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Woods Anticoag Antianem 09

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Woods Anticoag Antianem 09

  1. 1. Anticoagulant, Thrombolytic, and Antiplatelet Drugs Cooper Woods, Ph.D. [email_address]
  2. 2. Homeostasis: Cessation of bleeding from an injured blood vessel <ul><li>Primary Hemostasis </li></ul><ul><li>This stage occurs within seconds </li></ul><ul><li>1. Vasospasm : Vasoconstriction of the blood vessel by Prostacyclin (PI 2 ), Thromboxane A 2 (TXA 2 ) and serotonin (5-HT). Slows down the bleeding. </li></ul><ul><li>2. Platelet Plug : Adherence of platelets to collagen of damaged endothelial cells. Platelet aggregation: Role of thrombin, adenosine diphosphate (ADP), PI 2 , TXA 2 , 5-HT and prostaglandins. </li></ul><ul><li>Secondary Hemostasis </li></ul><ul><li>This stage takes several minutes. Stabilizes the soft clot and maintains vasoconstriction. </li></ul><ul><li>3. Fibrin Clot : Conversion of prothrombin to thrombin. Thrombin stimulates the conversion of fibrinogen (Blood protein) to polymerized fibrin (mesh). </li></ul><ul><li>4. Dissolution of the clot by fibrinolysis : Plasminogen is converted to plasmin, the enzyme that dissolves the fibrin. </li></ul>The hemostatic process is a protective mechanism to prevent blood loss from the circulatory system.
  3. 3. Platelet Adhesion and Aggregation <ul><li>Injury exposes collagen and von Willebrand Factor </li></ul><ul><li>GPIa/IIa (low shear) and Ib (high shear) on the platelet surface bind collagen and vWF </li></ul><ul><li>Platelets become activated </li></ul><ul><ul><li>Thrombin (IIa) activates PAR1/PAR4 </li></ul></ul><ul><ul><li>Activate gp IIb/IIIa receptors and Cox-1 </li></ul></ul><ul><ul><li>Release thromboxane A 2 , PAF, ADP </li></ul></ul><ul><ul><li>P2Y 1/ P2Y 12 activated by ADP </li></ul></ul>
  4. 4. Blood Coagulation : <ul><li>Initiated by the Extrinsic Pathway </li></ul><ul><ul><li>VII binds TF exposed by vascular injury </li></ul></ul><ul><ul><li>VIIa can also activate IX in the presence of TF </li></ul></ul><ul><ul><li>Activation of XII not required for hemostasis </li></ul></ul><ul><li>Each step of the cascades involves: </li></ul><ul><ul><li>Protease (from previous step) </li></ul></ul><ul><ul><li>Zymogen </li></ul></ul><ul><ul><li>Non-enzymatic cofactors </li></ul></ul><ul><ul><ul><li>V (Xa) </li></ul></ul></ul><ul><ul><ul><li>VIII (IXa) </li></ul></ul></ul><ul><ul><ul><li>TF (VIIa) </li></ul></ul></ul><ul><ul><li>Ca 2+ </li></ul></ul><ul><ul><li>Organizing surface (platelets) </li></ul></ul><ul><li>Thrombin cleaves peptides from fibrinogen to produce fibrin monomers (gel) </li></ul><ul><li>XIIIa crosslinks fibrin monomers with transglutamination </li></ul>
  5. 5. Clotting Time <ul><li>Prothrombin Time; Prothrombin Ratio(PR) and Internationalized Ratio(INR) </li></ul><ul><ul><li>Measures of the extrinsic/common pathway </li></ul></ul><ul><ul><ul><li>PT reference range: 12-15 sec; measures factors II,V,VII,X and fibrinogen.; Used in conjunction with aPTT </li></ul></ul></ul><ul><ul><ul><ul><li>PT : blood is combined with liquid citrate (chelates calcium; anticoagulant) in a testtube. There is a specific ratio of blood to citrate. The mixture is centrifuged and the plasma is collected. Thromboplastin (Tissue factor) is added to plasma and analyzed for clotting time. </li></ul></ul></ul></ul><ul><ul><ul><li>INR normal range: 0.8-1.2 </li></ul></ul></ul><ul><li>Activated Partial Thromboplastin Time (aPTT) </li></ul><ul><ul><li>Measure of the intrinsic pathway </li></ul></ul><ul><ul><ul><li>aPPT normal range: 25-37 seconds </li></ul></ul></ul><ul><ul><ul><li>aPPT :blood is combined with liquid citrate (chelates calcium; anticoagulant) in a testtube. There is a specific ratio of blood to citrate. The mixture is centrifuged and the plasma is collected. A phospholipid (silica, kaolin, etc) and calcium are added to the plasma sample and analyzed for clotting time. </li></ul></ul></ul><ul><ul><ul><li>Partial Thromboplastin: thromboplastin is not added to the plasma sample. </li></ul></ul></ul>
