5. Fibrinolytics & Antiplatelets.pdf

Fibrinolytics (Thrombolytics) These are drugs used to lyse thrombi/clot to recanalise occluded blood vessels (mainly coronary artery) They are therapeutic rather than prophylactic and work by activating the natural fibrinolytic system  In general, venous thrombi are...

Fibrinolytics (Thrombolytics) These are drugs used to lyse thrombi/clot to recanalise occluded blood vessels (mainly coronary artery) They are therapeutic rather than prophylactic and work by activating the natural fibrinolytic system  In general, venous thrombi are lysed more easily by fibrinolytics than arterial, and recent thrombi respond better They have little effect on thrombi > 3 days old The clinically important fibrinolytics are as follows: Alteplase (rt-PA) Streptokinase Reteplase Urokinase Tenecteplase  Streptokinase (Stk) Obtained from β haemolytic Streptococci group C First drug - used clinically Streptokinase is inactive as such - Combines with circulating plasminogen molecules to form an activator complex which then causes limited proteolysis of other plasminogen molecules to generate the active enzyme plasmin Stk. is non-fibrin specific - i.e. activates both circulating as well as fibrin bound plasminogen Therefore, it depletes circulating fibrinogen and predisposes to bleeding  Streptokinase (Stk) For MI: 7.5–15 lac IU infused i.v. over 1 hr. Anti streptococcal antibodies due to past infections inactivate considerable fraction of the initial dose of Stk A loading dose therefore is necessary Plasma t½ is 30–80 min Stk is antigenic — can cause hypersensitivity reactions Anaphylaxis occurs in 1–2% patients It cannot be used second time due to neutralization by antibodies generated in response to the earlier dose For deep vein thrombosis and pulmonary embolism: 2.5 lac IU loading dose over ½–1 hr, followed by 1 lac IU/hr for 24 hr. Adverse Effects: Fever, hypotension and arrhythmias  Urokinase It is an enzyme isolated from human urine Commercially prepared from cultured human kidney cells It activates plasminogen directly and has a plasma t½ of 10–15 min It is nonantigenic Fever occurs during treatment, but hypotension and allergic phenomena are rare It is Indicated in patients in whom streptokinase has been given for an earlier episode, but is seldom used now For MI: 2.5 lac IU i.v. over 10 min followed by 5 lac IU over next 60 min (stop in between if full recanalization occurs) or 6000 IU/min for upto 2 hr. For venous thrombosis and pulmonary embolism: 4400 IU/kg over 10 min i.v. followed by 4400 IU/kg/hr for 12 hr.  Alteplase (recombinant tissue plasminogen activator (rt-PA) Produced by recombinant DNA technology from human tissue culture It is moderately specific for fibrin-bound plasminogen, so that circulating fibrinogen is lowered only by ~ 50% It is rapidly cleared by liver and inactivated by plasminogen activator inhibitor-1(PAI-1) The plasma t½ is 4–8 min It needs to be given by slow i.v. infusion (due to short t½) and often requires heparin coadministration It is nonantigenic, but nausea, mild hypotension and fever may occur It is expensive  Alteplase (recombinant tissue plasminogen activator (rt-PA) USE:  For MI: (accelerated regimen) 15 mg i.v. bolus injection followed by 50 mg over 30 min, then 35 mg over the next 1 hr. (total 90 min)  For pulmonary embolism: 100 mg i.v. infused over 2 hr.  For ischaemic stroke: 0.9 mg/kg by i.v. infusion over 60 min, with 10% of the dose injected in the first minute  Reteplase It is a modified form of rt-PA that is longer acting, but somewhat less specific for fibrin-bound plasminogen The longer duration of action enables bolus dose administration (10 mg over 10 min repeated after 30 min)  Tenecteplase This is genetically engineered substitution mutant of native t-PA It has:  Higher fibrin selectivity  Slower plasma clearance (longer duration of action) and  Resistance to inhibition by PAI-1 It is the only fibrinolytic agent that can be injected i.v. as a single bolus dose over 10 sec, while Alteplase requires 90 min infusion This feature makes it possible to institute fibrinolytic therapy immediately on diagnosis of ST segment elevation myocardial infarction (STEMI), even during transport of the patient to the hospital Dose: 0.5 mg/kg single i.v. bolus injection  Uses of fibrinolytics  Acute Myocardial Infarction (MI) Chief indication Fibrinolytics are an alternative first line approach to emergency percutaneous coronary intervention (PCI) with stent placement Recanalization of thrombosed coronary artery has been achieved in 50–90% cases Time lag in starting the infusion is critical for reducing area of necrosis, preserving ventricular function and reducing mortality Aspirin with or without heparin is generally started concurrently or soon after thrombolysis to prevent reocclusion Alteplase has advantages over streptokinase, including higher thrombolytic efficacy Its stronger lytic effect on physiological hemostatic plugs may compensate for the lesser systemic fibrinolytic state  Uses of fibrinolytics  Deep vein thrombosis in leg, pelvis, shoulder etc. Up