These are drugs which interfere with platelet function and are useful in the prophylaxis of thromboembolic disorders.
ANTIPLATELET DRUGS
(Antithrombotic drugs)
These are drugs which
interfere with platelet function and are useful in the prophylaxis of
thromboembolic disorders.
Platelets express several glycoprotein (GP) integrin receptors
on their surface. Reactive proteins like collagen and von Willebrand factor
(vWF) are exposed when there is damage to vascular endothelium, and they react
respectively with platelet GPIa and GPIb receptors. This
results in platelet activation and release of pro-aggregatory and
vasoconstrictor mediators like TXA2, ADP and 5HT. The platelet GPIIb/IIIa
receptor undergoes a conformational change favouring binding of fibrinogen that
cross links platelets inducing aggregation. Thus, a ‘platelet plug’ is formed.
In veins, due to sluggish blood flow, a fibrinous tail is formed which traps
RBCs ‘the red tail’. In arteries, platelet mass is the main constituent of the
thrombus. Antiplatelet drugs are, therefore, more useful in arterial
thrombosis, while anticoagulants are more effective in venous thrombosis.
Prostacyclin (PGI2), synthesized in the intima of blood
vessels, is a strong inhibitor of platelet aggregation. A balance between TXA2
released from platelets and PGI2 released from vessel wall appears
to control intravascular thrombus formation. Platelets also play a role in
atherogenesis.
In the above scheme, various drugs act on different targets to
interfere with platelet function. The clinically important antiplatelet drugs
are:
Aspirin Clopidogrel
Dipyridamole Abciximab
Ticlopidine (GP IIb/IIIa antagonist)
Aspirin
It acetylates and
inhibits the enzyme COX1 and TXsynthase—inactivating
them irreversibly. Because platelets are exposed to aspirin in the portal
circulation before it is deacetylated during first pass in the liver and
because platelets cannot synthesize fresh enzyme (have no nuclei) TXA2
formation is suppressed at very low doses and till fresh platelets are formed.
Thus, aspirin induced prolongation of bleeding time lasts for 5–7 days. Effect
of daily doses cumulates and it has now been shown that doses as low as 40 mg/
day have an effect on platelet aggregation. Maximal inhibition of platelet
function occurs at ~160 mg aspirin per day.
Aspirin also inhibits COX1 and PGI2 synthesis in vessel
wall. However, since intimal cells can synthesize fresh enzyme, activity
returns rapidly. It is possible that at low doses (75–150 mg/day or 300 mg
twice weekly), TXA2 formation by platelets is selectively
suppressed, whereas higher doses (> 900 mg/day) may decrease both TXA2
and PGI2 production.
Aspirin inhibits the release of ADP from platelets and their
sticking to each other. However, it has no effect on platelet survival time and
their adhesion to damaged vessel wall.
ASA 50 mg tab., COLSPRIN, DISPRIN CV100: aspirin 100 mg soluble
tab, LOPRIN 75 mg tab, ASPICOT 80 mg tab, ECOSPRIN 75, 150 mg tab.
Other NSAIDs are reversible inhibitors of COX, produce short-lasting inhibition of platelet
function—are not clinically useful.
Dipyridamole
It is a vasodilator
which was introduced for angina
pectoris (see Ch. No. 39). It
inhibits phosphodiesterase and blocks uptake of adenosine to increase platelet
cAMP which potentiates PGI2 and interferes with aggregation. Levels
of TXA2 or PGI2, are not altered, but platelet survival
time reduced by disease is normalized.
Dipyridamole alone has
little clinically significant effect, but improves the response to warfarin,
along with which it is used to decrease the incidence of thromboembolism in
patients with prosthetic heart valves.
Dipyridamole has also
been used to enhance the antiplatelet action of aspirin, but trials have failed
to demonstrate additional benefit in prophylaxis of MI. Risk of stroke in
patients with transient ischaemic attacks (TIAs) may be additively reduced.