  6. 6. Bleeding Disorders <ul><li>Primary Hemostasis </li></ul><ul><ul><li>Platelet Defects, von Willenbrand Disease </li></ul></ul><ul><ul><li>Mucosal bleeding </li></ul></ul><ul><ul><ul><li>Gingiva </li></ul></ul></ul><ul><ul><ul><li>Skin </li></ul></ul></ul><ul><ul><ul><li>Heavy Menses </li></ul></ul></ul><ul><li>Secondary Hemostasis </li></ul><ul><ul><li>Defects in clotting mechanism – Hemophilia </li></ul></ul><ul><ul><li>Deep hemorrhage </li></ul></ul><ul><ul><ul><li>Joints </li></ul></ul></ul><ul><ul><ul><li>Muscle </li></ul></ul></ul><ul><ul><ul><li>Retroperitoneum </li></ul></ul></ul>
  7. 7. Thrombosis and Embolism <ul><li>White Thrombi </li></ul><ul><ul><li>Platelet rich </li></ul></ul><ul><ul><li>Formed in high shear/flow – artery </li></ul></ul><ul><ul><li>Can cause ischemia/organ failure </li></ul></ul><ul><li>Red Thrombi </li></ul><ul><ul><li>Fibrin rich / RBCs trapped </li></ul></ul><ul><ul><li>Often Deep Venous Origin </li></ul></ul><ul><ul><li>Swelling and Pain </li></ul></ul><ul><ul><li>Pulmonary Embolism </li></ul></ul><ul><ul><ul><li>Acute right heart failure  sudden death </li></ul></ul></ul><ul><ul><ul><li>Lung ischemia </li></ul></ul></ul>THR
  8. 8. Fibrinolysis <ul><li>Removal of unwanted clots </li></ul><ul><li>Balanced against removal of clots necessary for hemostasis </li></ul><ul><li>Activated by the conversion of plasminogen to plasmin </li></ul><ul><li>Plasmin </li></ul><ul><ul><li>non-specific protease that cleaves fibrin as well as other plasma proteins </li></ul></ul><ul><ul><li>Binds fibrin </li></ul></ul><ul><li>t-PA </li></ul><ul><ul><li>released from ECs </li></ul></ul><ul><ul><li>Binds fibrin (bound is blocked from inhibition) </li></ul></ul><ul><ul><li>Rapidly cleared </li></ul></ul><ul><ul><li>Inhibited by PAI 1/2 </li></ul></ul>
  9. 9. Natural Anti-coagulant Mechanisms <ul><li>Prostacyclin (PGI 2 ) </li></ul><ul><ul><li>Produced by ECs </li></ul></ul><ul><ul><li>Vasodilator/Inhibitor of Platelet Activation </li></ul></ul><ul><li>Antithrombin </li></ul><ul><ul><li>Plasma protein </li></ul></ul><ul><ul><li>Inhibits Intrinsic and Common Pathway </li></ul></ul><ul><li>Heparan Sulfate </li></ul><ul><ul><li>Produced by ECs </li></ul></ul><ul><ul><li>Stimulates anti-thrombin </li></ul></ul><ul><li>Protein C + Protein S </li></ul><ul><ul><li>Degrades Va and VIIIa </li></ul></ul><ul><ul><li>Activated by thrombin in the presence of anti-thrombin </li></ul></ul><ul><li>Tissue Factor Inhibitor Protein </li></ul><ul><ul><li>inhibits factor Xa and the factor VIIa–tissue factor complex </li></ul></ul>
  10. 10. Anticoagulants (Parenteral) <ul><li>Heparin Sodium, Heparin Calcium </li></ul><ul><ul><li>Glycosaminoglycan secreted by mast cells </li></ul></ul><ul><ul><li>Catalyzes the inhibition of multiple coagulation factors by antithrombin </li></ul></ul><ul><ul><li>Thrombin (IIa), IXa, and Xa </li></ul></ul><ul><li>Antithrombin </li></ul><ul><ul><li>“ suicide substrate” </li></ul></ul><ul><ul><li>Proteases become trapped (1:1) </li></ul></ul>
  11. 11. Anticoagulants (Parenteral) <ul><li>Heparin Sodium, Heparin Calcium: Unfractionated: 5000-30,000 g/mol. Naturally occurring mixture of sulfated muccopolysaccharides produced by mast cells and basophils. </li></ul><ul><ul><li>Clinical Use : Prevention and treatment of embolism (i.e., post-op or following myocardial infarction), deep vein thrombosis, pulmonary embolism. Initial management of unstable angina or acute myocardial infarction. </li></ul></ul><ul><ul><li>MOA: Increases the activity of antithrombin III and inactivates thrombin. High doses will inhibit platelet aggregation. </li></ul></ul><ul><ul><li>Pharmacokinetics : Administration: Not absorbed from the gut; i.v. and s.c.. Immediate onset (30-60 mins); Hepatic elimination and excretion, some excreted unchanged in urine. Dosage is determined by the activated partial thromboplastin time (aPPT; 1.5-2 times is normal). </li></ul></ul><ul><ul><li>Side effects : Thrombocytopenia (early or delayed), hemorrhage. </li></ul></ul><ul><ul><li>Contraindications : existing bleeding condition or bleeding tendency. </li></ul></ul><ul><ul><li>Drug Interactions: Risk of bleeding is increased by salicylates </li></ul></ul><ul><ul><li>In case of overdose : protamine sulfate (positive charge binds heparin). </li></ul></ul>
