Antiplatelet Drugs (Antithrombotic drugs)

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 GPI_a and GPI_b receptors. This results in platelet activation and release of pro-aggregatory and vasoconstrictor mediators like TXA₂, ADP and 5HT. The platelet GPII_b/III_a 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 II_b/III_a 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 P2Y_AC (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 GPII_b/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 II_b/III_a antagonists are a new class of potent platelet aggregation inhibitors which act by blocking the key receptor involved in platelet aggregation. The GP II_b/III_a is an adhesive receptor (integrin) for fibrinogen and vWF through which agonists like collagen, thrombin, TXA₂, ADP, etc. induce platelet aggregation. Thus, GP II_b/III_a antagonists block aggregation induced by all platelet agonists.

Abciximab

It is the Fab fragment of a chimeric monoclonal antibody against GP II_b/III_a. 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 II_b/III_a 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.