to 60% patients can be successfully treated Thrombolytics can decrease subsequent pain and swelling Main Advantage - preservation of venous valves and may be a reduced risk of pulmonary embolism  Pulmonary embolism Fibrinolytic therapy is indicated in large, life-threatening PE The lung function may be better preserved, but reduction in mortality is not established  Stroke: Thrombolytic therapy of ischaemic stroke is controversial Possibility of improved neurological outcome is to be balanced with risk of intracranial haemorrhage  Uses of fibrinolytics  Peripheral arterial occlusion Fibrinolytics recanalise ~40% limb artery occlusions, especially those treated within 72 hr. It is indicated only when surgical thrombectomy is not possible Regional intra arterial fibrinolytics are used for limb arteries with greater success Peripheral arterial thrombolysis is followed by short term heparin and long- term aspirin therapy  Uses of fibrinolytics  Evaluation All patients with STEMI are candidates for reperfusion therapy No consistent benefit of fibrinolytics has been demonstrated in non-STEMI cases, while possibility of haemorrhage is increased Only selected cases of NSTEMI may be treated with fibrinolytics Both short-term and long-term outcome is determined by early restoration of flow in the occluded artery, regardless of whether it is achieved by thrombolysis or by PCI Best results are obtained if perfusion can be restored within the first hour (the golden hour) While the efficacy of fibrinolytics in dissolving the thrombus diminishes with passage of time (little benefit after 6 hours of MI onset), reperfusion by PCI is affected to a lesser extent by the time lapse Thrombolysis may be favoured if it can be started within 1–2 hours of onset  Uses of fibrinolytics  Evaluation After 3 hours, PCI is favoured PCI has the advantage of lower bleeding risk, higher grade of flow in the reperfused artery and reduction in the rate of nonfatal recurrent MI compared to thrombolysis PCI has yielded superior results compared to fibrinolytics and is being preferred at centres where it can be performed swiftly with requisite expertise Primary PCI is the procedure of choice for patients with contraindications to thrombolytics Fibrinolytic therapy requires careful patient selection, but often can be instituted with less delay, and even at centres not well equipped for PCI Another approach is ‘facilitated PCI’ wherein full or reduced dose fibrinoytic therapy is followed at the earliest by PCI  Uses of fibrinolytics  Evaluation The results of this approach are comparable to those of primary PCI The European as well as American (ACC, AHA) guidelines provide that STEMI patients should be treated with primary PCI or with fibrinolytic drugs followed by immediate rescue PCI, if reperfusion fails with the fibrinolytic Aspirin and heparin are continued after thrombolysis  Antifibrinolytic Drugs These are drugs which inhibit plasminogen activation and dissolution of clot, and are used to check fibrinolysis associated bleeding  Antifibrinolytic Drugs  Epsilon Amino- Caproic Acid (EACA) It is a lysine analogue which combines with the lysine binding sites of plasminogen and plasmin so that the latter is not able to bind to fibrin and lyse it It is a specific antidote for fibrinolytic agents and has been used in many hyperplasminaemic states associated with excessive intravascular fibrinolysis resulting in bleeding The primary indication is to counteract the effect of fibrinolytic drugs and bleeding due to their use In haemophiliacs, it has adjunctive value for controlling bleeding due to tooth extraction, prostatectomy, trauma, etc. In haematuria it can cause ureteric obstruction by the unlysed clots - fibrinolysis must be established firmly before using it It can cause intravascular thrombosis Rapid i.v. injection results in hypotension, bradycardia and may be arrhythmias  Epsilon Amino- Caproic Acid (EACA) It should be used cautiously when renal function is impaired Myopathy occurs rarely The large dose needed is a limitation, and tranexamic acid is mostly preferred Initial priming dose is 5 g oral/i.v., followed by 1 g hourly till bleeding stops (max. 30 g in 24 hrs)  Tranexamic acid Like EACA, it binds to the lysine binding site on plasminogen and prevents its combination with fibrin leading to fibrinolysis It is 7 times more potent than EACA, and is preferred for prevention/control of excessive bleeding due to:  Fibrinolytic drugs  Cardio-pulmonary bypass surgery  Tonsillectomy, prostatic surgery, tooth extraction in haemophiliacs  Menorrhagia, especially due to IUCD  Recurrent epistaxis, hyphemia due to ocular trauma, peptic ulcer Side effects: Nausea and diarrhoea Thromboembolic events, disturbed color vision and allergic reactions are infrequent Thrombophlebitis of injected vein can occur Dose: 10–15 mg/kg 2–3 times a day or 1–1.5 g TDS oral, 0.5–1 g TDS by slow i.v. infusion  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 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 proaggregatory and vasoconstrictor mediators like TXA2, ADP and 