Antiplatelets, Anticoagulants, Anti-hemorrhagic Drugs PDF

Antiplatelets, anticoagulants, anti-hemorrhagic drugs Prof. Dr. Rehab Kamel  Antiplatelets P2Y12 receptor antagonists Ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor are P2Y12 ADP receptor inhibitors that also block platelet aggregation...

Antiplatelets, anticoagulants, anti-hemorrhagic drugs Prof. Dr. Rehab Kamel  Antiplatelets P2Y12 receptor antagonists Ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor are P2Y12 ADP receptor inhibitors that also block platelet aggregation. All of these agents are administered orally, with the exception of cangrelor, which is injectable. Mechanism of action: It inhibits the binding of ADP to its receptors on platelets and, thereby, inhibit the activation of the GP IIb/IIIa receptors required for platelets to bind to fibrinogen and to each other. Ticagrelor and cangrelor bind to the P2Y12 ADP receptor in a reversible manner. The other agents bind irreversibly. The maximum inhibition of platelet aggregation is achieved in 2 minutes with intravenous (IV) cangrelor, 1 to 3 hours with ticagrelor, 2 to 4 hours with prasugrel, 3 to 4 days with ticlopidine, and 3 to 5 days with clopidogrel. Therapeutic use: Clopidogrel is approved for prevention of atherosclerotic events in patients with a recent MI or stroke and in those with established peripheral arterial disease. Prasugrel and ticagrelor are approved to decrease thrombotic cardiovascular events in patients with acute coronary syndromes (eg unstable angina). Cangrelor is approved as an adjunct during percutaneous coronary intervention (PCI) to reduce thrombotic events. https://eurointervention.pcronline.com/article/antiplatelet-therapy-after-percutaneous- coronary-intervention Pharmacokinetics: These agents require oral loading doses for quicker antiplatelet effect, except cangrelor that has a fast onset of action with intravenous administration. Food interferes with the absorption of ticlopidine but not with the other agents. After oral ingestion, the drugs are extensively bound to plasma proteins. They undergo hepatic metabolism by the cytochrome P 450 (CYP) system to active metabolites. Clopidogrel is a prodrug, and its therapeutic efficacy relies entirely on its active metabolite, which is produced via metabolism by CYP 2C19. Genetic polymorphism of CYP 2C19 leads to a reduced clinical response in patients who are “poor metabolizers” of clopidogrel. Tests are currently available to identify poor metabolizers, and it is recommended that other antiplatelet agents (prasugrel or ticagrelor) be prescribed for these patients. In addition, other drugs that inhibit CYP 2C19, such as omeprazole and esomeprazole, should be avoided while on clopidogrel. Adverse effects: These agents can cause prolonged bleeding for which there is no antidote. While all of the P2Y12 inhibitors have a risk of thrombotic thrombocytopenic purpura (TTP), it is considered rare. Clopidogrel can cause neutropenia, but to a less extent than ticlopidine.  Glycoprotein IIb/IIIa receptor antagonists Eptifibatide and tirofiban Mechanism of action: The GP IIb/IIIa receptor plays a key role in stimulating platelet aggregation. Eptifibatide is a cyclic peptide that binds to GP IIb/IIIa at the site that interacts with fibrinogen. Tirofiban is not a peptide, but it blocks the same site as eptifibatide. Consequently, aggregation does not occur. Therapeutic use: These agents are given intravenously, along with heparin and aspirin, as an adjunct to PCI (percutaneous cardiac intervention) for the prevention of cardiac ischemic complications. Major adverse effect: Bleeding  Dipyridamole Dipyridamole, a coronary vasodilator, increases intracellular levels of cAMP by inhibiting phosphodiesterase, thereby resulting in decreased thromboxane A2 synthesis. The drug may potentiate the effect of prostacyclin to antagonize platelet stickiness and, therefore, decrease platelet adhesion to thrombogenic surfaces. Dipyridamole is used for stroke prevention and is usually given in combination with aspirin. Patients with unstable angina should not use dipyridamole because of its vasodilating properties, which may worsen ischemia (coronary steal phenomenon). Dipyridamole can lead to orthostatic hypotension (especially if administered IV).  Cilostazol Cilostazol is an oral antiplatelet agent that also has vasodilating activity. Cilostazol and its active metabolites inhibit phosphodiesterase type III, which prevents the degradation of cAMP, thereby increasing levels of cAMP in platelets and vascular tissues. The increase in cAMP levels in platelets and the vasculature prevents platelet aggregation and promotes vasodilation of blood vessels, respectively. Cilostazol is approved to reduce the symptoms of intermittent claudication. Cilostazol favorably alters the lipid profile, causing a decrease in plasma triglycerides and an increase in high-density lipoprotein cholesterol.  