PHARMACOLOGY

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PHARMACOLOGY

• ? ANTICOAGULANTS THROMBOLYTICS ?
• October 8, 2001
• ?
• Marisa B. Marques, MD
• Assistant Professor of Pathology
• University of Alabama at Birmingham

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Components of hemostasis and corresponding drugs

• Blood vessels
• Platelets
• Coagulation cascade
• Fibrinolytic system

• Vasoconstrictors
• Antiplatelet aggregation agents
• Anticoagulants
• Fibrinolytic or Antifibrinolytic

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Mechanisms of Hemostasis

• vascular constriction smooth muscle and
  endothelial cells, renin,angiotensin II and
  endothelin
• ?
• platelet plug adhesion, activation and
  aggregation
• ?
• fibrin formation coagulation cascade
• ?
• regulation of clot fibrinolysis
• ?
• repair of injury site

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• Other Drugs that Affect Platelet Function
• Antibioticspenicillins (carbenicillin,
  penicillin G, ticarcillin, nafcillin)
  cephalosporins (moxalactam, cefotaxime)
  nitrofurantoin
• Hydroxychloroquine
• Clofibrate
• Tricyclic antidepressants
• Phenothiazine
• Dextran

• Antiplatelet Agents
• Aspirin
• Nonsteroidal anti-inflammatory drugs (NSAIDS)
• Dipyridamole
• Ticlopidine hydrochloride
• Clopidogrel
• Anti- GPIIb/IIIa (Abciximab)

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Antiplatelet Drugs aspirin, NSAIDS

• Aspirin irreversibly inhibits cyclooxygenase ?
  blocks formation of thromboxane A2, PGG2, and
  PGH2 ? causes lack of aggregation and
  vasoconstriction.

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From Cleveland Clinic Journal of Medicine
66(10)615
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Anticoagulant drugs that affect secondary
hemostasis decrease the generation of thrombin
Intrinsic
Extrinsic
Common
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Heparin potentiates 1000-fold the inhibitory
action of antithrombin
Antithrombin heparin
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Heparin Structure

• Mixture of highly acidic mucopolysaccharides
  (3,000-30,000 daltons)
• Produced from porcine intestine or bovine lung

CH2OSO3
COO-
CH2OH
O
O
O
O
COO-
O
O
OH
OH
O
OH
OH
O
HNAc
OH
OH
NH3
Iduronic Acid
Glucuronic Acid
Sulfated N-acetyl Glucosamine
Glucosamine
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Absorption of Heparin

• Not absorbed in GI tract
• IV ? immediate effect
• SC ? 2-h delay in onset of action
• peak 2-4 hours
• Avoid IM ? unpredictable absorption, bleeding,
  irritation

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Metabolism of Heparin

• Binds to endothelial cells and macrophages, PF4,
  vitronectin, fibronectin, vWf, histidine-rich
  glycoprotein
• Inactivated by reticuloendothelial system in
  liver
• Renal failure reduces rate of clearance
• Not secreted in breast milk does not cross the
  placenta

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Prophylactic Indications for Heparin

• To prevent formation of a thrombus in high risk
  situations post-trauma, -surgery or -pregnancy
• Usually administered via SC route
• Less heparin needed to prevent formation of
  thrombin than to inhibit clot-bound thrombin
• Target dosage is 0.1-0.3 IU/mL
• Injections 2-3/day

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Therapeutic Indications for Heparin

• To prevent propagation of a thrombus following a
  thrombotic event.
• Arterial Thrombosis
• Acute myocardial infarction
• Peripheral
• Ischemic strokes
• Venous Thrombosis
• Deep vein thrombosis ? pulmonary emboli

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Laboratory Monitoring of Heparin

• Uses the partial thromboplastin time (PTT)
• Target for treatment of venous thrombosis PTT 2
  to 2.5 times control
• Anti-Xa assay used to calibrate PTT
• High doses prolong PT
• Daily platelet counts should be monitored

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Complication of Heparin Therapy

• Heparin-induced thrombocytopenia
• Type I - transient, not antibody-mediated
• Type II - antibody to heparin-PF4 complexes
• drop in platelet count by 40
• risk of thromboembolic complications
• heparin should be discontinued until process is
  ruled out

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Low Molecular Weight Heparins (LMWH)

