Prostaglandins, Thromboxanes, and Leukotrienes PDF

Prostaglandins, Thromboxanes and Leukotrienes PROSTAGLANDINGS (PG), THROMBOXANES (TX) AND LEUCKOTRIENES (LT) [EICOSANOIDS] Eicosanoids Chemistry Eicosanoids are signaling molecules made by the enzymatic or...

Prostaglandins, Thromboxanes and Leukotrienes PROSTAGLANDINGS (PG), THROMBOXANES (TX) AND LEUCKOTRIENES (LT) [EICOSANOIDS] Eicosanoids Chemistry Eicosanoids are signaling molecules made by the enzymatic or non- enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid. Arachidonic acid is is formed by biosynthesis of linoleic acid and can be deposited in animal fats. It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Arachidonic acid is important for cell membrane and provides energy for body functions. Some eicosanoids, such as prostaglandins, may also have endocrine roles as hormones to influence the function of distant cells. There are multiple subfamilies of eicosanoids, including most prominently the prostaglandins, thromboxanes, leukotrienes, lipoxins, resolvins, and eoxins. In the body PGs, TXs and LTs are all derived from eicosa (referring to 20 C atoms) tri/tetra/penta enoic acids. Therefore, they can be collectively called eicosanoids. Eicosanoids typically are not stored within cells but rather synthesized as required. They derive from the fatty acids that make up the cell membrane and nuclear membrane Eicosanoids are the most universally distributed autacoids in the body. Practically every cell and tissue is capable of synthesizing one or more types of PGs or LTs. Functions Eicosanoids Function In Diverse Physiological Systems And Pathological Processes Such As: Mounting Or Inhibiting Inflammation, Allergy, Fever and Other Immune Responses; Regulating The Abortion Of Pregnancy And Normal Childbirth; Contributing To The Perception Of Pain; Regulating Cell Growth; Controlling Blood Pressure; And Dept of Pharmacology, School of Pharmacy, MIT-WPU, Pune Page 1  Prostaglandins, Thromboxanes and Leukotrienes Modulating The Regional Flow Of Blood To Tissues. Prostaglandins Prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals.Chemically, PGs may be considered to be derivatives of prostanoic acid, though prostanoic acid does not naturally occur in the body. It has a five membered ring and two side chains projecting in opposite directions Prostaglandins are powerful, locally-acting vasodilators and inhibit the aggregation of blood platelets. Through their role in vasodilation, prostaglandins are also involved in inflammation. They are synthesized in the walls of blood vessels and serve the physiological function of preventing needless clot formation, as well as regulating the contraction of smooth muscle tissue Thromboxanes Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. Thromboxane-A synthase, an enzyme found in platelets, converts the arachidonic acid derivative prostaglandin H2 to thromboxane. Thromboxane is a vasoconstrictor and a potent hypertensive agent, and it facilitates platelet aggregation. Thromboxane A2 (TXA2), produced by activated platelets, has prothrombotic properties, stimulating activation of new platelets as well as increasing platelet aggregation. Their name comes from their role in clot formation (thrombosis). The widely used drug aspirin acts by inhibiting the ability of the COX enzyme to synthesize the precursors of thromboxane within platelets. Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. Leukotrienes Leukotrienes are so named because they were first obtained from leukocytes (leuko) and have 3 conjugated double bonds (triene). Dept of Pharmacology, School of Pharmacy, MIT-WPU, Pune Page 2  Prostaglandins, Thromboxanes and Leukotrienes Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase. The production of leukotrienes is usually accompanied by the production of histamine and prostaglandins, which also act as inflammatory mediators One of their roles (specifically, leukotriene D4) is to trigger contractions in the smooth muscles lining the bronchioles; their overproduction is a major cause of inflammation in asthma and allergic rhinitis. Leukotriene antagonists are used to treat these disorders by inhibiting the production or activity of leukotrienes Synthesis There are no preformed stores of PGs and LTs. They are synthesized locally and the rate of synthesis is governed by the rate of release of arachidonic acid from membrane lipids in response to appropriate stimuli. Eicosanoids are signaling molecules made by the enzymatic or non- enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid. The key enzymes involved in eicosanoid biosynthesis are cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 (CYP) enzymes. Eicosanoids are synthesized through the enzymatic oxidation of polyunsaturated fatty acids (PUFAs), primarily arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). The key enzymes involved in eicosanoid biosynthesis are cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 (CYP) enzymes. 