Anticoagulants

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Anticoagulants

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Anticoagulants

  1. 1. Prof. Aboubakr elnashar Email: elnashar53@hotmail.com Aboubakr Elnashar
  2. 2.  Vascular Phase  Platelet Phase  Coagulation Phase  Fibrinolytic Phase Aboubakr Elnashar
  3. 3. 1. Vascular Phase  V.C  Exposure to tissues activate tissue factor and initiate coagulation Tissue Factor Aboubakr Elnashar
  4. 4. 2. Platelet phase  Blood vessel wall (endothelial cells) prevent platelet adhesion & aggregation  Platelets contain receptors for fibrinogen and von Willebrand factor  After vessel injury: Platelets adhere & aggregate.  Release permeability increasing factors (e.g. vascular permeability factor, VPF)  Loose their membrane & form a viscous plug Aboubakr Elnashar
  5. 5. 3. Coagulation Phase  2 major pathways  Intrinsic pathway  Extrinsic pathway  Both converge at a common point  Clotting factors: 13 soluble Biosynthesis is dependent on Vitamin K1& K2 Most are proteases Normally inactive & sequentially activated Aboubakr Elnashar
  6. 6. Intrinsic Pathway  All clotting factors are within the blood vessels  Clotting: slower  aPTT Extrinsic Pathway  Initiating factor is outside the blood vessels: tissue factor  Clotting: faster in Seconds  PT Aboubakr Elnashar
  7. 7. Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin Thrombin Fibrinogen Fribrin monomer Fibrin polymer XIII Intrinsic Pathway Extrinsic Pathway Factors affected By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants Aboubakr Elnashar
  8. 8. Thrombi Acc to location& composition Arterial  Occur in areas of rapid flow (arteries)  In response to an injured or abnormal vessel wall  White  Composed: primarily of platelets, also fibrin & occasional leukocytes  Associated with MI Stroke ischemia Venous •Occur primarily in the venous circulation •In response to venous stasis or vascular injury •Red •Composed almost entirely of fibrin & erythrocytes •Associated with Congestive Heart Failure, Cancer Surgery. Aboubakr Elnashar
  9. 9. 4. Fibrinolysis Enhance degradation of clots Activation of endogenous protease Plasminogen (inactive form) is converted to Plasmin (active form) Plasmin breaks down fibrin clots Aboubakr Elnashar
  10. 10. Drug Class Prototype Action Effect 1. Anticoagulant Parenteral Heparin Inactivation of clotting factors Prevent DVT Oral Warfarin Decrease synthesis of clotting factors Prevent DVT 2. Antiplatelet Aspirin Decrease platelet aggregation Prevent arterial thrombosis 3. Thrombolytic Streptokinase Fibinolysis Breakdown of thrombi Aboubakr Elnashar
  11. 11. I. Anticoagulants 1. Heparin Structure Mucopolysaccharide Metabolism Partially in the liver by heparinase to uroheparin, which has only slight antithrombin activity. 20-50 % is excreted unchanged. {The heparin polysaccharide chain is degraded in the gastric acid} administered IV or SC. Heparin should not be given IM }danger of hematoma formation{. Aboubakr Elnashar
  12. 12. Unfractionated heparin (UFH) Mol weight: 3000-30000 Mechanism of action: •Primarily: interaction with antithrombin III: alters the molecular configuration of antithrombin III, making it 1,000 to 4,000 times more potent as an inhibitor of thrombin formation: limits conversion of fibrinogen to fibrin: prolongs aPTT •Also inhibits the effects of factor Xa on the coagulation cascade & limits platelet aggregation. Half-life: IV: 1 hr SC: 3 hrs. Aboubakr Elnashar
  13. 13. UFH inactivate factor IIa through formation of a tertiary complex (unlike LMWH). UFH binds more to plasma proteins, endothelium and macrophages: reduced bioavailability & greater patient variability to a given dose. UFH inactivates factors IIa and Xa & affects the aPTT (measure of anti-factor IIa activity). Aboubakr Elnashar
  14. 14. Heparin-induced thrombocytopenia 20% . Diagnosis: platelet count falls below the lower limits of normal or by 50% but remains in the normal range. a.Type 1 Mild, rarely dropping below 100,000 platelets/ML. Platelet count monitoring is important, but therapy usually can continue {platelet count returns to normal even with continued use}. {platelet activation & is not immune-mediated}. Aboubakr Elnashar
