Anticoagulants PDF

Lecture 3: Anticoagulants, Platelet Aggregation Inhibitors, and Thrombolytics Anemia: hematologic disease as a result of low hemoglobin concentration • Etiologies o Decrease formation of RBCs o Decrease Hb concentrations o Chronic blood loss o Hemolysis o Bone marrow abnormalities o Malignancies o N...

Lecture 3: Anticoagulants, Platelet Aggregation Inhibitors, and Thrombolytics Anemia: hematologic disease as a result of low hemoglobin concentration • Etiologies o Decrease formation of RBCs o Decrease Hb concentrations o Chronic blood loss o Hemolysis o Bone marrow abnormalities o Malignancies o Nutritional deficiency § During Pregnancy (vit B-12 deficiency) § During Lactation • Rule out vitamin b-12 deficiency before treatment Iron Deficiency Anemia (most common nutritional deficiency) • Due to a negative Fe++ balance as a consequence of deficiency or inadequate states • Fe++ is stored in intestinal mucosal cells as ferritin until needed • States of Deficiency o Acute or chronic blood loss o Increase demand as in accelerated growth o Heavy mensural pregnancy o Microscopically hypochromic microcytic anemia • RX: Oral Fe++ Supplement as Ferrous Sulfate (produces constipation) (old exam question, pick two: advise pregnant women w anemia: ferrous sulfate and foliate acid) Folic Acid Deficiency • Etiologies o Increase demand during pregnancy and lactation o Poor absorption o Alcoholism o Treatment w dihydrofolate reeducates inhibitors such as methotrexate and trimethoprim • RX: Folic acid supplements Cyanocobalamin Vit B-12 Pernicious Anemia • Deficiency due to low dietary levels or poor absorption (no production if intrinsic factor) o Intrinsic Factor: a glycoprotein produced by the parietal cells located at the gastric body and fundus. Intrinsic factor plays a crucial role in the transportation and absorption of the vital micronutrient vitamin B12 by the terminal ileum. • Formulations o Oral Intranasal Parenteral • Erythropoietin: hormone that stimulates production of RBC o A glycoprotein, kidney hormone which stimulate erythropoiesis o Recombinant technology has made it possible to administrate more readily (parenteral) o Application § End stage renal disease malignancies § HIV+ subjects o Patients w kidney failure § This agent isn’t produced adequately and leads to something similar to iron deficiency § Pts can benefit by giving this protein via parenteral admin • Improves manifestation of anemia • Give additional doses afterward for maintenance • Hydroxyurea (cancer drug) o Chronic Myelogenous Leukemia (CML) o Polycythemia vera (PV) o In sickle cell anemia (HbS disease) apparently increases the concentration of fetal hemoglobin (HbF) diluting the concentration of HbS Hemostasis (requires two different structures, proteins that are inactivates and platelets) • Normal healthy tissue o Hemostasis maintains a balance and blocks unwanted activation of clot formation o Healthy intact endothelium releases prostacyclin o Prostacyclin binds to platelet membrane receptors cAMP o cAMP stabilizes inactive GP IIb/IIa receptors Inhibiting degranulation • Platelets o Discoid cytoplasmic fragments from megakaryocytes o Circulate in the blood and are essential for clot formation and hemostasis • Thrombus o Pathologic formation of an outward clot w/in a blood vessel or the heart • Emboli o Thrombus which floats within the blood (arterial and venous) Clot Formation • Essential components o Dependent on platelet number and adequate function o Together, with the proper activation of the coagulation cascade for its stabilization • Begins w platelet activation o This process involves 3 steps: adhesion, degranulation, aggregation Platelet Aggregators (old exam questions) • Exposed collagen-most important • ADP released during platelet activation (also releases thromboxane A2 which promotes further aggregation) • Decrease concentration of prostacyclin • Thromboxane (produced during Arachidonic Acid catabolism by cyclooxygenase) • Exposure of platelet fibrin receptors Do not take ibuprofen with blood thinners Platelet Aggregator Inhibitors • Agents are used in prevention and treatment of cardiovascular disease & maintenance of vascular grafts • Aspirin o Irreversibly inhibits the cyclogeneses pathway of Arachidonic Acid (suppressing Thromboxane A2) o Effect lasts 7-10 days (old exam question) o Should use a loading dose followed by smaller maintenance doses • Dipyridamole o Coronary vasodilator, used prophylactically in CAD (angina) o Works by increasing cAMP levels which decrease formation of Thromboxane A2 o Effective in combination with warfarin preventing embolization in prosthetic heart valves o Used in CAD, reduces incidence of ischemic events/MI o MOA: suppress thromboxane A2 • Ticlopidine and Clopidogrel o Inhibits platelet aggregation by blocking ADP pathway (old exam question) involved in binding platelets to fibrinogen • • o Useful in preventing CVA, CVD, PVD o Used in stent insertion o Adverse Effects: neutropenia (old exam question), inhibition of CYP-450 Abciximab o Monoclonal antibody against GpIIb/IIa complex, blocking the binding of factors I and X, blocking platelet aggregation o Used for short term effects o Used IV and effects persist for 24-48 hours o Adverse Effects: bleeding Eptifibatide and Tirofiban o Similar in action and therapeutic use to Abciximab o Less side effects Anticoagulants • Heparin o Vitamin K antagonist o Rapid onset of action, indirectly binding to antithrombin III (heparin cofactor) which inhibits activation of several clotting factors (IIa, IXa, Xa, XIa, XIIa, XIIIa) o Use