1. Cyclooxygenase Pathway The COX pathway is responsible for the production of prostaglandins (PGs) and thromboxanes (TXs) from AA. This pathway is initiated by the enzyme phospholipase A2 (PLA2), which cleaves AA from the phospholipid membrane. The free AA is then converted into prostaglandin G2 (PGG2) through a series of enzymatic reactions. Dept of Pharmacology, School of Pharmacy, MIT-WPU, Pune Page 3  Prostaglandins, Thromboxanes and Leukotrienes The key enzyme in this pathway is cyclooxygenase (COX), also known as prostaglandin- endoperoxide synthase. COX catalyzes the oxygenation of AA to prostaglandin H2 (PGH2). There are two isoforms of COX: COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and plays a role in maintaining homeostatic functions, such as gastric cytoprotection and platelet aggregation. In contrast, COX-2 is inducible and upregulated during inflammation and other pathological conditions. It is primarily responsible for the production of prostaglandins involved in pain, inflammation, and fever. 2. Lipoxygnease pathway The LOX pathway involves the enzymatic oxidation of AA, EPA, or DHA by lipoxygenase enzymes. LOX enzymes are classified based on their positional specificity of oxygenation on the fatty acid chain. For example, 5-lipoxygenase (5-LOX) primarily acts on AA, while 15-lipoxygenase (15-LOX) acts on both AA and EPA. In the LOX pathway, the fatty acid is converted into hydroperoxyeicosatetraenoic acids (HPETEs), which serve as intermediates for the synthesis of leukotrienes and lipoxins. 5-LOX converts AA to 5-HPETE, which is further metabolized into leukotriene A4 (LTA4). LTA4 can be enzymatically converted into various leukotrienes, such as leukotriene B4 (LTB4), leukotriene C4 (LTC4), and leukotriene D4 (LTD4). Leukotrienes are potent mediators of inflammation and immune response. They play important roles in allergic reactions, asthma, and other inflammatory diseases. Lipoxins, on the other hand, are anti-inflammatory in nature and contribute to the resolution of inflammation. 3. Cytochrome P450 (CYP) Pathway The CYP route entails the cytochrome P450 enzymes' metabolism of PUFAs, mainly AA. In order to create epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs), these enzymes catalyze the oxygenation of AA. EETs have a significant role in controlling inflammation and vascular tone. Dept of Pharmacology, School of Pharmacy, MIT-WPU, Pune Page 4  Prostaglandins, Thromboxanes and Leukotrienes They influence blood pressure regulation and have vasodilatory effects. On the other hand, HETEs display a variety of actions based on the particular metabolite and its site of action. While some HETEs have a role in the control of vascular tone and immune response, others have pro-inflammatory characteristics. Lung and spleen can synthesize the whole range of COX products. Platelets primarily synthesize TXA2 which is—chemically unstable, spontaneously changes to TXB2. Endothelium mainly generates prostacyclin (PGI2) Lipoxygenase pathway appears to operate mainly in the lung, WBC and platelets. It is believed that eicosanoids produced by COX-1 participate in physiological (house keeping) functions such as secretion of mucus for protection of gastric mucosa, haemostasis and maintenance of renal function, while those produced by COX-2 lead to inflammatory and other pathological changes Dept of Pharmacology, School of Pharmacy, MIT-WPU, Pune Page 5  Prostaglandins, Thromboxanes and Leukotrienes Inhibition of synthesis Synthesis of COX products can be inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). Aspirin acetylates COX at a serine residue and causes irreversible inhibition while other NSAIDs are competitive and reversible inhibitors. NSAIDs do not inhibit the production of LTs Glucocorticosteroids inhibit the release of arachidonic acid from membrane lipids (by stimulating production of proteins called annexins which inhibit phospholipase A2)—indirectly reduce production