Transcript الشريحة 1
Drugs that affect hemostasis Ahmad Shihada Silmi Msc, FIBMS IUG Faculty of Sciences Medical Technology Dep. Drugs that affect hemostasis Drugs are categorized according to the process they target. An injured blood vessel Contracts Forms a platelet plug (1º hemostasis) Forms a protein clot (2º hemostasis) Once healed, solubilizes the clot (fibrinolysis) Drugs Affecting Hemostasis Anticoagulants Therapeutic overview Heparin and heparin derivatives Coumarins (warfarin) Directly acting thrombin inhibitors hirudin bivalirudin argatroban arterial thrombosis atrial fibrillation cardiomyopathy cerebral emboli heart valve disease hip surgery vascular prostheses Venous thromboembolism Oral anticoagulants 4-Hydrdroxycoumarin and indan-1,3-dione are the parent molecules. Warfarin Interferes with the synthesis of the vitamin K-dependent clotting factors MechanismDrugs Affecting Hemostasis Mechanism of Action Interferes with liver synthesis Vitamin K VII Synthesis IX of X Functional Coagulatio II n Factors C Synthesis of AntiS coagulatio Z n Proteins Drugs Affecting Hemostasis Vitamin K Action Drugs Affecting Hemostasis Warfarin Mechanism of Action Drugs Affecting Hemostasis Warfarin Pharmacokinetics ABSORPTION: Rapid, complete. Used orally. DISTRIBUTION: Vd is small; plasma protein binding ≈ 99%. [Maternal] = [Fetal]. Warfarin is not found in breast milk; other coumadins are! ELIMINATION: T1/2 = 40 hr. ONSET: 2-3 days. DURATION: 2-5 days. Drugs Affecting Hemostasis Warfarin: Adverse Actions Bleeding is the main concern vitamin K, clotting factors, fresh frozen plasma Crosses the placenta and is teratogenic during weeks 6-12 Alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramps, anorexia, skin necrosis Drugs Affecting Hemostasis Drug Interactions Drug interactions are particularly important with oral anticoagulants, and the result may be either an increase or a decrease in the effect of the anticoagulant. Frequent monitoring of the prothrombin time is essential when administering another drug with warfarin, and changing the dose of warfarin may be necessary. Drugs increase anticoagulation by 1. Displacement of protein bound warfarin. Because of the high degree of warfarin bound to plasma proteins, even a small decrease in the amount bound can lead to significant increases in free drug levels. Examples: salicylates such as aspirin. 2. Inhibition of the liver microsomal enzyme system that metabolizes warfarin will increase the availability of warfarin. Example: quinidine. 3. Increasing the warfarin “receptor site” affinity will increase the efficacy of a given plasma level of warfarin. Example: d-thyroxine. 4. Reducing the availability of vitamin K. Example: broad spectrum antibiotics, laxatives. 5. Inhibiting platelet function. Example, aspirin. Drugs depress anticoagulation by 1. Stimulation of the hepatic microsomal enzyme system. This decreases plasma half-life of warfarin. Example: barbiturates. 2. Stimulation of clotting factor synthesis. This antagonizes the effect of warfarin. Example: vitamin K, estrogens. 3. Inhibition of absorption. Example: cholestyramine. Drugs Affecting Hemostasis Heparin 2-40 kDa MW, naturally occurring N- & Osulfated sugars polymerized by glycoside bonds found in the secretory granules of mast cells. Drugs Affecting Hemostasis Heparin 2-40 kDa MW, naturally occurring N- & O-sulfated sugars polymerized by glycoside bonds found in the secretory granules of mast cells. Lower MW polymers possess most of the biological activity. Active in vitro as well as in vivo. The most acidic organic acid in the body. Is not absorbed following oral administration. Drugs Affecting Hemostasis Mechanism of Action Accelerates the inactivation of factors IIa, Xa, IXa, XIa and XIIa by the serine protease inhibitor, antithrombin III (AT III). Drugs Affecting Hemostasis Mechanism of Action Unique pentasaccharide sequence binds to antithrombin III (AT III) with high affinity but a polysaccharide of at least 18 units is required (5 for LMWH). Drugs Affecting Hemostasis AT III + Heparin Serine protease Inactive Drugs Affecting Hemostasis Ternary complex LMW Heparin MW 4,000 - 6,000 Preferentially binds to factor Xa T1/2 2x > standard heparin Less bleeding Less effect on platelet activation and factor XIII activation Clinically effective - e.g., enoxaparin Drugs Affecting Hemostasis AT III IIa Heparin Heparin > 18 monosaccharide units AT III < 18 monosaccharide units Heparin AT III LMWH Drugs Affecting Hemostasis Xa Heparin Pharmacokinetics No oral absorption; IV or subQ. Vd is small due to extensive binding. Binding can influence the effect of heparin. Onset: IV, immediate; subQ, 20-60 min Drugs Affecting Hemostasis Heparin Adverse Actions Bleeding is the main concern. Antidote: