Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes (PDF)

The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds  Eicosanoids are oxygenation products of polyunsaturated long-chain (20 Carbon) fatty acids. There are considered "local hormones" They have specific effects and they are multiple subfamilies of eicosanoi...

The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds  Eicosanoids are oxygenation products of polyunsaturated long-chain (20 Carbon) fatty acids. There are considered "local hormones" They have specific effects and they are multiple subfamilies of eicosanoids, e.g. Prostaglandins (PGs), Thromboxanes (TXs)&Leukotrienes (LTs). Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. The PGs, TXs and prostacyclin are collectively identified as Prostanoids.  The eicosanoids produce a wide range of biological effects on inflammatory responses, on the intensity and duration of pain and fever, and on reproductive function. They also play important roles in inhibiting gastrie acid secretion, regulating blood pressure through vasodilation or constriction, and inhibiting or activating platelet aggregation and thrombosis  1. Release of Arachidonic Acid Arachidonic acid is released from the phospholipid membrane by the action of phospholipase A2 (PLA2) in response to various stimuli. 2. Pathways of Eicosanoid Synthesis A. Cyclooxygenase Pathway (COX Pathway) Enzyme: Cyclooxygenase (COX-1 and COX-2) Products: Prostaglandins (PGs): These include PGD2, PGE2, PGF2q, and PG12 (prostacyclin). Thromboxanes (TXs): Mainly TXA2, which is involved in platelet aggregation and vasoconstriction.  B. Lipoxygenase Pathway (LOX Pathway) Enzyme: Lipoxygenases (5-LOX, 12-LOX, 15-LOX) Products: Leukotrienes (LTs): Such as LTB4, LTC4, LTD4, and LTE4, which are involved in inflammatory and allergic responses. Lipoxins: These are involved in the resolution of inflammation.  Synthesis: Prostaglandins are synthesized from arachidonic acid through the cyclooxygenase (COX) pathway. The key steps include: Arachidonic Acid Release: Phospholipase A2 releases arachidonic acid from membrane phospholipids. Cyclooxygenase Pathway: COX-1 and COX-2 enzymes convert arachidonic acid into prostaglandin G2 (PGG2) and then into prostaglandin H2 (PGH2). Specific Prostaglandins Synthesis: PGH2 is then converted into various prostaglandins (PGE2, PGD2, PGF2a), prostacyclin (PGI2), and thromboxanes (TXA2) by specific synthases Pharmacokinetics Absorption: Prostaglandin analogs are often administered via routes that bypass the gastrointestinal tract to avoid rapid degradation (e.g., intramuscular, intravenous, topical). Distribution: They have a high degree of protein binding and distribute widely in tissues. Metabolism: Rapidly metabolized in the lungs, liver, and kidneys primarily by oxidation and reduction. Excretion: Metabolites are excreted in urine and, to a lesser extent, in bile Pharmacodynamics Receptor Binding: Prostaglandins bind to specific G-protein- coupled receptors (EP, DP, FP, IP, TP receptors) on cell surfaces. Signal Transduction: Binding initiates intracellular signaling cascades (e.g., CAMP, calcium ion pathways). Mechanism of Action Vasodilation/Vasoconstriction: Prostaglandins can dilate or constrict blood vessels depending on the type (e.g., PGE2 causes vasodilation, TXA2 causes vasoconstriction). Inflammatory Response: They modulate inflammation by regulating cytokine release, leukocyte migration, and edema formation. Gastrointestinal Protection: PGE2 and PG12 protect the gastric mucosa by promoting mucus and bicarbonate secretion and maintaining mucosal blood flow. Platelet Aggregation: TXA2 promotes platelet aggregation, while PGI2 inhibits it. Smooth Muscle Function: They affect smooth muscle contraction in various organs, such as the uterus and bronchi. System Effects Cardiovascular System: Regulation of blood pressure, heart rate, and platelet function. Gastrointestinal System: Protection of the gastric mucosa, regulation of gastric acid secretion. Renal System: Regulation of renal blood flow and glomerular filtration rate. Respiratory System: Modulation of bronchial tone. Reproductive System: Induction of labor and control of menstrual flow. System Effects Obstetrics/Gynecology: Induction of labor (dinoprostone, misoprostol), management of postpartum hemorrhage. Gastroenterology: Prevention of NSAID-induced gastric ulcers (misoprostol). Cardiology: Treatment of pulmonary hypertension (epoprostenol). Ophthalmology: Management of glaucoma (latanoprost, bimatoprost). Neonatology: Maintenance of ductus arteriosus patency in congenital heart defects (alprostadil). Side Effects: Gastrointestinal: Diarrhea, nausea, vomiting. Cardiovascular: Hypotension, flushing, headache. Respiratory: Bronchospasm (rare). Reproductive: Uterine rupture or hyperstimulation (when used for labor induction). Ophthalmic: Eye irritation, changes in iris color (with glaucoma medications). Contraindications Pregnancy: Certain prostaglandins are contraindicated in pregnancy (except when used for labor induction) due to the risk of fetal harm. Asthma: Some prostaglandins can exacerbate asthma symptoms. Cardiovascular Disease: Patients with certain cardiovascular conditions may be at risk for adverse effects such as hypotension. Hypersensitivity: Known allergy to prostaglandin analogs. Prostaglandin-like drugs play vital roles in various medical