Applied Therapeutics 1 Lec.3 Dr. Qassim PDF

Al-Mustaqbal University College of Pharmacy 5th Stage Applied therapeutics I Lecture: 3 THROMBOSIS Dr. Qassim A. Zigam  THROMBOSIS Thrombosis is the process involved in the formation of a fibrin blood...

Al-Mustaqbal University College of Pharmacy 5th Stage Applied therapeutics I Lecture: 3 THROMBOSIS Dr. Qassim A. Zigam  THROMBOSIS Thrombosis is the process involved in the formation of a fibrin blood clot. An embolus is a small part of a clot that breaks off and is carried via the blood to another part of the vascular system. Abnormal thrombotic events may include: ✓Venous thromboembolism (VTE) ✓Deep Venous Thrombosis (DVT) ✓Pulmonary Embolism (PE) ✓Stroke ✓Others Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  CLOTTING CASCADE Endothelial damage results in activation of the clotting cascade. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  FIBRIN BLOOD CLOT FORMATION Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  FIBRIN BLOOD CLOT FORMATION Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  ANTICLOTTING DRUGS Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  Characterization of Thrombi Pathological thrombi are classified according to location and composition. Arterial thrombi occur in areas of rapid blood flow and are typically initiated by spontaneous or mechanical rupture of atherosclerotic plaques. Venous thrombi are found primarily in the venous circulation and are composed almost entirely of fibrin and erythrocytes. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  RISK FACTORS FOR THROMBOEMBOLISM Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  PATIENT ASSESSMENT DVT PE DVT typically presents as PE is often associated with unilateral leg swelling that is nonspecific symptoms often accompanied by (dyspnea, pleuritic chest pain, warmth and tenderness or apprehension, cough, and pain. sometimes hemoptysis). Many patients (>50%) can DVT precedes PE in 80% or present with asymptomatic more patients. disease. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  PATIENT ASSESSMENT Pregnancy: Prevention of thromboembolism: Pregnant Prevention of cardiogenic thromboembolism is needed in patients patients should with atrial fibrillation, after cardioversion, or cardiac valve receive UFH or replacements. LMWH. Prevention of VTE is important in patients undergoing surgery. Warfarin When PE is suspected, Rx should be initiated immediately. should not be Mortality associated with PE is as high as 17.5% over 3 months. used during pregnancy. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  DRUG THERAPY Bridge therapy is UFH, LMWH, factor often necessary to Xa inhibitors, direct Drugs that alter Selection of an reverse the effects of thrombin inhibitors, platelet function (e.g., Fibrinolytic agents are antithrombotic agent warfarin when an and warfarin are used aspirin, clopidogrel) used for rapid is influenced by the invasive procedure is for treatment and are used in the dissolution of type of thrombus to planned in order to prevention of both prevention of arterial thromboemboli. be treated. minimize the risk of arterial and venous clots. bleeding associated thrombi. with the procedure. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  DRUG THERAPY Drug Therapy 1.UFH 2.LMWH 3.Fondaparinux 4. Direct Thrombin Inhibitors 5.Oral Factor Xa Inhibitors 6.Warfarin Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  1. UFH A rapid acting anticoagulant that attaches to and irreversibly inactivates factor IIa (thrombin) and factor Xa. In addition to anticoagulant effects, it also inhibits platelet function and increases vascular permeability. UFH can be administered IV and SC, although bioavailability is greatly reduced with SC administration. IM administration should be avoided due to risk for hematoma formation. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  UFH A loading dose required to achieve therapeutic levels more quickly. Weight-based IV dosing (80 units/kg loading dose; 18 units/kg/hour initial infusion rate) increases the frequency of therapeutic activated partial thromboplastin time (aPTT) at 6 and 24 hours. Dosing can be based on body weight (use actual body weight [ABW] for patients 100 kg). Adjusted-dose weight = IBW + 0.3 (ABW − IBW) or IBW + 0.4 (ABW − IBW) Therapy is monitored and doses adjusted using aPTT. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  UFH Side effects include thrombocytopenia, bleeding (typically in soft tissue, GI, and urinary tracts), and osteoporosis (with long-term use of doses >20,000 units/day). Reductions in platelet counts of >50% from baseline suggest possibility of heparin induced thrombocytopenia (HIT). HIT occurs in 3% of patients after 5 days of UFH and in up to 6% of patients after 14 days of continuous UFH therapy. Heparin therapy should be discontinued in patients who develop HIT. Treatment alternatives include direct thrombin inhibitors like lepirudin and argatroban. LMWH use is contraindicated in patients with HIT. Pathophysiology of HIT Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  UFH Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  LMWH Like Dalteparin, Enoxaparin, and Tinzaparin. The anti-Xa properties of LMWH are more significant than their anti-IIa properties, so aPTT is not prolonged. Monitoring of therapy is not routinely required. LMWH has better SC bioavailability over UFH, resulting in a predictable dose response and a longer pharmacodynamic effect, making it a good choice when the goal is to treat patients at home. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  Fondaparinux Fondaparinux acts as a selective factor Xa inhibitor. It has a long elimination half-life allowing for once-daily SC dosing. Like LMWH, there is no need for routine monitoring. It is eliminated in the urine mainly as unchanged drug with an elimination half-life of 17 to 21 hours. It is contraindicated in patients with severe renal impairment. Bleeding is the major side effect of fondaparinux. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  UFH VS LMWH VS FONDAPARINUX Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  DIRECT THROMBIN INHIBITORS Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  DIRECT ORAL FACTOR Xa INHIBITORS Oral Xa inhibitors, including the small molecules rivaroxaban and apixaban, have a rapid onset of action and shorter half-lives than warfarin. These drugs are given as fixed oral doses and do not require monitoring. These small molecules directly bind to and inhibit both free factor Xa and factor Xa bound in the clotting complex. Rivaroxaban is approved for prevention of venous thromboembolism following hip or knee surgery and for prevention of stroke in patients with atrial fibrillation. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  Warfarin Warfarin acts as a vitamin K antagonist. Concentrations of clotting factors II, VII, IX, and X are gradually diminished in accordance with their elimination half-lives. The onset of effect of warfarin is delayed, typically taking 5 to 7 days to reach a steady state of anticoagulation. Heparin therapy should be continued for at least 5 days after initiating warfarin, because of the time required for adequate elimination of factors II and X by warfarin. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  Warfarin Patients who are more sensitive to warfarin are expected to require lower doses. Successful warfarin therapy depends on active participation by the patient. Therapy is monitored using prothrombin time or, more commonly, the INR. Side effects include bleeding (commonly in the nose, oral pharynx, soft tissue, and GI and urinary tracts), skin necrosis (rare, but serious side effect), and purple toe syndrome (rare). Vitamin K is used for reversal of an elevated INR caused by warfarin. Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  Warfarin Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  Warfarin Applied therapeutics I 5th stage Al-Mustaqbal University / College of Pharmacy Dr. Qassim A. Zigam  THANK YOU FOR YOUR ATTENTION Applied therapeutics II 5th stage Al-Mustaqbal University College / Pharmacy Department Dr. Qassim A. Zigam