A N T I P L A T E L E T & T H R O M B O L Y T I C A G E N T S
Dr. Mohammed Hilal Al-Ali L: 1&2
PLATELET INHIBITORS:
1) Cyclooxygenase-1(COX-1) inhibitors:
(Aspirin)
2)
P2Y12 ADP receptor inhibitors:
(Ticlopidine, Clopidogrel, Prasugrel, &
Ticagrelor)
3)
GP IIb/IIIa receptor inhibitors:
(Abciximab, Eptifibatide, & Tirofiban)
4) Phosphodiesterase inhibitors:
(Dipyridamole & Cilostazol)
PLATELET RESPONSE TO VASCULAR INJURY:
Physical trauma to the vascular system, such as a puncture or a cut, initiates a
complex series of interactions between platelets, endothelial cells, and the
coagulation cascade. These interactions lead to hemostasis or the cessation of
blood loss from a damaged blood vessel.
Initially, there is vasospasm of the
damaged blood vessel to prevent further blood loss. The next step involves the
formation of a platelet–fibrin plug at the site of the puncture.
The creation of an unwanted thrombus involves many of the same steps as normal
clot formation, except that the triggering stimulus is a pathologic condition in the
vascular system, rather than external physical trauma.
Chemical mediators, such as prostacyclin and nitric oxide, are synthesized by
intact endothelial cells and act as inhibitors of platelet aggregation.
Three main steps for platelet response to vascular injury this includes:
1)) Adhesion
2)) Activation
3)) Aggregation
1)) Platelet adhesion
When the endothelium is injured, platelets adhere to and virtually cover the
exposed collagen of the subendothelium. This triggers a complex series of
chemical reactions, resulting in platelet activation.
2)) Platelet activation
Receptors on the surface of the adhering platelets are activated by the collagen of
the underlying connective tissue. This causes morphologic changes in platelets and
the release of platelet granules containing chemical mediators, such as adenosine
A N T I P L A T E L E T & T H R O M B O L Y T I C A G E N T S
Dr. Mohammed Hilal Al-Ali L: 1&2
diphosphate (ADP), thromboxane A2, serotonin, platelet activation factor, and
thrombin. These actions are mediated by several messenger systems that ultimately
result in elevated levels of calcium and a decreased concentration of cAMP within
the platelet.
3)) Platelet aggregation
a\ The release of platelet granules containing mediators,
such as ADP and
serotonin that activate other platelets;
b\ Activation of thromboxane A2 synthesis;
c\ Activation of glycoprotein (GP) IIb/IIIa receptors that bind to fibrinogen
(soluble plasma GP) on two separate platelets, resulting in platelet cross-linking
and platelet aggregation
PLATELET AGGREGATION INHIBITORS
Platelet aggregation inhibitors decrease the formation of a platelet-rich clot or
decrease the action of chemical signals that promote platelet aggregation. The
platelet aggregation inhibitors described below inhibit cyclooxygenase-1 (COX-1)
or block GP IIb/IIIa or ADP receptors, thereby interfering with the signals that
promote platelet aggregation. Because these agents have different mechanisms of
actions, synergistic or additive effects may be achieved when agents from different
classes are combined. These agents are beneficial in the prevention and treatment
of occlusive cardiovascular diseases, in the maintenance of vascular grafts and
arterial patency, and as adjuncts to thrombin inhibitors or thrombolytic therapy in
MI.
A. Aspirin
1. Mechanism of action:
Stimulation of platelets by thrombin, collagen, and ADP results in activation of
platelet membrane phospholipases that liberate arachidonic acid from membrane
phospholipids. Arachidonic acid is first converted to prostaglandin H2 by COX-1.
Prostaglandin H2 is further metabolized to thromboxane A2, which is released into
plasma. Thromboxane A2 promotes the aggregation process that is essential for the
rapid formation of a hemostatic plug. Aspirin prevent thromboxane A2 synthesis
by inhibition of cyclooxygenase-1 (COX-1), thereby irreversibly inactivating the
A N T I P L A T E L E T & T H R O M B O L Y T I C A G E N T S
Dr. Mohammed Hilal Al-Ali L: 1&2
enzyme.
The inhibitory effect is rapid, and aspirin-induced suppression of
thromboxane A2 and the resulting suppression of platelet aggregation last for the
life of the platelet, which is approximately 7 to 10 days. Repeated administration of
aspirin has a cumulative effect on the function of platelets. Aspirin is the only
antiplatelet agent that irreversibly inhibits platelet function.
2. Therapeutic use:
Aspirin is used in the prophylactic treatment of transient cerebral ischemia, to
reduce the incidence of recurrent MI, and to decrease mortality in the setting of
primary and secondary prevention of MI. Complete inactivation of platelets occurs
with 75 mg of aspirin given daily. The recommended dose of aspirin ranges from
81 to 325 mg daily.
3. Pharmacokinetics:
When given orally, aspirin is absorbed by passive diffusion and quickly
hydrolyzed to salicylic acid in the liver. Salicylic acid is further metabolized in the
liver, and some is excreted unchanged in the urine. The half-life of aspirin ranges
from 15 to 20 minutes and for salicylic acid is 3 to 12 hours.