fields, and understanding their synthesis, mechanisms, and clinical applications is crucial for their effective and safe use. LEUKOTRIENES ➤Leukotrienes are synthesized by leucocytes, mast cells, lung, spleen etc. by lipoxygenase pathway of arachidonic acid. ➤Leukotrienes are 20- Carbon polyenoic fatty acids having a number of substituents. ➤Depending upon the substitutions, they are divided into LTA, LTB, LTD, and LTE. ➤Each type is divided into sub-groups depending upon the number of double bonds which vary from 3-5. ➤Leukotrienes possess no rings in their structure but have three characteristic conjugated double bonds. BIOSYNTHESIS OF LEUKOTRIENES LEUKOTRIENES RECEPTORS ➤Leukotrienes are mainly show their effect by binding with G- Coupled receptors. In Coupled receptors ➤They show their action after binding with this receptors, and produce its action like inflammation, smooth muscle constriction etc. LEUKOTRIENES INHIBITORS ➤Zileuton is a 5-lipoxygenase inhibitor which prevents the formation of leukotrienes from arachidonic acid. ➤ Leukotrienes antagonists involves Montelukast, Zafrilukast, Pranlukast to treat allergy and asthma DEGRADATION OF LEUKOTRIENES Biological activity of leukotrienes is terminated by oxidation carried out by a specific enzyme i.e. cytochrome P450 followed by beta oxidation on carboxyl group n BIOCHEMICAL ACTION OF LEUKOTRIENES In general LTs appear to act as mediator in inflammation and anap ➤Leukotrienes are a hundred times more potent than histamine. ➤LT-C4, D4 or E4 causes capillary dilation and vascular permeability; they causes erythema and wheal formtion like histamine. ➤Action on Bronical Muscles: Inhalation of LTs (C4, D4 or E4) causes bronchospasm. So these leukotrienes are responsible for constriction of broncial muscles like in asthma. ➤LTs- C4 and D4 are potent stimulators of mucus secretion from the respiratory tract. ➤So prolonged use of aspirin depresses cyclooxygenase system and PG synthesis but it did not show its action on lipoxygenase. ➤Inhibitors of 5-lipoxygenase and leukotrienes receptor antagonists (like montelulast, zefirlukast) are used in the treatment of allergy and asthma THROMBOXANES Named so because they are identified first in thrombocytes, it Humen clot formation ➤Structure is similar to PGs, but have an oxygen atom in the cyclic ring and contains a six numbered heterocyclic oxane ring. ➤The most common thromboxane, TXA2, contains an additional oxygen atom attached both to carbon 9 and carbon 11 of the ring. ➤TXA2- Vasoconstriction and platelet aggregation thus helping clot formation. Inhibited by aspirin. Pharmacokinetic and pharmacodynamic studies of a thromboxane synthetase inhibitor, ozagrel, in rabbits: The pharmacokinetic and pharmacodynamic (PK/PD) characteristics of ozagrel, a new potent and selective thromboxane synthetase inhibitor, were investigated in rabbits after its intravenous, oral, and rectal administration. Serum level of TXB2 (the stable metabolite of TXA2), a direct pharmacological marker, was measured after each dosing. A marked reduction of serum TXB2 within 30 min was shown after the three routes of administration, reflecting rapid onset of action.. Due to rapid and complete absorption (i.e., Tmax; 20 min, bioavailability; 100%) and longer duration of pharmacological action after rectal dosing, the rectum offers a practical delivery route for ozagrel. An Emax model was employed to fit the pharmacological data, and IC50 and Emax for thromboxane synthetase inhibition were estimated to be 56.0 ng/ml and 94%, respectively. These pharmacodynamic parameters were incorporated into an integrated mathematical model to simulate the PK/PD profiles of ozagrel after i.v., oral, and rectal administration at lower (50 mg) and higher (200 mg) doses, and good agreement between the experimental and calculated values was achieved. The present PK/PD model may be useful for optimizing the therapeutic regimens of ozagrel  Role of A2 in platelet aggregation: Thromboxane A2 (TXA2), produced by activated platelets, has prothrombotic properties, stimulating activation of new platelets as well as increasing platelet aggregation. Platelet aggregation is achieved by mediating expression of the glycoprotein complex GP IIb/IIIa in the cell membrane of platelets. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot BIOSYNTHESIS OF THROMOBXANES  ACTION OF THROMOBOXANES ➤As the concentration of Ca2+ve increases in the cytoplasm it leads to clot formation and vasoconstiction. ➤Thromboxanes are vasocontrictor but prostacylins are vasodilator in nature FUNCTION OF THROMOBOXANES ➤ Thromboxane is a vasoconstrictor and a potent hypertensive ager it facilitates platelet aggregation. ➤It is in homeostatic balance in the circulatory system with prostacyclin, a related compound. ➤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 thromboxaneA2 vasoconstriction, reducing blood flow at the site. that stimulate INHIBITION OF THROMOBOXANES ➤ The main drug for thromboxone A2 inhibtion is Aspirin which acts by blocking COX enzyme. ➤Thromboxane synthase inhibitors inhibit the final enzyme (thromboxane synthase) in the synthesis of thromboxane. Drugs e.g. Ifetroban, Dipyridamole. ➤The thromboxane receptor antagonists includes terutroban. ➤Picotamide has activity both as a thromboxane sythase inhibitor and as a thromboxane receptor antagonist. Ridogrel is another example.