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Drugs acting on bloodDrugs acting on blood

PROF. DR. SHAH MURADPROF. DR. SHAH MURAD

shahmurad65@gmail.comshahmurad65@gmail.com

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The physiological systems that control The physiological systems that control blood fluidity are both complex and blood fluidity are both complex and elegant. elegant.

Blood must remain fluid within the Blood must remain fluid within the vasculature and yet clot quickly when vasculature and yet clot quickly when exposed to nonendothelial surfaces at exposed to nonendothelial surfaces at sites of vascular injury. sites of vascular injury.

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When intravascular thrombi do occur, a When intravascular thrombi do occur, a system of fibrinolysis is activated to system of fibrinolysis is activated to restore fluidity. restore fluidity.

In the normal situation, a delicate In the normal situation, a delicate balance prevents both thrombosis and balance prevents both thrombosis and hemorrhage and allows physiological hemorrhage and allows physiological fibrinolysis without excess pathological fibrinolysis without excess pathological fibrinogenolysis. fibrinogenolysis.

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ANTICOAGULANTSANTICOAGULANTS

Many drugs have very different Many drugs have very different mechanisms of action, but all alter the mechanisms of action, but all alter the balance between procoagulant and balance between procoagulant and anticoagulant reactions. anticoagulant reactions.

With these drugs, efficacy and toxicity With these drugs, efficacy and toxicity are necessarily intertwined. are necessarily intertwined.

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For example, the desired therapeutic For example, the desired therapeutic effect of anticoagulation can be offset by effect of anticoagulation can be offset by the toxic effect of bleeding due to the toxic effect of bleeding due to overdosing of anticoagulant.overdosing of anticoagulant.

Similarly, overstimulation of fibrinolysis Similarly, overstimulation of fibrinolysis can lead to systemic destruction of can lead to systemic destruction of fibrinogen and coagulation factors. fibrinogen and coagulation factors.

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Blood fluidity is controlled byBlood fluidity is controlled by(1)(1) the parenteral anticoagulant the parenteral anticoagulant heparinheparin

and its derivatives, which stimulate a and its derivatives, which stimulate a natural inhibitor of coagulant proteases; natural inhibitor of coagulant proteases;

(2) the (2) the coumarin anticoagulantscoumarin anticoagulants, , which block multiple steps in the which block multiple steps in the coagulation cascade; coagulation cascade;

(3) fibrinolytic agents, which lyse (3) fibrinolytic agents, which lyse pathological thrombi; and pathological thrombi; and

(4) antiplatelet agents, especially (4) antiplatelet agents, especially aspirinaspirin

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HeparinHeparinis a heterogeneous mixture of sulfated is a heterogeneous mixture of sulfated (anionic) mucopolysaccharides named (anionic) mucopolysaccharides named because of its initial discovery in high because of its initial discovery in high concentrations in the liver. concentrations in the liver.

It is prepared from porcine intestinal It is prepared from porcine intestinal mucosa and bovine lung. mucosa and bovine lung.

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HEPARINHEPARIN

It acts indirectly to facilitate It acts indirectly to facilitate endogenous anticoagulants, endogenous anticoagulants, specifically antithrombin III and specifically antithrombin III and heparin cofactor II. heparin cofactor II.

These molecules form stable These molecules form stable complexes with (and thus inactivate) complexes with (and thus inactivate) clotting factors, especially thrombin. clotting factors, especially thrombin.

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Heparin is released in its active form after Heparin is released in its active form after inactivation of the clotting factor and thus inactivation of the clotting factor and thus can interact with other molecules. can interact with other molecules.

The effect is greater with low The effect is greater with low concentrations of heparin. concentrations of heparin.

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Heparin is also antithrombotic due to Heparin is also antithrombotic due to binding to endothelial cell walls, thus binding to endothelial cell walls, thus impairing platelet aggregation and impairing platelet aggregation and adhesion. adhesion.