  12. 12. Anticoagulants (Parenteral) cont. <ul><li>Enoxaparin, Dalteparin, Tinzaparin: Heparin Analog; Fractionated, Low molecular weight heparin (LMWH; 2000-9000 g/mol) </li></ul><ul><ul><li>Increased bioavailability (s.c.) </li></ul></ul><ul><ul><li>Less frequent dosing </li></ul></ul><ul><ul><li>Equal efficacy </li></ul></ul><ul><li>Factor IIa is thrombin </li></ul>
  13. 13. Anticoagulants (Parenteral) <ul><li>Enoxaparin, Dalteparin, Tinzaparin: Heparin Analog; Fractionated, Low molecular weight heparin (LMWH; 2000-9000 g/mol) Fondaparinux (Pentasaccharide of active heparin residues) </li></ul><ul><ul><li>Clinical Use : Prevention and treatment of embolism (i.e., post-op or following myocardial infarction), deep vein thrombosis. </li></ul></ul><ul><ul><li>MOA: Inhibits factor Xa, very little effect on factor IIa; aPPT is not used to measure its anticoagulant activity. Binds less to plasma proteins. </li></ul></ul><ul><ul><li>Pharmacokinetics : Administration: i.v. and s.c. outpatient basis for DVT patients. Immediate onset (30-60 mins); Hepatic elimination and excretion, some excreted unchanged in urine. </li></ul></ul><ul><ul><li>Side effects : Thrombocytopenia (early or delayed), hemorrhage. </li></ul></ul><ul><ul><li>Contraindications : existing bleeding condition or bleeding tendency. </li></ul></ul><ul><ul><li>In case of overdose : </li></ul></ul><ul><ul><ul><li>Enoxaparin, Dalteparin, Tinzaparin protamine sulfate (positive charge binds heparin). – Limited Effectiveness </li></ul></ul></ul><ul><ul><ul><li>Fondaparinux – none. </li></ul></ul></ul>
  14. 14. Anticoagulants (Parenteral) <ul><li>Lepirudin: Hirudin analog </li></ul><ul><ul><li>Clinical Use : Approved for use in patients with heparin-induced thrombocytopenia. Approved for use in PCI. </li></ul></ul><ul><ul><li>MOA : Binds and inhibits thrombin. </li></ul></ul><ul><ul><li>Pharmacokinetics : Administration: i.v. adjusted according to aPTT. Kidney excretion. </li></ul></ul><ul><ul><li>Side effects : Hemorrhage. </li></ul></ul><ul><ul><li>Contraindications : existing bleeding condition or bleeding tendency. Caution with patients with renal disfunction. </li></ul></ul><ul><ul><li>In case of overdose : No antidote. </li></ul></ul><ul><ul><li>Long-term treatment can lead to development of antibodies to the lepirudin-thrombin complex </li></ul></ul>
  15. 15. Anticoagulants (Parenteral) <ul><li>Bivalirudin: Hirudin analog </li></ul><ul><ul><li>Clinical Use : Approved for use in patients with as an alternative to Heparin in PCI patients. </li></ul></ul><ul><ul><li>MOA : Binds and inhibits thrombin. Also blocks platelet activation. Thrombin cleaves bivalirudin to eventually regain activity. </li></ul></ul><ul><ul><li>Pharmacokinetics : Administration: i.v. adjusted according to aPTT. Kidney excretion. </li></ul></ul><ul><ul><li>Side effects : Hemorrhage. </li></ul></ul><ul><ul><li>Contraindications : existing bleeding condition or bleeding tendency. Caution with patients with renal disfunction. </li></ul></ul>
  16. 16. Anticoagulants (Parenertal) <ul><li>Argatroban: L-arginine analog </li></ul><ul><ul><li>Clinical Use : Approved for use in patients with heparin-induced thrombocytopenia and PCI. </li></ul></ul><ul><ul><li>MOA : Binds reversibly to and inhibits thrombin. </li></ul></ul><ul><ul><li>Pharmacokinetics : Administration: i.v. adjusted according to aPTT. Hepatic metabolism and bile excretion. </li></ul></ul><ul><ul><li>Side effects : Hemorrhage. </li></ul></ul><ul><ul><li>Contraindications : existing bleeding condition or bleeding tendency. Caution with patients with hepatic dysfunction. </li></ul></ul><ul><ul><li>Argatroban vs. Lepirudin – Renal Insufficiency = Argatroban, Hepatic Insufficiency = Lepirudin </li></ul></ul>
  17. 17. Anticoagulants (Parenteral) <ul><li>Drotrecogin Alfa : recombinant activated Protein C </li></ul><ul><ul><li>Clinical Use : reduction of mortality in adult patients with severe sepsis. </li></ul></ul><ul><ul><li>MOA : Proteolytic inactivation of factors Va and VIIIa . </li></ul></ul><ul><ul><li>Pharmacokinetics : Administration: i.v. </li></ul></ul><ul><ul><li>Side effects : Hemorrhage. </li></ul></ul><ul><ul><li>Contraindications : existing bleeding condition or bleeding tendency. </li></ul></ul><ul><ul><li>In case of overdose : No antidote. </li></ul></ul>
