Fibrinolytics (Thrombolytics)

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Chapter: Essential pharmacology : Drugs Affecting Coagulation, Bleeding And Thrombosis

These are drugs used to lyse thrombi/clot to recanalize occluded blood vessels (mainly coronary artery). They are curative rather than prophylactic; work by activating the natural fibrinolytic system


FIBRINOLYTICS

(Thrombolytics)

 

These are drugs used to lyse thrombi/clot to recanalize occluded blood vessels (mainly coronary artery). They are curative rather than prophylactic; work by activating the natural fibrinolytic system (Fig. 44.3).

 


 

Haemostatic plug of platelets formed at the site of injury to blood vessels is reinforced by fibrin deposition to form a thrombus. Once repair is over, the fibrinolytic system is activated to remove fibrin. The enzyme responsible for digesting fibrin is a serine protease Plasmin generated from plasminogen by tissue plasminogen activator (tPA), which is produced primarily by vascular endothelium. Plasminogen circulates in plasma as well as remains bound to fibrin. The tPA selectively activates fibrin bound plasminogen within the thrombus, and any plasmin that leaks is inactivated by circulating antiplasmins. Fibrin bound plasmin is not inactivated by antiplasmins because of common binding site for both fibrin and antiplasmin.

 

When excessive amounts of plasminogen are activated (by administered fibrinolytics), the α2 antiplasmin is exhausted and active plasmin persists in plasma. Plasmin is a rather nonspecific protease: degrades coagulation factors (including fibrinogen) and some other plasma proteins as well. Thus, activation of circulating plasminogen induces a lytic state whose major complication is haemorrhage. Even selective activation of thrombus bound plasmin can cause bleeding by dissolving physiological thrombi. In general, venous thrombi are lysed more easily than arterial, and recent thrombi respond better: little effect on thrombi > 3 days old. The clinically important fibrinolytics are:

 

Streptokinase        Alteplase (rt-PA)

Urokinase             Reteplase

                             Tenecteplase

 

 

Streptokinase (Stk)

 

It is obtained from β haemolytic Streptococci group C. It is inactive as such: combines with circulating plasminogen to form an activator complex which then causes limited proteolysis of other plasminogen molecules to plasmin. Antistreptococcal antibodies present due to past infections inactivate considerable fraction of the initial dose of Stk: a loading dose is necessary in the beginning. Its t½ is estimated to be 30–80 min.

 

Streptokinase is antigenic; can cause hypersensitivity reactions and anaphylaxis, especially when used second time in a patient. Repeat doses are also less effective due to neutralization by antibodies. Fever is common, hypotension and arrhythmias are reported.

 

Because of the availability of newer fibrinolytics which do not pose some of the above problems, Stk is infrequently used now in developed countries. However, being the least expensive, it is still widely used in India and other developing countries.

 

STREPTASE, (freeze dried powder in vials) 2.5 lac, 7.5 lac and 15 lac IU/vial, ESKINASE, CARDIOSTREP 7.5 lac, 15 lac IU/vial.

 

For MI: 7.5–15 lac IU infused i.v. over 1 hr.

 

For deep vein thrombosis and pulmonary embolism: 2.5 lac IU loading dose over ½1 hr, followed by 1 lac IU/hr for 24 hr.

 

Urokinase

 

It is an enzyme isolated from human urine; now prepared from cultured human kidney cells, which 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. Indicated in patients in whom streptokinase has been used for an earlier episode, use has now declined due to introduction of newer fibrinolytics.

 

UROKINASE, KDUNASE, 2.5 lac, 5 lac, 10 lac IU per vial inj.

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 (rtPA)

 

Produced by recombinant DNA technology from human tissue culture, it specifically activates gel phase plasminogen already bound to fibrin, and has little action on circulating plasminogen. It is rapidly cleared by liver and has a plasma t½ of 4–8 min. Because of the short t½, it needs to be given by slow i.v. infusion and often requires heparin coadministration. It is nonantigenic, but nausea, mild hypotension and fever may occur. It is expensive.

 

ACTILYSE 50 mg vial with 50 ml solvent water.