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USES of HEPARINUSES of HEPARINthe prevention or treatment of venous or the prevention or treatment of venous or pulmonary embolism and embolization pulmonary embolism and embolization associated with atrial fibrillation. associated with atrial fibrillation.

It is also used as an anticoagulant for It is also used as an anticoagulant for diagnostic use and blood transfusions. diagnostic use and blood transfusions.

used in conjunction with blood and/or used in conjunction with blood and/or plasma for the treatment of disseminated plasma for the treatment of disseminated intravascular coagulopathy (DIC) and intravascular coagulopathy (DIC) and other hypercoagulable conditions. other hypercoagulable conditions.

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PKPKAbsorption and distribution of heparin are Absorption and distribution of heparin are limited by the large size and polarity of the limited by the large size and polarity of the molecule. molecule.

Oral absorption is poor; hence, it is a parenteral Oral absorption is poor; hence, it is a parenteral anticoagulant. anticoagulant.

Although anticoagulant activity is first order, Although anticoagulant activity is first order, half-life of the drug is dose-dependent, steady-half-life of the drug is dose-dependent, steady-state concentrations are difficult to achieve, state concentrations are difficult to achieve, and pharmacokinetics vary among individuals. and pharmacokinetics vary among individuals.

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Heparin is metabolized by heparinase Heparin is metabolized by heparinase in the liver and by reticuloendothelial in the liver and by reticuloendothelial cells. Metabolites of heparinase cells. Metabolites of heparinase activity are excreted in the urine. activity are excreted in the urine.

The half-life is prolonged in renal or The half-life is prolonged in renal or hepatic failure.hepatic failure.

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Heparin can be given IV (either Heparin can be given IV (either intermittently or as a constant infusion) intermittently or as a constant infusion) or SC. or SC.

Deep SC or intrafat injection prolongs Deep SC or intrafat injection prolongs persistence of therapeutic persistence of therapeutic concentrations. concentrations.

Large hematomas can develop after deep Large hematomas can develop after deep IM injection.IM injection.

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High-dose heparin therapy ( 150-250 High-dose heparin therapy ( 150-250 U/kg, tid ) has been recommended for U/kg, tid ) has been recommended for established thromboembolism. established thromboembolism.

Lower dosages ( 75 U/kg, tid) are Lower dosages ( 75 U/kg, tid) are indicated in the management of DIC. indicated in the management of DIC.

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Blood coagulation times (eg, Blood coagulation times (eg, activated partial thromboplastin activated partial thromboplastin time) should be monitored during time) should be monitored during HEPARIN therapy. HEPARIN therapy.

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Side effects and toxicitiesSide effects and toxicitiesof heparin are limited to of heparin are limited to

potential hemorrhage, potential hemorrhage,

and because heparin is a foreign protein, and because heparin is a foreign protein, possible allergic reactions. possible allergic reactions.

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ContraindicationsContraindications

Heparin is contraindicated in Heparin is contraindicated in bleeding animals and in bleeding animals and in DIC(disciminated intravas DIC(disciminated intravas Coagulopathy) unless replacement Coagulopathy) unless replacement blood or plasma therapy is also given blood or plasma therapy is also given

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Vitamin K antagonistsVitamin K antagonists ( oral anticoagulants) ( oral anticoagulants)differ from heparin primarily in their duration of differ from heparin primarily in their duration of activity and magnitude of effect. activity and magnitude of effect.

Their primary importance has been because of Their primary importance has been because of their toxic rather than therapeutic effects. their toxic rather than therapeutic effects.

Therapeutic indications include oral longterm Therapeutic indications include oral longterm treatment and prevention of recurrence of treatment and prevention of recurrence of thrombotic conditions (eg, aortic or pulmonary thrombotic conditions (eg, aortic or pulmonary thromboembolism and venous thrombosis)thromboembolism and venous thrombosis)

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There are several groups of vitamin K There are several groups of vitamin K antagonists.antagonists.