  18. 18. Anticoagulants (Oral) <ul><li>Coumarins: dicumarol and warfarin; warfarin is structurally related to vitamin K. </li></ul><ul><ul><li>Clinical Use : Treatment of embolism, deep vein thrombosis or atrial fibrillation, patients with prosthetic valves (at risk for thrombosis). </li></ul></ul><ul><ul><li>MOA: Inhibits the synthesis of factors II, VII, IX and X by inhibiting the production of active vitamin K. </li></ul></ul>Active form
  19. 19. Anticoagulants (Oral) <ul><li>Coumarins: dicumarol and warfarin; warfarin is structurally related to vitamin K. </li></ul><ul><ul><li>Pharmacokinetics : Route of administration: p.o.; 100% absorbed; 99% bound to plasma proteins; 8-12 hour delay of onset of activity; Hepatic elimination and excreted in the urine. Dicumarol is incompletely absorbed from the gut. </li></ul></ul><ul><ul><li>Side effects : Hemorrhage. </li></ul></ul><ul><ul><li>Contraindications : Patients with Hemophilia. Pregnancy. </li></ul></ul><ul><ul><li>Drug Interactions : Drugs that inhibit CytoP450 </li></ul></ul><ul><ul><li>Enzymes will increase levels, ie cimetidine, </li></ul></ul><ul><ul><li>Macrolide antibiotics, antifungal agents. Drugs that induce </li></ul></ul><ul><ul><li>CytoP450 enzymes will decrease levels, ie rifampin and </li></ul></ul><ul><ul><li>Barbituates. </li></ul></ul><ul><ul><li>In case of overdose : Vitamin K (phytonadione) </li></ul></ul>
  20. 20. Fibrinolytic Drugs: (Thrombolytics) <ul><li>Tissue Plasminogen Activator (t-PA); alteplase, reteplase, Tenecteplase </li></ul><ul><ul><li>MOA: It is a serine protease which activates plasminogen (bound to fibrin) and increases plasmin levels. Clot specific and must bind to fibrin. </li></ul></ul><ul><ul><li>Reteplase </li></ul></ul><ul><ul><ul><li>less fibrin specific </li></ul></ul></ul><ul><ul><li>Tenecteplase </li></ul></ul><ul><ul><ul><li>longer half-life </li></ul></ul></ul><ul><ul><ul><li>more fibrin specific </li></ul></ul></ul>
  21. 21. Fibrinolytic Drugs: (Thrombolytics) <ul><li>Urokinase; enzyme obtained from urine </li></ul><ul><ul><li>MOA: Directly activates plasminogen </li></ul></ul><ul><ul><li>isolated from human kidney, therefore less chance of evoking an allergic reaction. </li></ul></ul><ul><li>Streptokinase: </li></ul><ul><ul><li>protein obtained from streptocci </li></ul></ul><ul><ul><li>anistreplase (a preformed complex of streptokinase and plasminogen) </li></ul></ul><ul><ul><li>MOA: Combines with plasminogen to form an active complex that converts plasminogen to plasmin to dissolve the fibrin. </li></ul></ul>
  22. 22. Thrombolytics <ul><ul><li>Clinical Use: pulmonary embolism with hemodynamic instability, severe deep venous thrombosis, acute myocardial infarction. t-PA – acute ischemia stroke </li></ul></ul><ul><ul><li>Pharmacokinetics : Parental administration, i.v. </li></ul></ul><ul><ul><li>Side effects : hemorrhage, hypersensitivity reactions and reperfusion arrythmias. </li></ul></ul><ul><ul><li>Contraindications : Bleeding disorders; recent surgery; severe hypertension. </li></ul></ul><ul><ul><li>Drug Interactions : Increases risk of bleeding with dicumarol, warfarn, heparin, aspirin, ticlopidine, abciximab. </li></ul></ul><ul><ul><li>In case of overdose : Aminocaproic acid inhibits fibrinolysis by competitively blocking plasminogen activation. </li></ul></ul>
  23. 23. Inhibitors of Fibrinolysis <ul><li>Aminocaproic acid, Tranexamic acid </li></ul><ul><ul><li>MOA: lysine analog that competes for lysine binding sites on plasminogen and plasmin blocking binding to fibrin </li></ul></ul><ul><ul><li>Clinical Use : adjunctive therapy in hemophilia, as therapy for bleeding from fibrinolytic therapy, and as prophylaxis for rebleeding from intracranial aneurysms </li></ul></ul><ul><ul><li>Side Effects : intravascular thrombosis from inhibition of plasminogen activator </li></ul></ul><ul><ul><li>Contraindications : disseminated intravascular coagulation or genitourinary bleeding of the upper tract </li></ul></ul>