• Fractionated from standard porcine Heparin
• MW 3,000 - 14,000 D, mean 5,000 D
• 13-22 saccharide units
• Brands on the market
• Enoxaparin (Lovenox), Dalteparin (Fragmin),
  Adreparin (Normiflo), Danaparoid (Orgaran)
• Dosage of enoxaparin
• prophylactic 30 mg bid SC or 40 mg qd SC
• full-dose 1 mg/Kg bid SC

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Advantages of LMWH

• Predictable anticoagulant response
• No need for laboratory monitoring
• Longer half-life when given in fixed doses
  (allows dosing once per day)
• Greater bioavailability at low doses
• Less bleeding in therapeutic doses
• Lower incidence of heparin-induced
  thrombocytopenia

Harmening, DM. Clinical Hematology and
Fundamentals of Hemostasis. 1997.
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Clinical conditions that increase the risk of
bleeding with heparin therapy

• Advanced age
• Surgery within 10 days
• Elevated serum creatinine
• Recent intracranial hemorrhage or stroke
• Active peptic ulcer disease

• Hypertension (diastolic pressure120 mm Hg)
• Recent CPR
• History of bleeding diathesis
• Multiple comorbid conditions
• PTT2 times control

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Reversal of heparin effect

• When bleeding occurs or if an invasive procedure
  is mandatory stop heparin infusion first
• If neutralization of heparin is needed Protamine
  sulphate 1 mg for each 100 units of heparin
  circulating (as estimated by the anti-Xa test)
• Beware that excess protamine is also an
  anticoagulant

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Direct thrombin inhibitors

• Hirudin - extract from medicinal leeches
• Lepirudin - recombinant form of hirudin
• Argatroban
• Both are approved by the FDA to be used as
  anticoagulant in patients with heparin-induced
  thrombocytopenia (HIT) type II
• Lepirudin - accumulates in renal failure
• Argatroban - can be used in renal failure

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Fibrinolytic or Clotting Inhibition System

• Complex system of activators and inhibitors
  regulates the conversion of plasminogen to
  plasmin (enzyme that cleaves fibrin to dissolve
  the clot)
• Limits extent of clot formation
• Helps maintain a reserve of factors
• Acts on limiting generation of thrombin
• Allows remodeling and removal of thrombus to
  occur as wound healing proceeds.
• Abnormalities in plasminogen ? thrombosis
  tendency

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Plasmin activates factor XII ? amplifying system
Factor XII surface ? initiate intrinsic
plasminogen activating system
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Thrombolytic Agents (Plasminogen Activators)
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Plasminogen Activators

• Streptokinase complexes with plasminogen,
  activating other molecules
• Not selective for fibrin-bound plasminogen
• May cause severe fever
• Not universal dose-response
• Urokinase
• Extremely effective and dose-predictable
• No immunologic side- effects

• Tissue-type plasminogen activator (tPA)
• Produced by endothelial cells
• Produces plasmin within the thrombus healing
  sites as well as pathologic sites ? undesirable
  risk of bleeding

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Risks of Plasminogen activators

• tPA can directly lyse circulating fibrinogen
  without activating plasmin ? hypofibrinogenemia
• tPA can also cause activation of complement, and
  thrombocytopenia ? significant coagulopathy.
• Urokinase and streptokinase ? hypofibrinogenemia
• All 3 agents ? ? circulating plasminogen ? risk
  of spontaneous thrombosis
• Hypofibrinogenemia and plasminogenemia greatest
  in the first few hours after initiating therapy

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Absolute Contraindications to Thrombolytic Therapy
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Relative Contraindications to Thrombolytic Therapy
Pregnancy or recent delivery
Surgery or organ biopsy in prior 2 weeks
Hemostatic defects
Infective endocarditis
Recent trauma (including CPR)
Puncture of major noncompressible vessel within
10 days
Active or recent internal bleeding
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Inhibitors of Fibrinolysis

• ?-aminocaproic acid (EACA)
• Tranexamic acid
• Inhibit tissue plasminogen activator (tPA) and
  plasmin
• Can be used orally, IV or topically (I.e.,
  mucosal membranes)
• Useful in dental procedures of hemophiliacs,
  patients with von Willebrand disease, or on
  warfarin

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Drugs List

• Aspirin
• Clopidogrel, ticlopidine
• Glycoprotein IIb/IIIa inhibitors
• Heparin
• Low-molecular weight heparins
• Warfarin
• tPA, streptokinase, urokinase
• ?-aminocaproic acid (EACA), tranexamic acid