4. Adverse effects:
Higher doses of aspirin increase drug-related toxicities as well as the probability
that aspirin may also inhibit prostacyclin production. Bleeding time is prolonged
by aspirin treatment, causing complications that include an increased incidence of
hemorrhagic stroke and gastrointestinal (GI) bleeding, especially at higher doses of
the drug. Nonsteroidal anti-inflammatory drugs, such as ibuprofen, inhibit COX-1
by transiently competing at the catalytic site. Ibuprofen, if taken within the 2 hours
prior to aspirin, can obstruct the access of aspirin to the serine residue and,
thereby, antagonize platelet inhibition by aspirin. Therefore, immediate release
aspirin should be taken at least 60 minutes before or at least 8 hours after
ibuprofen. Although celecoxib (a selective COX-2 inhibitor ) does not interfere
with the antiaggregation activity of aspirin, there is some evidence that it may
contribute to cardiovascular events by shifting the balance of chemical mediators
in favor of thromboxane A2.
A N T I P L A T E L E T & T H R O M B O L Y T I C A G E N T S
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B. Ticlopidine, clopidogrel, prasugrel, and ticagrelor
These are P2Y12 ADP receptor inhibitors that also block platelet aggregation but
by a mechanism different from that of aspirin.
1. Mechanism of action:
These 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 and to each other. Ticagrelor binds to the P2Y12 ADP receptor in a
reversible manner. The other agents bind irreversibly. The maximum inhibition of
platelet aggregation is achieved in 1 to 3 hours with ticagrelor, 2 to 4 hours with
prasugrel, 3 to 4 days with ticlopidine, and 3 to 5 days with clopidogrel. When
treatment is suspended, the platelet system requires time to recover.
2. Therapeutic use:
Clopidogrel is approved for prevention of atherosclerotic events in patients with a
recent MI or stroke and in those with established peripheral arterial disease. It is
also approved for prophylaxis of thrombotic events in acute coronary syndromes
(unstable angina or non–ST-elevation MI). Additionally, clopidogrel is used to
prevent thrombotic events associated with percutaneous coronary intervention
(PCI) with or without coronary stenting.
Ticlopidine is similar in structure to clopidogrel. It is indicated for the prevention
of transient ischemic attacks (TIA) and strokes in patients with a prior cerebral
thrombotic event. However, due to life-threatening hematologic adverse reactions,
ticlopidine is generally reserved for patients who are intolerant to other therapies.
Prasugrel is approved to decrease thrombotic cardiovascular events in patients
with acute coronary syndromes (unstable angina, non–ST-elevation MI, and ST-
elevation MI managed withPCI). Ticagrelor is approved for the prevention of
arterial thromboembolism in patients with unstable angina and acute MI, including
those undergoing PCI.
A N T I P L A T E L E T & T H R O M B O L Y T I C A G E N T S
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3. Pharmacokinetics:
These agents require loading doses for quicker antiplatelet effect. Food interferes
with the absorption of ticlopidine but not with the other agents. After oral
ingestion, the drugs are extensively bound to plasma proteins. They undergo
hepatic metabolism by the cytochrome P450 (CYP) system to active metabolites.
Elimination of the drugs and metabolites occurs by both the renal and fecal routes.
Clopidogrel is a prodrug, and its therapeutic efficacy relies entirely on its active
metabolite, which is produced via metabolism by CYP 2C19. Genetic
polymorphism of CYP 2C19 leads to a reduced clinical response in patients who
are “poor metabolizers” of clopidogrel. Tests are currently available to identify
poor metabolizers, and it is recommended that other antiplatelet agents (prasugrel
or ticagrelor) be prescribed for these patients.
4. Adverse effects:
These agents can cause prolonged bleeding for which there is no antidote.
Ticlopidine is associated with severe hematologic reactions that limit its use, such
as agranulocytosis, thrombotic thrombocytopenic purpura (TTP), and aplastic
anemia. Clopidogrel causes fewer adverse reactions, and the incidence of
neutropenia is lower. However, TTP has been reported as an adverse effect for
both clopidogrel and prasugrel (but not for ticagrelor). Prasugrel is
contraindicated in patients with history of TIA or stroke. Prasugrel and ticagrelor
increase risk for bleeding. Additionally, ticagrelor can be diminishing their
effectiveness with concomitant use of aspirin doses above 100 mg.
C. Abciximab, eptifibatide, and tirofiban
1. Mechanism of action:
The GP IIb/IIIa receptor plays a key role in stimulating platelet aggregation. A
chimeric monoclonal antibody, abciximab, inhibits the GP IIb/IIIa receptor
complex. By binding to GP IIb/IIIa, abciximab blocks the binding of fibrinogen
and von Willebrand factor and, consequently, aggregation does not occur.
Eptifibatide and tirofiban act similarly to abciximab, by blocking the GP IIb/IIIa
receptor.
