Pharmacology Drugs Used Coagulation D/O (katzung) 19 February 08

Chapter 34 Drugs Used in Disorders of Coagulation Outline I. Blood Coagulation a. Mechanism b. Cascade II. Anticoagulant Drugs a. Indirect Thrombin Inhibitors b. Direct Thrombin Inhibitors c. Warfarin & Coumarin III. Fibrinolytic Drugs IV. Antiplatelet Agents a. Aspirin b. Clopidogrel & Ticlopidine c. GLP IIB/IIIA Receptor Blockers V. Drugs Used to prevent clotting VI. Drugs used in Bleeding Disorders a. Vitamin K b. Plasma Fractions c. Fibrinolytic Inhibitors: Aminocaproic Acid d. Serine Protease Inhibitors: Aprotinin Blood Coagulation Mechanism 1. Vascular injury exposes reactive subendothelial matrix proteins (collagen & vWf) 2. platelet adherence, activation, secretion and synthesis of vasoconstrictors & platelet-recruiting & activating molecules (TXA2, ADP, 5HT) 3. conformational change in IIB/IIIA receptors enabling it to bind fibrinogen 4. Aggregation & platelet plug formation • 1. 2. Simultaneous with these events: coagulation cascade activated thrombin generation & fibrin clot, stabilizing the platelet plug Endogenous anticoagulants Antithrombin SERPIN inactivates IIa, IXa, Xa. XIa, XIIa Protein C & S attenuate blood clotting cascade by proteolysis of Va & VIIIa Defects in natural anticoagulant – increased risk of venous thrombosis most common is Factor V (Leiden) defect Fibrinolysis - Process of fibrin digestion by plasmin 1. In response to injury, endothelial size synthesize & release tPA (converting plasminogen to plasmin) 2. plasmin remodels thrombus, limits its extension by proteolytic digestion of fibrin Negative regulators 1. Endothelial cells also release Plasminogen Activator Inhibitor – inhibits tPA 2. A2-antiplasmin – inactivate any plasmin not clot-bound Disseminated Intravascular Coagulation (DIC) pathologically activated coagulation & fibrinolytic systems, generalized intravascular clotting & bleeding may follow massive tissue injury, advanced cancers, OB emergencies tx is to control the underlying disease process Activators of Fibrinolytic system (for thrombotic disease) Tissue plasminogen activator Urokinase Streptokinase Inhibitors of Fibrinolysis Aminocaproic Acid Anticoagulant Drugs Indirect Thrombin Inhibitors Heparin (Unfractionated, Low-Molecular-Weight, & Fondaparinux) biologic activity dependent upon antithrombin functions as a cofactor without being consumed bind to antithrombin, cause conformational change, exposes active site to proteases, protease complex formed, heparin is released to bind to more antithrombin - Monitoring: aPTT & Protamine titration (UFH)

Diagnostic Significance:

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Defects in primary hemostasis (formation of platelet plug) – bleed from mucosal sites with injury Defects in secondary hemostasis (clotting) – bleed in deep tissues often with no apparent inciting event, may recur unpredictably

White Vs Red thrombi White – platelet-rich (arterial thrombi – limb amputation or organ failure) Red – fibrin-rich, contain large number of trapped RBC (venous thrombi – pulmonary embolism) Cascade Initiation of Clotting: Tissue Factor-VIIa Complex 1.exposure of TF on damaged epithelium binds TF to VIIa (regulated by TFPI) 2.complex formed activates IX , X 3.Xa with Va (prothrombinase complex) convert II to thrombin 4.thrombin activates V, VIII, XI resulting in amplification of thrombin generation Clinical Significance: • Patients with Factor VIII & IX deficiency (hemophilia A & B) have severe bleeding disorder Elyu, Brim & Virns

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Major ADR: bleeding (women & renal failure px more prone) Other ADR: allergy (animal source), alopecia, osteoporosis, spontaneous fractures, mineralocorticoid deficiency (long term) Heparin-Induced Thrombocytopenia (HIT) – systemic, hypercoagulable state; tx by discontinuing heparin & direct thrombin inhibitor or fondaparinux Consider: o Platelet counts done frequently o Thrombocytopenia and new thrombus suspicious for HIT Contraindication: HIT, hypersensitivity, active bleeding, hemophilia, significant thrombocytopenia, purpura, intracranial hemorrhage, severe HPN, infective endocarditis, active TB, GIT ulcer, threatened abortion, visceral

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Pharmacology – Drugs Used Coagulation Disorders by Katzung
carcinoma, advanced hepatic/renal disease, undergone surgery or lumbar puncture, anesthesia No placental transfer but used only in pregnant women when clearly indicated

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Direct Thrombin Inhibitors directly binds to active site of thrombin, inhibiting its effects Hirudin & Bivalirudin – bivalent DTIs binding both in active & substrate recognition site Argatroban & Melagatran – active site only

