DRUGS USED IN DISORDERS OF COAGULATION

1 DRUGS USED IN DISORDERS OF COAGULATION I. BASIC PHARMACOLOGY OF THE ANTICOAGULANT DRUGS Clots are formed by the action of thrombin which converts fibrinogen to fibrin monomer which then polymerises. In the presence of factor XIII a cross-linked polymer is then formed. A complex cascade of processes involving more than 12 different clotting factors may be involved in the initiation of clotting; calcium ions are essential at several points in the process and clotting does not normally take place in the absence of Ca 2+. Defects in the clotting process and clotting does not normally take place in the absence of Ca2+. Defects in the clotting process can be genetically determined (eg hemophilia) or produced by drugs (anticoagulants). Type A hemophilia lacks factor VIII; type B lacks factor IX (Christmas factor). Both are genetically determined with an incidence of about 1 in 10,000 in males and 1 in 100,000,000 in females. The mutant gene is usually passed on from the parent but mutations do occur spontaneously with an incidence of about 1 in 300,000. Genetic deficiency of factor VIII is called von Willebrand’s disease. It affects both sexes equally but otherwise is similar to hemophilia type A and is treated similarly. Blood platelets contribute to the clotting processs by aggregating and thus plugging damaged vessels. Many substances promote aggregation (collagen, adrenaline and the arachidonic acid metabolite thromboxane A 2. Drugs which inhibit aggregation are potentially useful in patients at risk from arterial trombi.  Drugs for use in vitro EDTA ( ethylene diamine tetraacetic acid) and citrate form a complex with Ca2+ in blood. Oxalate precipitates Ca2+ in an insoluble form (calcium oxalate) . All three make calcium which is essential to the clotting process unavailable and therefore prevent coagulation. Citric acid + sodium citrate + dextrose - ACD solution- is used to prevent clotting in blood given for transfusion. The ACD solution is metabolised in the body but too much can reduce calcium level which causes tetany and can depress cardiac contraction. Agents which interfere with calcium cannot be used effectively in vivo since calcium is essential for so many other body processes.  Drugs for use in vitro + in vivo HEPARIN Pharmacodynamics: Heparin is a naturally-occuring sulphated acidic polysaccharide present in most cell granules.Its biologic activity is dependent upon the plasma protease inhibitor antithrombin III- anticoagulant effect. Antithrombin inhibits clotting factor proteases by forming equimolar stable complexes with them. In the absence of heparin, these reactions are slow, in the presence of heparin, they are accelerated 1000-fold. The active heparin molecules bind tightly to antithrombin and cause a conformational change in this inhibitor. The conformational change of antithrombin exposes its active site for more rapid interaction with the proteases - the activated clotting factors. Heparin catalyzes the antithrombin-protease reaction without being consumed. Once the antithrombin-protease complex is formed, heparin is released intact for renewed binding to more antithrombin. The antithrombin binding region of commercial heparin consists of repeating sulfated disaccharide units. High-molecular-weight fractions (HMW) of heparin with high affinity for antithrombin markedly inhibit blood coagulation. These fractions have a MW range of 5000-30,000. Low-molecular-weight (LMW) fractions of heparin inhibit activated factor X- antithrombotic effect- but have less effect on thrombin and on coagulation in general. Enoxaparin, one of many LMW heparin fractions, has been approved for the primary prevention of deep venous thrombosis. Several LMW heparins, upon comparison with regular heparin, have shown equal or greater efficacy, lower rates of bleeding, increased bioavailability from the subcutaneous site of injection, less need for laboratory monitoring, and less frequent dosing. Heparin is not absorbed from the gut, is therefore given parenterally and acts within minutes, lasting 2 to 4 hours. Because commercial heparin consists of a family of molecules of different molecular weights, regular (HMW) heparin is standardized as units of activity by bioassay. Heparin sodium USP must contain at least 120 USP units per milligram. Heparin is generally used as the sodium salt, but calcium heparin is equally effective. Lithium heparin is used in vitro as an anticoagulant for blood samples. Heparin accelerates the clearing of postprandial lipemia by effecting the release of lipoprotein lipase from tissues Laboratory control 2  The activated partial thromboplastin time (APTT) tests factors VIII, IX,X,XI ,XII., V and VII. The prolongation (>45s) determines heparin or indicates hemophilia.Normal is 35-45 s.  