  24. 24. Inhibitors of Fibrinolysis <ul><li>Aprotinin </li></ul><ul><ul><li>MOA: serine protease inhibitor that inhibits fibrinolysis by free plasmin </li></ul></ul><ul><ul><li>Clinical Use : reduce bleeding associated with surgery </li></ul></ul><ul><ul><li>Side Effects : Minimal </li></ul></ul><ul><ul><li>Contraindications : disseminated intravascular coagulation or genitourinary bleeding of the upper tract </li></ul></ul>
  25. 25. Antiplatelet Agents
  26. 26. Antiplatelet Agents - Aspirin <ul><li>Clinical Use : Prevention of atherosclerosis, thrombosis, transient ischemic attacks; unstable angina. </li></ul><ul><li>MOA: Irreversible cyclooxygenase inhibitor and inhibits the formation of thromboxane A 2 . </li></ul><ul><li>Pharmacokinetics : Oral administration </li></ul><ul><li>Side effects : Bleeding; gastrointestinal irritation, hypersensitivity reactions and thrombocytopenia. </li></ul><ul><li>Contraindications : Bleeding disorders, hypersensitivity and Reye’s syndrome. </li></ul><ul><li>Drug Interactions : Increased hypoglycemic effects of sulfonylureas, inhibits uricosuric effect of probenecid. </li></ul><ul><li>In case of overdose : Forced Alkaline Diuresis </li></ul>
  27. 27. Antiplatelet Agents - Dipyridamole <ul><li>Clinical Use : Prosthetic valves; may be used as an adjunct with aspirin or warfarin therapy. Benefit of Dipyridamole + aspirin is debatable </li></ul><ul><li>MOA: Lowers platelet calcium and increases the formation of cAMP (weak antiplatelet drug) , coronary vasodilator. </li></ul><ul><li>Pharmacokinetics : Oral administration </li></ul><ul><li>Side effects : GI distress, headache, dizziness and rash. </li></ul><ul><li>Contraindications : Hypersensitivity to this drug </li></ul><ul><li>Drug Interactions : Increases risk of bradycardia with Beta adrenergic receptor antagonists. </li></ul>Platelet cAMP ATP Adenosine Adenosine A 2 Receptor Adenylate cyclase
  28. 28. Antiplatelet Agents - Ticlopidine (Ticlid ®) <ul><li>Clinical Use : Patients intolerant to aspirin; prevents thrombotic stroke. </li></ul><ul><li>MOA: Inhibits ADP-induced expression of platelet glycoprotein receptors and reduces fibrinogen binding and platelet aggregation. Effects on platelet function are irreversible. </li></ul><ul><li>Pharmacokinetics : Oral administration; eliminated in the urine and feces </li></ul><ul><li>Side effects : Nausea, diarrhea, bleeding; mild to moderate neutropenia, leukopenia, thrombocytopenia. </li></ul><ul><li>Contraindications : Bleeding disorders, severe liver disease </li></ul><ul><li>Drug Interactions : Inhibits cytoP450 drug metabolizing enzymes. </li></ul>
  29. 29. Antiplatelet Agents - Clopidogrel (Plavix®) <ul><li>Clinical Use : Prevention of atherosclerosis, thrombosis, transient ischemic attacks; unstable angina. Prevention of stent thrombosis. </li></ul><ul><li>MOA: Inhibits the binding of ADP to its receptor which is involved in the activation of platelet glycoprotein receptors binding to fibrinogen. </li></ul><ul><li>Pharmacokinetics : Oral administration; eliminated in urine and feces. </li></ul><ul><li>Side effects : Nausea, diarrhea, bleeding; mild to moderate neutropenia, leukopenia, thrombocytopenia. – Less severe than Ticlopidine </li></ul>
  30. 30. Antiplatelet Agents – Prasugrel (Effient) <ul><li>Clinical Use : Prevention of atherosclerosis, thrombosis, transient ischemic attacks; unstable angina. Prevention of stent thrombosis. </li></ul><ul><li>MOA: Inhibits the binding of ADP to its receptor which is involved in the activation of platelet glycoprotein receptors binding to fibrinogen. </li></ul><ul><li>Pharmacokinetics : Oral administration; eliminated in urine and feces. </li></ul><ul><li>Side effects : Nausea, diarrhea, bleeding; mild to moderate neutropenia, Leukopenia, thrombocytopenia. </li></ul>
  31. 31. Wiviott S et al. N Engl J Med 2007;357:2001-2015 Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points during the Follow-up Period
