Antithrombotics

Categories: Blood & Anti-Inflammatories

  • 1) Antiplatelet Drugs
    • COX Inhibitors
      • Acetylsalicylic Acid (Aspirin)
        • COX1 Inhibition (Thromboxane A2)
        • COX2 Inhibition at high doses
        • Overdose:
          • Gastric Lavage, Activated Charcoal
          • Alkalinization of the urine (IV Sodium Bicarb)
            • Goal of urine pH ≥7.5
          • Dialysis if Salicylate levels ≥90-100 with acute intoxication or ≥60 ng/mL in chronic administration
    • ADP Receptor Antagonists (P2Y12 Inhibitors)
      • Binds platelet ADP receptor
        • Inhibits platelet aggregation
        • Used in aspirin intolerant or in coronary stents
      • Require CYP450 activation
        • Clopidogrel (Plavix)
        • Prasugrel (Effient, 10x stronger, more rapid)
          • More bleeding risk than clopidogrel
          • CI in ≥75 y/o, renal impaired, CVD
        • Ticlopidine
      • Nucleotide/Nucleoside Analogs
        • Reversible, no activation needed to work
        • Ticagrelor (Brilinta)
          • More rapid onset, ≥ than clopidogrel
        • Cangrelor
          • Immediate onset – 1 hour
    • Prostaglandin Analogues (PGI2)
      • Treprostinil (Remoodulin)
    • Thromboxane Inhibitors
      • Dipyridamole
        • Blocks AMP BD, inhibit Platelet activation
    • GP IIb/IIIa antagonists
      • Abciximab (ReoPro)
        • PCI w/o ADPRA, not renally cleared
      • Eptifibatide (Integrilin)
      • Tirofiban (Aggrastat)
        • High risk unstable angina
    • PAR-1 Antagonist
      • Vorapaxar
    • Phosphodiesterase inhibitor
      • Intermittent claudication
      • Cilostazol
    • Combos
      • Aspirin + Clopidogrel
        • 4 weeks after bare metal stent
        • 6 months after drug eluting stent
        • Unstable angina
      • Aspirin + Prasugrel
        • Patients undergoing PCI
  • 2) Anticoagulants
    • A) Vitamin K Antagonists
      • Warfarin (Coumadin)
        • MOA: Vitamin K epoxide reductase inhibitor
          • Inhibits Prothrombin (II), VII, IX, X, C, S
        • Needs to be bridged for 5 days if HR (most surgeries)
          • Bridge when HR or valves: Use LMWH when INR <2
        • Monitored via INR ≥ PT, 97% bound to albumin
        • Can be used in breastfeeding
        • Reversal: INR ≥ 10 = oral vit k
            • bleeding = 4F-PCC (works in minutes), IV vitamin K (12-24hrs, risk of anaphylaxis) ≥ FFP
            • Four-Factor Prothrombin Complex (4F-PCC)
              • Contains Factors II, VII, IX, and X as a lyophilized powder
            • Indicated in brain hemorrhage
          • No bleeding, INR 4.5-10: withhold
          • No bleeding, INR 3-4.5: watch and wait
        • CI: Pregnancy (crosses placenta)
          • Vit k, nasal hypoplasia, stippled epiphyses in first trimester
        • Warfarin-Induced Skin Necrosis
          • 2-5 days after initiation
          • Well demarcated, center lesion necrotic, thrombi in microvasculature
          • Protein c or s def, initiation
          • Treatment
            • Vitamin K, heparin, discontinue warfatin
            • +/- Protein C (concentrated or in FFP)
        • Warfarin Metabolism
          • CYP450 Inhibitors (Increased Warfarin effect)
            • Risk of Hemorrhage
            • Acetaminophen, NSAIDs, Metronidazole, Amiodarone, Cimetidine, Cranberry Juice, Ginkgo biloba, VitE, omeprazole, Thyroid hormone, SSRIs
          • CYP450 Inducers (Decreased Warfarin effect)
            • Risk of Thrombosis
            • Carbamazepine, Phenytoin, Ginseng, St. John Wort, OCPs, Phenobarbital, Rifampin, Spinach/Sprouts (Vitamin K)
        • INR Management
          • INR <5 + none or minimal bleeding:
            • Hold warfarin for 1-2 days or decrease dose
          • INR 5-9 + none or minimal bleeding:
            • Hold warfarin and resume when INR is therapeutic, give 1-2.5mg oral VitK if increased risk of bleeding
          • INR ≥9 + none or minimal bleeding
            • Hold warfarin and give 2.5-5mg oral VitK
          • Any serious or life-threatening bleeding:
            • Hold warfarin, five 10mg IV Vitk, FFP, recombinant factor VIIa, or PCC
    • B) Factor Xa Inhibitors
      • I) Heparins/Glycosaminoglycans/Binds Antithrombin
        • A) Unfractionated Heparin (UFH) (Parenteral)
          • Must monitor using aPTT
          • Dose dependent, saturable, weaker binding to endothelial, macrophage, hbpps
          • Activates Antithrombin (III) ≥ binds fibrin
            • Accelerates Antithrombin clot inhibition
              • Inhibiting Thrombin and Factor Xa
            • Forms thrombin-antithrombin complex
            • Can cause platelet activation?
          • Causes TFPI release
          • Neutralized by PF4 (platelet rich thrombi)
          • Heparin Inducted Thrombocytopenia (HIT)
          • Protamine sulfate (1mg to 100U) to reverse
          • SE: Osteoporosis, increase bilirubin
        • B) Low-Molecular-Weight Heparin (LMWH) (Parenteral)
          • Enoxaparin (Lovenox)
            • Made from Unfractionated Heparin
            • Greater capacity to potentiate factor Xa inhibition than thrombin due to being a short chain (2:1 – 4:1 Xa to iia)
          • VTE + Cancer
          • Dose independent, renal clearance, rare resistance, no monitoring
          • Little aPTT affect, measure anti-Xa to monitor (Heparin-Xa)
            • Every 4 hours
            • Obesity, renal insufficiency, pregnant, valves
        • C) Antithrombin III Inhibitors (Indirect Factor Xa inhibitors) (Parenteral)
          • Fondaparinux (Arixtra)
            • (smallest heparin chains) AT3
          • Can be used in surgical, ortho, VTE patients, only binds AT3, no thrombin rate inhibition, Xa only, renal cleared, can use in HIT, no antidote, no need to monitor
      • II) Direct Factor Xa Inhibitors
        • Factor Xa for monitoring
          • Stroke prevent, long term anticoagulation in nonvalvular afib
          • VTE treatment w/o cancer
        • Apixaban (Eliquis)
          • 10mg BID for ??
          • 5-5mg PO BID
        • Rivaroxaban (Xarelto)
          • 15mg BID for 21 days for VTE
          • 20mg PO daily with dinner
          • Renal Excretion
        • Edoxaban (Lixiana, Savaysa)
          • 60mg PO daily

