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Flashcards in hemostasis disorder drugs Deck (30):
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platelet inhibitors 

Aspirin

ticlopidine

clopidogrel

abciximab

small mol receptor inhibitors (tirofiban, eptifibatide)

phosphodiesterase inhibitors (dipyridamole, cilostazol)

anagrelide

 

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aspirin (acetylsalicylic acid)

Inhibits the synthesis of thromboxan A2 (TxA2) by irreversible acetylation of COX-1 in platelets 

  • Use: reduce risk of MI and recurring transient ishcemic attacks (TIAs)
  • Antithrombotic effects on platelts are seen 1-2 days after administration and lasts for the duration of the platelets life span (7-10 days)
    • COX is irreversibly inhibited and the platelet has no way to make more 

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ticlopidine 

ADP antagonist

  • Inhibits ADP receptors on platelets which prevents activation of GPIIb-IIIa (GPIIb-IIIa promotes platelet aggregation (binds to fibrinogen))
  • Inhibits platelet adhesion (I would think it would inhibit aggregation) and platelet - platelet interactions
  • Use: alternative to aspirin to prevent an initial or recurrent thromboembolic stroke
  • Oral
  • AE: nausea, dyspnea, diarrhe (20%), hemorrhage (5%)
    • Rare: severe bone marrow toxicity 

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clopidogrel

  • Similar mech to ticlopidine but has a lower incidence of adverse effects
  • Use: in patients with history of recent stroke/MI or established peripheral vascular disease, and in patients with stents
  • Requires activation by CYP2C19 resulting in drug-drug interactions with other drugs metabolized by 2C-19 (its is better than ticlopidine if the patient is not taking other drugs)
    • Proton pump inhibitors
    • Anti-epileptics (diazepam, phenytoin, mephenytoin)
    • Amitryptiline, imiprimine
    • Propranolol
    • R-warfarin

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abciximab

  • Inhibits platelet aggregation by preventing binding of fibrinogen to glycoprotein receptor IIb-IIIa on activated platelets
  • Given IV to high risk patients undergoing coronary angioplasty and patients undergoing angioplasty, atherectomy and stent placement - often with clopidogrel
  • Expensive
  • Bleeding is most common side effect 

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tirofiban and eptifibatide

small molecule

tiro - peptidomimetic

epti - cyclic peptide

both have short half lifes 

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dipyridamole

phosphodiesterase inhibitors - act inside the cell

  • Coronary vasodilator that also inhibits platelet aggregation
  • Use: In combination with warfarin - inhibits embolism from prosthetic heart valves
    • In combo with aspirin, reduces thrombosis in patients with thrombotic disease 

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cilostazol

phosphodiesterase inhibitor - acts inside the cells

  • Antithrombotic, antiplastlets and vasodilatory action
  • Use: intermittent claudication and PVD

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anagrelide

  • Reduces platelet numbers directly
  • Inhibits megakaryocyte development in the late postmitotic stage
  • Use: treatment of thrombocytosis secondary to myeloproliferative disorders such as polycythemia vera and chronic myelogenous leukemia to reduce the risk of stroke and MI

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anticoagulants

calcium chelators

heparins

 

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calcium chelators

  • Inhibit blood coagulation in vitro - our bodies need Ca so we can’t use it on blood that is in the body
  • Examples: oxalic acid, sodium citrate, disodium edetate (EDTA)

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heparins

  • Accelerates the action of antithrombin 3 to neutralize thrombin and other coagulation factors
  • Standard heparin (UFH)
    • Sources: porcine intesintal mucosa and bovine lung
    • Structure: sulfated mucopolysaccharide (acidic molecule)
    • Formulations: standard, unfractionated heparin (UFH) polymer (3000-30000)
      • There are lots of heparins - with different weights - this is a mixture of all of them
    • Onset of action: immediate
    • Mech of action
      • Activates AT3 -> AT3 inactivates factor 2a and 10a

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AE of heparins 

  • Bleeding/hemorhage - minimized with carful monitoring of PTT and platelet counts
  • Allergic reaction (it is an animal prodouct)
  • Osteoporosis (long term therapy)
  • Transient and occasionally severe heparin induced thrombocytopenia (HIT)
    • Type 1 = transient and rapidly reversible
      • Antibodies are generated against platelets
      • Results in a decrease in platelet count
    • Type 2 = severe
      • Antibodies decrease platelet count
      • These antibodies also activate platelets
      • This may produce a thromboembolism, which may be life threatening 

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antidote for OD on standard heparin 