  15. 15. b. Type 2 7 to 14 days after starting therapy. Platelet counts frequently drop to 20,000/ML. {an immune response caused by antibodies to the heparin- platelet factor 4 complex}. It is related to: Mol wt, dose & duration of therapy. immediate withdrawal of all forms of heparin is mandatory. Platelet concentration should be monitored at least every 2 days. Aboubakr Elnashar
  16. 16. Dosing options. Preoperative: 5,000U 2 hours before surgery. {The single preoperative dose seems to be as effective as multiple preoperative doses}. Postoperative: 8 to 12 hrs after surgery & every 8 to 12 hrs until the patient is fully ambulatory. Antidote: Protamine sulphate Monitor: aPTT Use in pregnancy: {does not cross the placenta} safe Aboubakr Elnashar
  17. 17. Low-Molecular-Weight Heparin •Molecular weight 1000-10000 Da. •Produced by concentrating the low molecular component of UFH. Enzymatic or chemical controlled hydrolysis of UFH. •The mechanism of action Primarily by inhibiting factor Xa, which is higher in the coagulation cascade than antithrombin: LMWH is more efficient than UFH. {the molecular configuration of antithrombin III is not altered by LMWH} thrombin conversion is minimally inhibited and aPTT is not appreciably affected. Aboubakr Elnashar
  18. 18. LMWH inhibits factor Xa and minimally affects factor IIa; thus aPTT is not used to measure its anticoagulant activity.Aboubakr Elnashar
  19. 19. Mol WtManufacturerTradeGeneric 4500Rhone-Poulence-RorerLovenex, ClexaneEnoxaparin 4850NovoLogiparineTinzaparin 6370KabiFragminDalteparin Aboubakr Elnashar
  20. 20. Half-life: 4 hrs, by any route: longer dosing interval. Bioavailability More consistent than that of UFH: dosing is based on lean body mass & Less thrombocytopenia. Use in pregnancy: Does not cross the placenta: safe. Dosing options. Prophylaxis: Once a day Therapy: Twice-daily. Enoxaparin is an LMWH Moderate risk: 20 mg/d High risk: 40 mg/d. •Advantage Decreased need for monitoring Aboubakr Elnashar
  21. 21. LMWHUFH 1000-100003000-30000Mol Wt range 4000-500012000-15000Mo Wt average 2:1-4:11:1AntiXa: antiIIa activity NoYesaPTT monitoring required NoYesInactivation by platelet factor 4 YesNoCapable of inactivation of platelet bound factor Xa ++++++Inhibition of platelet function NoYesIncrease vascular permeability +++++Protein binding -+++Endothelial cell binding NoYesDose dependent clearance 2-5 times longer50-20 minElimination half life Aboubakr Elnashar
  22. 22. 2. Oral anticoagulants  Coumarins - warfarin, dicumarol Structure: small, lipid-soluble molecules, Structurally related to vitamin K, isolated from clover leaves Mechanism:  Inhibits production of active clotting factors  blocks the Vitamin K-dependent glutamate carboxylation of precursor clotting factors e.g. FII, VII, IX , X Metabolism:  Absorption: rapid  Binds to albumin  Clearance is slow: 36 hrs  Delayed onset: 8-12 hr {T1/2 of clotting factors in plasma} Aboubakr Elnashar
  23. 23. blocks the Vitamin K-dependent glutamate carboxylation of precursor clotting factors Aboubakr Elnashar
  24. 24. Use: To prevent the formation, recurrence or extension of DVT & PE Not used in pregnant women {cross placenta} Not used for arterial thrombi {No effect on platelets} Toxicity: bleeding birth defects Overdose: Reversed by vitamin K infusion Recovery needs synthesis of new clotting factors Aboubakr Elnashar
  25. 25. Warfarin tablets, 5, 3 and 1mg Aboubakr Elnashar
  26. 26. Drugs that Increase Warfarin Activity Decrease binding to Albumin Inhibit Degradation Decrease synthesis of Clotting Factors Aspirin Sulfonamides Cimetidine, Disulfiram Antibiotics (oral) Category Mechanism Representative Drugs Inhibition of platelets Aspirin Inhibition of clotting Heparin Factors Antimetabolites Drugs that promote bleeding Induction of metabolizing Barbiturates Enzymes Phenytoin Promote clotting factor Vitamin K Synthesis OC Reduced absorption Cholestyramine Colestipol Drugs that decrease Warfarin activity Aboubakr Elnashar