Clopidogrel & Ticlopidine inhibit ADP pathway of platelets ADR of ticlopidine – nausea, dyspepsia, diarrhea, hemorrhage, leucopenia, TTP ADR of clopidogrel – fewer ADR, associated with neutropenia, TTP, preferred over ticlopidine GLP IIB/IIIA Receptor Blockers acute coronary syndromes inhibit platelet IIb/IIIa receptor complex persons lacking this receptor – Glanzmann’s thrombasthenia (platelet aggregation) - Abciximab – directed against the receptor & vibronectin receptor - Eptifibatide and Tirofiban – inhibit ligand binding to the receptor by occupancy of the receptor but not the vibronectin Dipyridamole Vasodilator inhibit adenosine uptake & cGMP phosphodiesterase activity In combination with aspirin to prevent cerebrovascular ischemia With warfarin – primary prophylaxis of thromboemboli in px with prosthetic heart valves Cilostazol newer phosphodiesterase inhibitor promotes VD and inhibition of platelet aggregation treating intermittent claudication Drugs Used to Prevent Clotting Venous Thrombosis A. Inherited - tendency to form thrombi from normal anticoagulant abnormalities thrombophilia B. Acquired thromboembolism associated with atrial fibrillation & placement of mechanical valves, prolonged bed rest, highrisk surgical procedures, cancer, Antiphospholipic Antibody syndrome, and drugs (synergistic risk factor) Prevention heparin & warfarin to prevent venous thrombosis SC admin of low-dose unfractionated heparin, LMWH, or fondaparinux – prophylaxis (also warfarin but requires monitoring of Prothrombin Time) Tx of Established Disease initiated with unfractionated of LMW Heparin for first 5-7 days, with an overlap of warfarin pregnant women – subcutaneous heparin (warfarin crosses placenta) Arterial Thrombosis activation of platelets considered an essential process TIA, strokes, unstable angina, acute MI o Tx: PLATELET-INHIBITING DRUGS (aspirin, clopidogrel, ticlopidine) In angina & infarction: used in conjunction with B-blocker, Ca Channel Blockers, Fibrinolytic drugs Drugs used in Bleeding Disorders Vitamin K K2 menaquinone (found in human tissues) K3 menadione should never be used in therapeutics Vitamin K1 phytonadione (found in food)

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Hirudin specific, irreversible thrombin inhibitor from leech saliva - available in recombinant form – Lepirudin independent of antithrombin (reach & inactivate fibrinbound thrombin in thrombi) aPTT monitoring excreted by kidney (caution in renal insufficiency); anaphylaxis Bivalirudin – inhibits platelet activation; for percutaneous coronary angioplasty Argatroban – used in px with HIT with or without thrombosis; coronary angioplasty in px with HIT Ximelagatran (prodrug of melagatran) predictable PK & Bioavailability (for fixed dosing & predictable anticoag response) no need for monitoring; no interaction with P450interacting drugs hepatic toxicity

Warfarin (Coumarin) 100% bioavailability; as Na salt - block γ-carboxylation of factors II, VII, IX, X (vitamin K dependent) as well as endogenous anticoagulant (protein C and S) crosses the placenta should never used during pregnancy monitoring: Prothrombin time - the most serious drug interactions with warfarin – increase anticoagulant effect & risk of bleeding interactions with pyrazolones phenylbutazone & sulfinpyrazone – hypoprothrombinemia and inhibit platelet function, may induce PUD Fibrinolytic Drugs conversion of plasminogen to plasmin 1. Streptokinase- protein synthesized by strep

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Urokinase – human enzyme synthesized by kidney, directly converting plasminogen to plasmin Anistreplase – complex of human plasminogen & bacterial streptokinase t-PA - endogenous Alteplase & Reteplase – recombinant human t-PA Tenecteplase – mutant form of t-PA

Indications (through IV route): pulmonary embolism with hemodynamic instability severe deep venous thrombosis (SVC syndrome) ascending thrombophlebitis Antiplatelet Agents Aspirin inhibits synthesis of TXA2 primary prophylaxis of MI

Pharmacology – Drugs Used Coagulation Disorders by Katzung
o o o Available in oral or parenteral forms IV infusion should be slow (dyspnea, chest & back pain, death) In newborns (prevent HDN associated with Vit K deficiency)

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Plasma Fractions (see table 34-3 pp 557) Fibrinolytic Inhibitors: Aminocaproic Acid (EACA) Chemically similar to lysine synthetic inhibitor of fibrinolysis competitively inhibits plasminogen activation rapidly absorbed orally, cleared by kidney - Tranexamic acid – analog of EACA Adjunct tx for hemophilia Tx for bleeding from fibrinolytic tx Prophylaxis for rebleeding from intracranial aneurysms ADR: intravascular thrombosis from inhibition of plasminogen activator, Hypotension, myopathy, abdominal discomfort, diarrhea, nasal stuffiness CI: DIC, upper GUT bleeding because of potential excessive clotting Serine Protease Inhibitors: Aprotinin inhibits fibrinolysis inhibits plasmin-streptokinase complex reduce bleeding by 50% (surgical) ADR: MI, stroke, renal damage, anaphylaxis (small test dose done first)

Special thanks kina anne.. for sharing sa paggwa nito.. Detox corner…

Do What Heart Says . . . Horror gripped the heart of a World War-I soldier, as he saw his lifelong friend fall in battle. The soldier asked his Lieutenant if he could go out to bring his fallen comrade back. "You can go," said the Lieutenant, "but don't think it will be worth it. Your friend is probably dead and you may throw your life away.." The Lieutenant's words didn't matter, and the soldier went anyway. Miraculously, he managed to reach his friend, hoisted him onto his shoulder and brought him back to their company's trench. The officer checked the wounded soldier , then looked kindly at his friend. "I told you it wouldn't be worth it..," he said. "Your friend is dead and you are mortally wounded.." " It was worth it, Sir," said the soldier.. "What do you mean by worth it?" responded the Lieutenant. " Your friend is dead." "Yes Sir," the soldier answered, " but it was worth it because when I got to him,he was still alive and I had the satisfaction of hearing him say...." Jim...I knew you'd come..." Many times in life, whether a thing is worth doing or not, really depends on how u look at it. Take up all your courage and do something your heart tells you to do so that you may not regret not doing it later in your life . .