Antithrombotic drugs Fibrinolytics There are three main classes of antithrombotic drugs Anticoagulants Antiplatelets Thrombolytic or fibrinolytic drugs. Antiplatelet and anticoagulant drugs inhibit platelet activation and aggregation, and the coagulation process respectively and can therefore be administered acutely to prevent the initial formation of blood clots (thrombi) in patients with recognised risk factors (primary prevention) and chronically to treat and prevent recurrence of thrombi and their associated complications (secondary prevention). Thrombolytic or fibrinolytic drugs act by dissolving existing thrombi or emboli and therefore only play a role in the acute treatment of thrombosis. Fibrinolytics September 2007

Antithrombotic drugs Antithrombotic drugs Fibrinolytics September 2007

Antithrombotic drugs Antithrombotic drugs Fibrinolytics September 2007

Antithrombotic drugs Antithrombotic drugs Fibrinolytics September 2007

Antithrombotic drugs The role of platelets Following vascular injury, von Willebrand factor binds to collagen in the exposed subendothelium at the site of injury. The other site of the “rod-formed” von Willebrand factor binds to the platelet receptor GPIb and platelets are thereby anchored to the site of the injured entothelium. This is called adhesion. September 2007

Antithrombotic drugs The role of platelets Following adhesion, agonists such as collagen, thrombin, adenosine diphosphate (ADP), and thromboxane A2 activate platelets by binding to their respective platelet receptors. September 2007

Antithrombotic drugs The role of platelets As a result of agonist binding, platelets undergo a shape change and new structures such as phospholipids and GPIIb/IIIa receptors are exposed on the cell membrane. This is called activation. September 2007

Antithrombotic drugs The role of platelets The third step of platelet response is aggregation. After activation, fibrinogen binds to GPIIb/IIIa to connect platelets together into a loose platelet plug. September 2007

Antiplatelet drugs Antiplatelet drugs Acetylsalicylic acid (aspirin) Antithrombotic drugs Antiplatelet drugs Antiplatelet drugs Acetylsalicylic acid (aspirin) P2Y12 antagonists/Clopidogrel GPIIb/IIIa antagonists Dipyridamole Used widely in patients at risk of thromboembolic disease Beneficial in the treatment and prevention of ACS and the prevention of thromboembolic events Secondary prevention in patients following stroke, often in combination with aspirin Administered intravenously, are effective during percutaneous coronary intervention (PCI) Activation and aggregation of platelets play a key role in thrombus formation in the heart and arterial system. Antiplatelet drugs are therefore important for the prevention and treatment of intracardiac and arterial thrombosis and their consequences. There are four main classes of antiplatelet drugs: acetylsalicylic acid (ASA), better known as aspirin, is the most widely used antiplatelet therapy. ASA acts by inhibiting the synthesis of thromboxane A2 ADP-receptor antagonists/P2Y12 receptor antagonists (clopidogrel and ticlopidine); prasugrel, cangrelor (i.v.) and AZD6140 are in phase III clinical development dipyridamole, which increases levels of the second messengers cAMP and cGMP within platelets Glycoprotein IIb/IIIa antagonists that inhibit the binding of fibrinogen to its receptor. Thus, these agents inhibit platelet aggregation but not platelet activation. September 2007

Acetylsalicylic acid – mechanism of action Antithrombotic drugs Acetylsalicylic acid – mechanism of action Thromboxane A2 is synthesized in platelets, from which it can be released. Thromboxane A2 causes vasoconstriction and is also a platelet agonist. September 2007

Acetylsalicylic acid – mechanism of action Antithrombotic drugs Acetylsalicylic acid – mechanism of action When thromboxane A2 binds to its platelet receptor… September 2007

Acetylsalicylic acid – mechanism of action Antithrombotic drugs Acetylsalicylic acid – mechanism of action …the platelets are activated. September 2007

Acetylsalicylic acid – mechanism of action Antithrombotic drugs Acetylsalicylic acid – mechanism of action Aspirin irreversibly inhibits cyclo-oxygenase (COX), an enzyme in platelets that is involved in the synthesis of thromboxane A2. September 2007

Acetylsalicylic acid – mechanism of action Antithrombotic drugs Acetylsalicylic acid – mechanism of action Thus, as aspirin downregulates the synthesis of the platelet agonist thromboxane A2, it will also inhibit platelet activation. September 2007

