THROMBOLYTIC & ANTI- PLATELET

DRUGS

• COL® AZMAT ALI

SITARA-E=IMTIAZ(MILITARY)
 INTRODUCTION
• The principal aim of thrombolytic therapy is the removal
of a pathologic intraluminal thrombus or embolus that has
not been dissolved by spontaneous fibrinolysis.
• In certain clinical conditions such as acute myocardial
infarction, the speed of thrombus dissolution is critical
because only early reperfusion can reduce the infarct size
and improve jeopardized left ventricular function.
• The same concern for rapid lysis of emboli prevails in life-
threatening, massive pulmonary embolism.
• Although direct local delivery of thrombolytic
agents at the site of the vascular occlusion
may enhance its lysis, there is an inherent
time lag required for coronary and pulmonary
artery catheterization with its unavoidable
delay in drug administration.
 Thrombolytic drugs
• Streptokinase
• Urokinase
• Anistreplase
 tissue Plasminogen Activators (t-PA)
• Alteplase
• Reteplase
• Tenecteplase
Mechanism of Thrombolytic Drugs

They have a common mechanism of converting

the pro-enzyme plasminogen to the active
enzyme plasmin, which lyses fibrin clot

Plasminogen is converted to plasmin by cleavage

of the Arg-Val (560-561) peptide bond

Plasmin; is a nonspecific serine protease capable

of breaking down fibrin, fibrinogen, factors V and
VIII
 Plasminogen

• Plasminogen is a single-chain glycoprotein of 791 amino acids;

it is converted to an active protease by cleavage at Arg560.
•
Plasminogen’s five kringle domains mediate the binding of
plasminogen (or plasmin) to carboxyl-terminal lysine residues
in partially degraded fibrin; this
enhances fibrinolysis. A plasma carboxypeptidase termed
thrombin-activatable fibrinolysis inhibitor (TAFI) can remove
these lysine residues and thereby
attenuate fibrinolysis.
•
• α2-Antiplasmin. α2-Antiplasmin, a
glycoprotein of 452 amino acid residues,
forms a stable complex with plasmin, thereby
inactivating it.
• . The lysine binding kringle domains of
plasminogen are located between amino acids 80
and 165, and they also promote formation of
complexes of plasmin with α2-antiplasmin, the
major physiological plasmin inhibitor.
Plasminogen concentrations in human plasma
average 2 μM. A plasmin degraded form of
plasminogen termed lys-plasminogen binds to
fibrin with higher affinity than intact plasminogen
• Plasma concentrations of α 2-antiplasmin (1 μM) are
sufficient to inhibit about 50% of potential plasmin.
• When massive activation of plasminogen occurs, the
inhibitor is depleted, and free plasmin causes a “systemic
lytic state” in which hemostasis is impaired.
• In this state, fibrinogen is degraded and fibrinogen
degradation products impair fibrin polymerization and
therefore increase bleeding from wounds.
• α2-Antiplasmin inactivates plasmin nearly instantaneously,
as
long as the first kringle domain on plasmin is unoccupied by
fibrin or other antagonists, such as aminocaproic acid
Fibrinolysis
 Mechanism of Thrombolytic Drugs
• Fibrin-specific agents are much more active upon binding to fibrin, thereby
increasing their affinity for plasminogen at the clot surface
 Streptokinase

• Streptokinase is a nonenzymatic protein isolated from

the broth of Lancefield group C strains of beta-
hemolytic streptococci.
• It is a single polypeptide chain without carbohydrates,
with a molecular weight of 47 kilodaltons .

• The amino acid sequence of streptokinase is known

and is similar to that of streptomyces griseus and
human trypsin
Streptokinase is an indirect activator of plasminogen. It
initially forms a I: 1 stoichiometric complex with the zymogen
plasminogen, which thereby undergoes a transition,
allowing exposure of the active site within plasminogen
without apparent peptide bond cleavage
This modified streptokinase-plasminogen complex behaves as a
plasminogen activator . The activator complex can also induce a limited
proteolysis in the plasminogen molecule of
other streptokinase-plasminogen molecules whereby plasminogen is
converted to plasmin;
1. streptokinase progressively degrades to smaller fragments, resulting
in a gradual loss of activator activity
 Mode of action.

