2012 Drugs that promote or inhibit coagulation

Critical facts iconCRITICAL FACTS:
(if med school is a Minnesota forest with millions of trees, these are the red pines)

  1. There is a delicate balance between thrombosis and hemorrhage.

Drugs that inhibit coagulation (which tip the balance toward hemorrhage/fibrinolysis) are used to treat acute coronary syndromes (ACS) esp. myocardial infarctions, stroke, pulmonary embolism, disseminated intravascular coagulation (DIC) and deep vein thrombosis (DVT) --- all potentially life-threatening conditions. There are 3 treatment strategies: degrade fibrinogen/fibrin (thrombolytics), inhibit the clotting mechanism (anticoagulants) and prevent initial clot formation (anti-platelet drugs).  The most serious potential side effect of all of these agents is BLEEDING (especially hemorrhagic stroke).

Drugs that promote coagulation (which tip the balance toward clotting) either increase concentrations of natural clotting factors or are antagonists of thrombolytics. These drugs are used to treat bleeding disorders, such as hemophilia.

  1. The effectiveness of thrombolytics is INVERSELY RELATED to the time elapsed since the thrombic crisis began i.e. the ONSET of symptoms è 6 hours of for an MI; 3 hours for stroke.

  2. The major classes of anticoagulant drugs have distinctly different mechanisms of action, routes of administration and adverse effects.  The mechanisms of action include:  indirect inhibition of thrombin via activation of anticlotting factors (especially antithrombin III) or inhibition of factor Xa, direct inhibition of thrombin and inhibition of synthesis of blood coagulation factor precursors (zymogens).

  3. Indirect thrombin inhibitors either facilitate the actions of antithrombin III (e.g., HEPARIN) or inhibit factor Xa (e.g., RIVAROXABAN).  Side effects that are unique to HEPARIN include hemorrhage, hypersensitivity and thrombocytopenia (HIT).

  4. Direct thrombin inhibitors (DTIs; e.g. HIRUDIN) interfere with the thrombin active site.  The primary approved use of DTIs is the treatment of heparin-induced thrombocytopenia (HIT). It is thought that DTIs will eventually replace both HEPARIN and WARFARIN as the anticoagulants of choice in many clinical scenarios.

  5. WARFARIN decreases the synthesis of vitamin K dependent clotting factor zymogens (II, VII, IX, X) and:
    • has a NARROW THERAPEUTIC INDEX
    • is NEARLY COMPLETELY (99%) BOUND TO PLASMA ALBUMIN
    • is ELIMINATED BY HEPATIC METABOLISM (cytP450)

WARFARIN IS THE PROTOTYPE FOR DRUG-DRUG INTERACTIONS!

  1. Understanding cytochrome P450 metabolism is one key to managing drug-drug interactions.  Inhibitors and substrates of a specific CYP450 isozyme INCREASE the effectiveness of another drug metabolized by that isozyme; inducers DECREASE effectiveness.

  2. Drugs that inhibit platelet adhesion and/or aggregation are used for prophylactic and/or long term anticlotting treatment. Major mechanisms of action of antiplatelet drugs include: 1)  inhibition of prostaglandin synthesis, 2) blockade of the glycoprotein IIb/IIIa receptor, 3) inhibition of GPIIb/IIIa activation by ADP and 4) phosphodiesterase inhibition. As with thrombolytic and anticoagulant drugs, the major side effect of antiplatelet drugs is BLEEDING. Antiplatelet drugs are often used in combination with other agents: ABCIXIMAB and EPTIFIBATIDE with HEPARIN or ASA, DIPYRIDAMOLE with either WARFARIN or ASA.

Email: Dr. Janet Fitzakerley | ©2012 University of Minnesota Medical School Duluth | Last modified: 31-may-12 9:11 PM