Thrombin time-the time to clot formation on adding thrombin to plasma. Normal value is 15 s. It tests the final stage of the clotting process and prolongation reflects a reduced fibrinogen level or the presence of anticoagulants like heparin. A plasma concentration of heparin of 0,2 unit/mL usually prevents pulmonary emboli in patients with established venous thrombosis. This concentration of heparin will prolong the partial thromboplastin time (the APTT) to 2-21/2 times that of the control value. This degree of anticoagulant effect should be maintained throughout the course of continuous intravenous heparin therapy. When intermittent heparin administration is used, the APTT should be measured just before the next heparin dose to adjust this dose so as to maintain prolongation of the (the APTT) to 2-21/2 times that of the control value. Toxicity. The major adverse effect of heparin is bleeding. This risk can be decreased by careful control of dosage, and close monitoring of the activated partial thromboplastin time (PTT). Elderly women and patients with renal failure are prone to hemorrhage. Heparin is of animal origin and should be used cautiously in patients with allergy. Increased loss of hair and transient reversible alopecia have been reported. Long-term heparin therapy is associated with osteoporosis and spontaneous fractures. Heparin causes transient trombocytopenia in 25 % of patients and severe thrombocytopenia in 5 %. Contraindications. Heparin is contraindicated in patients who are hypersensitive to the drug, are actively bleeding, or have hemophilia, thrombocytopenia, purpura, severe hypertension, intracranial hemorrhage, infective endocarditis, active tuberculosis, ulcerative lesions of the gastrointestinal tract, threatened abortion, visceral carcinoma or advanced hepatic or renal disease. Heparin should not be given to patients during or after surgery of the brain, spinal cord, or eye or to patients undergoing lumbar puncture or regional anesthetic blocks. The continuous intravenous administration of heparin is accomplished via an infusion pump. After an initial bolus injection of 5000-10,000 units, a continuous infusion of about 900 units/h or 10-15 units/kg/h is required to maintain the APTT at 2-21/2 times control. Heparin must not be administered intramuscularly, because of the danger of hematoma formation at the injection site. Enoxaparin is given in a dosage of 30 mg twice daily after hip surgery. Excessive anticoagulant action of heparin is treated by discontinuance of the drug. If bleeding occurs, administration of a specific antidote such as protamine sulfate is indicated. Protamine is a highly basic peptide that combines with heparin as an ion pair to form a stable complex devoid of anticoagulant activity. For every 100 units of heparin remaining in the patient, administer 1 mg of protamine sulfate intravenously, the rate of infusion should not exceed 50 mg in any 10-minute period. Excess protamine must be avoided, it also has an anticoagulant effect. Hirudin. For a number of years, surgeons have used medicinal leeches (Hirudo medicinalis). Hirudin is a powerful and specific thrombin inhibitor from the leech which is now being prepared by recombinant DNA technology. Its action is independent of antithrombin III, which means it can reach and inactivate fibrin-bound thrombin in thrombi. Hirudin has little effect on platelets or the bleeding time. Like heparin, it must be administered parenterally and is monitored by the APTT.  Drugs for use in vivo THE COUMARIN ANTICOAGULANTS The clinical use of the coumarin anticoagulants can be traced to the discovery of an anticoagulant substance formed in spoiled sweet clover silage. It produced a deficiency of plasma prothrombin and a consequent hemorrhagic disease in cattle. The toxic agent was identified as bishydroxycoumarin and synthesized as dicumarol. This group is divided to congeners of dicoumarol -ethylbiscumacetat PELENTAN (CZ) and warfarin, and that of indanedione-phenindione. These drugs are often referred to as „oral anticoagulants“ because, unlike heparin, they are administered orally. Pharmacokinetics. Warfarin is generally administered as the sodium salt and has 100% bioavailability. Over 99% of racemic warfarin is bound to plasma albumin, which may contribute to its small volume of distribution, its long half-life in plasma (45 hours), and the lack of urinary excretion of the unchanged drug. Warfarin used clinically is a racemic mixture composed of equal amounts of two optical isomers. The levorotatory S-warfarin is four times more potent than the dextrorotatory R-warfarin. 