They interfere with the hepatic synthesis of They interfere with the hepatic synthesis of vitamin-K-dependent clotting factors by vitamin-K-dependent clotting factors by blocking the reduction of vitamin K epoxide blocking the reduction of vitamin K epoxide after clotting factor synthesis, thus effectively after clotting factor synthesis, thus effectively reducing the concentration of vitamin K.reducing the concentration of vitamin K.Their anticoagulant activity (and therefore Their anticoagulant activity (and therefore therapeutic or toxic effect) is delayed for 8-12 therapeutic or toxic effect) is delayed for 8-12 hr after administration or accidental ingestion hr after administration or accidental ingestion because of the persistence of factors because of the persistence of factors synthesized before administration. synthesized before administration. Factor VII has the shortest half-life and is the Factor VII has the shortest half-life and is the first factor to become deficient first factor to become deficient

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The vitamin K antagonistsThe vitamin K antagonistsare rapidly and completely absorbed after are rapidly and completely absorbed after administration PO. administration PO. Levels peak in 1 hr. Levels peak in 1 hr.

They are almost totally protein bound in the They are almost totally protein bound in the plasmaplasmavolume of distribution is limited to the plasma volume of distribution is limited to the plasma volume. volume.

They are metabolized by the liver to primary They are metabolized by the liver to primary metabolites and then conjugated to metabolites and then conjugated to glucuronides. glucuronides.

They undergo an enterohepatic cycle. They undergo an enterohepatic cycle.

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A variety of factors can increase the A variety of factors can increase the activity of these drugs, including activity of these drugs, including hypoproteinemia, antimicrobial therapy, hypoproteinemia, antimicrobial therapy, hepatic disease, hypermetabolic states, hepatic disease, hypermetabolic states, pregnancy, and the nephrotic syndrome. pregnancy, and the nephrotic syndrome. The potential for drug interactions is The potential for drug interactions is significant. significant. Because they are highly protein bound, they Because they are highly protein bound, they can be displaced by other drugs that are can be displaced by other drugs that are protein bound (eg, acetylsalicylic acid and protein bound (eg, acetylsalicylic acid and phenylbutazone), and their anticoagulant phenylbutazone), and their anticoagulant effects can be increased to the point of toxicity.effects can be increased to the point of toxicity. Drug interactions also are seen with other Drug interactions also are seen with other antihemostatics.antihemostatics.

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Warfarin sodiumWarfarin sodiumis the most commonly used therapeutic is the most commonly used therapeutic preparation. preparation.

The dosage is 0.1-0.2 mg/kg, POThe dosage is 0.1-0.2 mg/kg, PO

Toxicity, manifest as hemorrhage, is a major Toxicity, manifest as hemorrhage, is a major concern with vitamin K antagonists. concern with vitamin K antagonists.

Coagulation times (particularly prothrombin Coagulation times (particularly prothrombin time), and clinical evidence of bleeding (eg, time), and clinical evidence of bleeding (eg, occult blood in feces and urine) must be occult blood in feces and urine) must be monitored carefully during warfarin therapy. monitored carefully during warfarin therapy.

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Fibrinolytic agents(Fibrinolytic agents(Streptokinase and streptodornase)Streptokinase and streptodornase)

increase the activity of plasmin increase the activity of plasmin (fibrinolysin), the endogenous compound (fibrinolysin), the endogenous compound that is responsible for dissolving clots. that is responsible for dissolving clots.

The inactive precursor of plasmin is The inactive precursor of plasmin is plasminogen, which exists in 2 forms: plasminogen, which exists in 2 forms: plasma soluble form and fibrin (clot) plasma soluble form and fibrin (clot) bound form. bound form.

