Medical Pharmacology Topics   

Anticoagulants and Thrombolytics

Hemostasis is the arrest of bleeding. Throbosis is the agreggation of blood factors, mostly platelets and fibrin, often forming a trombus oir other vascular obstruction. An embolus is a blood clot that has traveled to another site, usually causing obstruction. Thrombocyttopenia is a decrease in the number of platelets. Drugs acting on the bloo are either aticoagulants, antiplatelets or thrombolitics.

The blood coagulation system is triggered by one of two pathways: intrinsic or extrinsic. The intrinsic pathway starts when tissue damage induces the release of Factor VII. The intrinsic pathway starts when damage to the blood vesel induces release of factors XII and XI, which in turn induce release of factors VIII and IX, as well as Ca and phospholipids The intrinsic and extrinsic pathways merge into a final common pathway with the release of factors X and V, leading to the conversion of prothrombin into thrombin. The fibrin responsible for the formation of throbi is cleaved from fibrinogen by thrombin.

Several steps in the coagulation system depend on vitamin K, namely the release of factors VII, IX and X, and the synthesis of prothrombin. The reduced form of vitamin K is a cofactor for the synthesis of prothrombin from decarboxyprothrombin. Ca is a cofactor for the synthesis of all factors through thrombin. Since removal of Ca prevents coagulation, citrate and EDTA are used to prevent coagulation in vitro.

Anticoagulants

Anticoagulants drugs may act directly on the blood coagulation system or indirectly by disrupting vitamin K homeostasis. They are most often used to prevent deep vein thrombosis after surgery.

The direct-acting anticoagulant drugs are heparin, the low molecular weight (LMW) heparins, heparinoids and lepirudin. Heparin is a natural polysacharide glycosaminoglycan made in mast cells and released into the blood, where it inhibits coagulation by binding to and activating the anticoagulant protein antithrombin III. The LMW heparins and heparinoids are derivatives of heparin. Lepirudin is a similar compound derived from leeches.

Heparin is obtained from either porcine intestinal mucosa or bovine lung, thus there is an allergy hazard. It is measured in USP units, which are defined as the amount of heparin that prevents 1 mL of citrated sheep blood from clotting within 1 hr after the addition of 0.2 mL of 1% CaCl2. Heparin will increase coagulation time 1.5-2.5 times.The half-life of heparin is "dose-dependent" (?), i.e. 1 hr at 100 units/kg, 2.5 hrs at 400 units/kg and 5 hrs at 800 units/kg.

The LMW heparins (enoxaparin, dalteparin and ardeparin) are depolimerized forms of heparin. They have a greater bioavailability after subcutaneous injection and a longer hal-life than heparin, and generally require no monitoring. They have limited FDA pproval fro use in abdominal surgery and hip and knee replacement surgery. Protamine is the antidote for both heparin and LMW heparins.

The LMW heparins are more effective than heparin and the indirect-cting anticoagulants. Although they have similar incidence of bleeding, LMW heparins have a lower icidence of thrombocytopenia. LMW heparins can be administered less often than heparin, once or twice daily.

Danaparoid is a heparinoid, a partially depolimerized mixture of heparan sulfate, dermatan sulfate and chondroitin sulfate, from porcine intestinal mucosa. It is more effective than the LMW heparins and heparin, have a longer half-life than the LMW heparins and does not require monitoring.

Lepidurin is a recombinant derivative of hirudin, a thrombin inhibitor from the slivary glands of the leech. It is approved for use in heparin-induced thrombocytopenia. Lepidurin is excreted renaly, with a half-time of 1.3 hrs. Antibodies to lepidurin may develop. There is no known antidote.

The indirect anticoagulants like warfarin, dicoumarol and anisindione are competitive inhivitors of the reduction of vitamin K to the reduced form, needed as cofactor for the biosynthesis of prothrombin. These agets are effctive orally, but act slower than the direct-acting anticoagulants (1-3 days). Side effects include bleeding, teratogeneicity and numerous drug interactions.

