Pharmacology - ANTICOAGULANTS & ANTIPLATELET DRUGS (MADE EASY)

In this lecture we will cover

anticoagulants

and

antiplatelet

agents, so let's get right into it. Anticoagulants and

antiplatelet

agents are used to treat thrombotic disorders or unwanted clots within a blood vessel that can lead to a heart attack or stroke, but before discussing their mechanism. of action let us quickly review the coagulation process, so that, in the absence of injury, the endothelial cells that form the inner surface of blood vessels release chemical mediators such as nitric oxide and prostacyclin. Now the role of nitric oxide is to dilate the blood vessels, while the role of prostacyclin is to bind them together. to receptors located on platelets, this binding triggers certain reactions that ultimately prevent platelet activation and aggregation.

Now, what happens when there is a damaged blood vessel, say due to a cut of skin? Suddenly, we have less nitric oxide and prostacyclin, so blood vessels and platelets constrict. They are activated, but first things first with the help of von Willebrand factors, the platelets adhere to the exposed collagen, which in turn causes them to change shape. These differently activated platelets then begin to release granules containing chemical mediators such as ADP, thrombin, thromboxane, serotonin A2, and platelet-activating factor. that attract and activate even more platelets that reach the site of injury. Now the final step involves the activation of glycoprotein 2b/3a receptors that bind circulating fibrinogen.

Fibrinogen simultaneously binds to these receptors on two separate platelets, thus cross-linking the platelets to form aggregates. There are now several medications that can alter the formation of the platelet plug. Collectively, we call them platelet aggregation inhibitors or simply antiplatelet

drugs

. One of the best-known medications that belongs to this class is aspirin. To understand how aspirin works, let's take a closer look. the inside of a platelet, so when the platelet is activated, arachidonic acid is released from the membrane phospholipids, then converted to prostaglandin H2 by the enzyme cyclooxygenase-1, also known as Cox-1, finally prostaglandin H2 is further metabolized into thromboxane A2, which is released from platelets to stimulate the activation of new platelets and promote their aggregation, so what aspirin does is it irreversibly inactivates the Cox-1 enzyme, effectively interrupting clot formation. .

Then we have platelet aggregation inhibitors that work by blocking the action of the ADP receptor, specifically

drugs

of the P2Y12 subtype that belong to this group include Clopidogrel, Ticagrelor, Ticlopidine and Prasugrel, as I mentioned before, activated platelets release chemical mediators, one of them is ADP, which binds to the P2Y12 receptor, leading to the activation of glycoprotein 2b/3a receptors, which are necessary for fibrin-mediated platelet cross-linking. By blocking P2Y12 ADP receptors, these drugs effectively inhibit platelet aggregation and therefore clot formation. Next, we have the glycoprotein 2b/3a receptor blockers, namely Abciximab Eptifibatide and Tirofiban.

These agents simply inhibit platelet aggregation by binding to glycoprotein 2b/3a receptors on platelets, thus preventing fibrinogen from being absorbed. bind to platelets and make them unable to cross-link, unlike the other medications we have discussed so far, glycoprotein 2b/3a inhibitors are administered only intravenously. Now the last group of antiplatelet medications that I wanted to briefly discuss are the phosphodiesterase inhibitors, namely dipyridamole and cilostazol, these two. The agents inhibit the enzyme called phosphodiesterase which is responsible for breaking down cyclic AMP into AMP, so by blocking this enzyme, dipyridamole and cilostazol increase intracellular levels of cyclic AMP, which in turn leads to a decrease in calcium intracellular and, ultimately, to the inhibition of platelet activation.

Additionally, these agents inhibit phosphodiesterase in the vascular wall as well as the absorption of adenosine, which promotes vasodilation, which is why cilostazol in particular is often used to treat symptoms of peripheral arterial disease, such as narrowing of the arteries. vessels that supply blood to the legs, when it comes to side effects, bleeding is a major risk associated. With all antiplatelet medications, in addition Dipyridamole and Cilostazol, due to their vasodilating properties, they can cause headaches. Now let's return to our review of clot formation, so the aggregation of platelets acting as a plug is generally not sufficient to secure the site of injury to strengthen the plug of platelets a clot must form the formation of a clot It involves a cascade of enzymatic reactions that transform various coagulation factors to their active forms and ultimately produce a net-like fibrin meshwork.

There are now two pathways involved in a coagulation cascade: the intrinsic pathway which is activated directly by damage. to the blood vessel wall and to the extrinsic pathway that is activated by trauma to the vascular wall as well as the surrounding tissue, so the intrinsic pathway begins with coagulation factor 12 that is activated when blood comes into contact with a collagen in the damaged vascular wall and here ""a" next to the Roman numeral means "activated", this sets up a series of reactions that lead to the activation of factor 11, which then activates factor 9, which then activates factor 10 , activated factor 10 then converts prothrombin to thrombin and finally thrombin converts fibrinogen to fibrin which forms a meshwork that strengthens the platelet plug Now let's look at the extrinsic pathway, so the extrinsic pathway is triggered by. tissue factor released by damaged cells out of the circulating blood.

It begins with an activation of factor 7 which then activates factor 10, so at this point the intrinsic and extrinsic pathways converge into a common pathway which again results in formation. of a fibrin clot and as a side note, please note that this is just a simplified description of the coagulation cascade and many details were intentionally left out, so now let's switch gears and talk about

anticoagulants

, that is, medications that They act by interrupting this coagulation cascade. Let's start by looking at one of the most recognized anticoagulants, which is heparin and low molecular weight heparin, such as enoxaparin and dalteparin.