 

For MI: 15 mg i.v. bolus injection followed by 50 mg over 30 min, then 35 mg over the next 1 hr.

 

For pulmonary embolism: 100 mg i.v. infused over 2 hr.

 

Reteplase

 

It is a modified form of rtPA 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

 

It is a mutant variant of rtPA with higher fibrin selectivity and longer duration of action. A single i.v. bolus dose (0.5 mg/kg) or split into two doses 30 min apart is given.

The clinical efficacy and risk of bleeding with reteplase and tenecteplase are similar to alteplase.

 

Uses Of Fibrinolytics

 

1. Acute Myocardial Infarction is the 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. The benefits of i.v. thrombolytic therapy have been established by large randomised studies. Aspirin with or without heparin is generally started concurrently or soon after thrombolysis to prevent re-occlusion.

Alteplase has advantages over streptokinase, including higher thrombolytic efficacy. However, incidence of haemorrhage is not lower; may even be higher. Its stronger lytic effect on physiological haemostatic plugs may compensate for the lesser systemic fibrinolytic state.

 

Fibrinolytic therapy has also been used in unstable angina, because many such patients have coronary thrombi.

 

2. Deep Vein Thrombosis in leg, pelvis, shoulder etc.; up to 60% patients can be successfully treated. Thrombolytics can decrease subsequent pain and swelling, but the main advantage is preservation of venous valves and may be a reduced risk of pulmonary embolism, though at the risk of haemorrhage. Comparable results have been obtained with Stk, urokinase and rtPA.

 

3. Pulmonary Embolism: Fibrinolytic therapy is indicated in large, lifethreatening pulmonary embolism. The lung function may be better preserved, but reduction in mortality is not established.

 

4. Peripheral Arterial Occlusion: Fibrinolytics recanalise ~40% limb artery occlusions, especially those treated within 72 hr. However, it is indicated only when surgical thrombectomy is not possible. Regional intraarterial fibrinolytics have been used for limb arteries with greater success. Peripheral arterial thrombolysis is followed by shortterm heparin and long-term aspirin therapy.

Fibrinolytics have no role in chronic peripheral vascular diseases.

 

5. Stroke: Thrombolytic therapy of ischaemic stroke is controversial. Trials showing improved neurological outcome with no change in mortality, as well as those finding significant risk of intracranial haemorrhage and increased mortality are on record. No net benefit was concluded by the ATLANTIS trial in patients treated at 3–5 hours of stroke onset. However, rtPA is approved for use in ischaemic stroke, and current opinion supports use of i.v. alteplase in carefully selected patients who can be treated within 3 hours of onset, and in whom intracranial haemorrhage is ruled out along with all risk factors for bleeding.

 

Evaluation

 

All patients with ST segment elevation myocardial infarction (STEMI) are candidates for reperfusion therapy. Both shortterm 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 not as much affected by the time lapse. Thrombolysis may be favoured if it can be started within 1–2 hours of onset. After 3 hours, PCI is favoured. Moreover, 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. As such, wherever available, PCI is being used in preference. Presence of risk factors for bleeding also favour PCI. However, the overall 6 month mortality has not been found to differ between either mode of reperfusion.

 

Invasive procedures, such as cardiac catheterization, should be avoided in patients who are to be given thrombolytics, because risk of bleeding is increased. With concurrent use of heparin, major bleeding (including intracranial haemorrhage) occurs in 2–4% patients. The incidence of bleeding is almost similar with Stk, urokinase and rtPA. Analysis of recent trials has shown that exclusion of heparin reduces bleeding, and that heparin affords no extra benefit over fibrinolytic + aspirin. Another analysis has shown that efficacy of Stk and rtPA in MI is similar, but certain other features favour the newer thrombolytics.

 

Thrombolytic therapy requires careful patient selection. It is contraindicated in all situations where the risk of bleeding is increased, such as— recent trauma, surgery, biopsies, haemorrhagic stroke or peptic ulcer, severe hypertension, aneurysms, bleeding disorders, diabetes, acute pancreatitis, etc. Its use in retinal vessel occlusion has been abandoned.

 

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