• After the injection of indium-l 3I-labeled

streptokinase, an immediate rapid clearance phase (half-life 18
minutes) is followed by a slower disappearance phase (half-life 83
minutes) .
• The initial rapid phase is interpreted as immune complexing of
streptokinase.
• Indeed, human plasma contains antibodies directed against
streptokinase, probably as a result of previous infections with beta
hemolytic streptococci. The titer of streptokinase antibodies
varies from person to person .
•
 .
• tPA binds to fibrin on the surface of the clot.
Activates fibrin-bound plasminogen
• Plasmin is cleaved from the plasminogen
associated with the fibrin
• Fibrin molecules are broken apart by the
plasmin and the clot dissolves
• Because streptokinase reacts with antibodies
and is thereby rendered biochemically inert,
sufficient amounts of streptokinase must be
infused
to neutralize the antibodies before fibrinolytic
activation is obtained .
• If a loading dose of streptokinase high enough
to overcome the streptococcal antibodies is
given, plasminogen will be activated to plasmin.
• Low doses of streptokinase may generate more
plasmin and less streptokinase plasminogen
complex; however, the plasmin formed will
soon be neutralized by circulating antiplasmin.
• However, the plasmin formed will soon be
neutralized by circulating antiplasmin. Only when
the 0'2-antiplasmin level is markedly reduced will
plasmin
be less rapidly neutralized and exert a proteolytic
effect on
several plasma proteins, among which the
coagulation components fibrinogen and factors V
and VIII are the most
• A high initial dose of streptokinase will be
associated
with a rapid and profound reduction in the level
of circulating plasminogen, antiplasmin and
fibrinogen .
• Provided a high maintenance dose of
streptokinase follows, high circulating activator
levels are obtained and fibrinogen levels start to
rise in the subsequent 24 hour
• Equimolar complexes of streptokinase and
human plasminogen have been used for
thrombolysis because their fibrinolytic activity
does not depend on the circulating
plasminogen content and also because the
plasminogen conformation is somewhat
changed in the complex, resulting in a better
catalytic activity
• Acyl derivatives. Stable acyl derivatives of an equimolar
streptokinase-plasminogen complex have been prepared by
acylation of the Ser 740 residue located in the catalytic
center of the light beta-chain of plasminogen
• Because the catalytic center is functionally separate from its
fibrin-binding site located in the heavy or alpha-chain of
plasmin, acylated streptokinase-human plasminogen is catalytically
inert so that it can circulate in the vascular system without reaction
with either plasma inhibitors or plasminogen, but still bind to fibrin
through the unmodified kringle domains of the plasminogen moiet
• These compounds deacylate under physiologic
conditions after first order kinetics, with half-
lives of 40 minutes (p-anisoyl derivative, BRL-
26921) and 17 hours (p-aminobenzoyl
derivative,
 Urokinase

• The presence of a fibrinolytic activity in urine

was discovered in 1913 by Johansson . Much
later, it was found that the urine activates
plasminogen ; the plasminogen converting
principle was recognized as a kinase, hence
the name urokinase
 Urokinase is a trypsin-like serine protease composed of
two polypeptide chains (20 and 30 kilodaltons) connected
by a single disulfide bridge.
• Urokinase may occur in two molecular forms: a high
molecular weight form (54 kilodaltons) and its proteolytic
product or a low molecular weight form (31 kilodaltons)
that contains mainly the heavy chain (the high molecular
weight form apparently predominates in humans) .
• The complete primary structure of urokinase has been
elucidated (47); the heavy and light chains
contain, respectively, 253 and 157 amino acid
 Mode of action.

• Urokinase is a direct activator of plasminogen and

cleaves, by first order kinetics, a single Arg 560-Val 561
bound in the plasminogen molecule .
• Although in vitro high molecular weight urokinase has
greater clot-dissolving activity than
does the low molecular weight form , this difference
could not be confirmed in vivo .
• Urokinase prepared from either urine or tissue culture
is not antigenic in humans and both have a similar
esterase and fibrinolytic activity in vitro and in vivo
 Tissue Plasminogen Activator

• t-PA is a serine protease of 527 amino acid residues. It is a

poor plasminogen activator in the absence of fibrin.

• t-PA binds to fibrin via its finger domain and second lysine-
binding kringle domain and activates fibrin-bound
plasminogen several hundredfold more rapidly than it
activates plasminogen in the circulation.
• The finger domain is homologous to a similar site on
fibronectin, whereas the lysine binding kringle
domain is homologous to the kringle domains on
plasminogen.
• Because it has little activity except in the presence of fibrin,
physiological t-PA concentrations of 5-10 ng/mL do not
induce systemic plasmin generation.

• During therapeutic infusions of t-PA, however, when

concentrations rise to 300-3000 ng/mL, a systemic lytic
state can occur.
• Clearance of t-PA primarily occurs
by hepatic metabolism, and its t1/2 is ∼5 min.
• t-PA is effective in lysing thrombi during treatment of acute
myocardial infarction or acute ischemic stroke.
 THERAPEUTICS
• t-PA (alteplase, ACTIVASE) is produced by
recombinant DNA technology.
• The currently recommended (“accelerated”)
regimen for coronary thrombolysis is a 15-mg
intravenous bolus, followed by 0.75 mg/kg of
body weight over 30 minutes (not to exceed 50
mg) and 0.5 mg/kg (up to 35 mg accumulated
dose) over the following hour.
• Recombinant variants of t-PA now are available
(reteplase, RETAVASE and tenecteplase, TNKASE).
• They differ from native t-PA by having longer plasma
half-lives that allow convenient bolus dosing;
• reteplase is administered in two bolus doses given 30
minutes apart, while tenecteplase requires only a
single bolus. In contrast to t-PA and reteplase,
tenecteplase is relatively resistant to inhibition by PAI-
1. Despite these apparent advantages, these agents are
similar to
t-PA in efficacy and toxicity
Hemorrhagic Toxicity of Thrombolytic
Therapy.

