Antiplatelet drugs (VK)
•Download as PPT, PDF•
74 likes•25,319 views
This document discusses different types of antithrombotic and thrombolytic drugs. It describes antiplatelet drugs like aspirin and P2Y12 antagonists that work by inhibiting platelet aggregation. It also discusses fibrinolytics/thrombolytics that work by dissolving blood clots. The major uses of these drugs include preventing heart attacks, strokes, and deep vein thrombosis. However, risks include bleeding complications with antiplatelets and thrombolytics.
Recommended
More Related Content
What's hot
What's hot (20)
Viewers also liked
Similar to Antiplatelet drugs (VK)
Similar to Antiplatelet drugs (VK) (20)
More from Dr. Abhavathi Vijay Kumar
More from Dr. Abhavathi Vijay Kumar (20)
Recently uploaded
Recently uploaded (20)
Antiplatelet drugs (VK)
- 1. LIFEBLOOD THE Thrombosis CHARITY Antiplatelet and thrombolytic drugs These slides were kindly provided by AstraZeneca
- 6. The role of platelets
- 7. The role of platelets
- 8. The role of platelets
- 9. The role of platelets
- 10. Antiplatelet drugs Antiplatelet drugs Acetylsalicylic acid (aspirin) P2Y12 antagonists Dipyridamole GPIIb/IIIa antagonists 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)
- 11. Acetylsalicylic acid – mechanism of action
- 12. Acetylsalicylic acid – mechanism of action
- 13. Acetylsalicylic acid – mechanism of action
- 14. Acetylsalicylic acid – mechanism of action
- 15. Acetylsalicylic acid – mechanism of action
- 16. 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)
- 17. 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
- 18. 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
- 19. ADP-receptor antagonists – mechanism of action
- 20. ADP-receptor antagonists – mechanism of action
- 21. ADP-receptor antagonists – mechanism of action
- 22. ADP-receptor antagonists – mechanism of action
- 23. 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
- 24. 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
- 25. 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
- 26. Dipyridamole – mechanism of action
- 27. Dipyridamole – mechanism of action
- 28. Dipyridamole – mechanism of action
- 29. 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
- 30. Dipyridamole – major use • Secondary prevention of ischaemic complications after transient ischaemic attack (TIA) or ischaemic stroke (in combination with aspirin)
- 31. 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
- 32. GPIIb/IIIa-receptor antagonists – mechanism of action
- 33. GPIIb/IIIa-receptor antagonists – mechanism of action
- 34. GPIIb/IIIa-receptor antagonists – mechanism of action
- 35. GPIIb/IIIa-receptor antagonists – mechanism of action
- 36. GPIIb/IIIa-receptor antagonists – mechanism of action
- 37. 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 temination 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
- 38. 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
- 39. 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
- 40. Thrombolytic drugs – mechanism of action
- 41. Thrombolytic drugs – mechanism of action
- 42. Thrombolytic drugs – mechanism of action
- 43. Thrombolytic drugs – mechanism of action
- 44. 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 34 minutes, must be administered an initial bolus followed by infusion
- 45. 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
- 46. 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
Editor's Notes
- 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.
- 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.
- Following adhesion, agonists such as collagen, thrombin, adenosine diphosphate (ADP), and thromboxane A2 activate platelets by binding to their respective platelet receptors.
- 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.
- The third step of platelet response is aggregation. After activation, fibrinogen binds to GPIIb/IIIa to connect platelets together into a loose platelet plug.
- 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.
- Thromboxane A2 is synthesized in platelets, from which it can be released. Thromboxane A2 causes vasoconstriction and is also a platelet agonist.
- When thromboxane A2 binds to its platelet receptor…
- …the platelets are activated.
- Aspirin irreversibly inhibits cyclo-oxygenase (COX), an enzyme in platelets that is involved in the synthesis of thromboxane A2.
- Thus, as aspirin downregulates the synthesis of the platelet agonist thromboxane A2, it will also inhibit platelet activation.
- Reference: Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287–94.
- 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.
- Ticlopidine and clopidogrel are irreversible inhibitors of the ADP receptor…
- …and thereby prevent binding to the agonist.
- 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.
- Adenosine is a compound that binds to its platelet receptor, but in contrast to ADP, this binding results in a stabilisation of the platelet.
- Dipyridamole increases the levels of adenosine available for binding to platelets by inhibiting adenosine uptake in erythrocytes and endothelial cells.
- Thus, more adenosine will be available to bind to platelets and thereby prevent activation and aggregation.
- The glycoprotein IIb/IIIa receptor is exposed on the platelet membrane after activation and is responsible for mediating platelet aggregation.
- 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.
- GPIIb/IIIa antagonists hava a high affinity for the fibrinogen receptor…
- …and when binding is completed…
- …they will prevent fibrinogen from binding to the receptors.
- Thrombolytic drugs are used in the acute setting of thromboembolic events to dissolve thrombi. They are administered by intravenous infusion.
- Thrombolytic drugs catalyse the conversion of the proenzyme plasminogen to plasmin, which, when in proximity to a thrombus or embolus…
- …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’.
- 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.
- Reference: Nordt TK, Bode C. Thrombolysis: newer thrombolytic agents and their role in clinical medicine. Heart 2003;89:1358–62.