Anticoagulants The anticoagulant drugs inhibit either the action of the coagulation factors (for example, heparin) or interfere with the synthesis of the coagulation factors (for example, vitamin K antagonists such as warfarin). Parenteral anticoagulants Heparin and low molecular weight heparins Heparin is an injectable, rapidly acting anticoagulant that is often used acutely to interfere with the formation of thrombi. Heparin occurs naturally as a macromolecule complexed with histamine in mast cells, where its physiologic role is unknown. It is extracted for commercial use from porcine intestinal mucosa. Unfractionated heparin is a mixture of straight-chain, anionic glycosaminoglycans with a wide range of molecular weights. The realization that low molecular weight forms of heparin (LMWHs) can also act as anticoagulants led to the isolation of enoxaparin, produced by enzymatic depolymerization of unfractionated heparin. The LMWHs are heterogeneous compounds about one-third the size of unfractionated heparin. Mechanism of action The anticoagulant effect of heparin is a consequence of binding to antithrombin III, with the subsequent rapid inactivation of coagulation factors. Antithrombin III is an α globulin that inhibits thrombin (factor IIa) and factor Xa. In the absence of heparin, antithrombin III interacts very slowly with thrombin and factor Xa. When heparin molecules bind to antithrombin III, a conformational change occurs that catalyzes the inhibition of thrombin about 1000- fold. LMWHs complex with antithrombin III and inactivate factor Xa but do not bind as avidly to thrombin. A unique pentasaccharide sequence contained in heparin and LMWHs permits their binding to antithrombin III. Therapeutic use: Heparin and the LMWHs limit the expansion of thrombi by preventing fibrin formation. These agents are used for the treatment of acute venous thromboembolism. Heparin and LMWHs are also used for prophylaxis of postoperative venous thrombosis in patients undergoing surgery (for example, hip replacement) and those with acute MI. These drugs are the anticoagulants of choice for treating pregnant women, because they do not cross the placenta, due to their large size and negative charge. LMWHs do not require the same intense monitoring as heparin, thereby saving laboratory costs and nursing time. These advantages make LMWHs useful for both inpatient and outpatient therapy. Pharmacokinetics: Heparin must be administered subcutaneously or intravenously, because the drug does not readily cross membranes. The LMWHs are usually administered subcutaneously. The anticoagulant effect with heparin occurs within minutes of IV administration (or 1-2 hours after subcutaneous injection), whereas the maximum anti–factor Xa activity of the LMWHs occurs about 4 hours after subcutaneous injection. Adverse effects: The chief complication of heparin and LMWH therapy is bleeding. Careful monitoring of the patient and laboratory parameters is required to minimize bleeding. Excessive bleeding may be managed by discontinuing the drug or by treating with protamine sulfate. When infused slowly, the latter combines ionically with heparin to form a stable, 1:1 inactive complex. It is very important that the dosage of protamine sulfate is carefully titrated (1 mg for every 100 units of heparin administered), because protamine sulfate is a weak anticoagulant, and excess amounts may trigger bleeding episodes or worsen bleeding potential. Heparin preparations are obtained from porcine sources and, therefore, may be antigenic. Possible adverse reactions include chills, fever, urticaria, and anaphylactic shock. Heparin-induced thrombocytopenia (HIT) is a serious condition, in which circulating blood contains an abnormally low number of platelets. This reaction is immune-mediated and carries a risk of venous and arterial embolism. Heparin therapy should be discontinued when patients develop HIT or show severe thrombocytopenia. In case of HIT, heparin can be replaced by other anticoagulants such as argatroban.  Argatroban Argatroban is a synthetic parenteral anticoagulant that is derived from l-arginine. It is a direct thrombin inhibitor. Argatroban is used for the prophylaxis or treatment of venous thromboembolism in patients with HIT, and it is also approved for use during PCI in patients who have or are at risk for developing HIT. Anticoagulant effects are immediate. Argatroban is metabolized in the liver and has a half-life of about 39 to 51 minutes. Dose reduction is recommended for patients with hepatic impairment. As with other anticoagulants, the major side effect is bleeding.  