SC or IV, NEVER IM (could cause hematoma w IM admin) o Clinical Use § DVT § PE § Extracorporeal devices o Choice of anticoagulation during pregnancy (doesn’t cross the placenta) o IV use as bolus or slow continuous infusion for 7-10 days o Dose should be titrated to maintain PTT 1.5-2.5 its control time, INR o Metabolized in the Liver o Excreted by the kidney o Disorders effecting the liver or kidney increase the half-life o Adverse Effects § Hemorrhage (resolved by discontinuation or administration of protamine sulfate in emergency situations) § Hypersensitivity (obtained from animal sources): thrombocytopenia § Contraindications • Bleeding disorder • Hypersensitivity • Post operative stages (eye, brain, or spinal cord) • Warfarin (rat poison) o Anticoagulant which antagonizes the function of Vitamin K (factors 3, 5, 8, 9, and 10) o Action observed 8-12 hours after administration o 99% bound to albumin (may be displaced by other drugs with elevation of half-life) o CI in pregnancy bc it crosses the placenta and is teratogenic o Follow up: PT 1.5-2.5 its control time, INR o Adverse Effects § Hemorrhage § Minor bleeding treated by discontinuation, and administration of Vit. K • Severe bleeding requires a greater dose of Vit. K • Fresh frozen Plasma • Specific blood factors Interactions § Inhibit metabolism and increase concentration in blood • Acute Alcohol, Cimetidine, Chloramphenicol, Cotrimoxazole, Metronidazole, Phenylbutazone § Increase metabolism and decrease concentration in blood • Chronic Alcohol, Barbiturates, Glutethimide, Griseofulvin, Rifampin Other Parenteral Anticoagulants (thrombin antagonists) • Lepirudin o Thrombin antagonist w little or no activity on platelet function o Half-life: 1 hour o Mostly eliminated by urine o Side effects: bleeding o Follow Up: renal function, and aPTT, INR • Argatroban o Thrombin inhibitor o Used prophylactically in heparin induced thrombocytopenia (HIT) (old exam question) o Side effects: bleeding o Follow Up: aPTT, INR • Fondaparinux o Purely synthetic pentasaccharide o Approved for DVT in orthopedic surgery of hip and knee o Binds to factor Xa o Contraindicated in Renal Impairment o May be used in HIT Thrombolytic Agents • Alteplase (tPA)-ACTIVASE • Reteplase- RETAVASE • Streptokinase • Tenecteplase- TNKASE • Urokinase- KINLYTIC • MOA: act directly to convert plasminogen to plasmin which cleaves fibrin (lysing a thrombi) • Dissolution and reperfusion (dissolution of blood clot) occurs w high frequency when therapy is instituted early after clot formation. But may lead to further clot formation • Therapeutic use o Originally indicated for DVT and acute PE, now has extended to Acute MI o Window period of 2-6 hours for myocardial salvage in Acute Cerebral Ischemia (CVA) o Peripheral arterial thrombus o Un-clotting catheters and shunts • Adverse effects o Hemorrhage o Decreased wound healing • Contraindications (old exam question, what isn’t a contraindication? Catheter) o HX of CVA o Pregnancy o Metastatic Carcinoma • Profile (old exam question) o Antigenicity: Streptokinase is highest o o Fibrin Specificity (coupling w fibrin vs free fibrinogen): Alteplase and Urokinase are highest o Half-Life: Streptokinase is highest • Alterplase (tPA) (tissue plasminogen activator) o Serine protease obtained from recombinant DNA o At low levels, couples specifically w fibrin in a thrombus (fibrin selective) (old exam question) and not on free fibrinogen o Unfortunately, at therapeutic doses, may activate circulating plasminogen related w hemorrhages o Clinical Use § Acute myocardial infarction § PE § Acute ischemic infarct (CVA) (if given prior to 3 hours of onset improves outcome and ability to perform daily activities) o Pharmacokinetics § Very short half-life (>5 min) § Use in a bolus of 100 mg (10 mg. STAT followed by slow infusion in 90 min) • Streptokinase o Has no enzymatic activity but couples 1:1 with plasminogen converting it into its active state o Also catalyze degradation of fibrinogen and state factors V and VII o Clinical use § Acute MI § DVT § Acute PE § Arterial Embolism § Occluded access shunts o Pharmacokinetics § MI: given IV constant infusion for 1 hour § Thromboplastin time is maintained 2 to 5 times its control (afterwards patient is continued on anticoagulation) § Aminocaproic acid is used to counteract life threatening bleeding o Side Effects § Bleeding § Hypersensitivity 3% of pts: since it’s a foreign protein (Strp. B-hemol.) allergic reactions may occur even anaphylaxis • Anti-Streptococcal Ab may combine w drug, diminishing its efficiency • Anistreplase (anysolated plasminogen streptokinase) o Modified streptokinase molecule semiselective for clot site since it binds to only fibrin o Half-life: 90 minutes o Given for 2-5 minutes Drugs used for stopping bleeding • Specific procoagulant factors deficiency lyophilized (F VIII) (Hemophilia) • Fresh Frozen Plasma (FFP) for immediate hemostasis (contains all coagulation factors) (old exam question) • Aminocaproic Acid o Synthetic agent that inhibits plasminogen activation o Complication: intravascular thrombus • Protamine Sulfate o Antagonize anticoagulant effect of heparin o Side Effects: hypersensitivity, dyspnea, bradycardia, and hypotension when given IV rapidly • Vitamin K o May stop bleeding 2ndary to oral anticoagulants (slow response >24 hours) • Apoprotein o Serine proteases inhibitor blocks plasmin o Prophylactic use to reduce perioperative blood loss (before sx) Antidotes for Bleeding • Aminocaproic Acid & Tranexamic Acid à Fibrinolytic State • Protamine sulfate à heparin • Vitamin K1 à Warfarin