  • Protamine sulfate
    • Protamine is a basic protein that binds to heparin (anion/cation interaciton)
    • Excessive antidote must be avoided because protamine itself is an anticoagulant
      • Need to titrate it - just need enough so that all the heparin is bound but no more
    • Protamine is much less capable of reversing the effects of LMWH

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LMWH

  • Advantages over UFH
    • Dose dependent kinetics
    • Conviencnec - can be admin subcutanous, don’t need PTT monitoring
    • Safety
  • Contrainication: HIT
  • Not readily reversed with protamine sulfate (no antidote)
  • Monitored by anti-Xa activity assay when needed (not a good eval)

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fondaparinux

  • Synthetic pentasaccharide anticoagulant
    • It is the 5 saccharides of the active site of heparin
  • Unlike UHF or LMWHs it has no effect on thrombin (F2a) - it only hits Fxa
  • Once daily dosing - given subcutaneously
  • Uses
    • Venous thromboembolism prophylaxis follwing ortho surgery
    • Treatment of pulmonary embolism
    • Treatment of DVT
    • Treatment of coronary artery thromboembolism; promising but still under study 

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Direct thrombin inhibitors 

Rudins

argatroban

oral drugs(dabigatran, rivaroxaban, apixaban)

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Rudins

  • Hirudin
    • 65 amino acid peptide
    • Specific thrombin inhibitor obtained from leeches
  • Lepirudin - recombinant yeast derived form of hirudin
    • Use: anticoagulant in patients with heparin induced thrombocytopenia (HIT)
  • Desirudin and bivalirudin - new recombinant hirudin analogs 

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argatroban

  • Argatroban - 2nd gen agent approved for HIT
    • IV
    • Cleared by the liver Unlike lepirudin - the other drug for HIT) - can be used in patients with end stage renal disease 

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dabigatran etexilate (pradaxa)

oral drug

  • First oral direct thrombin inhibitor
  • Use: atrial fibrillation, DVT, PE (prophylaxis and treatment)
  • Pro-drug (ester) - rapidly hudrolyzed
  • Excreted in urine

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rivaroxaban (carelto)

oral 

  • Direct FXa inhibitor
  • Same indications as dabigatran
  • Oral - but variable bioavalibility
  • Metabolized and inactivated by CYP3A4/5
  • Excreted in both urine and feces 

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apixaban

oral

  • Direct FXa inhibitor
  • Same indications as dabigatran and rivaroxaban
  • Excreted in urine and feces

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coumarin derivatives

warfarin 

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warfarin 

  • Interfere with hepatic synthesis of functional vitamin K dependent clotting factors
  • Plasma protein binding
    • Extensive which accounts for:
      • Low volume of distribution
      • Long half life
      • Lack of urinary excretion of unchanged drug
  • Metabolism
    • Metabolized to inactive metabolites by cytochrome P450 (CYP2C9) in liver - site of numerous drug interactions 
  • Target: vitamin K epoxide reductase
  • Reisstance: mutations in vit K epoxide reductase - confers heritable resistance to warfarin
    • There is a large variation as to how people will react to this drug
  • Speed of onset: slow
    • Several days to reach max
  • Antidotes
    • Discontinue drug, administer large doses of vit K and FFP

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thrombolytic drugs

t-PA

streptokinase

urokinase

recombinant thrombolytic agents (alteplase, reteplase, tenecteplase)

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t-PA

More effectors than streptokinase or anistreplase for thrombolytic therapy in MI but carries higher risk of hemorrhagic stroke

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streptokinase

  • Non enzymatic protein produced by group C beta hemolytic streptococci
  • Facilitates thrombolysis through formation of activator complex whith plasminogen results in formation of plasmin
  • Plasmin degrades fibrin, fibrinogen and procaogulant factors 5 and 8
  • Aspirin plus streptokinase may be as effective as t-PA
  • Hypersensitivity may occur

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urokinase

  • Parenteral thormbolytic agent (from human cultured kidney cells)
  • Indicated for lysis of pulmonary emboli, lysis of coronary artery thrombi associated with evolving transmural myocardial infarction
  • Hypersensitivity reactions occur less frequency than with streptokinase 

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alteplase

reteplase

tenecteplase 

  • Recombinant thrombolytic agents
    • Alteplase
      • Biosynthetic recombinant form of t-PA
      • Considerably more expsensive than streptokinase
      • Not assoicated with hypersensitivity reactions
    • Reteplase
      • Recombinant plasminogen activator
      • Longer HL than alteplase
    • Tenecteplase (TNK-t-PA)
      • Modified human t-PA
      • Compared to alteplase it has a prolonged half life, increased specificity for fibrin and increased resistance to plasminogen activator inhibitor 

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