Anticoagulant, Antiplatelet, and Thrombolytic Drugs

This lecture actually has learning outcomes... or rather, a learning outcome: "Describe the pharmacology, use and monitoring of anticoagulant, antiplatelet and fibrinolytic agents." It looks like I'll be mainly making up my own headings. Le sigh.

This post will mainly cover drugs that are for preventing thrombosis (inappropriate clotting), rather than drugs that are for preventing excessive bleeding.

Warfarin

Warfarin is derived from coumarin, which in turn is derived from some plants. It inhibits vitamin K epoxide reductase, preventing inactive vitamin K from being recycled. As vitamin K is a cofactor in the processes leading to production of factors II, V, IX, and X, administration of warfarin leads to reduced formation of these factors over time. Because warfarin is affecting production of the clotting factors, rather than the factors themselves, warfarin takes a long time to kick in and lasts for a long time once it does (it has a half-life of around 1 day). Reversing warfarin (which can be done with vitamin K) can also be a lengthy process because re-forming the factors takes time. A haemorrhaging patient who is on warfarin may be given fresh frozen plasma instead which already has the clotting factors made.

Many factors affect the activity of warfarin. Levels of vitamin K affect how well warfarin works, as does hepatic disease (can increase activity as there is already impaired synthesis of coagulation factors) and pregnancy (can decrease activity). Also, just like pretty much every other drug, warfarin can interact with other drugs. The main test used to monitor warfarin is the INR (see here).

Heparin

Heparin is a highly sulfated glycosaminoglycan derived from pig or cow mucosa that mimics the effect of human heparan sulfate. It has a highly variable molecular weight (since it varies between animals) but the active part (a repeating pentasaccharide) is pretty much the same no matter where you get the heparin from. Heparin has a strong negative charge and can bind to and increase the activity of antithrombin III which, as you can guess from the name, inhibits thrombin as well as other coagulation proteins (namely IX, X, and XI). After the heparin-antithrombin complex has done its job, the heparin is released and an inactive antithrombin complex is left behind. Over time, it is possible to run out of antithrombin, resulting in desensitisation to heparin.

Heparin works much more quickly than warfarin but is not available orally. It can be monitored by APTT and reversed by protamine sulfate if necessary. There are also low molecular weight versions of heparin in which the inactive parts of the protein have been removed. Low molecular weight heparin is more potent but cannot be reversed. There are also pentasaccharide versions that only have the repeating pentasaccharide part. The pentasaccharides are even more potent but they also cannot be reversed.

New/Direct Oral Anticoagulants (NOACs/DOACs)

Some of the newer oral anticoagulants directly inhibit thrombin (IIa) and/or factor Xa. Many of the thrombin inhibitors, such as dabigatran, end with -gatran, and many of the Xa inhibitors, such as rivaroxaban, end with -xaban. Since they bind directly to thrombin, they don't rely on the patient's antithrombin levels to work. Unfortunately, factor Xa inhibitors are currently (as of March 2019) irreversible in Australia as recombinant Xa, which would serve as an antidote, is not yet approved here (it is approved in the US though).

Profibrinolytics

Profibrinolytics activate plasminogen to plasmin, which in turn breaks down blood clots. There are three main profibrinolytics. Streptokinase and urokinase are derived from bacteria and are inexpensive, but because they are antigenic they can only be used once (well, streptokinase is antigenic at least, I'm not 100% sure about urokinase). Alteplase is human-derived so does not have the problem of antigenicity, but is very expensive. Profibrinolytics can be given to rapidly break down an existing blood clot if necessary (whereas the anticoagulants I've discussed so far are mainly for prevention of future blood clots).

Anti-platelet agents

Aspirin

Aspirin irreversibly inhibits cyclooxygenase, reducing the production of thromboxane A2 (which activates platelets). It can also inhibit production of prostacyclin (which would normally inhibit platelets) in endothelial cells, but this pathway is less sensitive to aspirin. Therefore, aspirin tips the balance towards reduced platelet activation. (I've also discussed this towards the end of this earlier post.) Note that since aspirin irreversibly inhibits cyclooxygenase, the effect on platelets is also irreversible.

Fibrinogen receptor inhibitors

Fibrinogen receptor inhibitors, as the name suggests, blocks fibrinogen receptors (a.k.a. glycoprotein IIb/IIIa). These drugs therefore block fibrinogen binding to the platelets, preventing them from aggregating. Fibrinogen receptor inhibitors are only effective if injected acutely.

Thienopyridines (ADP receptor antagonists)

Thienopyridines, or P₂Y₁₂ antagonists, or ADP receptor antagonists (so many names!) can inhibit amplification of the platelet response by blocking ADP receptors. (Remember, ADP helps in activation of platelets.) Many of these drugs are metabolised in the liver and are thus prone to drug-drug interactions with other drugs metabolised in the liver.

Others

Other drugs that I haven't mentioned, but seemed kind of important, included vorapaxar (inhibits a thrombin receptor called PAR-1) and PDE inhibitors such as dipyridamole and cilostazol (inhibit destruction of the signalling molecules cAMP and cGMP, so that they can go on to inhibit platelet activation).