Dose: 150–300 mg/day. PERSANTIN 25, 100 mg
tabs,
THROMBONIL 75, 100 mg tabs, DYNASPRIN: dipyridamole 75 mg + aspirin
60 mg e.c. tab.
Ticlopidine
It is the first
thienopyridine which alters surface
receptors on platelets and inhibits ADP as well as fibrinogen-induced platelet aggregation.
The Gi coupled P2YAC (also labelled P2Y12) type of
purinergic receptors which mediate adenylyl cyclase inhibition by ADP are
blocked irreversibly by ticlopidine. As a result, activation of platelets is interfered.
It prevents fibrinogen binding to platelets without modifying GPIIb/IIIa
receptor. There is no effect on platelet TXA2, but bleeding time is
prolonged and platelet survival in extracorporeal circulation is increased.
Because of different mechanism of action, it has synergistic effect on
platelets with aspirin: combination is a potent platelet inhibitor.
Ticlopidine is well absorbed
orally, is converted in liver to an active metabolite, cumulates in the
body—peak antiplatelet effect is produced after 8–10 days therapy. The plasma
t½ after single dose is 8 hr, but after multiple doses it is 8 days.
Ticlopidine has produced beneficial effects in stroke
prevention, TIAs, intermittent claudication, unstable angina, PCI, coronary
artery bypass grafts and secondary prophylaxis of MI. Combined with aspirin, it
has markedly lowered incidence of restenosis after PCI and stent thrombosis. Because
of its potential for serious adverse reactions, use of ticlopidine is
restricted to supplementing aspirin or when aspirin is contraindicated.
Side Effects: Diarrhoea, vomiting,
abdominal pain, headache, tinnitus,
skin rash. Serious adverse effects are bleeding, neutropenia, thrombocytopenia
and jaundice. Several fatalities have occurred.
Dose: 250 mg BD with meals;
effect persists several days after discontinuation;
TYKLID,
TICLOVAS, TICLOP, 250 mg tab; ASTIC ticlopidine 250 mg + aspirin 100 mg tab.
Clopidogrel
This newer congener of
ticlopidine has similar mechanism
of action, ability to inhibit platelet function and therapeutic efficacy, but
appears to be safer and better tolerated (CLASSICS study). The clopidogrel vs aspirin in patients at risk of ischaemic
events (CAPRIE) trial has found clopidogrel recipients to have a slightly lower
annual risk of primary ischaemic events than aspirin recipients. The most
important adverse effect is bleeding. Addition of aspirin to clopidogrel has
been found to double the incidence of serious bleeding among high risk stroke
patients (MATCH study). A lower frequency of neutropenia, thrombocytopenia and
other bone marrow toxicity compared to ticlopidine has been recorded. Side
effects are diarrhoea, epigastric pain and rashes.
Clopidogrel + aspirin is as effective in stented patients as
ticlopidine + aspirin. Clopidogrel is 50% absorbed orally and like ticlopidine,
it is a prodrug; action lasts for upto 7 days.
Dose: 75 mg OD; CLODREL, CLOPILET, DEPLATT
75 mg tab.
Glycoprotein (GP) IIb/IIIa Receptor Antagonists
GP IIb/IIIa
antagonists are a new class of potent platelet aggregation inhibitors which act
by blocking the key receptor involved in platelet aggregation. The GP IIb/IIIa
is an adhesive receptor (integrin) for fibrinogen and vWF through which
agonists like collagen, thrombin, TXA2, ADP, etc. induce platelet
aggregation. Thus, GP IIb/IIIa antagonists block
aggregation induced by all platelet agonists.
Abciximab
It is the Fab fragment
of a chimeric monoclonal antibody
against GP IIb/IIIa. Given along with aspirin + heparin
during PCI it has markedly reduced the incidence of restenosis, subsequent MI
and death. After a bolus dose platelet aggregation remains inhibited for 12–24
hr, while the remaining antibody is cleared from blood with a t½ of 10–30 min.
Dose: 0.25 mg/kg i.v. 10–60
min before PCI, followed by 10 μg/min for 12 hr. REOPRO 2 mg/ml inj.