    • C) Direct Thrombin Inhibitors (DTIs) (Parenteral)

      • Inhibit Thrombin (IIa)
      • Bivalent
        • Lepirudin/Desirudin (Revasc): Renal clearance, no metab
        • Bivalirudin (Angiomax)
          • Not renal, no metab
          • Activated clotting time, aptt
          • PCI instead of heparin
      • Univalent
        • Argatroban (acova)
          • Liver metabolism, not renal
          • HIT treatment
          • aPTT, prolongs INR
            • measure Factor X instead to monitor warfarin
        • Dabigatran (Pradaxa, Oral)
          • 150mg PO BID or 75mg PO BID if Crcl = 15-30
          • Direct Thrombin Inhibitor, Renally excreted, aPTT to monitor
            • PPIs decrease absorption
    • D) Other
      • Antithrombin III, Protein C
  • 3) Fibrinolytic Agents
    • Degrade thrombi
    • Systemic administration: Acute MI, Acute Ischemic stroke, most Massive PE
    • Catheter based: Peripheral arterial thrombi, proximal deep veins
    • Drugs
      • All convert plasminogen to plasmin (zymogen to enzyme)
        • Degrades fibrin matrix
      • rtPA, alteplase
        • ibrin specific, plasminogen bound, activated (converts to plasmin)
        • higher fibrin affinity, works better around clots
        • <75 w/<6h of symptoms of Acute MI, Iv for 1-1.5h
      • Nonspecific – fibrin bound and circulating plasminogen activation – plasmin can cause lytic state
        • Streptokinase – no fibrin affinity
          • IV for Acute MI – reduce mortality
            • hypotension
        • Urokinase – not immunogenic, catheter lysis of thrombi

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