  32. 32. Antiplatelet Agents <ul><li>Abciximab </li></ul><ul><ul><li>Clinical Use : Percutaneous transluminal coronary angioplasty as adjunct with aspirin and heparin. </li></ul></ul><ul><ul><li>MOA: Binds to platelet glycoprotein IIb/IIIa receptors and prevents binding to fibrinogen. Also binds the vitronectin receptor. </li></ul></ul><ul><ul><li>Pharmacokinetics : Parental administration, i.v. </li></ul></ul><ul><ul><li>Side effects : Bleeding, thrombocytopenia, hypotension and bradycardia. </li></ul></ul><ul><ul><li>Contraindications : Aneurysm, bleeding, recent surgery, stroke </li></ul></ul><ul><ul><li>Drug Interactions : Unknown </li></ul></ul>
  33. 33. Antiplatelet Agents – Eptifibatide, Tirofiban <ul><li>Clinical Use : Percutaneous transluminal coronary angioplasty as adjunct with aspirin and heparin. </li></ul><ul><li>MOA: Binds to platelet glycoprotein IIb/IIIa receptors and prevents binding to fibrinogen. </li></ul><ul><ul><li>Does not bind vitronectin. </li></ul></ul><ul><li>Pharmacokinetics : Parental administration, i.v. </li></ul><ul><li>Side effects : Bleeding, thrombocytopenia, hypotension and bradycardia. </li></ul><ul><li>Contraindications : Aneurysm, bleeding, recent surgery, stroke </li></ul><ul><li>Drug Interactions : Unknown </li></ul>
  34. 34. Hemostatic Agents for Bleeding Disorders <ul><li>Vitamin K </li></ul><ul><ul><li>confers biologic activity upon prothrombin and factors VII, IX, and X </li></ul></ul><ul><li>Plasma Fractions </li></ul><ul><ul><li>Factor VIII – Hemophilia A </li></ul></ul><ul><ul><li>Factor IX – Hemophilia B </li></ul></ul><ul><ul><li>Freeze-dried concentrates </li></ul></ul><ul><ul><ul><li>Factor IX </li></ul></ul></ul><ul><ul><ul><li>Factor X </li></ul></ul></ul><ul><ul><ul><li>Factor VII </li></ul></ul></ul><ul><li>Desmopressin Acetate </li></ul><ul><ul><li>increases the factor VIII activity </li></ul></ul>
  35. 35. Anti-anemics
  36. 36. Hematopoiesis <ul><li>Countinous replacement of blood cells </li></ul><ul><ul><li>Mature erythrocytes </li></ul></ul><ul><ul><ul><li>Lack nucleus – cannot synthesize proteins/lipids </li></ul></ul></ul><ul><ul><ul><li>Finite lifespan = ~120 days </li></ul></ul></ul><ul><ul><li>Anemia </li></ul></ul><ul><ul><li>Hypoxemia </li></ul></ul><ul><li>Requires </li></ul><ul><ul><li>Minerals – iron, cobalt, and copper </li></ul></ul><ul><ul><li>Vitamins – folic acid, B 12 , pyridoxine, ascorbic acid, and riboflavin </li></ul></ul><ul><ul><li>Deficiencies in these factors  Anemia </li></ul></ul>
  37. 37. Hematopoiesis – Erythropoietin <ul><li>Stimulates proliferation and maturation of committed erthroid progenitors </li></ul><ul><li>Kidney senses changes in oxygen and modifies erythropoietin secretion </li></ul><ul><li>Anemia or hypoxemia – serum levels increase </li></ul><ul><li>Suppressed by infection or inflammation </li></ul>
  38. 38. Antianemia Agents – Erythropoietins <ul><li>Recombinant human erythopoietin (epoetin alfa), Epogen, Procrit, and exprex, darbapoetin alfa (Aranesp) </li></ul><ul><ul><li>Clinical Use : anemia of renal insufficiency, inflammation, and associated with cancer or the therapy of cancer </li></ul></ul><ul><ul><li>MOA: Stimulates proliferation and maturation of red blood cells. </li></ul></ul><ul><ul><li>Pharmacokinetics : Route of administration: i.v., s.c. Hematocrit should be monitored to determined appropriate dose. </li></ul></ul><ul><ul><li>Side effects : Aggravation of hypertension. Thrombosis. </li></ul></ul><ul><ul><li>Contraindications : Pre-existing uncontrolled hypertension. </li></ul></ul><ul><ul><li>Iron deficiency : Virtually all patients will develop iron deficiency as a result of an inability to mobilize iron stores in support of increased erythropoiesis. </li></ul></ul>
  39. 39. Iron Metabolism Essential Iron Male(mg/kg) Female(mg/kg) Hemoglobin 31 28 Myoglobin & Enzymes 6 5 Storage 13 4 Total 50 37
  40. 40. Iron Deficiency <ul><li>Most common nutritional disorder </li></ul><ul><li>Insufficient dietary intake </li></ul><ul><ul><li>Usually mild </li></ul></ul><ul><li>Blood loss </li></ul><ul><ul><li>Usual cause of severe cases </li></ul></ul><ul><li>Poor absorbance </li></ul><ul><ul><li>Gastrectomy </li></ul></ul><ul><ul><li>Malabsorption in the small intestine </li></ul></ul><ul><li>Pregnancy </li></ul><ul><li>Infancy </li></ul>
