This page intentionally left blank r r e e t t p p a CChh 6.1 1.4 Coagulants and Pharmacodynamics (Mode of Action of Drugs) Anticoagulants Thrombogenesis is an abnormal state of haemostasis leading to the formation of arterial and venous thrombus, also known as white and red thrombus respectively Haemostasis is the spontaneous arrest of bleeding from the damaged blood vessels The immediate haemostatic response to a damaged blood vessel is vasospasm and, after few seconds, platelets stick to the exposed collagen of the damaged endothelium (platelet adhesion) and to each other (platelet aggregation) Certain agents e.g thromboxane A2 (from arachidonic acid metabolic pathway) is synthesized within platelets and induces thrombogenesis and vasoconstriction and prostacyclin I2 (PGI2) inhibits thrombogenesis Coagulation of blood comprises the formation of fibrin There are thirteen factors (synthesized in liver) which are involved in the coagulation of blood Review of Clotting Mechanism Haemostasis: Haemostasis refers to the arrest of blood loss from a damaged blood vessel i.e stoppage of bleeding The mech- anism is essential to maintain life In case of any damage to a blood vessel, the haemostatic response must be: • Quick • Controlled & localised to region of damage Three basic measures taken by the body to reduce and stop blood loss are: i Vascular spasm ii Platelet plug formation iii Clotting or coagulation Clotting: Normally, blood remains liquid as long as it is flowing within intact smooth blood vessels But on damage to the blood vessel and/or if blood is extracted from the blood vessel, there is conversion of liquid to gel state This gel, on solidification gives a clot The process of conversion of liquid to gel is termed as coagulation Clotting involves several factors called clotting factors These include calcium, several inactive enzymes synthesized by hepatocytes and various molecules associated with platelets and/or released by the damaged tissue The clotting factors are Section 6/ Drug Acting on Blood 240 denoted by Roman numeral, denoting the order of their discovery (Table 6.1.1) Table 6.1.1: Clotting factors I Fibrinogen II III IV V VI VII VIII IX X XI Prothrombin Thromboplastin Calcium Proaccelerin Accelerin Serum prothrombin conversion accelerator Antihaemophilic factor Plasma thomboplastin component Stuart Prower factor Plasma thromboplastin antecedent XII Hageman factor XIII Fibrin stabilizing factor Stages of Clotting Formation of prothrombinase: It can be formed by extrinsic pathway and intrinsic pathway Extrinsic pathway: This pathway has fewer steps than the intrinsic pathway and occurs rapidly, within a matter of seconds if the trauma is severe It is called the extrinsic pathway because a protein tissue factor, also called thromboplastin or coagulation factor III, takes into the blood stream from outside and initiates the formation of prothrombinase Tissue factor is released from the surface of the damaged cells It activates factor VII Factor VII combines with factor X, activating it Factor X in the presence of Ca++ combines with factor V to give active enzyme prothrombinase Intrinsic pathway: This pathway is more complex and is much slower It is so named as the activators are in direct contact with the blood in the intact blood vessels No outside tissue damage is required Rough vessels with exposed collagen is sufficient Contact with collagen activates factor XII This in turn activates factor IX Factor IX joins factor VIII and this gives active factor X Factor X joins with calcium to bring about the formation of prothrombinase Once prothrombinase has been formed, the common pathway is followed In stage 2, prothrombinase and calcium catalyze the conversion of prothrombin to thrombin In stage 3, thrombin, in the presence of calcium converts soluble fibrinogen to insoluble fibrin threads COAGULANTS These are the agents which promote coagulation and are mainly used in any haemorrhagic condition They are classified as in table 6.1.2 VITAMIN K Vitamin K is a fat soluble vitamin found primarily in leafy green vegetables There are two normal forms exist, K found in food (called phytonadione), K found in human tissue (synthesized by intestinal bacteria) known as menaquinone The synthetic compound is known as K Synthetic analogues of natural vitamin also show biological activity Most of the vitamin K is synthesized by intestinal microorganisms and there is a risk of vitamin K deficiency in new born infants Vitamin K is necessary for final stage of Coagulants and Anticoagulants 241 Table 6.1.2: Classification of coagulants I Vitamin K (along with other vitamins available) Vitamin K analogues Menapthone (KAPLIN) Menadione (STYPINDON) Phytomenadione Botropase Ethamsylate (ALSTAT) Adenochrome monosemicarbazone (STYPTOCID) Feracrylum (HEMOLOK) Aprotinin (APROTIN) II Other Tranexamic acid (TEXID) Polidocanol (SCLEROL) Sodium tetradecyl (SETROL) synthesis of coagulation factors (mainly factor II, VII, IX and X) in liver In synthesis of coagulant proteins vitamins K