FIBRINOLYTICS (Thrombolytics) AND ANTIPLATELET DRUGS
FIBRINOLYTICS (Thrombolytics):
These are drugs used to lyse thrombi/clot to recanalize occluded blood vessels
(mainly coronary artery). They are therapeutic rather than prophylactic and work
by activating the natural fibrinolytic system.
The plasminogen-plasmin system
t-PA-Tissue plasminogen activator; rt-PA-Recombinant t-PA; PAI-1 Plasminogen
activator inhibitor-1
The clinically important fibrinolytics are:
Streptokinase
Urokinase
Alteplase (rt-PA)
Reteplase
Tenecteplase
Streptokinase: Obtained from hemolytic Streptococci group C, it is the first
fibrinolytic drug to be used clinically, but is not employed now except for
considerations of cost. 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.
It is non-fibrin specific, i.e. activates both circulating as well as fibrin bound
plasminogen. Therefore, it depletes circulating fibrinogen and predisposes to
bleeding. Compared to newer more fibrin-specific tissue plasminogen activators
(alteplase, etc.) it is less effective in opening occluded coronary arteries, and
causes less reduction in MI related mortality.
There are several other disadvantages as well with streptokinase. Antistreptococcal
antibodies due to past infections inactivate considerable fraction of the initial dose
of Stk. A loading dose therefore is necessary. Plasma t½ is estimated to be 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. Fever, hypotension and arrhythmias are
reported. However, being less expensive, it is still used in resource poor areas, but
not in Europe or USA.
Urokinase: It is an enzyme isolated from human urine; but commercially prepared
from cultured human kidney cells. It activates plasminogen directly and has a
plasma t½ of 10–15 min. It is non-antigenic. Fever occurs during treatment, but
hypotension and allergic phenomena are rare. Urokinase is indicated in patients in
whom streptokinase has been given for an earlier episode, but is seldom used now.
Alteplase (recombinant tissue plasminogen activator (rt-PA): It is 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. Because of the short t½, it needs to
be given by slow i.v. infusion and often requires heparin co-administration. It is
non-antigenic, but nausea, mild hypotension and fever may occur. It is expensive.
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 genetically engineered substitution mutant of native t-PA 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. Several randomized
multicentric trials have assessed its efficacy in STEMI and found it to be at least
equally efficacious to alteplase. Risk of noncerebral bleeding may be lower with
tenecteplase, but cranial bleeding incidence is similar.
Uses of fibrinolytics:
1. Acute myocardial infarction is the chief
2. Deep vein
3. Pulmonary
4. Peripheral arterial occlusion
5. Stroke
ANTIPLATELET DRUGS: