Drugs for Coagulation and Bleeding PDF

HEMOSTASIS STEPS IN HEMOSTASIS ▪Hemostasis is a complex process I. Vascular phase involving multiple steps and many Cutting or damaging blood vessels leads clotting factors....

HEMOSTASIS STEPS IN HEMOSTASIS ▪Hemostasis is a complex process I. Vascular phase involving multiple steps and many Cutting or damaging blood vessels leads clotting factors. to vascular spasm that produces a ▪Hemostasis is the balance between vasoconstriction which will slow or even clot formation and clot breakdown stop blood flow. Steps in Hemostasis: 1. Vascular Phase II. Platelet phase 2. Platelet Phase In larger blood vessels, platelets begin 3. Coagulation Phase to stick to the surfaces of endothelial 4. Clot formation cells. 5. Fibrinolysis Aggregation of platelets leads to the formation of a platelet plug. STEPS IN HEMOSTASIS III. Coagulation phase The overall process involves the formation of the insoluble protein Fibrin from the plasma protein Fibrinogen through the action of the enzyme Thrombin. Fibrin forms a network of fibers which traps blood cells and platelets forming a thrombus or clot. Two pathways leading to the formation of the thrombus: a. Extrinsic pathway b. Intrinsic pathway STEPS IN HEMOSTASIS Extrinsic Initiated with material outside of the blood. pathway Very rapid process Smaller clots Initiated by the blood coming in contact Intrinsic with exposed collagen in the blood pathway vessel wall Slower Larger clots  Blood clotting factors STEPS IN HEMOSTASIS IV. Clot Retraction After 2 or 3 days, the clot begins to contract. Platelets in the clot contain contractile proteins. These proteins pull the edges of the wound together and reduces the chance of further hemorrhage. This activity also assists the repair processes. STEPS IN HEMOSTASIS BLOOD CLOTS V. Fibrinolysis Dissolution of the clot. ▪Once a stationary clot forms (thrombus), it often grows The breakdown of the clot is due to the production of a larger as more fibrin is added. powerful proteolytic enzyme Plasmin. ▪Pieces of the clot may break off and travel in the blood stream Removing a blood clot is essential to restoring normal to possibly lodge elsewhere. circulation. ▪A traveling clot is know as an embolus *This step complete the HEMOSTASIS ▪When clots or emboli form, drug therapy becomes necessary.  DRUGS FOR COAGUALTIVE & BLEEDING DISORDER ANTICOAGULANTS A. Anticoagulants - used to prevent the formation of clots Anticoagulants prevent the formation and enlargement of clots. B. Antiplatelets – used to inhibit platelet aggregation Examples: Warfarin, Heparin & LMWH C. Thrombolytics - used to dissolve such life-threatening clots ACTIONS: D. Hemostatics - used to speed clot formation, or to limit 1) Inhibit certain clotting factors bleeding from a surgical site. 2) Lengthen clotting time 3) Prevent thrombi from forming or growing larger ANTICOAGULANTS WARFARIN HEPARIN Chemistry Coumarin Sulfated glycosaminoglycan MOA Inhibits vitamin K Activates antithrombin III synthesis Route Oral or IV IV or SC IM is contraindicated= Hematoma Monitoring PT-INR aPTT Target INR 2-3 1.5-2.5x control ANTICOAGULANTS ANTICOAGULANTS WARFARIN HEPARIN Uses Prophylactic for acute MI, prevention of venous prevention of progression or thrombosis, tx of recurrence of acute deep- pulmonary embolism and vein thrombosis or acute myocardial pulmonary embolism infarction Side Bleeding, Teratogenic Bleeding, allergy, effects thrombocytopenia Antidote Vitamin K Protamine SO4 20  VITAMIN K ANTICOAGULANTS ❑A procoagulant used as antidote for Warfarin toxicity. LOW MOLECULAR WEIGHT HEPARIN (LMWH) ❑Foods high in Vitamin K (must be avoided during Warfarin Therapy): DRUGS: ▪Green leafy vegetables Go to fullsize image Enoxaparin (Lovenox) ▪Milk and milk products Tinzaparin (Fragmin) ▪Some cereals Dalteparin (Innohep) ▪Orange juice USES: ▪Cauliflower anticoagulants of choice for treating pregnant women with ▪Cucumbers prosthetic heart valves or venous thromboembolism NOTES: Do not require intense monitoring Longer half-life than heparin With less bleeding ANTICOAGULANTS ANTICOAGULANTS DIRECT THROMBIN INHIBITORS Fondaparinux LEPIRUDIN is a small synthetic drug that contains Polypeptide that is closely related to the biologically active pentasaccharide hirudin effective in the treatment of HIT present in unfractionated and LMW CI: streptokinase or alteplase heparins Desirudin, Bivalirudin ARGATROBAN directly inhibits thrombin prophylactic for the treatment of thrombosis in patients with HIT DABIGATRAN -oral ANTICOAGULANTS ADVERSE EFFECT Most common and potentially serious adverse effect is bleeding. Signs: Go to fullsize image Go to fullsize image Bruising Bleeding gums Nosebleed Blood in urine or stool Go to fullsize image USE: Idarucizumab is a Mgt of thrombosis associated humanized monoclonal antibody Fab with Heparin induced fragment that binds to dabigatran and reverses the anticoagulant effect. thrombocytopenia  ANTICOAGULANTS Antithrombotic -- Antiplatelet Drugs DIRECT ORAL Factor XA INHIBITORS Overview: antithrombotic agents rivaroxaban, apixaban, and 1. Regulation of platelet function -- Three types of substances: edoxaban ◦Substances developed outside the platelet but have a rapid onset of action and shorter half-lives than warfarin interacts with platelet membrane receptors: MOA: directly bind to and inhibit both free factor Xa and factor ◦ catecholamines Xa bound in the clotting complex. ◦ collagen ◦ thrombin ◦ prostacyclin 2. Agents generated internal to the platelet 3. Agents generated internal to the platelet and interact with membrane receptors: and interact within the platelet: ADP prostaglandin endoperoxidases prostaglandin D2 thromboxane A2 cAMP prostaglandin E2 cGMP serotonin Ca2+ ANTIPLATELET DRUGS Antiplatelet agents prolong bleeding time by interfering with platelet aggregation. Four primary subclasses: 1. TXA2 synthesis blocker: Aspirin 2. Adenosine diphosphate (ADP) receptor blockers 3. Glycoprotein IIb/IIIa receptor blockers 4. PDE inhibitors  ASPIRIN ASPIRIN Acetylsalicylic acid MOA: Irreversible inhibition of ADVERSE EFFECTS: COX ▪ increased incidence of hemorrhagic stroke ▪ gastrointestinal bleeding USES: ▪ Salicylism= Tinnitus Prophylactic for transient cerebral ischemia and to reduce CONTRAINDICATION: the incidence of recurrent MI Anticoagulants – increase bleeding Ibuprofen – antagonize platelet inhibition DOSE: 100 to 325 mg ADP RECEPTOR ADP RECEPTOR BLOCKERS BLOCKERS MOA: Irreversibly inhibit the binding of ADP to its receptors NOTES: on platelets ▪ Clopidogrel is the preferred agent in ischemic heart Also known as: Thienopyridines disease events ▪ Clopidogrel is safer than ticlopidine Examples: ▪ Ticlopidine causes: neutropenia/agranulocytosis, Clopidogrel (Plaxix) thrombotic thrombocytopenic purpura (TTP), and Ticlopidine (Ticlid) aplastic anemia Prasugrel (Effient) Ticagrelor GLYCOPROTEIN IIA/IIB BLOCKERS DRUGS: ▪ Abciximab (Reopro) ▪ Eptifibatide (Integrilin) ▪ Tirofiban (Aggrastat) ABCIXIMAB chimeric monoclonal antibody Given IV along with heparin or ASA as an adjunct for patients undergoing angioplasty S/E: bleeding PHOSPODIESTERASE INHIBITOR Example: Dipyridamole coronary vasodilator usually given in combination with aspirin or warfarin; it is ineffective when used alone S/E: Coronary steal phenomenon THROMBOLYTICS Thrombolytics are used to dissolve existing clots. Prescribed for disorders in which a clot has already formed, including the ff: 1. Acute MI 2. Pulmonary embolism 3. Cerebrovascular accident (CVA) 4. DVT 5. Arterial or Coronary thrombosis Tissue Plasminogen Activators THROMBOLYTICS (t-PA) Alteplase: 1. STREPTOKINASE (Streptase) Protein from streptococci unmodified human t-PA S/E: allergy, bleeding recombinant human plasminogen 2. TISSUE PLASMINOGEN ACTIVATORS Alteplase (Activase) , Reteplase (Retavase) activator derived from cultured human melanoma cells More selective than streptokinase Reteplase: S/E: Bleeding modified human t-PA 3. ANISTREPLASE mutated form of human t-PA Anisoylated plasminogen streptokinase activator complex a prodrug S/E: bleeding Tenecteplase is another 4. UROKINASE mutated form of t-PA with a longer half-life.  HEMOSTATICS HEMOSTATICS Hemostatics are used to promote the formation of Hemostatics are used to promote clots. the formation of clots. Vitamin K Used in Hemophilia: required for biological activity of: ✓a consequence of a prothrombin deficiency in plasma factors VII, IX, X coagulation factors fat-soluble, available from diet & synthesized by human intestinal bacteria a rare disorder in which your Two natural forms: blood doesn't clot normally vitamin K1 - phytonadione, from food because it lacks sufficient blood- vitamin K2 menaquinone, found in human tissue, clotting proteins (clotting factors). bacterial synthesis Vitamins K1 and K2-- require bile salts for absorption from intestinal tract TYPES OF HEMOPHILIA TYPES OF HEMOPHILIA 3) Von Willebrand disease- genetic disorder caused by missing 1) Hemophilia A-factor VIII (FVIII) deficiency or classic or defective von Willebrand factor,a clotting protein. VWF binds hemophilia factor VIII, a key clotting protein, and platelets in blood vessel walls, which help form a platelet plug during the clotting process Hemophilia occurs in approximately 1 in 5,000 live births. Hemophilia A is 4x as common as hemophilia B while more than half of patients with hemophilia A have the severe form of ▪Type 1 VWD -60%-80% of patients. hemophilia. ▪Type 2 VWD -15%-30% of patients. ▪Type 3 VWD -5%-10% of patients. 2) Hemophilia B- factor IX (FIX) deficiency or Christmas disease ▪Acquired VWD- results after a diagnosis of an autoimmune disease, such as lupus, or from heart disease or some types of cancer. It can also occur after taking certain medications. COAGULATION TEST Coagulation time test- measurement of the intrinsic power of the blood to convert fibrinogen to fibrin Prothrombin time test- measures how quickly your blood clots. aka pro time test or PT test, INR HEMOSTATICS 1. AMINOCAPROIC & TRANEXAMIC ACID ▪ Synthetic ▪ Inhibit plasminogen activation ▪ Potential side effect of treatment is intravascular thrombosis 2. APROTININ ▪ Stops bleeding by blocking plasmin ▪ SERINE protease inhibitor ▪ Approved for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass surgery.