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.
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)
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
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
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
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
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
Notes de l'éditeur
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.