1. 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

2. Antithrombotic drugs
Antithrombotic drugs
Fibrinolytics
September 2007

3. Antithrombotic drugs
Antithrombotic drugs
Fibrinolytics
September 2007

4. Antithrombotic drugs
Antithrombotic drugs
Fibrinolytics
September 2007

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

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

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

13. 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

14. 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

15. 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 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

16. 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

17. 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

18. 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

19. 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

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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. Thrombolytic drugs – pharmacokinetics
Antithrombotic drugs
Thrombolytic drugs – pharmacokinetics
The plasma half-life of the third generation drugs is 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

44. 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

45. 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