of all eicosanoids. Degradation: Biotransformation of arachidonates occurs rapidly in most tissues, but fastest in the lungs. Most PGs, TXA2 and prostacyclin have plasma t½ of a few seconds to a few minutes. eicosanoids—PGs, TXs and LTs. Metabolites are excreted in urine. PGI2 is catabolized mainly in the kidney. PHYSIOLOGICAL ROLES (PG AND TX) CVS PGE2 and PGF2α cause vasodilatation in most, but not all, vascular beds. PGF2α constricts many larger veins including pulmonary vein and artery. Fall in BP occurs when PGE2 is injected i.v., but PGF2α has little effect on BP Platelets TXA2, which can be produced locally by platelets, is a potent inducer of aggregation and release reaction. On the other hand, PGI2 (generated by vascular endothelium) is a potent inhibitor of platelet aggregation. Aspirin interferes with haemostasis by inhibiting platelet aggregation. TXA2 produced by platelet COX-1 plays an important role in amplifying aggregation.Thus, in low doses, aspirin selectively inhibits TXA2 production and has antithrombotic effect lasting > 3 days. Uterus PGE2 and PGF2α uniformly contract Human uterus, in vivo, both pregnant as well as nonpregnant. The sensitivity is higher during pregnancy Bronchial muscle Dept of Pharmacology, School of Pharmacy, MIT-WPU, Pune Page 6  Prostaglandins, Thromboxanes and Leukotrienes PGF2α, PGD2 and TXA2 are potent bronchoconstrictors (more potent than histamine) while PGE2 is a powerful bronchodilator. PGI2 produces mild dilatation. Asthmatics are more sensitive to constrictor as well as dilator effects of PGs GIT In isolated preparations, the longitudinal muscle of gut is contracted by PGE2 and PGF2α while the circular muscle is either contracted (usually by PGF2α) or relaxed (usually by PGE2). Kidney PGE2 and PGI2 increase water, Na+ and K+ excretion and have a diuretic effect. PGE2 has been shown to have a furosemide-like inhibitory effect on Cl¯ reabsorption as well. PGE2 antagonizes ADH action, and this adds to the diuretic effect CNS PGs injected i.v. penetrate brain poorly, so that central actions are not prominent. However, injected intracerebroventricularly PGE2produces a variety of effects—sedation, rigidity, behavioral changes and marked rise in body temperature. ANS Depending on the PG, species and tissue, both inhibition as well as augmentation of NA release from adrenergic nerve endings Eye: PGF2α induces ocular inflammation and lowers i.o.t by enhancing uveoscleral and trabecular outflow. Endocrine system PGE2 facilitates the release of anterior pituitary hormones—growth hormone, prolactin, ACTH, FSH and LH as well as that of insulin and adrenal steroids. Metabolism PGEs are antilipolytic, exert an insulin like effect on carbohydrate metabolism Side Effects of PG 1. Nausea, 2. Vomiting, 3. Watery Dept of Pharmacology, School of Pharmacy, MIT-WPU, Pune Page 7  Prostaglandins, Thromboxanes and Leukotrienes 4. Diarrhoea, 5. Uterine cramps, 6. Unduly forceful 7. Uterine contractions, 8. Vaginal bleeding, 9. Flushing, 10. Shivering, 11. Fever, 12. Malaise, 13. Fall in BP, 14. Tachycardia, 15. Chest pain. Uses of PG Clinical application of PGs and their analogues is rather restricted because of limited availability, short lasting action, cost and frequent side effects. However, their use in glaucoma and in obstetrics is now common place. 1. Peptic ulcer: Stable analogue of PGE1 (misoprostol) is occasionally used for healing peptic ulcer 2. Glaucoma: To maintain patency of ductus arteriosus in neonates with congenital heart defects, till surgery is undertaken. 3. To avoid platelet damage: PGI2 (Epoprostenol) can be used to prevent platelet aggregation and damage during haemodialysis or cardiopulmonary bypass. It also improves harvest of platelets for transfusion. Few cases of primary pulmonary hypertension have been successfully maintained on epoprostenol infusion. 4. Peripheral vascular diseases: PGI2 (or PGE1) infused i.v. can relieve rest pain and promote healing of ischaemic ulcers in severe cases of intermittent claudication and in Raynaud’s disease. 