Anticoagulants as therapeutic agents

• The most common anticoagulants are Heparin (parenteral, used in the hospital setting) and Coumarins (often Warfarin, which stands for Wisconsin Alumni Research Foundation, and was originally designed as a rat poison). These drugs are indicated for arterial thrombosis, atrial fibrillation, cardiomyopathy, cerebral emboli, hip surgery, vascular prostheses, heart valve disease (not including bacterial endocarditis or microvalve disorders), and venous thromboembolism.


• The fibrinolytics are almost always used to dissolve the formed clot. Usually its either a deep vein thrombosis or acute myocardial infarction that the fibrinolytics act against, pulmonary embolisms are more controversial. The drugs listed are Streptokinase, urokinase, and tissue plasminogen activator (t-PA).


• When the intrinsic cascade is activated, thrombin and fibrin will form the thrombus – this in conjunction with the role of platelets will be disastrous. When anti-platelet drugs are not sufficient, we must use an anti-coagulant.


• Warfarin interferes with various factors, including factor 10a, which are necessary for the conversion of prothrombin to thrombin. Warfarin is able to influence the production of these cofactors, and therefore prothrombin, and therefore prothrombin time. So Warfarin’s measure of its anticoagulation activity is by a change in its prothrombin time.


• Warfarin is ineffective in vitro, Heparin can work in vitro. Warfarin acts on the liver to affect those factors.


• With regard to the fibrinolytics, once you have a fibrin clot formed (RBC’s are trapped) inappropriately and is occluding a blood vessel like the coronary artery, you want to dissolve this clot by fibrinolytic activity. The key player is plasminogen forming plasmid, and that has fibrinolytic action. This is the normal process, the reason we don’t have spontaneous fibrin clots is that we have good tissue plasminogen activation. When that is deficient the MD can inject t-PA or streptokinase which will accentuate the role of plasmin. So the plasminolytics are used in an acute coronary setting, not in an ordinary medical practice.


• Heparin is unique among the anticoagulants because it has a shorter half life, it can be used acutely, it can be titrated, it is a polysaccharide, and acts to bind to anti-thrombin 3, so there is an enhanced inhibition of the formation of thrombin. Heparin is usually derived from natural sources.


• If your pt is on anticoagulants, they will usually be on Warfarin, rarely on dicoumarol. Vitamin K is found in green vegetables and produced by bacterial action in the gut. It is vulnerable to blockade by Warfarin. Warfarin inhibits vitamin K so that the cofactors are not produced. So the antidote for Warfarin overdose is the administration of vitamin K.


• The differences between warfarin and Aspirin include the fact that warfarin has a much shorter than aspirin – but aspirin has actions that last much longer than its half-life. It takes a long time also for Coumadin to be dissipated and for the prothrombin time to return to normal.


• Urokinase, streptokinase and tissue plasminogen factor (t-PA) activate plasminogen to form more plasmin, which is plasminolytic. These drugs must be administered parenterally.

Category: Pharmacology Notes