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Streptokinase and streptodornaseStreptokinase and streptodornaseare synthesized by streptococci and are synthesized by streptococci and activate both forms of plasminogen. activate both forms of plasminogen. They are used locally as a powder, They are used locally as a powder, infusion, or irrigation in the treatment of infusion, or irrigation in the treatment of selected chronic wounds (eg, burns, selected chronic wounds (eg, burns, ulcers, chronic eczemas, ear hematomas, ulcers, chronic eczemas, ear hematomas, otitis externa, osteomyelitis, chronic otitis externa, osteomyelitis, chronic sinusitis, or other chronic lesions) that sinusitis, or other chronic lesions) that have not responded to other therapy. have not responded to other therapy. Tissue-type plasminogen activator (tPA) Tissue-type plasminogen activator (tPA) preferentially activates the fibrin-bound preferentially activates the fibrin-bound form of plasminogenform of plasminogen

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Unlike parenterally administered streptokinase, Unlike parenterally administered streptokinase, (tissue type plasminogen activator), tPA does (tissue type plasminogen activator), tPA does not induce a systemic proteolytic state. not induce a systemic proteolytic state.

Selective clot lysis occurs without increasing Selective clot lysis occurs without increasing circulating plasmin; thus, tPA has a lower risk of circulating plasmin; thus, tPA has a lower risk of bleeding than does parenteral streptokinase. bleeding than does parenteral streptokinase.

While tPA has been used to treat aortic While tPA has been used to treat aortic thromboembolism in (0.25-1.0 mg/kg/hr, IV, for thromboembolism in (0.25-1.0 mg/kg/hr, IV, for a total dosage of 1-10 mg/kg), a total dosage of 1-10 mg/kg),

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both the risk of death due to both the risk of death due to reperfusion (and release of toxic reperfusion (and release of toxic metabolites) and the expense of this metabolites) and the expense of this genetically engineered product may genetically engineered product may limit its use. limit its use.

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Antithrombotic drugs (ASPIRIN)Antithrombotic drugs (ASPIRIN)

affect platelet activity, which is normally affect platelet activity, which is normally controlled by substances (such as controlled by substances (such as prostaglandins) generated both outside prostaglandins) generated both outside and within the platelet. and within the platelet.

Platelet activity can be modulated by Platelet activity can be modulated by interacting with these substances. interacting with these substances.

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NSAID inhibit the formation of NSAID inhibit the formation of cyclooxygenase, the enzyme cyclooxygenase, the enzyme responsible for the synthesis of responsible for the synthesis of prostaglandin products from prostaglandin products from arachidonic acid that has been arachidonic acid that has been released into cells and platelets.released into cells and platelets.

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The formation of all prostaglandins is The formation of all prostaglandins is inhibited, including that of thromboxane, a inhibited, including that of thromboxane, a potent platelet aggregator and potent platelet aggregator and vasoconstrictor. vasoconstrictor.

In addition to its inhibitory effects on In addition to its inhibitory effects on cyclooxygenase, aspirin irreversibly cyclooxygenase, aspirin irreversibly acetylates thromboxane synthetase, the acetylates thromboxane synthetase, the specific enzyme responsible for the specific enzyme responsible for the synthesis of thromboxane. synthesis of thromboxane.

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Aspirin is a potent inhibitor of Aspirin is a potent inhibitor of platelet activity; new platelets must platelet activity; new platelets must be generated before the effects of be generated before the effects of aspirin on platelet activity disappear. aspirin on platelet activity disappear.

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At higher dosages, aspirin inhibits At higher dosages, aspirin inhibits prostacylin, a prostaglandin product that prostacylin, a prostaglandin product that counteracts the thrombogenic effects of counteracts the thrombogenic effects of thromboxane. thromboxane.

Thus, the drug must be used cautiously Thus, the drug must be used cautiously for antiplatelet effects. for antiplatelet effects.

The antiplatelet dosage for is 5-10 The antiplatelet dosage for is 5-10 mg/kg, every 24-48 hr mg/kg, every 24-48 hr