Drugs in Blood Disorders

  1. Anticoagulants: General
    • Drugs that decrease the formation of fibrin clots
    • Oral anticoagulants (ie warfarin) inhibit hepatic synthesis of clotting factors 9, 7, 2, 10
    • IV anticoagulants (ie heparin) inhibits activity of several activated clot factors (IIa, Xa) via activation of antithrombin III
    • Endogenous anticoagulants (Protein C & S) = proteolysis of factors 5a & 8a
  2. Anticoagulant: Heparin
    • Chemical Nature: large polysaccharide, water soluble
    • Kinetics: IV, t1/2 = 2 hours, no placental access
    • Mechanism: heparin catalyzing binding of antithrombin III (serine protease inhibitor) to factors 2a, 4a, 10a, 11a, 12a = rapid inactivation
    • Monitoring: PTT
    • Antagonist: protamine sulfate - chemical antagonism (the + charge binds to the negative heparin charge), fast onset
    • Clinical use: rapid anticoagulation for thromboses, emboli, unstable angina, DIC, open heart surgery
    • Toxicity: bleeding, osteoporosis, HIT, hypersensitivity (II)
  3. Heparin Induce Thrombocytopenia
    Heparin binds to platelets = autoanibody production that destroys platelets & overactivates the remaining ones = thrombocytopenic, hypercoagulable state

    Tx: Agatroban: direct thrombin inhibitor, doesn't require ATIII, does not interact w/ heparin-induced antibodies
  4. Anticoagulant: Warfarin (coumarins)
    • Chemical nature: small, lipid soluble derivatives of vit K
    • Kinetics: PO, 98% protein bound, liver metabolism, t1/2 = 30 hours, placental access
    • Mechanism: decreases hepatic synthesis of 9, 7, 2, 10 (vit K dep factors), Y-carboxylation by inhibiting vit K epoxide reductase; no effect on factors alreayd present, in vivo effects nly
    • Monitoring: PT; INR
    • Antagonist: vit K = increased cofactor synthesis, slow onset, frest frozen plasma (fast), acts on extrinsic pathway
    • Uses: LT anticoagulation (controlled), for thromboses, emboli, post MI, heart valve damage, atrial arrhythmias, etc.
    • Toxicity: bleeding, skin necrosis (if low protein C, drug interactions, teratogenic (bone dysmorphogenesis)
    • Drug interactions: PO absorption decreased by cholestyramine, any drug that displaces warfarin from the protein (ASA, sulfonamides, phenytoins)
    • SLOW hepatic metabolizers via P450:
    • inducers: (barbiturates, carbamazepine, rifampin) = decrease PT
    • Inhibitors (cimetidine, macrolies, azole antifungals, grapefruit juice) = increase PT

    the EX-PresidenT went to WAR(farin)
  5. Low Molecular weight heparins
    • Drugs: enoxaparin, danaparoid
    • act more on Xa, better bioavailability, 2-4X longer half-life
    • Administration: subQ
    • Monitoring: no labs needed
    • Not easily reversible
  6. Protein C Deficiency
    • Transient Protein C deficiency when initating tx of warfarin bc factors 8 and C have shortest half life = extrinsic pathway and Protein C are inacrivated, whilst intrinsic pathway remains active for a few days
    • Hypercoagulability occurs = hermal vascular thrombosis, skin necrosis
  7. Anticoagulants: Lepirudin, Bivalirudin
    • Hirudin derivatives
    • Mechanism: directly inhibit thrombin
    • Clinical use: alternative to heparin for anticoagulating in pts with HIT, used with ASA in unstable angina when undergoing percutaneous transluminal coronary angioplasty
  8. Thrombolytics (Fibronolytics)
    • Drugs: streptokinase, urokinase, tPA (alteplase), APSAC (anistreplase)
    • Mechanism: directly or indirectly aid in conversion of plasminogen to plasmin = cleaves thrombin and fibrin clots = increased PT, PTT and no change in platelet count
    • Clinical use: IV for ST use in early MI, early ischemic stroke, PE, DVT
    • Toxicity: bleeding, contraindicated in active bleeding, hx of intracranial bleeding, recent surgery, known bleeding diatheses, severe htn
    • Toxicity tx: aminocaproic acid (fibrinolysis inhibitor)
  9. Thrombolytic: Streptokinase
    • Derived from bacteria = antigenic (foreign protein derived from B-hemolytic streptococci); may cause problems if recent/past infection bc strep antibodies can decrease activity
    • Acts on both bound and free plasminogen (not clot specific), dpelets circulating plasminogen and factors 5 & 8
  10. Thrombolytic: Atelplase
    • Clot specific, acts mainly on fibrin-bound plasminogin
    • natural activator
    • no allergy problems
  11. Clinical features of Thrombolytics
    • early administration is key (>60% decrease in post-MI mortality if administered w/in 3 hours)
    • ASA, beta blockers, nitrates = decrease mortality (MONA tx)
    • adenosine decreases infarct size
  12. Antiplatelet Drugs:
    • ASA
    • Ticlopidine & Clopidogrel
    • Abciximab, epifibatide, tirofiban
  13. Thrombous (clot) formation involves 3 things:
    • 1. Platelet adhesion to side of vascular injury
    • 2. Activation of platelets by factors: TxA2, ADP, collagen, 5HT, thrombin = increased expression of glycoprotein IIb/IIIa receptors
    • 3. Aggregation of platelets by cross-linking reaction between fibrinogen & glycoprotein IIb/IIIa receptors
  14. Antiplatelet Drug: ASA
    • Mechanism: acetylates & irreversibly inhibits COX in platelets = prevents conversion of arachidonic acid to TxA2 = increased bleeding time, no effect on PT or PTT
    • Clinical use: low doses prevents MI and recurrence; prophylaxis in atrial arrhythmia and TIA
    • Toxicity: gastric ulcers, bleeding, hyperventilation, Reye's syndrome, tinnitus (CN 8)
  15. Antiplatelet Drug: Ticlopidine & Clopidogrel
    • Mechanism: blocks ADP receptors on platelets = decreased activation & inhibits fibrinogen binding by preventing glycoprotein IIb/IIIa expression
    • Clinical use: alternatives to ASA in TIA, post-MI, unstable angina
    • Toxicity: neutropenia
  16. Antiplatelet Drug: Abciximab, epfibatide, tirofiban
    • Mechanism: monoclonal antibody, binds to glycoprotein recepotr IIb/IIIa on activated platelets, prevents aggregation
    • Clinical use: acute coronary syndromes, angioplasty
    • Toxicity: bleeding, thrombocytopenia
Card Set
Drugs in Blood Disorders
Drugs in Blood Disorders