Drugs Acting On Blood

Drugs acting on blood PROF. DR. SHAH MURAD [email protected]

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

Blood must remain fluid within the vasculature and yet clot quickly when exposed to nonendothelial surfaces at sites of vascular injury. 2

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

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

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

With these drugs, efficacy and toxicity are necessarily intertwined.

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

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

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Blood fluidity is controlled by the parenteral anticoagulant heparin

and its derivatives, which stimulate a natural inhibitor of coagulant proteases; (2) the coumarin anticoagulants, which block multiple steps in the coagulation cascade; (3) fibrinolytic agents, which lyse pathological thrombi; and (4) antiplatelet agents, especially aspirin 6

Heparin

is a heterogeneous mixture of sulfated (anionic) mucopolysaccharides named because of its initial discovery in high concentrations in the liver. It is prepared from porcine intestinal mucosa and bovine lung.

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HEPARIN It acts indirectly to facilitate endogenous anticoagulants, specifically antithrombin III and heparin cofactor II. These molecules form stable complexes with (and thus inactivate) clotting factors, especially thrombin. 8

Heparin is released in its active form after inactivation of the clotting factor and thus can interact with other molecules. The effect is greater with low concentrations of heparin.

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

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USES of HEPARIN

the prevention or treatment of venous or pulmonary embolism and embolization associated with atrial fibrillation. It is also used as an anticoagulant for diagnostic use and blood transfusions. used in conjunction with blood and/or plasma for the treatment of disseminated intravascular coagulopathy (DIC) and other hypercoagulable conditions. 11

PK

Absorption and distribution of heparin are limited by the large size and polarity of the molecule. Oral absorption is poor; hence, it is a parenteral anticoagulant. Although anticoagulant activity is first order, half-life of the drug is dose-dependent, steadystate concentrations are difficult to achieve, and pharmacokinetics vary among individuals. 12

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

The half-life is prolonged in renal or hepatic failure. 13

Heparin can be given IV (either intermittently or as a constant infusion) or SC. Deep SC or intrafat injection prolongs persistence of therapeutic concentrations.

Large hematomas can develop after deep IM injection. 14

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

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

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

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Side effects and toxicities of heparin are limited to

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

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

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Vitamin K heparin antagonists ( oralinanticoagulants) differ from primarily their duration of activity and magnitude of effect. Their primary importance has been because of their toxic rather than therapeutic effects. Therapeutic indications include oral longterm treatment and prevention of recurrence of thrombotic conditions (eg, aortic or pulmonary thromboembolism and venous thrombosis) 19

There are several groups of vitamin K antagonists. They interfere with the hepatic synthesis of vitamin-K-dependent clotting factors by blocking the reduction of vitamin K epoxide after clotting factor synthesis, thus effectively reducing the concentration of vitamin K. Their anticoagulant activity (and therefore therapeutic or toxic effect) is delayed for 8-12 hr after administration or accidental ingestion because of the persistence of factors synthesized before administration. Factor VII has the shortest half-life and is the first factor to become deficient 20

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

They are almost totally protein bound in the plasma volume of distribution is limited to the plasma volume. They are metabolized by the liver to primary metabolites and then conjugated to glucuronides. They undergo an enterohepatic cycle.

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

Drug interactions also are seen with other antihemostatics. 22

Warfarin sodium

is the most commonly used therapeutic preparation. The dosage is 0.1-0.2 mg/kg, PO Toxicity, manifest as hemorrhage, is a major concern with vitamin K antagonists. Coagulation times (particularly prothrombin time), and clinical evidence of bleeding (eg, occult blood in feces and urine) must be monitored carefully during warfarin therapy.

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Fibrinolytic agents(Streptokinase and streptodornase)

increase the activity of plasmin (fibrinolysin), the endogenous compound that is responsible for dissolving clots. The inactive precursor of plasmin is plasminogen, which exists in 2 forms: plasma soluble form and fibrin (clot) bound form.

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Streptokinase and streptodornase

are synthesized by streptococci and activate both forms of plasminogen. They are used locally as a powder, infusion, or irrigation in the treatment of selected chronic wounds (eg, burns, ulcers, chronic eczemas, ear hematomas, otitis externa, osteomyelitis, chronic sinusitis, or other chronic lesions) that have not responded to other therapy. Tissue-type plasminogen activator (tPA) preferentially activates the fibrin-bound form of plasminogen 25

Unlike parenterally administered streptokinase, (tissue type plasminogen activator), tPA does not induce a systemic proteolytic state. Selective clot lysis occurs without increasing circulating plasmin; thus, tPA has a lower risk of bleeding than does parenteral streptokinase. While tPA has been used to treat aortic thromboembolism in (0.25-1.0 mg/kg/hr, IV, for a total dosage of 1-10 mg/kg), 26

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

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

Platelet activity can be modulated by interacting with these substances.

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

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The formation of all prostaglandins is inhibited, including that of thromboxane, a potent platelet aggregator and vasoconstrictor. In addition to its inhibitory effects on cyclooxygenase, aspirin irreversibly acetylates thromboxane synthetase, the specific enzyme responsible for the synthesis of thromboxane. 30

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

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

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

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

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