3 Pharmacodynamics. Coumarin anticoagulants block the -carboxylation of several glutamate residues in prothrombin and factors VII, IX, and X as well as the endogenous anticoagulant protein C. The blockade results in incomplete molecules that are biologically inactive in coagulation. This protein carboxylation is physiologically coupled with the oxidative deactivation of vitamin K. The anticoagulants prevent the reductive metabolism of the inactive vitamin K epoxide from returning back to its active hydroquinone form. Mutational change of the responsible enzyme, vitamin K epoxide reductase, can give rise to genetic resistance to these anticoagulants in humans and especially in rats. This type of drug acts after a delay of 1-4 days (the latency) since pre-formed factors in the plasma (none of which have very long half-lives) must be used up before the action of the drug becomes effective in reducing clotting.. Its anticoagulant effect results from a balance between partially inhibited synthesis and unaltered degradation of the four vitamin K-dependent clotting factors. These half-lives are 6, 24, 40, and 60 hours for factors VII, IX, X, and II, respectively. Offset depends mainly on half-life as well. The effect of Warfarin (half-life 45 h) lasts 2 to 6 days; that of Pelentan for 36-48 h. If surgery is to be carried out therapy should not stop completely as a rebound thrombosis may occur leading to myocardial infarction as a clot lodges in a coronary artery. If uncontrolled bleeding does occur, vitamin K can be given (but may take 12 h to become affective due to the time required to synthesise new clotting factors). Minor bleeding may be controlled by the anti-fibrinolytic agent tranexamic acid. Laboratory control:- The Quick test which reflects the activity of prothrombin in blood and is also affected by the levels of factors V, VII and X. Normal is 9-16 s. The prothrombin time should be increased to a level representing 25% of normal activity and maintained there for long-term therapy. When the activity is less than 20%, the drug dosage should be reduced or omitted until the activity rises above 20%. The therapeutic range for oral anticoagulant therapy has recently been defined in terms of an international normalized ratio (INR). The INR is the prothrombin time ratio (test/control) obtained if the more sensitive international reference thromboplastin made from the human brain is used rather than the less sensitive rabbitbrain thromboplastin. An INR of 2.0-2.5 indicates prevention deep venous thrombosis; that of 2.0-3.0 treatment of deep venous thrombosis and pulmonary emboli; 3.0-4.5 the same as the previous plus arterial thrombosis and acute myocardial infarction. Values >5.0 indicate a high risk of bleeding. Toxicity. The coumarin anticoagulants cross the placenta readily and can cause a hemorrhagic disorder in the fetus. Fetal proteins with -carboxyglutamate residues found in bone and blood may be affected by them. The drug can cause a serious birth defect characterized by abnormal bone formation. Thus, the coumarin anticoagulants should never be administered during pregnancy. Cutaneous necrosis with reduced activity of protein C sometimes occurs during the first weeks of therapy. Drug Interactions. The oral anticoagulants often interact with other drugs and with disease states. These events can be broadly divided into pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic mechanisms for drug interaction with oral anticoagulants are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. Pharmacodynamic mechanisms for interactions with the coumarin anticoagulants are synergism (impaired hemostasis, reduced clotting factor synthesis, as in hepatic disease), competitive antagonism (vitamin K), and an altered physiologic control loop for vitamin K (hereditary resistance to oral anticoagulants). The most dangerous of these interactions are the pharmacokinetic interactions with the pyrazolones phenylbutazone and sulfinpyrazone. These drugs not only augment the hypoprothrombinemia but also inhibit platelet function and may induce peptic ulcer disease.The mechanisms for their hypoprothrombinemic interactions are a stereoselective inhibition of oxidative metabolic transformation of S-warfarin and displacement of albumin-bound warfarin, increasing the free fraction. Phenytoin may displace warfarin from plasma binding sites. Metronidazole, miconazole, and trimethoprim-sulfamethoxazole also stereoselectively inhibit the metabolic transformation of S-warfarin, whereas aminodarone, disulfiram, and cimetidine inhibit the metabolism of both enantiomorphs of warfarin. Phenobarbitone and rifampin induce microsomal enzymes which biotransform coumarins and therefore reduce their effects. Aspirin, hepatic disease, and hyperthyroidism augment warfarin pharmacodynamically: aspirin decreases platelet aggregation and the latter two by increasing the turnover rate of clotting factors. The third-generation cephalosporins eliminate the bacteria in the intestinal tract that produce vitamin K, and, like warfarin, also directly inhibit vitamin K epoxide reductase. Heparin directly prolongs the prothrombin time by inhibiting the activity of several clotting factors .Oral contraceptives increase blood coagulability and therefore more coumarins are needed to produce an adequate effect.Note however that if warfarin is needed it may be that oral contraceptives are contraindicated. 