Abciximab is
nonantigenic. The main risk is haemorrhage, incidence of which can be reduced
by carefully managing the concomitant heparin therapy. Thrombocytopenia is another
complication. Constipation, ileus and arrhythmias can occur. It is very
expensive, but is being used in unstable angina and as adjuvant to coronary
thrombolysis/PCI with stent placement.
Eptifibatide and Tirofiban respectively are peptide and nonpeptide GP IIb/IIIa
receptor antagonists, developed as alternatives to abciximab.
Uses Of Antiplatelet Drugs
For certain
indications like maintenance of vascular recanalization, stent placement,
vessel grafting, etc. potent inhibition of platelet function is required. This
is achieved by combining antiplatelet drugs which act by different mechanisms.
Coronary Artery
Disease
MI: Low dose aspirin
started immediately after MI has been
found to reduce mortality and prevent reinfarction. It also improves survival
when used along with thrombolytic therapy. Ticlopidine and clopidogrel are
alternatives.
Aspirin is now
routinely used to prevent re-occlusion after thrombolytic therapy. It is also
given along with heparin to cover PCI, and then continued indefinitely.
Ticlopidine, clopidogrel or abciximab used along with aspirin have markedly
improved the outcome of PCI and stent procedures.
Unstable Angina: Aspirin reduces the risk of MI and sudden death in patients with
unstable angina. For maximum benefit aspirin (100–150 mg/day) is given along
with heparin—followed by warfarin. Ticlopidine or clopidogrel can be used as
alternatives or adjuvant to aspirin.
The Clopidogrel in
unstable angina to prevent recurrent events (CURE) trial has found that addition
of clopidogrel to aspirin further reduced cardiovascular mortality, nonfatal MI
and stroke by 20%.
Primary And Secondary Prevention Of MI: On the basis of trials in postMI as well as in
those with no such history, it has been recommended that aspirin 75–150 mg/day
be given to all individuals with evidence of coronary artery disease and in
those with risk factors for the same, but routine use in the whole population
is not warranted. Aspirin reduces the incidence of fatal as well as nonfatal
MI, but increases the risk of cerebral haemorrhage; overall mortality is marginally
reduced.
Cerebrovascular Disease
Antiplatelet drugs do not alter the
course of stroke due to cerebral thrombosis. However, aspirin has reduced the
incidence of TIAs, of stroke in patients with TIAs or persistent atrial
fibrillation and in those with history of stroke in the past. It is recommended
in all such individuals. The European stroke prevention study2 (ESPS) has found
combination of dipyridamole with low dose aspirin to be synergistic in
secondary prevention of stroke. Ticlopidine and clopidogrel also reduce TIAs
and stroke.
Coronary Angioplasty,
Stents, Bypass Implants
The patency of
recanalized coronary artery or implanted bypass vessel is improved and
incidence of re-occlusion is reduced by aspirin aolne and in combination with
ticlopidine/ clopidogrel. Abciximab used along with aspirin and heparin has
markedly reduced restenosis and subsequent MI after coronary angioplasty.
Prosthetic
Heart Valves And Arteriovenous Shunts
Antiplatelet drugs,
used with warfarin reduce formation of microthrombi
on artificial heart valves and the incidence of embolism. Aspirin is clearly
effective but increases risk of bleeding due to warfarin. Dipyridamole does not
increase bleeding risk, but incidence of thromboembolism is reduced when it is
combined with an oral anticoagulant. Antiplatelet drugs also prolong the
patency of chronic arteriovenous shunts implanted for haemodialysis and of
vascular grafts.
Venous Thromboembolism
Anticoagulants are routinely used. Trials have shown
antiplatelet drugs also to have a prophylactic effect, but their relative value
in comparison to or in addition to anticoagulants is not known.
Peripheral
Vascular Disease
Aspirin/ ‘ticlopidine/clopidogrel may produce some
improvement in intermittent claudication and reduce the incidence of
thromboembolism.
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