Understanding Coagulants, Anti-Coagulants, and Blood Components in Pharmaceuticals
Mrs. Sashmitha Samuel, an Associate Professor in the Department of Pharmaceutical Chemistry, delves into the importance of coagulants, anti-coagulants, and the components of blood. Blood, a vital fluid in the body, carries nutrients, oxygen, and helps remove waste products. Learn about the process of coagulation, from blood clot formation to haemostasis, and the roles of red and white blood cells, platelets, and plasma in maintaining health.
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COAGULANTS COAGULANTS & & ANTI COAGULANTS ANTI COAGULANTS Mrs.SASHMITHA SAMUEL M.Pharm. (Ph.D.) Associate Professor DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
BLOOD It is a constantly circulating body fluid in humans and other animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells. Blood is mostly liquid, with numerous cells and proteins suspended in it, making blood "thicker" than pure water. The average person has about 5 liters (more than a gallon) of blood. A liquid called plasma makes up about half of the content of blood. Plasma contains proteins that help blood to clot, transport substances through the blood, and perform other functions. Blood plasma also contains glucose and other dissolved nutrients. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 2
COMPONENTS OF BLOOD DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 3
About half of blood volume is composed of blood cells: Red blood cells, which carry oxygen to the tissues White blood cells, which fight infections Platelets, smaller cells that help blood to clot Blood is conducted through blood vessels (arteries and veins). Blood is prevented from clotting in the blood vessels by their smoothness, and the finely tuned balance of clotting factors. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 4
Coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in haemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves: Activation adhesion aggregation of platelets deposition and maturation of fibrin DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 5
Coagulation begins almost instantly after an injury to the blood vessel has damaged the endothelium lining the blood vessel. Exposure of blood to the subendothelial space initiates two processes: 1. changes in platelets, and 2. the exposure of subendothelial tissue factor to plasma factor VII, which ultimately leads to cross-linked fibrin formation. Platelets immediately form a plug at the site of injury; this is called primary haemostasis. Secondary haemostasis occurs simultaneously: additional coagulation (clotting) factors beyond factor VII respond in a cascade to form fibrin strands, which strengthen the platelet plug. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 6
BLOOD COAGULANTS The three main types of drug that are used to promote the formation of blood clots and to prevent or reduce abnormal bleeding are: blood products vitamin K and antifibrinolytic drugs DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 8
BLOOD PRODUCTS Normal blood clotting depends on the presence in the blood of certain proteins called clotting factors. For example, a blood product called Factor VIII is needed for the treatment of the inherited bleeding disorder haemophilia, in which a defective gene causes a deficiency of natural Factor VIII in the blood. Another blood product, fresh frozen plasma, is given to counteract abnormally prolonged or severe bleeding due to causes such as an excessive dose of anticoagulants. All blood products are administered intravenously, and may be used regularly as a preventive treatment or given when abnormal bleeding occurs. Some people experience side effects, including chills and fever, when being given blood products. These side effects may result from an allergic reaction. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 9
Vitamin K This vitamin is essential for the production of several vital blood-clotting factors. Newborn babies (who are born with no stores of vitamin K) and people who are deficient in vitamin K may need a supplement, which is either given by injection or taken orally. Vitamin K is also used to reverse the effect of an excessive dose of oral anticoagulants. No side effects are known to be associated with its use. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 11
MENADIONE A synthetic naphthoquinone without the isoprenoid side chain and biological activity, but can be converted to active vitamin K2, menaquinone, after alkylation in vivo. Menadione (Vitamin K3) is a fat-soluble vitamin precursor that is converted into menaquinone in the liver. The primary known function of vitamin K is to assist in the normal clotting of blood, but it may also play a role in normal bone calcification. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 12
ACETOMENADIONE Acetomenadione is used for the treatment, control, prevention, & improvement of the following diseases, conditions and symptoms: Coagulation disorders due to vitamin k deficiency Anticoagulant-induced prothrombin deficiency DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 13
ANTI-FIBRINOLYTIC DRUGS These drugs may be used when bleeding is difficult to control, as may occur after surgery, or to reduce menstrual bleeding that is excessively heavy. Some examples of antifibrinolytic drugs are aprotinin, tranexamic acid (TXA), epsilon-aminocaproic acid and aminomethylbenzoic acid. Doctors sometimes give these drugs to patients having surgery to prevent blood loss. These drugs might also stop blood loss in seriously injured patients and help to save lives. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 14
