Drugs Used in Bleeding Disorders PDF

2024/09/26 Drugs used in Bleeding disorders Dr Sarentha Chetty BPharm, MSc, PhD Objectives Introduction Mechanism of action Therapeutic indications SEs and ADRs Drug Interactions  2024/09/26 VITAM...

2024/09/26 Drugs used in Bleeding disorders Dr Sarentha Chetty BPharm, MSc, PhD Objectives Introduction Mechanism of action Therapeutic indications SEs and ADRs Drug Interactions  2024/09/26 VITAMIN K Co-factor for prothrombin and factors VII, IX, and X Fat soluble vitamin found primarily in leafy green vegetables Obtain from diet and it is synthesized by bacteria in the human intestine Two natural forms exist: vitamins K1 and K2 Vitamin K1 (phytomenadione) obtained from food Vitamin K2 (menaquinone) is synthesized by intestinal bacteria. Vitamin K1 - oral and parenteral forms Onset of action ± 6 hours and is complete by 24 hours. I/V Vitamin K1 – must be slow As rapid infusion can produce dyspnea, chest, back pain, even death Vitamin K1 - currently administered to all newborns to prevent the hemorrhagic disease of Vitamin K deficiency, especially common in premature infants.  2024/09/26 Vitamin K deficiency frequently occurs in ICUs because of poor diet, parenteral nutrition, recent surgery, multiple antibiotic therapy, and uremia In severe hepatic failure → diminished protein synthesis and a hemorrhagic diathesis that is unresponsive to vitamin K Tx of depression of prothrombin activity e.g. excess warfarin or vitamin K deficiency Plasma coagulation deficiencies Deficiencies in plasma coagulation factors can cause bleeding Spontaneous bleeding occurs when factor activity is less than 5–10% of normal  2024/09/26 Haemophilia Rare inherited disease in which causes the blood to clot less, which results in an increased risk of bleeding or bruising. Deficiency or dysfunction of certain clotting factors Factor VIII (classic hemophilia, or hemophilia A) Factor IX (Christmas disease, or hemophilia B) “Inhibitors” in hemophilia are IgG alloantibodies to exogenous clotting factor VIII (FVIII) or factor IX (FIX) Inhibitors are more frequently with severe disease than in those with moderate or mild haemophilia More commonly in patients with hemophilia A than in those with hemophilia B  2024/09/26 Haemophilia Treatment Concentrated plasma fractions and recombinant protein preparations Lyophilized factor VIII concentrates are prepared from large pools of plasma Transmission e.g. hepatitis B and C and HIV ↓ or eliminated by pasteurization and by extraction of plasma with solvents and detergents. Does not remove other potential causes of transmissible diseases e.g. prions. Recombinant clotting factor preparations – therefore recommended Von Willebrand Disease Bleeding disorder in which blood does not clot properly Symptoms: nosebleeds, easy bruising, heavy menstruation, longer than normal bleeding after injury, surgery, dental work, childbirth Low levels of von Willebrand factor Von Willebrand factor in the blood functions as a carrier for factor VIII to maintain its levels and help in platelet adhesion and binding after a vascular injury.  2024/09/26 Desmopressin acetate Desmopressin acetate: synthetic analog of vasopressin ↑ the factor VIII activity Patients with mild hemophilia A or von Willebrand disease Prep for minor surgery e.g. tooth extraction High-dose intranasal desmopressin - efficacious and well tolerated by patients Blood coagulation Factors  2024/09/26 Fresh human plasma Fresh frozen plasma or lyophilized equivalent (Bioplasma) Sources for all coagulation factors Preferable for bleeding associated with multiple clotting factor deficiencies Emergency use –massive bleeding Life-threatening bleeding due to overcoagulation with warfarin Used for factor deficiencies for which no recombinant form of the protein is available Recombinant activated factor VII (NovoSeven) MOA: Binding of factor VIIa to exposed tissue factor This complex activates factor IX into factor IXa and factor X into factor Xa, leading to the initial conversion of small amounts of prothrombin into thrombin. Thrombin leads to the activation of platelets and factors V and VIII at the site of injury and to the formation of the haemostatic plug by converting fibrinogen into fibrin.  2024/09/26 Used to treat: Coagulopathy associated with liver disease and major blood loss in trauma and surgery Congenital haemophilia In patients with acquired haemophilia Haemophilia patients with inhibitors to factor VIII and IX for life- threatening bleeds or surgical interventions Cryoprecipitate Plasma protein fraction obtained from whole blood Used to treat deficiencies or qualitative abnormalities of fibrinogen e.g. disseminated intravascular coagulation and liver disease Source of fibrinogen, factor VIII, von Willabrand factor, factor XIII, fibronectin Indications: Treatment or prophylaxis of bleeding in significant hypofibrinogenaemia Factor XIII deficiency Emergency treatment of bleeding – haemophilia A if factor VIII is not available  2024/09/26 Cryoprecipitate is not treated to ↓ the risk of viral exposure Rh negative women with potential for childbearing should receive only Rh negative cryoprecipitate because of possible contamination of the product with Rh positive blood cells. Factor VIII Endogenous glycoprotein factor VIII available as a pooled lyophilized (freeze-dried) virus–inactivated antihaemophilia factor concentrate Indications: Treatment and prophylaxis of haemorrhage in haemophillia A and von Willebrand disease (with factor VIII deficiency)  2024/09/26 Factor VIII inhibitor bypassing activity (FEIBA) Contains an inti-inhibitor-coagulant complex Prepared from pooled human plasma Indications: o Treatment and prophylaxis of haemorrhage in Haemophilia A with actor VIII inhibitor Haemophillia B with IX inhibitor Factor IX Complex /Prothrombin Complex Contains vitamin K–dependent factors II, VII, IX, and X Used for rapid reversal of warfarin overdose in bleeding patients Treatment and prophylaxis of haemorrhage in hereditary or acquired disorders of coagulation with factor IX deficiency e.g. haemophilia  2024/09/26 Human Fibrinogen (factor I) Treatment of haemorrhage in congenital or acquired hypofibrinogenaemia Other haemostatics Romiplostin and Elthrombopag: Thrombopoetin receptor agonists Indications: Chronic thrombocytopaenia in patients refractory to corticosteroids, immunoglobulins or who have had a splenectomy  2024/09/26 Emicizumab Bi-specific monoclonal antibody to factor IXa and factor X It bridges factor Ixa and X thereby restoring the function of the missing factor VIII in Haemophilia A Prophylaxis of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors. FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID Aminocaproic acid (EACA), which is chemically similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis Competitively inhibits plasminogen Tranexamic acid is an analog of aminocaproic acid and has the same properties.