Drugs used in Disorder of coagulation

Introduction
Hemostasis is spontaneous arrest of bleeding from a damaged blood vessel. Steps: Vascular
injury Æ vasospasmÆ platelate adhesionÆ platelate aggregation Æ coagulation cascadesÆ
fibrin formation
Anticoagulants are the drugs which inhibit fibrin formation.
Classification
Based on mechanism of action

1. Fast and direct acting
   e.g: Heparin
2. Slow and indirect acting

• Oral anticoagulants
  e.g Warfarin and Dicumarol
  Heparin
  It is a heterogeneous mixture of sulfated mucopolysaccharides
  Mechanism of action
  Heparin activates antithrobimin III (AT III) which inhibits clotting factor proteases and hence it
  inhibits the formation of fibrin clots, inhibits the conversion of fibrinogen to fibrin, and inactivates
  several of the factors necessary for the clotting of blood.
  Clinical Uses
  Prevention and treatment of venous thrombosis, atrial fibrillation with embolus formation,
  prevention of post operative thrombosis and embolism, in open heart surgery, in arterial
  embolus, treatment of coronary occlusion, acute myocardial infarction and peripheral arterial
  embolism
  Administration:
  Can be given IV or subcutaneous. Oral therapy is ineffective because it is inactivated by gastric
  acids and absorption is minimal because of large molecular size.Heparin must never be
  administered intramuscularly because of danger of hematoma formation at injection site.
  
  Side effects:
  Bleeding is the major side effect, allergy, alopecia, osteoporosis and thrombocytopenia
  Contraindications
  Contraindicated in patients who are hypersensitive to the drug, are actively bleeding or have
  hemophilia, thrombocytopenia, purpura, sever hypertension, intracranial hemorrhage, infective
  endocarditis, active tuberculosis, etc.
  ORAL ANTICOAGULANTS
  WARFARIN
  This compound was originally employed as a rodent poison. It is the most widely used coumarin
  anticoagulant and may be considered to be the drug of choice as an oral anticoagulant.
  Mechanism of action
• The anticoagulant prevents reductive metabolism of the inactive vitamin K epoxide back
  to its active form
  Pharmacokinetics:
• It is administered orally as sodium salt and has 100% bioavailability.
• The drug has slow onset of action, and long half-life in plasma (36hr) because 99% of
  the drug is bound to albumin.
  Clinical uses
  Prevention and treatment of deep vein thrombosis, treatment of atrial fibrillation with thrombus
  formation, prevention and treatment of pulmonary embolus, as part of the treatment of coronary
  occlusion and prevention of thrombus formation after value replacement
  Side effects
  Birth defect in pregnancy, hemorrhagic disease of newborn, hemorrhagic infarcts and
  cutaneous necrosis
  Contraindications – similar to heparin and the drug should never be administered during
  pregnancy.
  Drug interactions
  ƒ The effect of warfarin will be increased when it is used with the following drugs.
  
  Cimitidine, dsulfiram, metronidazole, phenylbutazone, ASA and cephalosporin (3rd generations)
• The effect of warfarin will be decreased when it is used with the following drugs.
  Barbiturates, Cholestyramine, Rifampincin, Diuretics, vit K
  THROMBOLYTIC AGENTS
  Fibrinolytic agents rapidly lyse thrombi by catalyzing the formation of plasmin from plasminogen.
  All thrombolytic agents currently in use act directly or indirectly as plasminogen activators. The
  presently used plasminogen activators are:
  a. Streptokinase- a protein synthesized by streptococci, combines with plasminogen to
  convert it to active plasmin.
  b. Urokinase-human enzyme synthesized by the kidneys that directly converts plasminogne
  to active plasmin
  c. Anistreptase (Acylated plasminongen -streptokinase activator)- bacterial streptokinase
  plus human plasminogen
  d. Tissue plaminogen activator (tPA)-this activates preferentially plasminogen that is bound
  to fibrin.
  Indications:
  Multiple pulmonary emboli, central deep vein thrombosis and acute myocardial infarction.
  Adverse Reactions:
  Bleeding and allergic reactions are most common adverse effects thrombolytics.
  Contra-indications:
  Severe hypertension, recent cranial trauma and history of cerebrovascualr accident.
  ANTIPLATELET DRUGS
  Platelet function is regulated by three categories of substances

1. Agents outside the platelet that interact with platelet membrane receptors, e.g.
   catecholamines, prostacyclin
2. Agents generated within the platelets and interact with the membrane receptors, e.g.
   prostaglandin E2 and serotonin
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3. Agents generated within the platelet and act within the platelet, e.g. thromboxane A2 and
   calcium ions
   Antiplatelets act on any one of the above processes. They include aspirin, ticlopidine,
   dipyridamole.
   ASPIRIN (ASA)
   Thromoboxane A2 is an arachidonate product that causes platelet to change shape, to release
   their granules and to aggregate. Drugs that antagonize this pathway interfere with platelet
   aggregation and prolong bleeding time. Asprin at low dose is the prototype of this class of
   drugs. It inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme
   cyclo-oxygenase.
   Therapeutic Uses:
   Prophylaxis against myocardial infarction and prevention of stroke in patients at risk, e.g. those
   with transient ischemic attacks.