4 Pharmacodynamic reductions of anticoagulant effect occur with vitamin K (increased synthesis of clotting factors), the diuretics chlorthalidone and spironolactone (clotting factor concentration), hereditary resistance (mutation of vitamin K reactivation cycle), and hypothyroidism (decreased turnover rate of clotting factors). Excessive anticoagulant effect and bleeding from warfarin can be reversed by stopping the drug and administering large doses of vitamin K1 and fresh-frozen plasma of factor IX concentrates, and sometimes even transfusion of the whole blood. II. BASIC PHARMACOLOGY OF THE FIBRINOLYTIC DRUGS The clotting system (producing fibrin) is balanced by the fibrinolytic system (which removes fibrin and fibrinogen ). The balance retains the blood in a non-coagulated form in the body but allows clotting to take place in response to for example, injury. Clotting can be produced by stimulating the clotting process or by inhibiting the activity of the fibrinolytic system. .This system is held in check by endogenous inhibitors (antiplasmins) which hold plasmin activity at a low level which will balance the slow normal production of fibrin. Inhibition of these endogenous inhibitors will release plasmin from their control and produce an anticoagulant effect. Fibrinolytic drugs rapidly lyse thrombi by catalyzing the formation of the serine protease plasmin from its precursor zymogen, plasminogen. These drugs create a generalized lytic state when administered intravenously. Thus, both protective hemostatic thrombi and target thromboemboli are broken down. Two new approaches have been proposed to reduce the nonselective systemic effects. First, intra-arterial use of a fibrinolytic drug, as in intracoronary injection, may reduce systemic bleeding by localizing the drug. Second, a new generation of prothrombolytic drugs, tissue plasminogen activators, may induce thrombolysis with less systemic fibrinolysis or fibrinogen breakdown. Streptokinase, Anistreplase, Tissue plasminogen activator, Urokinase. Streptokinase is a protein synthesized by streptococci that combines with the proactivator plasminogen. This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin. Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins, which allows it to lyse the thrombus from within. Anistreplase consists of a complex of purified human plasminogen and bacterial streptokinase that has been acylated to protect the enzyme`s active site. When administered, the acyl group spontaneously hydrolyzes, freeing the activated streptokinase-proactivator complex. This product allows for rapid intravenous injection, greater clot selectivity (ie, more activity on plasminogen associated with clots than on free plasminogen in the blood), and more thrombolytic activity. Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PA). These activators preferentially activate plasminogen that is bound to fibrin, which confines fibrinolysis to the formed thrombus and avoids systemic activation. Human t-PA is manufactured by means of recombinant DNA technology. Urokinase is a human enzyme synthetized by the kidney that directly converts plasminogen to active plasmin. Use of fibrinolytic drugs by the intravenous route is indicated in cases of multiple pulmonary emboli that are not massive enough to require surgical intervention. Intravenous fibrinolytic drugs are also indicated in cases of central deep venous thrombosis. Thrombolytic therapy in the management of acute myocardial infarction requires careful patient selection. Streptokinase is administered by intravenous infusion of a loading dose of 250,000 units, followed by 100,000 units/h for 24-72 hours. Patients with antistreptococcal antibodies can develop fever, allergic reactions, and therapeutic resistance. Urokinase requires a loading dose of 300,000 units given over 10 to 12 hours, and a maintenance dose of 300,000 units/h. Alteplase (t-PA) is given by intravenous infusion of 60 mg over the first hour and then 40 mg at a rate of 20 mg/h. Anistreplase is given as a single intravenous injection of 30 units over 3-5 minutes. When thrombolytic enzyme therapy is completed, it should be followed by administration of heparin and then warfarin. III. BASIC PHARMACOLOGY OF ANTITHROMBOTIC DRUGS The first group consists of agents generated outside the platelet that interact with platelet membrane receptors, eg, catecholamines, collagen, thrombin, and prostacyclin. The second category contains agents generated within the platelet that interact with the membrane receptors, eg, ADP, prostaglandin D2, prostaglandin E2, and serotonin. The third contains agents generated within