5-HT The platelet GPIIb/IIIa receptor undergoes a conformational change favouring binding of fibrinogen and vonWillebrand factor (vWF) that crosslink platelets inducing aggregation and anchorage to vessel wall/other surfaces  Antiplatelet Drugs (Antithrombotic drugs) 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 controls intravascular thrombus formation Platelets also play a role in atherogenesis Antiplatelet Drugs (Antithrombotic drugs) Various drugs act on different targets to interfere with platelet function The clinically important antiplatelet drugs are:  Aspirin It acetylates and inhibits the enzyme COX1 and TX-synthase — inactivating them irreversibly TXA2 is the major arachidonic acid product generated by platelets Platelets are exposed to aspirin in the portal circulation before it is deacetylated during first pass in the liver  Aspirin 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 Doses as low as 40 mg/day have an effect on platelet aggregation Maximal inhibition of platelet function occurs at 75–150 mg aspirin per day Aspirin may not effectively inhibit platelet aggregation in some patients  Aspirin Inhibition of COX-1 by aspirin in vessel wall decreases PGI2 synthesis as well Intimal cells can synthesize fresh enzyme, activity returns rapidly 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, but has no effect on platelet survival time and their adhesion to damaged vessel wall Other NSAIDs are reversible inhibitors of COX, produce short-lasting inhibition of platelet function — are not clinically useful  Dipyridamole It is a vasodilator - was introduced for angina pectoris It inhibits phosphodiesterase as well as blocks uptake of adenosine to increase platelet cAMP which in turn 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 Used to enhance the antiplatelet action of aspirin This combination additionally lowers the risk of stroke in patients with transient ischaemic attacks (TIAs) Dose: 150–300 mg/day  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 P2Y12 (also labelled P2YAC) type of purinergic receptors which mediate adenylyl cyclase inhibition due to ADP are blocked irreversibly by the active metabolite of Ticlopidine - activation of platelets is interfered Fibrinogen binding to platelets is prevented without modification of GPIIb/IIIa receptor There is no effect on platelet TXA2, but bleeding time is prolonged and platelet survival in extra-corporeal circulation is increased Because of different mechanism of action, it has synergistic effect on platelets with aspirin Their combination is a potent platelet inhibitor Ticlopidine is well absorbed orally, is converted in liver to an active metabolite, and is eliminated with a plasma t½ of 8 hours  Ticlopidine It causes irreversible blockade of P2Y12 receptors - the effect on platelets cumulates Peak platelet inhibition is produced after 8–10 days therapy and the effect lasts 5– 6 days after discontinuing the drug USE:  In stroke prévention  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 Side effects: Diarrhoea, vomiting, abdominal pain, headache, tinnitus, skin rash. Serious adverse effects are bleeding, neutropenia, thrombocytopenia, haemolysis and jaundice Dose: 250 mg BD with meals  Clopidogrel Newer and more potent congener of Ticlopidine Has similar mechanism of action, ability to irreversibly inhibit platelet function and range of therapeutic efficacy Safer and better tolerated Combination of clopidogrel and aspirin is synergistic in preventing ischaemic episodes, and is utilized for checking restenosis of stented coronaries About 50% of the ingested dose is absorbed, and only a fraction of this is slowly activated in liver by CYP2C19, while the rest is inactivated by other enzymes It is a slow acting drug - antiplatelet action takes about 4 hours to start and develops over days Clopidogrel is also a prodrug - The activation and consequently its antiplatelet action shows high inter individual variability  Clopidogrel Omeprazole, an inhibitor of CYP2C19, reduces metabolic activation of clopidogrel and its antiplatelet action The action of clopidogrel lasts 5–7 days due to irreversible blockade of platelet P2Y12 receptors The most important adverse effect is bleeding Addition of aspirin to clopidogrel double the incidence of serious bleeding among high risk stroke patients Neutropenia, thrombocytopenia and other bone marrow toxicity is rare Side effects: Diarrhoea, epigastric pain and rashes Dose: 75 mg OD  Prasugrel Latest, most potent and faster acting P2Y12 purinergic receptor blocker Used in acute coronary syndromes (ACS) and when strong antiplatelet action is required It is also a prodrug - more rapidly absorbed and more rapidly as well as more completely activated - in faster and more consistent platelet inhibition - particularly suitable for use in STEMI It is the preferred for ACS to cover angioplasty with or without stent placement Patients with history of ischaemic stroke and TIAs are at greater risk of intracranial haemorrhage Prasugrel is contraindicated in such patients Dose: 10 mg OD; elderly or those