Acetylsalicylic acid – pharmacokinetics Antithrombotic drugs Acetylsalicylic acid – pharmacokinetics Rapid absorption of aspirin occurs in the stomach and upper intestine, with the peak plasma concentration being achieved 15-20 minutes after administration The peak inhibitory effect on platelet aggregation is apparent approximately one hour post-administration Aspirin produces the irreversible inhibition of the enzyme cyclo-oxygenase and therefore causes irreversible inhibition of platelets for the rest of their lifespan (7 days) Reference: Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287–94. September 2007

Acetylsalicylic acid – major use Antithrombotic drugs Acetylsalicylic acid – major use Secondary prevention of transient ischaemic attack (TIA), ischaemic stroke and myocardial infarction Prevention of ischaemic events in patients with angina pectoris Prevention of coronary artery bypass graft (CABG) occlusion September 2007

Acetylsalicylic acid – major drawbacks Antithrombotic drugs Acetylsalicylic acid – major drawbacks Risk of gastrointestinal adverse events (ulceration and bleeding) Allergic reactions Is not a very effective antithrombotic drug but is widely used because of its ease of use Lack of response in some patients (aspirin resistance) The irreversible platelet inhibition September 2007

ADP-receptor antagonists – mechanism of action Antithrombotic drugs ADP-receptor antagonists – mechanism of action Ticlopidine and clopidogrel are ADP receptor antagonists, which bind to the receptor, but in contrast to the agonist ADP, they do not induce an intracellular response. September 2007

ADP-receptor antagonists – mechanism of action Antithrombotic drugs ADP-receptor antagonists – mechanism of action Ticlopidine and clopidogrel are irreversible inhibitors of the ADP receptor… September 2007

ADP-receptor antagonists – mechanism of action Antithrombotic drugs ADP-receptor antagonists – mechanism of action …and thereby prevent binding to the agonist. September 2007

ADP-receptor antagonists – mechanism of action Antithrombotic drugs ADP-receptor antagonists – mechanism of action In addition to preventing platelet aggregation induced by ADP, blockade of this receptor will also partly prevent aggregation intitated by other agonists, as ADP is released from all activated platelets irrespective of agonist. September 2007

ADP-receptor antagonists – pharmacokinetics Antithrombotic drugs ADP-receptor antagonists – pharmacokinetics Both currently available ADP-receptor antagonists are thienopyridines that can be administered orally, and absorption is approximately 80-90% Thienopyridines are prodrugs that must be activated in the liver September 2007

ADP-receptor antagonists – major use Antithrombotic drugs ADP-receptor antagonists – major use Secondary prevention of ischaemic complications after myocardial infarction, ischaemic stroke and established peripheral arterial disease Secondary prevention of ischaemic complications in patients with acute coronary syndrome (ACS) without ST-segment elevation September 2007

ADP-receptor antagonists – major drawbacks Antithrombotic drugs ADP-receptor antagonists – major drawbacks Clopidogrel is only slightly more effective than aspirin As with aspirin, clopidogrel binds irreversibly to platelets In some patients there is resistance to clopidogrel treatment September 2007

Dipyridamole – mechanism of action Antithrombotic drugs Dipyridamole – mechanism of action Adenosine is a compound that binds to its platelet receptor, but in contrast to ADP, this binding results in a stabilisation of the platelet. September 2007

Dipyridamole – mechanism of action Antithrombotic drugs Dipyridamole – mechanism of action Dipyridamole increases the levels of adenosine available for binding to platelets by inhibiting adenosine uptake in erythrocytes and endothelial cells. September 2007

Dipyridamole – mechanism of action Antithrombotic drugs Dipyridamole – mechanism of action Thus, more adenosine will be available to bind to platelets and thereby prevent activation and aggregation. September 2007

Dipyridamole – pharmacokinetics Antithrombotic drugs Dipyridamole – pharmacokinetics Incompletely absorbed from the gastrointestinal tract with peak plasma concentration occuring about 75 minutes after oral administration More than 90% bound to plasma proteins A terminal half-life of 10 to 12 hours Metabolised in the liver Mainly excreted as glucuronides in the bile; a small amount is excreted in the urine September 2007

Dipyridamole – major use Antithrombotic drugs Dipyridamole – major use Secondary prevention of ischaemic complications after transient ischaemic attack (TIA) or ischaemic stroke (in combination with aspirin) September 2007

Dipyridamole – major drawbacks Antithrombotic drugs Dipyridamole – major drawbacks Is not a very effective antithrombotic drug Dipyridamole also has a vasodilatory effect and should be used with caution in patients with severe coronary artery disease; chest pain may be aggravated in patients with underlying coronary artery disease who are receiving dipyridamole September 2007

