Platelet Aggregation Inhibitors PDF

Platelet aggregation inhibitors. Prof. Kawa Dizaye Platelet aggregation inhibitors The mechanisms of platelet aggregation and the sites of antiplatelet drug action Platelets adhere to damaged endothelium via linkage of glycoprotein (GP)-1a receptors with exposed collagen an...

Platelet aggregation inhibitors. Prof. Kawa Dizaye Platelet aggregation inhibitors The mechanisms of platelet aggregation and the sites of antiplatelet drug action Platelets adhere to damaged endothelium via linkage of glycoprotein (GP)-1a receptors with exposed collagen and via linkage of GP-1b receptors with von Willebrand factor (vWF). This activates the platelets and leads to the synthesis and release (degranulation) of various mediators of platelet aggregation, including thromboxane A2 (TXA2), adenosine diphosphate (ADP), and 5-hydroxytryptamine (or serotonin), which interact at their target receptors on the platelets. These mediators increase the expression of GP receptors and promote platelet aggregation via the binding of fibrinogen to GP-2b/3a receptors. (1) NSAIDs inhibit the synthesis of thromboxane A2 by blocking cyclooxygenase (COX). (2) Clopidogrel, prasugrel, ticagrelor, and others block the target of ADP, the purine 2Y12 receptor (P2Y12). (3) Eptifibatide, tirofiban, abciximab, and other agents bind to GP-2b/GP3a proteins and prevent fibrinogen cross- linking of platelets. (4) Vorapaxar is an antagonist at PAR-1 receptors, which is the target of thrombin on platelets. Dipyridamole, inhibits the reuptake of adenosine, increasing adenosine A2 receptors that are positively coupled to adenylate cyclase, increasing cAMP and phosphate, reducing calcium, and decreasing platelet aggregation. Cilostazol, inhibits PDE3 and increases cAMP levels. Platelet aggregation inhibitors decrease the formation of a platelet-rich clot or decrease the action of chemical signals that promote platelet aggregation. 1  Platelet aggregation inhibitors. Prof. Kawa Dizaye Aspirin Aspirin is a non-steroidal antiinflammatory drug (NSAID) that has analgesic, antipyretic, and antiinflammatory effects. It also inhibits platelet aggregation Mechanisms and Pharmacologic Effects: Aspirin and most other NSAIDs inhibit the synthesis of prostaglandins from arachidonic acid. The most important prostaglandins affecting platelet aggregation are prostacyclin (also called prostaglandin I2 [PGI2]) and Thromboxane A2 (TXA2). Prostacyclin is synthesized by vascular endothelial cells and inhibits platelet aggregation, whereas TXA2 is synthesized by platelets and promotes platelet aggregation. Under normal conditions, prostacyclin serves to prevent platelet aggregation and thrombosis, whereas TXA2 becomes predominant during thrombus formation. Low doses of aspirin (about 100 mg) have been found to selectively inhibit the synthesis of TXA2 without having as much effect on prostacyclin, whereas higher doses inhibit the synthesis of both prostaglandins. Hence the dosage of aspirin used to inhibit platelet aggregation is usually lower than that used for other pharmacologic effects. Unlike other NSAIDs, aspirin irreversibly inhibits cyclooxygenase, the enzyme that catalyzes an early step in TXA2 synthesis. For this reason, aspirin inhibits platelet aggregation for the life of the platelet and effectively reduces platelet aggregation when administered once a day. Indications Aspirin is often used to prevent arterial thrombosis in patients with ischemic heart disease and stroke, but it has many other indications as well. In patients with a previous MI or stroke, Adverse Effects Aspirin can cause bleeding, especially in the gastrointestinal tract, where it inhibits the synthesis of prostaglandins that promote secretion of bicarbonate and mucus. Contraindication: Pregnancy especially in the 3rd trimester. Hypersensitivity, gastric ulcer. Dipyridamole Dipyridamole is a coronary vasodilator and a relatively weak antiplatelet drug. It inhibits platelet aggregation by blocking platelet uptake of adenosine, leading to increased activation of platelet adenosine A2 receptors that are positively coupled with adenylate cyclase. This action increases platelet cyclic adenosine monophosphate (cAMP) levels, which reduces calcium release and decreases platelet aggregation. The drug has a limited role in the treatment of thromboembolic disorders. A product containing dipyridamole and aspirin (Aggrenox) has been shown to be more effective for stroke prevention than either drug alone, but a study of thousands of patients with ischemic stroke found that Aggrenox was no more effective than Clopidogrel for stroke prevention but caused more major bleeding episodes. As a vasodilator, dipyridamole is used during myocardial perfusion imaging (thallium imaging) to dilate and evaluate the arteries of patients with coronary artery disease. 