the platelet that act within the platelet, eg. prostaglandin endoperoxides and thromboxane A2, cAMP and calcium ion. From this list of agents, 5 two targets for platelet inhibitory drugs have been identified: inhibition of prostaglandin metabolism (aspirin) and inhibition of ADP-induced platelet aggregation (ticlopidine). The prostaglandin thromboxane A2 is an arachidonate product that causes platelets to change shape, to release their granulates and to aggregate. Drugs that antagonize this pathway interfere with platelet aggregation in vitro and prolong the bleeding time in vivo. Aspirin is the prototype of this class of drugs. Aspirin inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme cyclooxygenase. Because the anuclear platelet cannot synthesize new proteins, it cannot manufacture new enzymes during its 10-day lifetime. Two large prospective, randomized trials in healthy American and British physicians were conducted to evaluate the use of aspirin for 4-5 years in the primary prophylaxis of cardiovascular mortality, ie, prevention of first heart attacks. The American study showed a significant reduction in the incidence of nonfatal myocardial infarctions (and was prematurely terminated because of this finding), while the British study showed no significant change. Furthermore, the British study confirmed previous evidence that at a dose of 500 mg/d, aspirin increases the incidence of peptic ulcer disease and gastrointestial bleeding. Thus, the risk-versus-benefit measure of aspirin as an over-the-counter prophylactic drug is questionable for patients with hypertension or peptic ulcer disease. The FDA has approved the use of 325 mg/d for primary prophylaxis of myocardial infarction. Ticlopidine reduces platelet aggregation by inhibiting the ADP pathway of platelets. Unlike aspirin, the drug has no effect on prostaglandin metabolism. Randomized clinical trials with ticlopidine report efficacy in the prevention of vascular events among patients with transient ischemic attacks, completed strokes and unstable angina pectoris. The dosage of ticlopidine is 250 mg twice daily. It is particularly useful in patients who cannot tolerate aspirin. IV. BASIC PHARMACOLOGY OF DRUGS USED TO TREAT THROMBOSIS THROMBOSIS VENOUS Antithrombotic Management  Prevention: Primary prevention of venous thrombosis reduces the incidence of and mortality rate from pulmonary emboli. Heparin is used to prevent venous thrombosis. Intermittent administration of low-dose heparin subcutaneously provides effective prophylaxis. Oral anticoagulants are also effective, but the risk of bleeding and the necessity for laboratory monitoring of the prothrombin time limit their use for prophylaxis. Enoxaparin (LMW heparin) is approved only for prophylaxis in patients undergoing hip replacement.  Treatment of Established Disease: Established venous thrombosis is treated with maximal dosages of heparin and oral anticoagulants. Heparin is used for the first 7-10 days, with a 3- to 5- day overlap with an oral anticoagulant. Therapy with an oral anticoagulant is continued after hospital discharge for 6 weeks (first episode) to 6 months (recurrent episodes). Deficiencies of proteins C or S are important diagnostic considerations in patients with recurrent thrombi who have a positive family history. Antithrombin III concentrate may be useful in deficient patients. Heparin resistance associated with antithrombin III deficiency can be overcome with this concentrate. Note: As mentioned above the oral anticoagulants readily cross the placenta. They can cause hemorrhage at any time during pregnancy, as well as developmental defects when administered during the first trimester. Therefore, venous tromboembolic disease in pregnant women should be treated with heparin, best administered by subcutaneous injection. Laboratory monitoring is mandatory. Fibrinolytic Therapy Early treatment with fibrinolytic drugs of a less than massive pulmonary embolus may improve survival and may preserve long-term pulmonary function. The standard course of fibrinolytic therapy should be followed by anticoagulant therapy with heparin and oral anticoagulants. Concomitant invasive procedures must be avoided, since bleeding may occur. ARTERIAL THROMBOSIS In patients with arterial thrombin, consumption of platelets is excessive. Thus, treatment with plateletinhibiting drugs such as aspirin and ticlopidine is indicated in patients with transient ischemic attacks and strokes or unstable angina and acute myocardial infarction. In angina and infarction, these drugs are often use in conjunction with beta-blockers or calcium channel blockers and fibrinolytic drugs. 6 V. DRUGS USED IN BLEEDING DISORDERS ARRESTING HEMORRHAGE  Locally applied haemostatics. Oxidized regenerated cellulose gauze and fibrin, gelatin and alginate foams form a meshwork which provide an increased surface area to help activate the clotting mechanism and give some mechanical support to the clot. They can be packed into the socket and the socket margins sutured if necessary.  