Fondaparinux Fondaparinux is a synthetic pentasaccharide anticoagulant. This agent selectively inhibits only factor Xa. By selectively binding to antithrombin III, fondaparinux potentiates (300- to 1000-fold) the innate neutralization of factor Xa by antithrombin III. Fondaparinux is approved for use in the treatment of DVT and pulmonary embolism (PE) and for the prophylaxis of venous thromboembolism. The drug is well absorbed from the subcutaneous route with and requires less monitoring than heparin. Bleeding is the major side effect of fondaparinux.  Oral anticoagulants Vitamin K antagonist: Warfarin The coumarin anticoagulants owe their action to the ability to antagonize the cofactor functions of vitamin K. The only therapeutically relevant coumarin anticoagulant is warfarin. The international normalized ratio (INR) is the standard by which the anticoagulant activity of warfarin therapy is monitored. The goal of warfarin therapy is an INR of 2 to 3 for most indications. Warfarin has a narrow therapeutic index. Therefore, it is important that the INR is maintained within the optimal range as much as possible, and frequent monitoring may be required. Mechanism of action Factors II, VII, IX, and X require vitamin K as a cofactor for their synthesis by the liver. These factors undergo vitamin K– dependent posttranslational modification, whereby a number of their glutamic acid residues are carboxylated to form γ-carboxyglutamic acid residues. In the carboxylation reactions, the vitamin K–dependent carboxylase fixes CO2 to form the new COOH group on glutamic acid. The reduced vitamin K cofactor is converted to vitamin K epoxide during the reaction. Vitamin K is regenerated from the epoxide by vitamin K epoxide reductase, the enzyme that is inhibited by warfarin. Warfarin treatment results in the production of clotting factors with diminished activity (10% to 40% of normal) due to the lack of sufficient γ-carboxyglutamyl side chains. Unlike heparin, the anticoagulant effects of warfarin are not observed immediately after drug administration. Instead, peak effects may be delayed for 72 to 96 hours, which is the time required to deplete the pool of circulating clotting factors. The anticoagulant effects of warfarin can be overcome by the administration of vitamin K. Therapeutic use: Warfarin is used in the prevention and treatment of DVT and PE, stroke prevention, stroke prevention in case of atrial fibrillation or prosthetic heart valves Pharmacokinetics: Warfarin is rapidly absorbed after oral administration. Warfarin is highly bound to plasma albumin. Drugs that have a greater affinity for the albumin-binding site, such as sulfonamides, can displace the anticoagulant and lead to a transient, elevated activity. Drugs that affect warfarin binding to plasma proteins can lead to variability in the therapeutic response to warfarin. The mean half-life of warfarin is approximately 40 hours. Warfarin is metabolized by the CYP450 system (including the 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4 isoenzymes) to inactive components. Accordingly, warfarin has numerous drug interactions that may potentiate or attenuate its anticoagulant effect. Adverse effects: The principal adverse effect of warfarin is hemorrhage. Therefore, it is important to frequently monitor the INR and adjust the dose of warfarin. Minor bleeding may be treated by withdrawal of the drug or administration of oral vitamin K1, but severe bleeding may require greater doses of vitamin K given intravenously. Whole blood, frozen plasma, and plasma concentrates of blood factors may also be used for rapid reversal of warfarin. Warfarin is teratogenic.  Direct oral anticoagulants Dabigatran Mechanism of action: Dabigatran etexilate is the prodrug of the active moiety dabigatran, which is an oral direct thrombin inhibitor. Therapeutic use: Dabigatran is approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation. It may also be used in the treatment of DVT and PE in patients who have already received parenteral anticoagulants and as prophylaxis to prevent or reduce the risk of recurrence of DVT and PE.  