PHARMACOLOGY of DRUGS in HEMOSTASIS DISORDER

Major Drugs

1. ANTICOAGULANTS
   
2. ANTITHROMBOTICS
   
3. THROMBOLYTICS
   
4. HEMOSTATICS
   

• Coagulation is Complex
  
• BLOOD COAGULATION
  
• Disorders of Hemostasis
  
• Vascular disorders
  
  • Scurvy, easy bruising,
    
• Platelet disorders
  
  • Low Number or abnormal function
    
• Coagulation disorders
  
  • Factor deficiency.
    
• Mixed/Consumption: DIC (Disseminated intravascular coagulation)
  
• ANTICOAGULANTS
  
• Parenteral Anticoagulant
  

    * Heparin

• Oral Anticoagulant
  

    * Warfarin

• Heparin
  
• Abundance in liver
  
• Water soluble mucopollysaccharide
  
• Strongly acidic ( because of its content of covalently linked sulphate and carboxylic acid groups)
  
• Prepared from bovine lung and porcine intestinal mucosa or from sheep and whales
  
• Anti Factor-Xa activity and plasma lipolytic activity of porcine intest. muc. heparin is more potent than is that of bovine lung. But, all heparins are biologically equivalent. However, the incidence of thrombocytopenia is lower with porcine intestinal mucosa heparin
  
• Heparinoid
  
• Heparin from mammalian tissue sources is in limited supply
  
• Semisynthetic sulphated polymers that have been prepared from disaccharides composed of D-glucosamine and D-glucuronic acid
  
• Have high anticoagulant and lipolytic activities
  
• Parmacological Properties
  

Action on Blood Coagulation and Antithrombin III :

     * The anticoagulant effect is essentially         immediate

    * Heparin acts indirectly by means of a             plasma cofactor (antithrombin III)

    * Antithrombin III neutralizes several             activated clotting factors

• cont.
  
• Activated clotting factors :
  

    * XII a

    * Kallikrein (activated Fletcher factor)

    * XI a

    * IX a

    * X a

    * II a

    * XIII a

• Heparin Absorption
  
• Crosses membranes poorly because of its polarity and large molecule size
  
• Not absorbed from GI and sublingual sites
  
• Can't passage across placenta and hindered into maternal milk
  
• The deep subcutaneous or intrafat injection site is used when therapy with low doses of heparin is chosen and for treatment of ambulatory patients
  
• Intramuscular injection of heparin should be avoided because large hematomas can form at the site of injection
  
• Miscellaneous Action of Heparin
  
• When added to blood, it doesn't alter routine chemical determination
  
• But, it distorts the morphology of red and white blood cells
  

It has been reported

• to suppress the secretory rate of aldosterone
  
• increase the concentration of free thyroxine in plasma
  
• Inhibit fibrinolytic activators
  
• Retard wound healing
  
• Depress cell-mediated immunity
  
• Accelerate the healing of thermal burns
  
• II. ANTITHROMBOTICS
  
• Aspirin
  
• Dipyridamol
  
• Dextran
  
• Ticlopidine
  
• Clopidogrel
  

    The action of Antithrombotics

• = Platelet aggregation inhibitors
  
• = Suppress platelet function
  
• = Prevent platelet aggregation
  
• III. THROMBOLYTICS
  
• = Fibrinolytics
  
• = Promote the dissolution of thrombi by stimulating the activation of endogenous plasminogen to plasmin (fibrinolysin = a proteolytic enzyme that hydrolyzes fibrin)
  
• STREPTOKINASE
  
• = Interact with and activates plasminogen
  
• = The complex of Streptokinase and plasminogen
  

     has protease activity and catalyzes the conver-     sion of plasminogen to plasmin

• = Following the administration of Strkase. there is a high incidence of bleeding from sites of per- cutaneous trauma and in wounds (because plasmin lyses fibrin in hemostatic plugs and degrades fibrin
  

ogen and factors V and VII)

• ADVERSE REACTION
  
• Fever
  
• Allergic reaction and even anaphylaxis
  

    

ADMINISTRATION

• Intravenously loading dose of 250.000 I.U. over a 30 min. period
  
• Followed by 100.000 I.U. /hour, adjusted according to the thrombin time
  
• Therapy is continued for 24 to 72 hours and must be monitored by the thrombin time
  
• UROKINASE
  
• = Originally isolated from human urine
  
• = Prepared from cultures of human renal cell
  
• = Contraindicated in children or in patients with any kind of healing wound, recent trauma visceral or intracranial malignancy, pregnancy or recent cerebrovascular accident
  
• = IV loading dose 4400 IU/kg over a period of 10 minutes. Followed by a continous infusion of 4400 IU/kg/hour for 12 hours and then by heparin or oral anticoagulants.
  

