stimulation results in the contraction of GI smooth muscles, inhibition of gastric secretion, increased gastric mucus secretion and stimulation of contraction of the pregnant uterus. Signal transduction involves inhibition of adenylate cyclase and decrease in cAMP. - It may stimulate the release of erythropoietin from the kidney. - PGE2 is hyperalgesic. PGE1 and PGE2 cause increase in body temperature although it is not clear which receptors mediate this. 


    The student is advised to study the role of the prostanoids in acute and chronic inflammatory responses.

    Clinical uses

     The prostanoids are used in a wide variety of clinical conditions: 1. Obstetrics and Gynaecology. PGE2 (Dinoprostone) and its analog misoprostol are given per vagina for abortions. Dinoprostone is also given per vagina for ripening of the cervix for induction of labour in pregnancy at term. It is also used for the management of post-partum haemorrhage when there is no response to oxytocics. PGF2α (Carboprost) is no longer used via intra amniotic route for abortions in countries like USA but may still be used to facilitate labour in some countries. Vaginal application of these PGs limits side effects as the drug can very easily be retrieved.

     2. PGE1 (Aprostadil) which causes vasodilatation can be injected intracavernosally for the management of male erectile dysfunction. It may also be combined with drugs such as papaverine or phentolamine for this purpose. Penile pain is a disadvantage but priapism is less common. Suppository formulation may remove the cumbersome nature of injection into the penis. The introduction of penile-specific phosphodiesterase inhibitors such as sildanefil has limited the use of aprostadil.

     3. Gastroenterology. PGE2 analog Misoprostol is used to prevent gastric and duodenal ulcers particularly in patients taking NSAIDs although the advent of selective COX-2 inhibitors seems to have limited this application to some extent. 

    4. Alprostadil (PGE1) is given i.v. for the maintenance of the patency of the ductus arteriosus prior to surgery. 

    5. To inhibit platelet aggregation during haemodialysis, PGI2 preparation (Epoprostenol) is used.

     6. Latanoprost is a stable long-acting PGF2α derivative that is used as eye drops in glaucoma.  


    The Role of Prostanoids in Pain, Inflammation and Fever

     At the initiation of acute inflammatory process, PGE2 and PGI2 are released from the local tissues including blood vessels. Mast cells also release PGD2 which is hyperalgesic. In chronic inflammation, monocytes/macrophages also release PGE2 and TXA2. These PGs cause vasodilatation which account for the redness and increased blood flow to the site of inflammation. They potentiate the effect of substances such as histamine and bradykinin in causing increased vascular permeability. PGD2 for example also potentiates the hyperalgesic effect of bradykinin. PGE series are believed to be involved in the production of fever because high concentrations of these PGs are found in CSF during infections. The anti-pyretic effect of the NSAIDs is believed to be via the inhibition of PGs synthesis. 

       The Leukotrienes 

    Arachidonic acid may also be metabolized through 5-, 12-, and 15-lipoxygenase pathways (Figure 2). Lipoxygenases are soluble cytosolic enzymes found in the lungs, platelets, mast cells and white blood cells. The most actively investigated are the products of 5-lipoxygenase – leukotrienes (leuko = from leukocytes; triene = conjugated triene ring system, abbreviated LTs). The pathway is of great importance as it is associated with asthma and anaphylactic shock. LTC4, LTD4, LTE4 and LTF4 are all referred to as the cysteinyl-leukotrienes. The first three constitute the so-called slow reacting substances of anaphylaxis (SRS-A).

    The receptors for leukotrienes are named after the type (e.g. LTC4 receptor). Signal transduction involving the leukotrienes results in the generation of IP3 and consequently, increased intracellular Ca2+ concentration. 

    LTE4 is less potent than LTC4 and LTD4 in causing dose-related contraction of human bronchiolar muscle in vitro. The leukotrienes also cause increase in mucus secretion. In the cardiovascular system, they may cause decrease in blood pressure and significant vasoconstriction in small coronary vessels. These leukotrienes also cause wheal and flare as histamine. LTB4 causes the production of oxygen radicals in neutrophils and stimulates cytokine release from macrophages and lymphocytes. 


     LTB4 is metabolized to 20-hydroxy-LTB4 by a membrane-bound cytochrome P450 enzyme (which is found in neutrophils) and then to its 20-carboxyderivative. LTC4 and LTD4 are metabolized to LTE4 by γglutamyl transpeptidase and then a dipeptidase.  The metabolic products of LTE4 are then excreted in urine. 

     Clinical uses 

    Agents which inhibit 5-lipoxygenase pathway are now used as anti-asthmatic agents. For example the drug Zileuton has a bronchodilator effect in human and is currently prescribed for asthma.

     Evidence that they contribute to the early and late phases of asthma has led to the emergence of receptor antagonists. Zafirlukast is used as an adjunct to other anti-asthmatic drugs while montelukast is used for the prevention of acute attack. Many other receptor antagonists are being developed

    Leukotrienes and Inflammation There are scientific evidences that the cysteinyl-leukotrienes may be involved in some inflammatory conditions such as rheumatoid arthritis, psoriasis and ulcerative colitis. These LTs are detectable in the sputum of patients with chronic obstructive airway diseases and the exudates of allergic rhinitis. LTB4 is a powerful chemotatic agent for neutrophils and macrophages. It has been found in inflammatory sites and may play significant roles in rheumatoid arthritis, psoriasis and ulcerative colitis. However, it is not yet known whether drugs which interfere with the actions of these LTs will emerge someday as antiinflammatory drugs

    Questions 1. Present a scheme for the biosynthesis of PGI2 and PGF2α and discuss their clinical uses. 2. Write an essay entitled “Leukotrienes and their pharmacological relevance”   


    Figure 2. Schematic representation of the pathways for the synthesis of the eicosanoids. The intermediate unstable products such as the cyclic endoperoxides (PGG2 and PGH2) are not shown. The various synthase enzymes (e.g. prostacyclin synthase) are also not shown. The focus of the lecture is on products of cyclooxygenase and 5-lipoxygenase pathways. PLA2, phospholipase A2; AA, arachidonic acid (arachidonates); HETE, hydroxyeicosatetraenoic acid; PG, prostaglandin; LT, leukotriene; TXA, thromboxane; PAF, platelet activating factor. Modified from Textbook of Pharmacology by Rang HP, Dale MM and Ritter JM (1995). Churchill Livingstone, Londo

    Prof. Ray I.O. 
    Pharmacol & Toxicol Uniben 
    November, 2015 

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