Now these agents bind to our natural anticoagulant that circulates in the blood called antithrombin 3, the main function of antithrombin is to inactivate factor 10a and thrombin, so what heparin medications do is bind to antithrombin and, by doing so, they accelerate their activity; In the case of heparin, its binding to antithrombin results in rapid inactivation of both factors 10a. and thrombin, however, unlike heparin, low molecular weight heparins have very little effect on thrombin inactivation and instead selectively accelerate factor 10a inactivation. Another agent worth mentioning here that also selectively accelerates factor 10a inactivation is fondaparinux, however, unlike low molecular weight heparin.

Heparins Fondaparinux does not bind to any other plasma proteins and has no direct effect on thrombin. When it comes to side effects, bleeding is a major risk. Fortunately, there is a reversal agent called protamine sulfate that can be used to treat excessive bleeding caused by heparin medications. Protamine sulfate simply acts by binding to heparin or low molecular weight heparins to form a stable inactive complex. Fondaparinux, on the other hand, does not have any specific antidote at this time, another important possible side effect that is particularly associated with the use of heparin agents. is heparin-induced thrombocytopenia "HIT" for short HIT is a disorder caused by the immune system producing antibodies against heparin when it binds to a platelet-derived protein called platelet factor 4, once the antibodies bind to these complexes of platelet factor 4 of heparin, begin to activate. platelets that clump together causing unwanted clots to form and a decrease in platelet count.

Now let's move on to another group of anticoagulants that are direct inhibitors of factor 10a. The agents that belong to this group are Apixaban and Rivaroxaban, the mechanism of action of these drugs is very simple. both bind directly to the active side of factor 10a, thus preventing it from converting prothrombin to thrombin. The biggest advantage of these agents over the other anticoagulants we reviewed is that they are available in an oral formulation. Unfortunately, bleeding remains a significant risk and is a specific antidote. It is currently not available. Now let's move on to the next group of anticoagulants, which are direct thrombin inhibitors.

Now, depending on how they interact with the thrombin molecule, agents in this group can be subdivided into two classes. First, we have univalent direct thrombin inhibitors that bind only to the active site example of drugs that belong to this class are Argatroban and Dabigatran. The second class are bivalent direct thrombin inhibitors that bind to both the active site and exosite-1, which is the fibrinogen binding site. This bivalent binding contributes to its high affinity and high specificity for thrombin. Some examples of drugs that belong to this class are bivalirudin and desirudin. Currently, one of the greatest advantages of direct thrombin inhibitors over indirect thrombin inhibitors, such as heparin, is that they do not bind to platelet factor 4, which makes them very useful in the treatment of heparin-induced thrombocytopenia. ;

However, as with other anticoagulants, bleeding is a significant risk and there is no specific antidote available at this time. There is one more anticoagulant that I wanted to talk about, which is warfarin. Warfarin is one of the oldest anticoagulants still in use. On the market and now has its own unique mechanism of action To understand how warfarin works, it is important to first understand the role of vitamin K in the coagulation cascade, which is why vitamin K is necessary for the synthesis of the factors 2, 7, 9 and 10, these coagulation factors. They are biologically inactive until they are carboxylated by vitamin K.

This carboxylation reaction occurs when we have a reduced form of vitamin K available in this reaction. Reduced vitamin K is oxidized to vitamin K epoxide in the presence of oxygen and carbon dioxide, producing fully active carboxylated coagulation factors. In the last step of this reaction, the oxidized vitamin K is recycled back to its reduced form by an enzyme called vitamin K epoxide reductase. This is where warfarin comes in as it inhibits this enzyme and therefore disrupts this vitamin K dependent synthesis of biologically active coagulation factors such as In addition to some other regulatory factors, now one of the biggest disadvantages of warfarin is that it has a narrow therapeutic window and has been associated with many drug-food interactions, for these reasons doctors should closely monitor patients taking warfarin by using the International Normalized Ratio measurement, also known as INR, and adjust the dose when necessary to balance the risk of bleeding with the risk of clotting.

Fortunately, in the event of bleeding, the anticoagulant effects of warfarin can be overcome by the administration of vitamin K; However, reversal may take up to 24 hours, therefore, in an emergency, an infusion of fresh frozen plasma may be necessary. Now the last group of medications that I wanted to discuss in this conference are thrombolytics, while antiplatelets and anticoagulants prevent the clot from forming. First of all, thrombolytics act on the existing clot. clot that causes it to dissolve and the way they do this is by directly or indirectly activating a circulating protein called plasminogen which is then converted into plasmin.

Now plasmin is an enzyme that breaks the cross-links between fibrin molecules, thus dissolving the clot. Examples of thrombolytics include alteplase, reteplase and tenecteplase, which is produced using recombinant DNA technology to mimic our natural tissue plasminogen activator, another example is an agent called urokinase, which is a natural thrombolytic produced from cultured kidney cells. human and lastly we have an agent called streptokinase, which is now derived from streptococcal bacteria. One of the main differences between these agents is their selectivity for fibrin-bound plasminogen versus free circulating plasminogen, so while tissue plasminogen activator such as alteplase is more selective for clots andacts to dissolve fibrin in the thrombus, streptokinase and urokinase are less selective for clots and therefore more likely to cause internal bleeding in any organ system these bleeding complications resulting from thrombolytic therapy can be controlled by administration of aminocaproic acid or tranexamic acid these two agents can stop fibrinolysis by inhibiting the binding of plasminogen to fibrin as well as the conversion of plasminogen to plasmin and with that I wanted to thank you for watching.

I hope you enjoyed this lecture and, as always, stay tuned for more.