    Thrombin time should be evaluated before heparin is given

• IV. HEMOSTATICS
  
• 1. Absorbable hemostatics
  

    = Arrest bleeding when applied directly to denuded     or bleeding surfaces:

         * by formation of an artificial clot

         * by providing a mechanical matrix that facili-     tates clotting

    = Absorbed from the site of application after periods     of time

    = Used to control oozing from minute vessels

    = Will not effective combat bleeding from arteries     or veins

• 2. Orally and parenterally hemostatics
  
• Vitamin K
  

    = Coagulation vitamin

    = A dietary principle essential for the normal bio –

        synthesis of several factors required for clotting     of blood

    = Fat soluble substance

    = Synthezised by the bacteria in the intestinal tract

    = In plants : is concentrated in the chloroplast of     plant leaves and in many vegetable oils

• Hemostasis
  
• Clot retraction: platelets contract and pull the torn edges of the damaged vessel closer together.
  
• Fibrinolysis: here the clot gradually dissolves through the action of plasmin, the activated form of circulating plasminogen.
  
• Manipulation of hemostasis: clotting may be prevented by administering drugs that depress the clotting response or dissolve existing clots. Important anticoagulant drugs include heparin, dicumarol, coumadin, streptokinase, urokinase and aspirin.
  
• Disorders of hemostasis
  
• Thromoboembolytic disorders: undesirable clot formation
  
• Thrombocytopenia-a deficit of platelets, causes spontaneous bleeding. Hemophilia. Liver disease can cause this because the liver manufactures many of the coagulation proteins.
  
• ABSORBABLE HEMOSTATICS
  
• Absorbable gelatin sponge
  

    = Sterile, absorbable, water insoluble, gelatin base     sponge

    = Used for the control of capillary oozing and frank     hemorrhage, particularly from highly vascular areas that     are difficult to suture

    = Before use, it is frequently moistened with sterile     isotonic sodium chloride solution or with thrombin     solution

    = When implanted in tissues it is absorbed completely     in 4     to 6 weeks without inducing excessive formation of scar     tissue

 

• Thrombin
  
• = Applied topically to control capillary oozing in     operation procedures
  
• = To shorten the duration of bleeding from     punctured sites in heparinized patients (e.g. after     hemodialysis)
  
• = Thrombin should never be injected, because of the     possibility of thrombosis and death
  
• = Thrombin is dusted as a powder , applied as a     solution or combined with a suitable sponge     matrix (e. g. , absorbable gelatin sponge)
  
• VITAMIN K
  
• Physiological function in animals and man:
  

    *To promote the hepatic biosynthesis of     #prothrombin (factor II)

        #proconvertin (factor VII)

        #plasma thromboplastin component (PTC,             Christmas factor, factor IX)

        #Stuart factor (factor X)

• Human requirement : 0.5 - 1µg/kg of BW/day
  
• PREPARATIONS of VITAMIN K
  
• Phytonadione (phylloquinone, vitamin K1)
  

    Toxicity:

        Rapid intravenous administration has produced     flushing, dyspnea, chest pains, cardiovascular     colapse and rarely death

• Menadione (vitamin K3)
  

    Toxicity:

        *Large doses of menadione and its derivatives     irritating to the skin and the respiratory tract.     *In new born (especially premature infants), pro-

        duce hemolytic anaemia, hyperbilirubinemia,     kern icterus.

• Menadione also can induce hemolysis in individuals who are genetically deficient in glucose-6-phosphate dehydrogenase (G6PD)
  
• ! In patients who have severe hepatic disease, the administration of large doses of menadione or phytonadione may further depress function of the liver
  

 

Hematology Lecture from Department of pharmacology Faculty of Medicine Gadjah Mada University