A N T I P L A T E L E T & T H R O M B O L Y T I C A G E N T S
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2. Therapeutic use:
These agents are given intravenously, along with heparin and aspirin, as an
adjunct to PCI for the prevention of cardiac ischemic complications. Abciximab is
also approved for patients with unstable angina not responding to conventional
medical therapy when PCI is planned within 24 hours.
3. Pharmacokinetics:
Abciximab is given by IV bolus, followed by IV infusion, achieving peak platelet
inhibition within 30 minutes. The metabolism of abciximab is unknown. After
cessation of abciximab infusion, platelet function gradually returns to normal, with
the antiplatelet effect persisting for 24 to 48 hours. When IV infusion of
eptifibatide or tirofiban is stopped, both agents are rapidly cleared from the
plasma. Eptifibatide and its metabolites are excreted by the kidney. Tirofiban is
excreted largely unchanged by the kidney and in the feces.
4. Adverse effects:
The major adverse effect of these agents is bleeding, especially if used with
anticoagulants .
D. Dipyridamole
Dipyridamole, a coronary vasodilator, increases intracellular levels of cAMP by
inhibiting cyclic nucleotide phosphodiesterase, thereby resulting in decreased
thromboxane A2 synthesis. The drug may potentiate the effect of prostacyclin to
antagonize platelet stickiness and, therefore, decrease platelet adhesion to
thrombogenic surfaces. Dipyridamole is used for stroke prevention and is usually
given in combination with aspirin. The drug undergoes hepatic metabolism and is
excreted mainly in the feces. Patients with unstable angina should not use
dipyridamole because of its vasodilating properties, which may worsen ischemia
(coronary steal phenomenon). Dipyridamole commonly causes headache and can
lead to orthostatic hypotension (especially if given IV).
A N T I P L A T E L E T & T H R O M B O L Y T I C A G E N T S
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E. Cilostazol
Cilostazol is an oral antiplatelet agent that also has vasodilating activity.
Cilostazol and its active metabolites inhibit phosphodiesterase type III, which
prevents the degradation of cAMP, thereby increasing levels of cAMP in platelets
and vascular tissues. The increase in cAMP levels in platelets and the vasculature
prevents platelet aggregation and promotes vasodilation of blood vessels,
respectively. Cilostazol favorably alters the lipid profile, causing a decrease in
plasma triglycerides and an increase in high-density lipoprotein cholesterol. The
drug is approved to reduce the symptoms of intermittent claudication. The primary
route of elimination is via the kidney. Headache and GI side effects (diarrhea,
abnormal stools, dyspepsia, and abdominal pain) are the most common adverse
effects observed with cilostazol. Phosphodiesterase type III inhibitors have been
shown to increase mortality in patients with advanced heart failure. As such,
cilostazol is contraindicated in patients with heart failure.
THROMBOLYTIC DRUGS
1)) Alteplase, reteplase & tenecteplase:
tissue Plasminogen Activator {tPA}
2)) Streptokinase
3)) Urokinase
Acute thromboembolic disease in selected patients may be treated by the
administration of agents that activate the conversion of plasminogen to plasmin, a
serine protease that hydrolyzes fibrin and, thus, dissolves clots. Streptokinase, one
of the first such agents to be approved, causes a systemic fibrinolytic state that can
lead to bleeding problems. Alteplase acts more locally on the thrombotic fibrin
toproduce fibrinolysis. Urokinase is produced naturally in human kidneys and
directly converts plasminogen into active plasmin compares the thrombolytic
agents. Fibrinolytic drugs may lyse both normal and pathologic thrombi.
A N T I P L A T E L E T & T H R O M B O L Y T I C A G E N T S
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Common characteristics of thrombolytic agents
1. Mechanism of action:
The thrombolytic agents share some common features. All act either directly or
indirectly to convert plasminogen to plasmin, which, in turn, cleaves fibrin, thus
lysing thrombi. Clot dissolution and reperfusion occur with a higher frequency
when therapy is initiated early after clot formation because clots become more
resistant to lysis as they age. Unfortunately, increased local thrombi may occur as
the clot dissolves, leading to enhanced platelet aggregation and thrombosis.
Strategies to prevent this include administration of antiplatelet drugs, such as
aspirin, or antithrombotics such as heparin.
2. Therapeutic use:
Originally used for the treatment of DVT and serious PE, thrombolytic drugs are
now being used less frequently for these conditions. Their tendency to cause
bleeding has also blunted their use in treating acute peripheral arterial thrombosis.
For MI, thrombolytic agents are usually administered intravenously within 6-12
hours from onset of MI “therapeutic window”. Thrombolytic agents are helpful in
restoring catheter and shunt function, by lysing clots causing occlusions. They are
also used to dissolve clots that result in strokes.
3. Adverse effects:
The thrombolytic agents do not distinguish between the fibrin of an unwanted
thrombus and the fibrin of a beneficial hemostatic plug. Thus, hemorrhage is a
major side effect. For example, a previously unsuspected lesion, such as a gastric
ulcer, may hemorrhage following injection of a thrombolytic agent. These drugs
are contraindicated in pregnancy, and in patients with healing wounds, active
bleeding, history of cerebrovascular accident, brain tumor, head trauma,
intracranial bleeding, and metastatic cancer.