Coagulant & Anticoagulants Dr. Saurabh C. Khadse COAGULANTS • Several pathologic and toxicologic conditions can result in excessive bleeding from inadequate coagulation • Depending on the severity of the hemorrhagic condition, several blood coagulants are therapeutically used. • Vitamin K is effective in the treatment hemorrhagic condition • Vitamin K1 (phytonadione) is most often used therapeutically. • Vitamin K1 is safe for use in infants, pregnant womens • Phytonadione is more lipid soluble, has a faster onset than vitamin K3 (menadione) or vitamin K4 (menadiol sodium diphosphate) 10/4/2020 Saurabh Khadse 2 • Only advantage of vitamins K3 and K4 over vitamin K1 is that they dont require presence of bile for absorption • Vit K3 & K4 because are absorbed via a passive process directly from the intestine 10/4/2020 Saurabh Khadse 3 Role of Vitamin K in coagulation • Vitamin K helps to regulate the process of blood coagulation by helping in the formation of some coagulation factors • Without vitamin K, our bodies would be unable to control clot formation. • Vitamin K is required to produce coagulation factors II, VII, IX, and X 10/4/2020 Saurabh Khadse 4 Role of Vitamin K in activation of coagulation factors 10/4/2020 Saurabh Khadse 5 Scheme of blood coagulation and fibrinolysis.( vitamin K–dependent factor; †, inhibition 10/4/2020 Saurabh Khadse 6 by heparin and antithrombin III.) Examples of coagulants O O CH3 CH3 H3C O O Menadione Acetomenadione 2-methylnaphthalene-1,4-dione 2-methylnaphthalene-1,4-diyl diacetate Acetomenadione is also known as davitamon-K or Acetomenaphthone 10/4/2020 Saurabh Khadse 7 MOA of Menadione • Menadione acts as a vitamin K analogue • Which acts as a cofactor in the synthesis of Factor II, VII, IX, X in the liver. • The Vitamin K analogue is needed in the step of gamma carboxylation of these factors to activate them • which makes them capable of binding Ca ++ ions to phospholipid surfaces which is essential for the coagulation cascade. 10/4/2020 Saurabh Khadse 8 Anticoagulants and antiplatelet drugs • Venous thromboembolism (VTE) is a complicating condition responsible for high morbidity and mortality worldwide • Thrombotic disorders involves the major vasculature, heart, brain, and lungs • In the heart, a thrombotic condition may be involved in the disease state of acute myocardial infarction, valvular heart disease, unstable angina, and atrial fi brillation • as surgical procedures, such angioplasty and prosthetic heart valve replacement. • Thrombosis in lungs result in pulmonary embolism (PE). • In such cases two different classes of antithrombotic agents are used namely anticoagulants and antiplatelet drugs 10/4/2020 Saurabh Khadse 9 ORAL ANTICOAGULANTS • There are two different chemical classes of orally active anticoagulants Coumarin derivatives : Warfarin 1,3-indandiones : Anisindione 3-(α- acetonylbenzyl)-4-hydroxycoumarin 2-(p-methoxyphenyl)-1,3-indandione sodium10/4/2020 salt Saurabh Khadse 10 MOA of anti-coagulants • Activation (carboxylation) of coagulation factors requires reduced form of vitamin K • The warfarin like anticoagulants (i.e., vitamin K antagonists) exert their anticoagulant activity through the inhibition of vitamin K quinone reductase enzyme. • inhibition of vitamin K quinone reductase inhibits activation of the four coagulation factors • Therefore, warfarin like compounds acts as vitamin K antagonists 10/4/2020 Saurabh Khadse 11 MOA of warfarin like compounds 10/4/2020 Saurabh Khadse 12 SAR of warfarin like compounds in vivo formation of cyclic hemiketal conformer Coumarin derivatives with 3,4-substitution •Substitution of the lactone ring, specifically in positions 3 and 4 is important •The acidity of the proton on the 4-hydroxy group allows formation of water- soluble sodium salts • in vivo formation of cyclic hemiketal conformers is important for activity 10/4/2020 Saurabh Khadse 13 Platelet aggregation inhibitor • Antiplatelet drugs work by inhibiting platelet activation via a number of different mechanisms • The antiplatelet drugs are mainly used in patients with coronarydiseases • These drugs also are effective in combination with moderate- intensity anticoagulants for patients with atrial fibrillation. Clopidogrel is an antiplatelet agent, or blood thinner 10/4/2020 belonging to chemicalSaurabh class Khadse- thienopyridine 14 Platelet aggregation • Pathological formation of clots within the circulatory system creates serious clinical situation • Platelets bind to collagen in the vessel wall and trigger other platelets to adhere to them • Calcium binding to the platelet membrane cause adhesiveness • ADP released by the first few adhering cells further stimulates aggregation process. 10/4/2020 Saurabh Khadse 15 Inhibition of platelet aggregation • While, increased levels of cAMP inhibit platelet aggregation • cAMP activates specific dependent kinases, which form protein- phosphate complexes that chelate calcium ions. • The reduced levels of calcium inhibit aggregation • Inhibitors of platelet aggregation can increase cAMP levels by either stimulating adenylate cyclase or inhibiting phosphodiesterase 10/4/2020 Saurabh Khadse 16 Role of adenosine 3,5-cyclic monophosphate (cAMP) in inhibition of platelet aggregation ADP binds to platelet P2Y Purinergic Receptor & promotes platelet aggregation • Purinergic receptors P2Y1 and P2Y12 in platelet are activated by ADP • P2Y1 and P2Y12 are G protein-coupled purinergic receptors • Initial binding of ADP to the P2Y1 induces platelet shape changes, causes intracellular calcium mobilization, and initiates aggregation • Subsequent binding of ADP to the P2Y12 leads to sustained platelet aggregation by inhibiting adenylate cyclase and, thereby, decreasing cellular cAMP levels 10/4/2020 Saurabh Khadse 17 MOA of Clopidogrel • The antithrombotic drugs ticlopidine and clopidogrel are irreversible antagonists of P2Y12 purinergic receptor • Antagonism of P2Y12 receptor increases cellular cAMP levels • Increased cAMP levels initiates chelation of calcium ions • The reduced levels of calcium inhibits aggregation Clopidogrel 10/4/2020 Saurabh Khadse 18 10/4/2020 Saurabh Khadse 19 synthesis of warfarin 10/4/2020 Saurabh Khadse 20.