is converted to an epoxide which is subsequently reduced to vitamin K Vitamin K is metabolised in liver and metabolites are excreted in bile and urine The deficiency of vitamin K occur due to liver disease, jaundice, malabsorption syndromes and chronic use of antimicrobial agents Adverse effects include haemolysis especially in infants and person with G-6PD deficiency Menadione can cause jaundice, and haemolysis in infants Therapeutically, vitamin K is used in prophylaxis and treatment of deficiency of clotting factor due to dietary deficiency of vitamin K, chronic antimicrobial therapy, malabsorption syndrome, obstructive jaundice, liver diseases such as cirrhosis and hepatitis, in neonates to prevent or treat haemorrhagic disease of new born; to counteract the overdosing of oral anticoagulants 0.66 mg OD-BD 5-20 mg/day 10-30 mg TDS 10 mg/ml IM/day ml BD-TDS IM 250-500 mg TDS 10-30 mg BD-TDS Applied locally on affected surface Upto million KIU IV injection 15-25 mg/kg BD-QID oral, 10-15 mg/kg slow IV TDS Local application 1-3% solution (phytomenadione is most effective as it acts most rapidly) BOTROPASE It is a aqueous solution of haemocoagulase isolated from venom of Bothrops jararaca and B atorox containing normal saline It is indicated in primary and secondary postoperative internal and external haemorrhage ETHAMSYLATE It inhibits prostacyclin synthetase enzyme resulting in the prevention of prostacyclin induced vasodilatation and corrects abnormal platelet function It is mainly used to control haemorrhage in epistaxis, haemoptysis, haematemesis, menorrhagia and postsurgical conditions ADENOCHROME MONOSEMICARBAZONE It exerts its haemostatic action by reducing capillary fragility, and is indicated in epistaxis, haematuria, retinal 242 haemorrhage and secondary haemorrhage from wounds FERACRYLUM It is a local haemostatic and antiseptic agent The haemostatic effect of feracrylum is based on the formation of synthetic complex consisting of its adduct with plasma proteins principally albumin Like other biodegradable polymers, the feracrylum-albumin complex formed gets broken down over a period of time Adverse effects include burning sensation It is indicated as adjunct to conventional haemostatic procedures in capillary and venule oozing in various surgical and diagnostic procedures, dental extraction and oral surgeries APROTININ It is a naturally occurring proteolytic enzyme inhibitor acting on plasmin and kallikrein It inhibits plasmin and kallikrein, thus directly affecting fibrinolysis It also inhibits the contact phase activation of coagulation which both initiates coagulation and promotes fibrinolysis After IV injection rapid distribution of aprotinin occurs into the total extracellular space leading to a rapid initial decrease in plasma concentration It has a plasma halflife of 2.5 hours After a single IV dose 2540% is excreted in the urine over 48 hours It is accumulated primarily in the kidney (it is actively absorbed by the proximal tubules) Section 6/ Drug Acting on Blood Adverse effects include local thrombophlebitis, hypersensitivity reactions (skin eruptions, tachycardia, pallor/cyanosis, dyspnoea, nausea or anaphylactic shock) may occur It is indicated in patients at high risk of blood loss following open heart surgery with extracorporeal circulation, life threatening haemorrhage due to hyperplasminaemia, hyperfibrinolytic haemorrhage occurring post-traumatically and postoperatively e.g in obstetrics and gynaecology TRANEXAMIC ACID Tranexamic acid produces an antifibrinolytic effect by blocking the lysine binding site on plasminogen which is essential for binding to fibrin and thereby prevents the activation of plasminogen on the surface of fibrin Tranexamic acid is absorbed from the GIT with peak plasma concentration at about three hours Bioavailability is about 30 to 50 percent It is widely distributed throughout the body and has very low protein binding It diffuses across the placenta and is distributed into breast milk It has a plasma half life of about two hours It is excreted in the urine mainly as unchanged drug Adverse effects include dose related gastrointestinal disturbances, hypotension particularly after rapid IV administration and transient disturbance in colour vision rarely It is used for prophylaxis and control of bleeding in gynaecological and obstetric surgery, haemorrhage associated with IUCD insertion, conisation of the cervix, intra- and ... antecedent XII Hageman factor XIII Fibrin stabilizing factor Stages of Clotting Formation of prothrombinase: It can be formed by extrinsic pathway and intrinsic pathway Extrinsic pathway: This pathway... gives active factor X Factor X joins with calcium to bring about the formation of prothrombinase Once prothrombinase has been formed, the common pathway is followed In stage 2, prothrombinase and... is based on the formation of synthetic complex consisting of its adduct with plasma proteins principally albumin Like other biodegradable polymers, the feracrylum-albumin complex formed gets broken