5. Abortion Dept of Pharmacology, School of Pharmacy, MIT-WPU, Pune Page 8  Prostaglandins, Thromboxanes and Leukotrienes 6. Induction/augmentation of labour 7. Cervical priming (ripening) 8. Postpartum haemorrhage (PPH) THROMBOXANES Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring. Thromboxane is named for its role in blood clot formation (thrombosis). Thromboxane-A synthase, an enzyme found in platelets, converts the arachidonic acid derivative prostaglandin H2 to thromboxane. Thromboxane acts by binding to any of the thromboxane receptors, G-protein-coupled receptors coupled to the G protein Gq Biological roles Thromboxane is a vasoconstrictor and a potent hypertensive agent, and it facilitates platelet aggregation. It is in homeostatic balance in the circulatory system with prostacyclin, a related compound. The mechanism of secretion of thromboxanes from platelets is still unclear. They act in the formation of blood clots and reduce blood flow to the site of a clot. If the cap of a vulnerable plaque erodes or ruptures, as in myocardial infarction, platelets stick to the damaged lining of the vessel and to each other within seconds and form a plug. These "Sticky platelets" secrete several chemicals, including thromboxane A2 that stimulate vasoconstriction, reducing blood flow at the site. Thromboxanes Inhibitors Thromboxane inhibitors are broadly classified as either those that inhibit the synthesis of thromboxane, or those that inhibit the target effect of it. Thromboxane synthesis inhibitors, in turn, can be classified regarding which step in the synthesis they inhibit: The widely used drug aspirin acts by inhibiting the ability of the COX enzyme to synthesize the precursors of thromboxane within platelets. Dept of Pharmacology, School of Pharmacy, MIT-WPU, Pune Page 9  Prostaglandins, Thromboxanes and Leukotrienes Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks. Thromboxane synthase inhibitors inhibit the final enzyme (thromboxane synthase) in the synthesis of thromboxane. Ifetroban is a potent and selective thromboxane receptor antagonist. Dipyridamole antagonizes this receptor too, but has various other mechanisms of antiplatelet activity as well. High-dose naproxen can induce near-complete suppression of platelet thromboxane throughout the dosing interval and appears not to increase cardiovascular disease (CVD) risk, whereas other high-dose NSAID (non-steroidal-anti-inflammatory) regimens have only transient effects on platelet COX-1 and have been found to be associated "with a small but definite vascular hazard". The inhibitors of the target effects of thromboxane are the thromboxane receptor antagonist, including terutroban. Picotamide has activity both as a thromboxane synthase inhibitor and as a thromboxane receptor antagonist. Ridogrel is another example. And there are other inhibitors LEUCOTRIENES Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase Leukotrienes use lipid signaling to convey information to either the cell producing them (autocrine signaling) or neighboring cells (paracrine signaling) in order to regulate immune responses. The production of leukotrienes is usually accompanied by the production of histamine and prostaglandins, which also act as inflammatory mediators. One of their roles (specifically, leukotriene D4) is to trigger contractions in the smooth muscles lining the bronchioles; their overproduction is a major cause of inflammation in asthma and allergic rhinitis. Dept of Pharmacology, School of Pharmacy, MIT-WPU, Pune Page 10  Prostaglandins, Thromboxanes and Leukotrienes Leukotriene antagonists are used to treat these disorders by inhibiting the production or activity of leukotrienes. Synthesis Leukotrienes are synthesized in the cell from arachidonic acid by arachidonate 5-lipoxygenase. The catalytic mechanism involves the insertion of an oxygen moiety at a specific position in the arachidonic acid backbone. The lipoxygenase pathway is active in leukocytes and other immunocompetent cells, including mast cells, eosinophils, neutrophils, monocytes, and basophils. When such cells are activated, arachidonic acid is liberated from cell membrane phospholipids by phospholipase A2 Leukotrienes Roles CVS and blood LTC4 and LTD4 injected i.v. evoke a brief rise in BP followed by a more prolonged fall. Smooth muscle LTC4 and D4 contract most smooth muscles. They are potent bronchoconstrictors and induce spastic contraction of g.i.t. at low concentrations. They also increase mucus secretion in the airways. Afferent nerves Contributes to pain and tenderness of inflammation PROBABLE QUESTIONS 1. What are Eicosanoids? Explain their chemistry, synthesis, inhibition and degradation 2. Write down physiological role of PG and TX 3. Write Physiological role of LT 4. Write uses of PG with their adverse effects. Dept of Pharmacology, School of Pharmacy, MIT-WPU, Pune Page 11