Antiplatelets

Platelets respond to endothelial injury by adhering to injured tissue and releasing thromboxane (TBX), which promotes platelet aggregation and the release of more TBX. This process allows a solid plug to form as the clotting cascade proceeds. TBX inhibits the formation of cAMP, which at high concentrations prevents platelet adhesion. TBX is synthesized from endoperoxides by thromboxane synthase. Endoperoxides are formed from arachidonic acid by cyclooxygenases. Antiplatelet drugs may be inhibitors of cyclooxygenases, phosphodiesterase, purinergic receptors or glycoprotein IIb/IIIa.

Cyclooxygenase inhibitors like aspirin prevent the formation of endoperoxides thus decreasing TBX levels. Aspirin inhibition of COX in platelets is irreversible because platelets cannot synthezise new COX. However, COX inhibition in the endothelium is relatively reversible because endothelial cells can synthesize new COX. This is important because endoperoxides in endothelial cells are converted to prostacyclin, which has the opposite effectof TBX, i.e. stimulation of adenylyl cyclase.

Dipyridamole prevents platelet adhesion by inhibiting phosphodiesterase. It also inhibits adenosine uptale (?). Used alone, dipyridamole is no better than aspirin.But when used in combination with aspirin in patients with prior stroke, it prevents additional strokes, although it did not prevent mortality (?). Aggrenox is a formulation with 25 mg aspirin and 200 mg dipyridamole.

The purigenic receptor P2Y seems to inhibit (?) adenylyl cyclase when bound to ADP. Ticlopidine and clopidogrel inhibit platelet activation by blocking the purinergic P2Y receptor. These are prodrugs with a slow onset of action (10 days to peak with ticlopidine), therefore a loading dose may be needed. They are used with aspirin in angioplaty patients, but may lead to neutropenia in 1% of patients.

Glycoprotein IIb/IIIa (aIIIbb3) is a receptor fro fibrinogen and von Willebrnd factor that anchors platelets to foreing surfaces and to each otherit is activated by TBX, thrombin and collagen (?). Vitronectin, another cell surface receptor, binds collagen and promotes cell adhesion and migration. Abcixiab is a Fab fragment of humanized monoclonal antibody that binds both aIIIbb3 and vitronectin, and its antiplatelet action presists 18-12 hrs. Eptifibate and tirofiban are antibodies specific for aIIIbb3 and their action persists for 6-12 hrs. these agents may cause bleeding and are used parenterally for a sort-term to prevent myocardial infarction in unstable angina and during angioplasty

Thrombolitics

Fibrinolysis occurs by the degradation of fibrin by plasmin. Plasmin is generated from plasminogen in response to blood activators and tissue activators like t-PA, urokinase or streptokinase. t-PA is released from endothelial cells, but it is usually cleared rapidly or inactivated. If t-PA binds to fibrin, it converts plasminogen (also bound to fibrin) to plasmin, which digests fibrin. Homeostasis of this system is rigidly maintained with a fine balance of inhibitors and activators of plasminogen. Thrombolitic therapy overwhelms the inhibitory controls, and cause massive fibrinolysis.

t-PA is a poor activator of plasminogen in the absence of fibrin, and its specificity for fibrin-bound plasminogen is dose-related. it has a half-life of 5-10 min and is available as the recombinant variants altelase and reteplase.

Streptokinase is obtained from b-hemolitic streptococci, and has a half-time of 40-80 min. A large dose is needed because antibodies will develop, and there is also danger of allergic reactions. Urokinase is obtained from cultured human kidney cells and has a half-time of 15-20 min.

Hemorrhagic toxicity of fibrinolytic therapy results from two factors: lysis of fibrin at sites of vascular injury and systemic lysis due to destruction of othe coagulation factors (V, VIII, etc.). The severity is related to duration of treatment. Thrombolitic agents are contraindicated when there is GI bleeding, recent surgety (10 days), history of hypertension, previous CVA (?), aortic dissection and acute pericarditis.

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