  27. 27. WarfarinHeparin OralParentral onlyAbsorption 7.6-13.9 LPlasma vol (0.07 L/kg)Vol of distribution HepaticHepatic metabolism & uptake by reticulo endothelial system Also by thrombin & other clotting factors Metabolism/Clearance 36-42 hr50-90 minElimination t1/2 99.4% bound to albuminBound to antithrombin III & other serine proteases Protein binding 1.5 mg/L0.2-0.4 U/mlPlasma concentration (therapeutic) Bleeding Skin necrosis Drug interactions Bleeding Thrmbocytopenia Osteoporosis Side effects •Mild: hold 1-2 doses, observe, restart at lower dose •Severe: Vit K or fresh frozen plasma •Mild: Slow or stop infusion •Severe: Protamine 1 mg/100 u of estimated heparin remaining in body Treatment of bleeding Aboubakr Elnashar
  28. 28. II. Antiplatelet Drugs Activation and aggregation of platelets is a major component of thrombosis especially in arteries Targets for platelet inhibitory drugs: (a) inhibition of prostaglandin metabolism through inhibition of cyclooxygenase (aspirin) (b) inhibition of ADP-induced platelet aggregation (ticlopidine)Aboubakr Elnashar
  29. 29. Platelet Activation: •Endothelial damage of vessel: exposes collagen •Activated platelets release ADP, serotonin (5-HT)& thromboxane A2 (TXA2-) from arachidonic acid: platelet aggregation by causing the appearance of binding sites for fibrinogen on platelet membrane •Fibrinogen is involved: platelet to platelet adhesion (aggregation) •Thrombin causes further platelet activation by releasing platelet ADP & stimulating PG synthesis prostacyclin (PGI2) - synthesized within vessel walls inhibits thrombogenesis by increasing platelet cAMP. Nitric oxide (NO) - released by endothelium - increases cAMPAboubakr Elnashar
  30. 30. (a) NSAIDS Aspirin - prototype Mechanism: inhibits cyclooxygenase (COX) COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins). Inhibits platelet aggregation long acting because new proteins must be synthesized other NSAIDS: shorter duration because of reversible competitive inhibitory action potency varies, e.g. Naproxen, meclofenamic acid, Ibuprofen, Indomethacin, phenylbutazare Contraindication: Patients with glucose 6-PO4 dehydrogenase deficiency Aboubakr Elnashar
  31. 31. Dose:  Low dose daily (180 mg/day): Prevents ischemic attack (ministroke) and MI  335 mg/day: reduced the risk of heart attack in patients over 50 Use:  Prevention of recurrent infarcts in patients with myocardial infarction, also reduces the incidence of first infarcts  low-dose aspirin, compared with placebo, reduces by 36% the risk of VTE after orthopaedic surgery  Meta-analysis of trials in surgical and medical patients: significant reduction in DVT and PE with antiplatelet prophylaxis. (Pulmonary embolism prevention (PEP) Trial . Aboubakr Elnashar
  32. 32. (b) Ticlopidine decrease platelet aggregation by inhibiting ADP pathway of platelets no effect on PG metabolism used as alternative for patients intolerant to aspirin expensive (C) Other antiplatelet drugs: Dipyridamole, sulfinpyrazone Aboubakr Elnashar
  33. 33. III. Thrombolytic Agents Agents which reduce the formation of arterial platelet thrombi Mechanism:  Rapid lysis of thrombi by catalyzing the formation of plasmin from plasminogen  Endogenous plasmin breaks down fibrin promoting clot dissolution Use:  Emergency treatment of coronary artery thrombonís in M.I.  IV or intracoronary injection  DVT: rapid recanalization of occluded vessels Toxicity:  Bleeding (intracranial, G.I.)  Allergic reactions (i.e. streptokinase) Aboubakr Elnashar
  34. 34. Aboubakr Elnashar
  35. 35. Streptokinase: Purified from bacteria Continuous use: immune reaction Forms a complex with plasminogen & catalyzes it: rapid conversion to plasmin Urokinase: From cultured human kidney cells No immune response Directly converts plasminogen to plasmin tPA: Produced by recombinant techniques No immune reaction - EXPENSIVE Promotes conversion of plasminogen (that is found to fibrin) to plasmin In theory, selective for formed clots Aboubakr Elnashar
  36. 36. CostDosing administration Average dose Potential antigenicity Fibrin specificity Enzymatic efficiency for clot lysis Low1 hr IV infusion1.5 MUYesMinimalHighStreptokinase Moderate2-5 min IV infusion30 uYesMinimalhighAntistreplase Moderate15 mg IV bolus, 50 mg over 30 min, then 35 mg over 60 min 100 mgNoModerateHighTissue plasminogen activator high1 mu IV bolus, 1 mu over 60 min 2 muNomoderatelowUrokinase Aboubakr Elnashar
  37. 37. Thank you Aboubakr Elnashar Aboubakr Elnashar

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