Apixaban and rivaroxaban Mechanism of action: They are oral inhibitors of factor Xa. Inhibition of factor Xa reduces the production of thrombin (IIa) from prothrombin. Therapeutic use: These agents are approved for prevention of stroke in atrial fibrillation, as well as the treatment of DVT and PE. They are also used as prophylaxis to prevent or reduce the risk of recurrence of DVT and PE. In addition, rivaroxaban can be used to prevent major cardiovascular events associated with coronary artery disease or peripheral artery disease. Pharmacokinetics: These drugs are adequately absorbed after oral administration. Rivaroxaban is metabolized by the CYP3A4/5 to inactive metabolites. About one-third of the drug is excreted unchanged in the urine, and the inactive metabolites are excreted in the urine and feces. Apixaban is primarily metabolized by CYP3A4,; approximately 27% is excreted renally. These drugs are substrates of P-glycoprotein (P-gp), and dosages should be reduced (in some cases concomitant use should be avoided) with P-gp inhibitors such as clarithromycin, verapamil, and amiodarone. Concomitant administration of apixaban and rivaroxaban with drugs that are strong P-gp and CYP 3A4 inducers (for example, phenytoin, carbamazepine, rifampin) should be avoided due to the potential for reduced efficacy of the factor Xa inhibitors.  Thrombolytic agents Alteplase, Tenecteplase Mechanism of action: The thrombolytic agents act either directly or indirectly to convert plasminogen to plasmin, which, in turn, cleaves fibrin, thus lysing thrombi. Clot dissolution occur with a higher frequency when therapy is initiated early after clot formation because clots become more resistant to lysis as they age. Unfortunately, increased local thrombi may occur as the clot dissolves, leading to enhanced platelet aggregation and thrombosis. Strategies to prevent this include administration of antiplatelet drugs, such as aspirin, or antithrombotics such as heparin. Therapeutic uses: Originally used for the treatment of DVT and serious PE, thrombolytic drugs are now being used less frequently for these conditions because of the tendency to cause serious bleeding. They are also used to dissolve clots that result in strokes. Adverse effects: The thrombolytic agents do not distinguish between the fibrin of an unwanted thrombus and the fibrin of a beneficial hemostatic plug. Thus, hemorrhage is a major side effect. For example, a previously unsuspected lesion, such as a gastric ulcer, may hemorrhage following injection of a thrombolytic agent. These drugs are contraindicated in pregnancy and in patients with healing wounds, a history of cerebrovascular accident, intracranial bleeding. Alteplase (formerly known as tissue plasminogen activator) has a low affinity for free plasminogen in the plasma, but it rapidly activates plasminogen that is bound to fibrin in a thrombus or a hemostatic plug. Thus, alteplase is said to be “fibrin selective” at low doses. Alteplase is approved for the treatment of MI, massive PE, and acute ischemic stroke. Alteplase has a very short half-life (5-30 minutes), and therefore, a portion of the total dose is injected intravenously as a bolus and the remaining drug is administered over 1 to 3 hours. Tenecteplase has a longer half-life and, therefore, may be administered as an intravenous bolus.  Drugs used to treat bleeding Bleeding problems may have their origin in naturally occurring pathologic conditions, such as hemophilia, or as a result of fibrinolytic states that may arise after some types of surgery. The use of anticoagulants may also give rise to hemorrhage. Certain natural proteins and vitamin K, as well as synthetic antagonists, are effective in controlling this bleeding. Concentrated preparations of coagulation factors are available from human donors. However, these preparations carry the risk of transferring viral infections. Blood transfusion is also an option for treating severe hemorrhage. Tranexamic acid Fibrinolytic states can be controlled by the administration of tranexamic acid. It is synthetic, orally active, excreted in the urine, and inhibit plasminogen activation. A potential side effect is intravascular thrombosis. Protamine sulfate Protamine sulfate antagonizes the anticoagulant effects of heparin. It is a basic protein. The positively charged protamine interacts with the negatively charged heparin, forming a stable complex without anticoagulant activity Vitamin K Vitamin K1 (phytonadione) administration can stop bleeding problems due to warfarin. Vitamin K1 may be administered via the oral, subcutaneous, or intravenous route. The response to vitamin K1 is slow, requiring about 24 hours to reduce INR (time to synthesize new coagulation factors). Thus, if immediate hemostasis is required, fresh frozen plasma should be infused. Factor Xa Factor Xa is a recombinant modified human protein administered parenterally for the reversal of apixaban or rivaroxaban in the setting of life-threatening or uncontrolled bleeding. References Pharmacology (Lippincott's Illustrated Reviews) by Karen Whalen. Wolter Kluwer-8th edition (2023). Other websites used are mentioned in the slides.