2  Platelet aggregation inhibitors. Prof. Kawa Dizaye Cilostazol Cilostazol is a vasodilator and antiplatelet drug that inhibits type 3 phosphodiesterase (PDE3) and the breakdown of cAMP, thereby increasing cAMP levels in platelets and blood vessels. The drug is indicated for the treatment of intermittent claudication, a form of peripheral vascular disease characterized by pain and weakness in a limb leading to limping or lameness. Headache is the most common side effect of cilostazol. Adenosine Diphosphate Inhibitors: Clopidogrel, Prasugrel, Cangrelor, Ticagrelor Mechanism and Effects Clopidogrel and related drugs inhibit 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. Clopidogrel and prasugrel are irreversible P2Y12 antagonists that inhibit platelet function for the life of the platelet. Cangrelor and ticagrelor are reversible receptor blockers, which can be advantageous in patients about to undergo surgery. Pharmacokinetics They are well absorbed after oral administration. Clopidogrel, and prasugrel, are prodrugs that are metabolized to active antiplatelet metabolites, whereas ticagrelor does not require activation and appears to exert antiplatelet effect more rapidly. Prasugrel has a higher potency and a more rapid onset of action than Clopidogrel because of the more efficient generation of its active metabolite. Prasugrel also produces a higher and more consistent level of platelet inhibition than Clopidogrel. Adverse Effects and Interactions As with aspirin, all the ADP blockers increase the risk of bleeding. In addition, ticagrelor may cause dyspnea. Glycoprotein IIb/IIIa Antagonists: Abciximab, tirofiban Abciximab is monoclonal antibody drug. It prevents platelet aggregation by binding to platelet GP IIb/ IIIa receptors. Abciximab is given by IV bolus, followed by IV infusion, achieving peak platelet inhibition within 30 minutes. After cessation of abciximab infusion, platelet function gradually returns to normal, with the antiplatelet effect persisting for 24 to 48 hours Therapeutic use: The drug is given intravenously, along with heparin and aspirin to prevent platelet aggregation and thrombosis in patients undergoing percutaneous coronary interventions (PCI), Vorapaxar Vorapaxar is a new drug with a new mechanism of action in preventing platelet aggregation. It is a protease-activated receptor-1 (PAR-1) antagonist approved for patients with a history of MI or with peripheral arterial disease (PAD). By occupying the PAR-1 receptor, vorapaxar competitively inhibits thrombin access to its target receptor and prevents thrombin-mediated platelet aggregation. In clinical trials, vorapaxar reduced thrombotic cardiovascular events and mortality. 3  Platelet aggregation inhibitors. Prof. Kawa Dizaye Thrombolytic Drugs The Thrombolytic drugs are enzymes that convert plasminogen to plasmin. Plasmin breaks down fibrin and fibrinogen and thereby lyses a clot. Thrombolytic drugs are indicated for any patient with acute myocardial infarction for whom the benefit is likely to outweigh the risk of treatment. First-Generation Thrombolytics: Streptokinase, Urokinase Streptokinase is a protein obtained from streptococci. It forms a complex with plasminogen, altering its conformation to facilitate its conversion to plasmin. Urokinase is an enzyme produced by human kidney cells that directly converts plasminogen to active plasmin. Second-Generation Thrombolytics: Alteplase, Reteplase. They are recombinant forms of human tissue plasminogen activator. They catalyze the conversion of plasminogen to plasmin. Alteplase 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 haemostatic plug. Thus, alteplase is said to be “fibrin selective” at low doses. Alteplase has a very short half-life (5 to 30 minutes), and therefore, 10% of the total dose is injected intravenously as a bolus and the remaining drug is administered over 60 minutes. Reteplase has longer half-life than Alteplase Third generation: Reteplase and Tenecteplase Both bind to fibrin in the blood clot and activate plasminogen. Therapeutic use: Thrombolytic drugs are administered intravenously. They are indicated for the management of severe pulmonary embolism, deep vein thrombosis, and arterial thromboembolism and are especially important therapy after myocardial infarction and acute ischemic stroke. Thrombolytic agents should be administered as soon as possible and preferably within 6 hours of symptom onset. Alteplase should be given within 6–12 hours of symptom onset, Reteplase and streptokinase within 12 hours of symptom onset, but ideally all should be given within 1 hour; use after 12 hours requires specialist advice. Tenecteplase should be given as early as possible and usually within 6 hours of symptom onset. Alteplase, streptokinase and urokinase p. 153 can be used for other thromboembolic disorders such as deep-vein thrombosis and pulmonary embolism. Alteplase is also used for acute ischaemic stroke. Adverse effects: The thrombolytic agents do not distinguish between the fibrin of an unwanted thrombus and the fibrin of a beneficial haemostatic plug. Thus, hemorrhage is a major side effect. 4