  41. 41. Iron Deficiency - Diagnosis <ul><li>Microcytic anemia </li></ul><ul><ul><li>indicator of iron deficiency </li></ul></ul><ul><ul><li>other tests must be used to confirm the diagnosis </li></ul></ul><ul><li>Iron deficiency vs. iron deficient erythropoiesis due to inflammation </li></ul><ul><ul><li>Iron stores are increased, but release from RE is blocked </li></ul></ul><ul><ul><ul><li>Elevated plasma ferritin </li></ul></ul></ul><ul><ul><li>Plasma Iron is decreased </li></ul></ul><ul><ul><li>Erythroid marrow supply is inadequate </li></ul></ul>
  42. 42. Antianemia Agents Oral Iron Therapy <ul><li>Ferrous sulfate , ferrous gluconate, ferrous fumarate, polysaccharide-iron complex. </li></ul><ul><ul><li>Clinical Use : Iron Deficiency. </li></ul></ul><ul><ul><li>MOA: Replaces the iron necessary for RBC’s to transport oxygen. Treatment requires several months. </li></ul></ul><ul><ul><li>Pharmacokinetics : Route of administration: p.o.; Eliminated in the feces, urine and sweat. </li></ul></ul><ul><ul><li>Side effects : Nausea, gastrointestinal discomfort, heartburn, diarrhea or constipation. </li></ul></ul><ul><ul><li>Contraindications : Patients with Peptic Ulcer disease, Ulcerative Colitis and Hemolytic Anemia. </li></ul></ul><ul><ul><li>Drug Interactions : Antacids may inhibit absorption. </li></ul></ul><ul><ul><li>Iron Poisoning : High concentrations of ferric salts are toxic. Fatalities are rare and may occur in children 1-2 yrs. Poisoning: Abdominal pain, diarrhea, vomiting drowsiness, cyanosis. </li></ul></ul><ul><ul><ul><li>Treatment: Administer a laxative (clean out intestine) or IV deferoxamine mesylate (chelates iron) or GI lavage (pump stomach) with sodium bicarbonate or phosphate solution. </li></ul></ul></ul>
  43. 43. Antianemia Agents Parenteral Therapy <ul><li>Sodium ferric gluconate, Iron Dextran, Iron sucrose, </li></ul><ul><ul><li>Clinical Use : Iron Deficiency. Alternative to oral therapy. </li></ul></ul><ul><ul><li>MOA: Replaces the iron necessary for RBC’s to transport oxygen. </li></ul></ul><ul><ul><li>Pharmacokinetics : Route of administration: i.m. or i.v.; Eliminated in the feces, urine and bile. Sodium ferric gluconate and iron sucrose are i.v. only. </li></ul></ul><ul><ul><li>Side effects : Anaphylaxis. </li></ul></ul><ul><ul><ul><li>Sodium ferric gluconate – far fewer hypersensitivity reactions </li></ul></ul></ul><ul><ul><ul><li>Iron Dextran – second line to sodium ferric gluconate </li></ul></ul></ul><ul><ul><ul><li>Iron sucrose – similar to sodium ferric gluconate – limited data </li></ul></ul></ul><ul><ul><li>Contraindications : Patients with liver disease and asthma. </li></ul></ul><ul><ul><ul><li>Iron Dextran – patients with rheumatoid arthritis or allergies </li></ul></ul></ul>
  44. 44. Copper Deficiency <ul><li>Extremely Rare </li></ul><ul><ul><li>Intestinal bypass </li></ul></ul><ul><ul><li>Parenteral nutrition </li></ul></ul><ul><ul><li>Malnourished infants </li></ul></ul><ul><ul><li>Excessive amounts of Zinc </li></ul></ul><ul><li>Low plasma copper + Leukopenia or anemia </li></ul><ul><ul><li>Cupric sulfate, p.o. </li></ul></ul>
  45. 45. Pyridoxine (Vitamin B 6 ) <ul><li>Sideroblastic anemia </li></ul><ul><ul><li>Impaired hemoglobin synthesis </li></ul></ul><ul><ul><li>Accumulate iron in the perinuclear mitochondria of the erythroud precursor </li></ul></ul><ul><li>Proven benefit in correcting sideroblastic anemia associated with isoniazid and pyrazinamide (anti-tuberculous drugs, vitamin B 6 antagonists) </li></ul><ul><li>Drug interaction: Levodopa (Parkinson’s) </li></ul><ul><li>Poor responsiveness in sideroblastic abnormalities associated with lead, chlorampenicol and idiopathic acquired sideroblastic anemia </li></ul>
  46. 46. Megaloblastic Anemias Vitamin B 12 and Folic Acid
  47. 47. Vitamin B 12 and Folic Acid Function <ul><li>Key roles in purine and pyrimidine synthesis – DNA </li></ul><ul><li>Deficiency of either </li></ul><ul><ul><li>Decreased protein synthesis </li></ul></ul><ul><ul><li>Disrupted Methylation Reactions </li></ul></ul><ul><ul><li>Decreased polyamine synthesis </li></ul></ul><ul><ul><li>Shunting of folate into methyltetrahydrofolate </li></ul></ul><ul><li>Ultimately leads to megaloblastic anemia </li></ul>