TRANEXAMIC ACID (TXA) Huge asset in the world of emergency medicine when it comes to controlling haemorrhage. TXA is an antifibrinolytic agent. TXA is available in both oral and intravenous formulations. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 15
MOA: It reversibly binds plasminogen which prevents plasmin activation. Decreased plasmin activation results in inhibition of fibrin clot degradation, thereby stabilizing the clot. This increase in clot formation and stabilization is how TXA works to control hemorrhage. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 16
Despite the many uses of TXA, there are only two indications for which it is approved: tooth extractions for hemophiliac patients (to be given prior to the procedure) and control of heavy menstrual bleeding (this is given orally on an outpatient basis). DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 17
APROTININ It is a protein-based drug that is also known as bovine pancreatic trypsin inhibitor (BPTI). It is used to reduce the risk for perioperative blood loss and the need for blood transfusion in high-risk patients during cardiopulmonary bypass for coronary artery bypass graft surgery. Since it demonstrates the capacity to slow fibrinolysis, it has been employed to reduce bleeding during complex surgery such as heart and liver surgery. For this use, it is typically administered by injection. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 18
The goal of using of aprotinin was subsequently to minimize end-organ damage resulting from hypotension due to blood loss in surgery and to reduce the necessity for blood transfusions during surgery. Nevertheless, the drug was formally withdrawn worldwide in May of 2008 after studies confirmed that its use enhanced the risk of complications or death. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 19
CALCIUM SALTS Given as calcium intravenous injections. It does not help unless there is deficiency of calcium in the blood. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 20
ANTI COAGULANTS Anticoagulants are medicines that help prevent blood clots. Anticoagulants prolong the coagulation time of blood. They occur naturally in leeches and other blood-sucking insects. Used in medical equipment such as test tubes, blood transfusion bags and renal dialysis equipment. In humans, they are administered as a medication for thrombotic disorders. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 21
They're given to people at a high risk of getting clots, to reduce their chances of developing serious conditions such as strokes and heart attacks. Anticoagulants are used in therapy for thrombotic disorders(pulmonary and venous thrombosis), Myocardial infarction, etc. CLASSIFICATION Directly acting oral anticoagulants (DOACs) 1. Indirectly acting anticoagulants 2. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 22
MOA OF ANTICOAGULANTS DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 23
These drugs can also be classified as: 1. COUMARINS (vitamin K antagonists) These oral anticoagulants are derived from coumarin, which is found in many plants. A prominent member of this class is warfarin (Coumadin). It takes around 48 to 72 hours for the anti coagulant effect to develop. Where an immediate effect is required, heparin must be given concomitantly. These anticoagulants are used to treat patients with deep-vein thrombosis (DVT), pulmonary embolism (PE) and to prevent emboli in patients with atrial fibrillation (AF), and mechanical prosthetic heart valves. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 24
WARFARIN Warfarin is a vitamin K antagonist which acts to inhibit the production of vitamin K by vitamin K epoxide reductase. It is used for 1) Prophylaxis and treatment of venous thromboembolism and related pulmonary embolism. 2) Prophylaxis and treatment of thromboembolism associated with atrial fibrillation. 3) Prophylaxis and treatment of thromboembolism associated with cardiac valve replacement. 4) Use as adjunct therapy to reduce mortality, recurrent myocardial infarction, and thromboembolic events post myocardial infarction. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 25
MOA Inhibit vitamin K dependent synthesis of biologically active forms of calcium dependent clotting factors II, VII, IX and X. Also inhibit regulatory factors protein C, protein S and protein Z. Other proteins not involved in blood clotting such as osteocalcin, or matrix Gla protein may also be effected. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 26
2. HEPARIN AND DERIVATIVE SUBSTANCES Heparin is a naturally occurring glycosaminoglycan. It is a biological substance usually made from pig intestines. It works by activating antithrombin III, which blocks thrombin from clotting blood. It can be used in vivo(by injection) and also in vitro to prevent blood or plasma clotting in or on medical devices. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 27
There are three major categories of heparin: unfractionated heparin (UFH), low molecular weight heparin (LMWH), and ultra-low-molecular weight heparin (ULMWH). LMWH, a more highly processed product, is useful as it does not require monitoring of APTT coagulation parameter and has fewer side effects. Enoxaparin sodium DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 28