GPIIb/IIIa-receptor antagonists – mechanism of action Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action The glycoprotein IIb/IIIa receptor is exposed on the platelet membrane after activation and is responsible for mediating platelet aggregation. September 2007

GPIIb/IIIa-receptor antagonists – mechanism of action Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action Once activated, the receptor becomes functional and binds fibrinogen, leading to the formation of platelet aggregates. Glycoprotein IIb/IIIa receptors therefore mediate the final common pathway of platelet aggregation. September 2007

GPIIb/IIIa-receptor antagonists – mechanism of action Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action GPIIb/IIIa antagonists hava a high affinity for the fibrinogen receptor… September 2007

GPIIb/IIIa-receptor antagonists – mechanism of action Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action …and when binding is completed… September 2007

GPIIb/IIIa-receptor antagonists – mechanism of action Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action …they will prevent fibrinogen from binding to the receptors. September 2007

GPIIb/IIIa-receptor antagonists – pharmacokinetics Antithrombotic drugs GPIIb/IIIa-receptor antagonists – pharmacokinetics Available only for intravenous administration Intravenous administration of a bolus dose followed by continuous infusion produces constant free plasma concentration throughout the infusion. At the termination of the infusion period, free plasma concentrations fall rapidly for approximately six hours then decline at a slower rate. Platelet function generally recovers over the course of 48 hours, although the GP IIb/IIIa antagonist remains in the circulation for 15 days or more in a platelet-bound state September 2007

GPIIb/IIIa-receptor antagonists – major use Antithrombotic drugs GPIIb/IIIa-receptor antagonists – major use Prevention of ischaemic cardiac complications in patients with acute coronary syndrome (ACS) without ST-elevation and during percutaneous coronary interventions (PCI), in combination with aspirin and heparin September 2007

GPIIb/IIIa-receptor antagonists – major drawbacks Antithrombotic drugs GPIIb/IIIa-receptor antagonists – major drawbacks Can only be administered by intravenous injection or infusion and are complicated to manufacture Oral drugs have been investigated but were not effective and have therefore not reached the market September 2007

Thrombolytic drugs – mechanism of action Antithrombotic drugs Thrombolytic drugs – mechanism of action Thrombolytic drugs are used in the acute setting of thromboembolic events to dissolve thrombi. They are administered by intravenous infusion. September 2007

Thrombolytic drugs – mechanism of action Antithrombotic drugs Thrombolytic drugs – mechanism of action Thrombolytic drugs catalyse the conversion of the proenzyme plasminogen to plasmin, which, when in proximity to a thrombus or embolus… September 2007

Thrombolytic drugs – mechanism of action Antithrombotic drugs Thrombolytic drugs – mechanism of action …degrades fibrin into soluble peptides, known as fibrin degradation products (FDPs) and D-dimers, thus dissolving the main body of the clot. These drugs are therefore often referred to as ‘clot busters’. September 2007

Thrombolytic drugs – mechanism of action Antithrombotic drugs Thrombolytic drugs – mechanism of action Streptokinase, the first thrombolytic drug, has now been replaced by the second generation agent, tissue type plasminogen activator (t-PA). t-PA is naturally occuring but typically manufactured using recombinant DNA technology. The third generation thrombolytic drugs, which are recombinant mutant variants of t-PA and have been shown to have comparable efficacy with that of t-PA, have now also reached clinical practice. These include reteplase and tenecteplase. They differ from native t-PA by having increased plasma half-lives that allow more convenient dosing. September 2007

Thrombolytic drugs – pharmacokinetics Antithrombotic drugs Thrombolytic drugs – pharmacokinetics The plasma half-life of the third generation drugs is 14-45 minutes, allowing administration as a single or double intravenous bolus. This is in contrast to second generation t-PA, which with a half-life of 3- 4 minutes, must be administered an initial bolus followed by infusion Reference: Nordt TK, Bode C. Thrombolysis: newer thrombolytic agents and their role in clinical medicine. Heart 2003;89:1358–62. September 2007

Thrombolytic drugs – major use Antithrombotic drugs Thrombolytic drugs – major use Thrombolysis in patients with acute myocardial infarction (MI) Thrombolysis in patients with ischaemic stroke Thrombolysis of (sub)acute peripheral arterial thrombosis Thrombolysis in patients with acute massive pulmonary embolism Thrombolysis of occluded haemodialysis shunts September 2007

Thrombolytic drugs – major drawbacks Antithrombotic drugs Thrombolytic drugs – major drawbacks Treatment is limited to acute in-hospital treatment. There is a high risk of bleeding inherent in this treatment Patients using anticoagulants are contraindicated for treatment with thrombolytics September 2007