  48. 48. Antianemia Agents <ul><li>Cyanocobalamin, Crystalline </li></ul><ul><ul><li>Clinical Use : Vitamin B 12 Deficiency or intrinsic factor deficiency. </li></ul></ul><ul><ul><li>MOA: Converted to methylcobalamin or deoxyadenosyl-cobalamin, cofactors for biochemical reactions which is essential for growth, cell replication, hematopoiesis. </li></ul></ul><ul><ul><li>Pharmacokinetics : Route of administration: p.o., or i.m. ; Eliminated in the feces, urine and breast milk </li></ul></ul><ul><ul><li>Adverse effects : Rare hypersensitivity. </li></ul></ul>
  49. 49. Antianemia Agents <ul><li>Hydroxycobalamin, crystalline </li></ul><ul><ul><li>Clinical Use : Vitamin B 12 Deficiency or intrinsic factor deficiency. </li></ul></ul><ul><ul><li>MOA: Converted to methylcobalamin or deoxyadenosyl-cobalamin, cofactors for biochemical reactions which is essential for growth, cell replication, hematopoiesis. </li></ul></ul><ul><ul><li>Pharmacokinetics : Route of administration: p.o., or i.m. ; Eliminated in the feces, urine and breast milk </li></ul></ul><ul><ul><li>Adverse effects : Rare hypersensitivity. </li></ul></ul><ul><ul><li>More sustained effect compared to cyanocobalamin </li></ul></ul>
  50. 50. Anemia due to Folic Acid Deficiency <ul><li>Iron deficiency as a result of intestinal disease or pregnancy (increased demand on the system). </li></ul><ul><li>Megaloblastic anemia </li></ul><ul><ul><li>Folic Acid </li></ul></ul><ul><ul><li>Leucovorin Calcium </li></ul></ul><ul><ul><li>(Folinic Acid) </li></ul></ul>
  51. 51. Antianemia Agents <ul><li>Folic Acid: </li></ul><ul><ul><li>Clinical Use : Folic acid Deficiency in alcoholism and malabsorptive syndromes. </li></ul></ul><ul><ul><li>MOA: Replaces the folic acid necessary for DNA synthesis, cell proliferation and development. </li></ul></ul><ul><ul><li>Pharmacokinetics : Route of administration: p.o., or i.m. ; Eliminated in the feces, urine and breast milk </li></ul></ul><ul><ul><li>Side effects : Flushing and allergy. </li></ul></ul><ul><ul><li>Contraindications : Patients with other anemias, i.e., pernicous, aplastic or normocytic due to incomplete treatment. </li></ul></ul>
  52. 52. Antianemia Agents <ul><li>Leucovorin Calcium (Folinic Acid), folic acid metabolite (Derivative of tetrahydrofolic acid) </li></ul><ul><ul><li>Clinical Use : Folic acid Deficiency. </li></ul></ul><ul><ul><li>MOA: Replaces the folic acid necessary for DNA synthesis. </li></ul></ul><ul><ul><li>Pharmacokinetics : Route of administration: p.o., or i.m. ; Eliminated in the feces, urine and breast milk </li></ul></ul><ul><ul><li>Side effects : Flushing and allergy. </li></ul></ul><ul><ul><li>Contraindications : Patients with other anemias, i.e., pernicous, aplastic or normocytic. </li></ul></ul>
  53. 53. Myeloid and Megakaryocyte Growth Factors
  54. 54. Myeloid Growth Factors <ul><li>G-CSF </li></ul><ul><ul><li>Stimulates proliferation of progenitor cells committed to the neutrophil lineage </li></ul></ul><ul><ul><li>Activates neutrophil phagocytic activity </li></ul></ul><ul><ul><li>Prolongs their lifetime </li></ul></ul><ul><li>GM-CSF </li></ul><ul><ul><li>Broader stimulatory activity </li></ul></ul><ul><ul><li>Similar Neutrophil stimulatory activity </li></ul></ul><ul><li>Clinical Use: Neutropenia (esp. Chemotherapy related), Autologous stem cell transplant </li></ul><ul><li>Toxicity: </li></ul><ul><ul><li>G-CSF- Bone pain </li></ul></ul><ul><ul><li>GM-CSF - fever, malaise, arthralgias, myalgias, and a capillary leak syndrome </li></ul></ul>
  55. 55. Megakaryocyte Growth Factors <ul><li>IL-11 </li></ul><ul><ul><li>MOA : Stimulates the growth of primitive megakaryocytic progenitors, Increases peripheral platelets and neutrophils </li></ul></ul><ul><ul><li>Clinical Use : Thrombocytopenia </li></ul></ul><ul><ul><li>Side Effects : fatigue, headache, dizziness, and cardiovascular effects </li></ul></ul><ul><li>Thrombopoietin </li></ul><ul><ul><li>MOA : stimulates the growth of primitive megakaryocytic progenitors </li></ul></ul><ul><ul><li>Clinical Use : INVESTIGATIONAL - thrombocytopenia </li></ul></ul>

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