protamine sulfate. Thrombocytopenia (<5%, within a few days). Disappears with cessation of therapy. Rapid and profound thrombocytopenia (<5%, 8-10 days) with paradoxical arterial or venous thrombosis. Results from the formation of anti-heparin antibodies. Heparin-Ab bind to platelets causing inappropriate aggregation and thrombus formation. May be lifethreatening. Reversible osteoporosis (6 months). If it occurs, it is usually after 6 months therapy with >15,000 U/day. Drugs Affecting Hemostasis Antiplatelet Drugs Drugs Affecting Hemostasis Therapeutic overview Platelet aggregation inhibitors Aspirin Cerebrovascular accident, stroke, coronary bypass surgery, coronary angioplasty/stenting or thrombolysis, myocardial infarction, transient ischemic attack Clopidogrel Coronary artery disease, cerebrovascular accident, stroke, peripheral arterial disease Glycoprotein IIb/IIIa inhibitors Acute coronary syndromes, after coronary artery stenting Aspirin Mechanism of Action Aspirin irreversibly inactivates cyclooxygenase by covalent acetylation. Drugs Affecting Hemostasis Aspirin inhibits Aspirin inhibits Selectivity of aspirin for platelet COX 1. Platelet COX is acetylated in the portal circulation before aspirin is deacylated in the liver. 2. The systemic vasculature is unaffected because platelets are not affected by salicylate. Drugs Affecting Hemostasis Aspirin Pharmacokinetics ABSORPTION: 70% DISTRIBUTION: at low doses most is protein bound in plasma; at high doses a smaller percentage is bound and more is available to tissues ELIMINATION: hepatic metabolites (75%) and parent compound excreted in urine. At low doses half-life is 4 hr and is 1st order. High doses show saturation kinetics and half-life is 15 hr. Faster in alkaline urine. ONSET: 30 min DURATION: 7-10 days Drugs Affecting Hemostasis Aspirin Adverse Actions Primarily gastrointestinal Epigastric pain, heartburn, nausea GI blood loss Gastric ulcer Others: rash, tinnitus, nasal polyps, gout, acid-base disturbances Drugs Affecting Hemostasis Aspirin Drug Interactions Decreases the effectiveness of antihypertensives: usually not a problem with low doses. Increases the effect of warfarin. Attenuates the actions of uricosuric agents, e.g. probenecid. Drugs Affecting Hemostasis Ticlopidine and Clopidogrel P2Y2 purine receptor antagonists. Drugs Affecting Hemostasis Other Antiplatelet Drugs Ticlopidine and Clopidogrel: P2Y2 purine receptor antagonists clopidogrel P2Y2R A C J. L. et Hemostasis al. J. Biol. Chem. 1998;273:2024-2029 DrugsDaniel, Affecting P2Y1 R Clopidogrel Reduces the incidence of stroke and myocardial ischemia. Particularly effective combined with aspirin. Currently the drug of choice in the prophylaxis of subacute stent thrombosis and post ischemic stroke treatment. Drugs Affecting Hemostasis Glycoprotein IIb/IIIa Inhibitors GP IIb/IIIa is a platelet surface integrin (aIIb3) GP IIb/IIIa is the receptor for fibrinogen and von Willebrand factor. Thrombin, collagen, TXA2 activate platelets exposing binding sites for vWf and fibrinogen. Drugs Affecting Hemostasis Basal platelet with GP IIb/IIIa receptors in inactive state Activated platelet with functional GP IIb/IIIa receptors Agonis t Fibrinog en GP IIb/IIIa antagonis t () Fibrinogen binding to platelets blocked by GP IIb/IIIa receptor antagonist Fibrinogen mediated platelet aggregation Glycoprotein IIb/IIIa Inhibitors Abciximab -- Fab fragment directed to the GPIIb/IIIa receptor. Can be used only once. Eptifibatide -- a cyclic peptide Tirofiban -- a nonpeptide inhibitor Drugs Affecting Hemostasis Fibrinolytics Restore blood flow to an injured area by lysing the thrombus into soluble fibrin degradation products. Drugs Affecting Hemostasis Alteplase (rtPA) Urokinase Streptokinase Anistreplase Drugs Affecting Hemostasis Site of action of drugs acting on the fibrinolytic system. Fibrinolytic drugs accelerate the conversion of plasminogen to plasmin, which is a protease that breaks down fibrinogen and fibrin to degradation products. © 2005 Elsevier tPA Plasminogen Plasminogen L L Plasmin tPA L Fibrin Clot tPA Plasmin L L L tPA, tissue plasminogen activator Fibrin Clot L, lysine binding sites PI PI, plasmin inactivator Plasmin Drugs Affecting HemostasisSoluble fibrin digestion products Treatment Goals Rapid reperfusion of the infarcted area to preserve more tissue. Drugs Affecting Hemostasis Fibrinolytic success is dependent upon the time lapse between the onset of symptoms and administration of the fibrinolytic. • DVT: < 7 days • Pulmonary embolism: < • Myocardial infarction: • Stroke: < 3 hr Drugs Affecting Hemostasis 2 days 2 - 4 hr Fibrinolytics: Adverse Actions Unwanted BLEEDING is the MAJOR side effect. Drugs Affecting Hemostasis The End Drugs Affecting Hemostasis