Haemostatic drugs for systemic administra-tion. Vitamin K confers biologic activity upon prothrombin and factors VII, IX and X by participating in their postribosomal modification. Severe hepatic failure results in a loss of protein synthesis and a hemorrhagic diathesis that is unresponsive to vitamin K. Two natural vitamins K are fat-soluble substances. K1 is found primarily in green vegetables especially in spinach, K2 is synthetized by intestinal bacteria. Vitamins K require bile salts to permit absorption from the intestinal tract. The effect is delayed for 6 hours but is complete within 24 hours when treating depression of the prothrombin activity by excess oral anticoagulant or vitamin K deficiency. Intravenous administration of vitamin K1 should be slow, because rapid infusion can produce dyspnea, chest and back pain, and even death. Vitamin K1 is currently administered to all newborns to prevent the hemorrhagic disease of vitamin K deficiency, which is especially common in premature infants. Vitamin K deficiency frequently occurs in hospitalized patients in intensive care units because of poor diet, parenteral nutrition, recent surgery, multiple antibiotic therapy and uremia. Plasma fractions Deficiencies in plasma coagulation factors can cause bleeding. Spontaneous bleeding occurs when factor activity is less than 5% of normal. Factor VIII deficiency (hemophilia A) and factor IX deficiency (Christmas disease or hemophilia B) account for most of the heritable coagulation defects (sex-linked, recessive, X-chromosome) and the disease is exhibited only in males; females act as symptom less carriers of the gene. Concentrated plasma fractions are available for the treatment of these deficiencies. Even trivial procedures (eg injections of local anaesthetics) may produce severe and prolonged bleeding and regional blocks must be avoided.  Factor VIII There are two preparations of concentrated human factor VIII. Cryoprecipitate is a plasma protein fraction and is obtainable from whole blood. Lyophilized factor VIII concentrates are prepared from large pools of plasma. Desmopressin acetate (arginine vasopressin) increases the factor VIII activity of patients with mild hemophilia A or von Willebrand`s disease. It can be used in preparation for minor surgery such as tooth extraction.  Factor IX Some preparations of factor IX concentrate contain activated clotting factors, which has led to their use in treating patients with inhibitors or antibodies to factor VIII or IX. Autoplex (with factor VIII correctional activity) and Feiba (with factor VIII inhibitor bypassing activity).  Fibrinogen Fibrinogen may be administered to patients as plasma, cryoprecipitate of factor VIII, or lyophilized concentrates of factor VIII. Fibrinolytic inhibitors  Aminocaproic acid (EACA), which is a synthetic inhibitor of fibrinolysis. It is a plasmin inhibitor which will also inhibit competitively plasminogen activation. Thus plasmin activity in blood is reduced and a coagulant effect is produced. Thrombin is not affected. This drug is used to treat excessive bleeding due to overactivity in the fibrinolytic (plasmin) system. It is rapidly absorbed orally. The effect is very short (1h).  Tranexamic acid is an analogue of aminocaproic acid. It is administered orally as well.  Aprotinin is an antifibrinolytic agent which also inhibits some enzymes in the coagulation system (eg those responsible for the conversion of prothrombin to thrombin) Aprotinin must be given by injection since it is a polypeptide and will be destroyed in the GIT system. 7 Treatment success has also been reported in patients with postsurgical gastrointestinal bleeding, postprostatectomy bleeding, bladder hemorrhage secondary to radiation-and drug-induced cystitis. Adverse effects of the drug include intravascular thrombosis from inhibition of the plasminogen activator, hypotension, myopathy, abdominal discomfort, diarrhea and nasal stuffiness. Content: Drugs used in disorders of coagulation     Basic pharmacology of the anticoagulant drugs. drugs for use in vitro drugs for use in vitro + in vivo (heparin, hirudin) drugs for use in vivo ( the coumarin anticoagulants)  Basic pharmacology of the fibrinolytic drugs  Streptokinase, Anistreplase, Tissue plasminogen activator, Urokinase.  Basic pharmacology of antithrombotic drugs  Aspirin, ticlopidin.  Pharmacology of drugs used to treat thrombosis  Venous thrombosis A.Prevention. B. Treatment  Arterial thrombosis      Drugs used in bleeding disorders arresting hemorrhage Locally applied Haemostatic drugs for systemic administration Vitamin K, Plasma fractions: f.VIII, f.IX, fibrinogen, Fibrinolytic inhibitors (Aminocaproic acid, Tranexamic acid, Aprotinin)