MOA Heparin and its derivatives bind to the enzyme inhibitor anti thrombin III (AT) causing a conformational change that result in its activation through an increase in the flexibility of its reactive site loop. The activated AT then inactivates thrombin and other proteases involved in blood clotting, mostly factor Xa. They are effective in preventing DVT and pulmonary emboli in patients at risk. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 29
3. DIRECTLY ACTING ORAL ANTICOAGULANTS These are called DOACs - rivaroxaban, apixaban, edoxaban and betrixaban. They were also previously referred to as "new/novel" and "non-vitamin K antagonist" oral anticoagulants (NOACs). DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 30
These are direct factor Xa inhibitors. They work by inhibiting factor Xa directly unlike other drugs which work via antithrombin activation. Apixaban Rivaroxaban DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 31
4. INDANEDIONE DERIVATIVES ANISINDIONE Anisindione is a synthetic anticoagulant and an indanedione derivative. Its anticoagulant action is mediated through the inhibition of the vitamin K-mediated gamma-carboxylation of precursor proteins that are critical in forming the formation of active procoagulation factors II, VII, IX, and X, as well as the anticoagulant proteins C and S, in the liver. It reduces the prothrombin activity of the blood. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 32
PHENINDIONE It was introduced in the early 1950s. It acts similar to warfarin, but it has been associated with hypersensitivity reactions, so it is rarely used and warfarin is preferred. Indicated for the treatment of pulmonary embolism, cardiomyopathy, atrial fibrillation and flutter, cerebral embolism. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 33
5. SYNTHETIC PENTASACCHARIDE INHIBITORS OF FACTOR Xa The pentasaccharides are completely synthetic compounds that bind to and potentiate the effect of ATIII in blocking factor Xa. They are derived from the five-saccharide effector site found on molecules of heparin but, like LMWH, are too small to form the ternary complex. Fondaparinux is currently the only approved member of this group. The specific anti factor Xa effect of fondaparinux is much greater than that of LMWH (approximately sevenfold higher). DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 34
Fondaparinux can be given subcutaneously or intravenously, with almost 100% bioavailability. Other examples include Idraparinux, Idrabiotaparinux(the biotinylated form of Idraparinux). Idraparinux Fondaparinux DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 35
6. DIRECT THROMBIN INHIBITORS Include: 1. Bivalent drugs Hirudin, Lepirudin 2. Monovalent drugs Argatroban, Dabigatran DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 36
HIRUDIN It is a naturally occurring peptide in the salivary glands of blood-sucking leeches (such as Hirudo medicinalis) that has a blood anticoagulant property. This is fundamental for the leeches' habit of feeding on blood, since it keeps a host's blood flowing after the worm's initial puncture of the skin. LEPIRUDIN It is a recombinant hirudin derived from yeast cells. It is almost identical to hirudin except for substitution of leucine for isoleucine at the N-terminal end of the molecule and the absence of a sulfate group on the tyrosine at position 63. It is a protein-based direct thrombin inhibitor used to reverse and prevent thrombus formation in heparin-induced thrombocytopenia. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 37
ARGATROBAN It is used to treat the symptoms of blood clots in adults (Thrombocytopenia) and Percutaneous Coronary Intervention. DABIGATRAN It is used for prevention of stroke and venous embolism in patients with chronic atrial fibrillation. It is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 38
7. ANTI THROMBIN PROTEIN THERAPEUTICS Antithrombin (AT-III) is a small protein molecule that inactivates several enzymes of the coagulation system. Antithrombin is a glycoprotein produced by the liver and consists of 432 amino acids. It contains three disulfide bonds and a total of four possible glycosylation sites. Antithrombin itself is used as a protein therapeutic that can be purified from human plasma or produced recombinantly (for example, Atryn, which is produced in the milk of genetically modified goats). Antithrombin is approved by the FDA as an anticoagulant for the prevention of clots before, during, or after surgery or birthing in patients with hereditary antithrombin deficiency. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 39
8. IN VITRO ANTI COAGULANTS 1. EDTA Ethylenediaminetetraacetic acid (EDTA) is an amino polycarboxylic acid which strongly and irreversibly chelates(binds) calcium ions to prevent blood from clotting. 2. CITRATE Citrate is a potent binder of metal ions and is one of the major anions in human seminal plasma. It is in liquid form and is used for coagulation tests and also in blood transfusion bags. It can be in the form of sodium citrate or acid citrate dextrose. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 40
3. OXALATE It has a mechanism similar to that of citrate. It is used as anti coagulant in fluoride oxalate tubes and also to determine glucose and oxalate levels. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 41
ADVERSE EFFECTS 1. Hemorrhage 2. Heparin thrombocytopenia, osteoporosis, spontaneous fractures on prolonged use, alopecia, hypersensitivity. 3. Warfarin teratogenic effects, alopecia, dermatitis, diarrhea DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 42
THANK YOU DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 43
