Medical Pharmacology Topics   

Preliminary Outline

Antiplatelet Drugs   Enzyme Inhibitors      COX          Aspirin      Phosphodiesterase          Dipyridamole   Receptor Inhibitors      P2Y          Ticlopidine          Clopidogrel      Alpha-IIb-beta3          Abciximab          Eptifibatide          Tirofiban Thrombolytic Drugs      Fibrinolytic          Streptokinase          Urokinase          t-PA              * Altelase              * Reteplase

Drugs Acting on the Blood

Hemostasis is the arrest of bleeding. Thrombosis is the aggregation of blood factors (mostly platelets and fibrin), frequently causing vascular obstruction (formation, development or presence of a thrombus). Embolus is a blood clot that has traveled to another site, usually causing obstruction. Thrombocytopenia is a decreased number of platelets. Drugs acting on blood may be antiplatelet, thrombolytic or anticoagulants.

Platelets adhere to injured tissue and release thromboxane (TBX). Endothelial cells also release TBX. TBX promotes aggregation, a solid plug forms and the clothing cascade proceeds. Antiplatelet drugs include inhibitors of enzymes required for TBX synthesis and inhibitors of platelet receptors needed for anchoring.

Aspirin is an irreversible COX inhibitor. Cyclooxygenases (COX) catalyze the synthesis of endoperoxidases, which are precursors to TBX. Other drugs like acetaminophen and ibuprofen are competitive COX inhibitors, but are not effective antiplatelet drugs. The effect of aspirin is greater on platelet because they do not synthesize their own COX, while endothelial cells do.

TBX acts by inhibiting adenylate cyclase (high cAMP concentrations inhibit aggregation).  Phosphodiesterases degrade cAMP. Dipyridamole acts as an antiplatelet drug by inhibiting phosphodiesterase and the uptake of adenosine. Used alone, dipyridamole is no better than aspirin. But in combination with aspirin it has prevented strokes in patients with prior TIA (?) or ischemic stroke. Aggrenox is a formulation with 25 mg of aspirin and 200 mg of dipyridamole.

Ticlopidine and clopidogrel inhibit platelet activation by blocking the purinergic P2Y receptor. When active, the P2Y receptor inhibits adenylate cyclase, therefore these drugs prevent the inhibition, allowing the formation of cAMP. Since these are prodrugs, they have a slow onset of action and a loading dose may be needed.

Alpha-IIb-beta3  is a receptor for fibrinogen and von Willebrand factor that anchors platelets to foreign substances and to each other. It is activated by thromboxane, thrombin and collagen. Inhibitors of glycoprotein alpha-IIb-beta3 include Abciximab, Eptifibatide and Tirofiban. Abciximab is a fab (?) fragment of a humanized monoclonal antibody. It binds the alpha-IIb-beta3 and vitronectin receptors, and its antiplatelet action persists 18-24 hours. Eptifibatide and Tirofiban are specific for alpha-IIb-beta3  and their action persist 6-12 hours. These agents are given parenteraly to prevent myocardial infraction in unstable angina, angioplasty, etc. Their use is short term and their main side effect is bleeding.

Fibrinolysis refers to the resolution of a clot by degradation of fibrin. During normal fibrinolysis, plasminogen  is converted to plasmin by tissue plasminogen activator factor (t-PA). Plasmin digests fibrin clots and plasma proteins, including several coagulation factors. t-PA is released from endothelial cells but is cleared rapidly or inactivated (does not affect circulating plasmin, only local plasmin). Homeostasis of this  system is rigidly maintained with a fine balance of inhibitors and  activators of plasminogen.

Thrombolytic therapy overwhelms the inhibitory controls of plasminogen and causes massive fibrinolysis. Fibrinolytic agents include streptokinase, Urokinase and t-PA. Streptokinase is from beta-hemolytic streptococci, is administered in a large loading dose (antibodies?), has a life time of 40-80 min and may cause allergic reactions. Urokinase is cultured from human kidney cells and has a half-life of 15-20 min.  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 in recombinant variants (altelase and reteplase).

Hemorrhagic toxicity of  fibrinolytic therapy may occur because the agents cannot distinguish the fibrin in the problem area from systemic fibrin. Thrombolytic agents are contraindicated when there is  GI bleeding, surgery within 10 days, history of hypertension, previous CVA (?), aortic dissection and acute pericarditis.

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