• The major toxicity of all thrombolytic agents is

hemorrhage, which results from two factors:
• 1) the lysis of fibrin in hemostatic plugs at sites of
vascular injury,
• 2) the systemic lytic state that results from systemic
plasmin generation, which produces fibrinogenolysis
and degradation of other coagulation factors
(especially factors V and VIII).
• Bleeding events are classified according to the
GUSTO definitions.
• Major bleeding events included severe or life-
threatening bleeding events and moderate
bleeding events.
• Severe or life-threatening bleeding events were those
that caused haemodynamic compromise requiring
intervention (e.g. blood or fluid replacement, inotropic
support, surgical repair) or that resulted
in death.
•
• Moderate bleeding events were those that
required blood transfusion but did not lead to
haemodynamic compromise requiring intervention.
• Other bleeding events were classified as minor
bleeding events.

• Intracranial haemorrhages occured in advancing age,

lower weight, female sex and history of hypertension
 Absolute Contraindications

• Prior intracranial hemorrhage

• Known structural cerebral vascular lesion
• Known malignant intracranial neoplasm
• Ischemic stroke within 3 months
• Suspected aortic dissection
• Active bleeding or bleeding diathesis (excluding
menses)
• Significant closed-head trauma or facial trauma
within 3 months
 Relative Contraindications

• Uncontrolled hypertension (systolic blood pressure

>180 mm Hg or diastolic blood pressure >110 mm Hg)
• Traumatic or prolonged CPR or major surgery within
3 weeks
• Recent (within 2-4 weeks) internal bleeding
• Noncompressible vascular punctures
• For streptokinase: prior exposure (more than 5 days
ago) or prior allergic reaction to streptokinase
• Pregnancy
• Active peptic ulcer
• Current use of warfarin and INR >1.7
• If heparin is used concurrently with t-PA, serious hemorrhage will
occur in 2-4% of patients.
• Intracranial hemorrhage is by far the most serious problem.

• Hemorrhagic stroke occurs with all regimens and is more common

when heparin is used.
• In several large studies, t-PA was associated with an excess of
hemorrhagic strokes of about 0.3% of treated patients.
• Fibrinolytic therapy remains the treatment of choice for patients
with acute ischemic stroke who present within 3 hours of symptom
onset.
 Inhibitors of Fibrinolysis

• Aminocaproic Acid;. Aminocaproic acid (AMICAR, generic) is a lysine analog that

competes for lysine binding sites on plasminogen and plasmin, blocking the
interaction of plasmin with fibrin. Aminocaproic acid is thereby a potent inhibitor
of fibrinolysis and can reverse states that are associated with excessive
fibrinolysis.
• The main problem with its use is that thrombi that form during treatment with the
drug are not lysed. For example, in patients with hematuria,
ureteral obstruction by clots may lead to renal failure after treatment with
aminocaproic acid.
• Aminocaproic acid has been used to reduce bleeding after prostatic
surgery or after tooth extractions in hemophiliacs.
• Use of aminocaproic acid to treat a variety of other bleeding disorders has been
unsuccessful, either because of limited benefit or because of thrombosis (e.g.,
after subarachnoid hemorrhage).
 PHARMACOKINETICS
• Aminocaproic acid is absorbed rapidly after oral
administration, and 50% is excreted unchanged in the
urine within 12 hours.
• For intravenous use, a loading dose of 4-5 g is given
over 1 hour, followed by an infusion of 1-1.25 g/hour
until bleeding is controlled. No more than 30 g should
be given in a 24-hour period.

• Rarely, the drug causes myopathy and muscle necrosis.

 Tranexamic Acid.

• Tranexamic acid (CYKLOKAPRON, LYSTEDA) is a

lysine analog that, like aminocaproic acid,
competes for lysine binding sites on plasminogen
and plasmin, thus blocking their interaction with
fibrin. Tranexamic acid can be used for the same
indications as aminocaproic acid and can be given
intravenously
or orally.
• Like aminocaproic acid, tranexamic acid is
excreted in the urine and dose reductions are
necessary in patients with renal impairment. The
FDA approved oral
tranexamic acid tablets for treatment of heavy
menstrual bleeding in 2009.
• When used for this indication, tranexamic acid
usually is given at a dose of 1 g four times a day
for 4 days.
Antiplatelet drugs
 PLATELETS
• Platelets are anulceate blood cells that
circulate at the periphery of the blood stream,
being displaced there by the larger and denser
erythrocytes. From this position, they
constantly survey the endothelium for defects,
either larger injuries that would result in
hemorrhage, or smaller defects that perturb
the vessel’s barrier function.
• Under normal circumstances, the platelets do
not adhere to intact endothelium, attaching to
the vessel wall only upon exposure of
subendothelial proteins at sites of vessel
injury. These adhesive interactions, coupled
with exposure to platelet agonists generated
at the site or released from other platelets,
cause the platelets to attach to each other and
form an occlusive plug.
• Under some unusual pathological
circumstances, the platelets can also form
thrombi on intact endothelium, sometimes
leading to occlusion of small blood vessels.[