Download Blood Drugs

Drugs used in the coagulation
disorder
Haemostasis



Haemostasis is a physiological process that aims
to maintain the blood in a fluid state under normal
condition
It refers to the normal response of the vessel to
injury
Haemostatic mechanisms involve a complex
interplay b/w three components:
1) Blood cells
2) Vascular wall
3) Coagulation factors
Disturbances of haemostasis result in several
pathological conditions
Haemostasis

A wound causes vasoconstriction, accompanied
by:
1) Adhesion and activation of platelets
2) Fibrin formation


Platelets first adhere to macromolecules in the
subendothelial regions of the injured blood vessel,
where they become activated
Adherent platelets release substances that
activate nearby platelets, thereby recruiting them
to the site of injury
Haemostasis
 Activated platelets then aggregate to form the
primary hemostatic plug
 In addition to triggering platelet adhesion and
activation, vessel wall injury also exposes
tissue factor (TF), which initiates the
coagulation system
Physical trauma to the vascular system, such as a puncture or a
cut, initiates a complex series of interactions between platelets,
endothelial cells, and the coagulation cascade
Drugs affecting haemostasis



Drug therapy to promote haemostasis is rarely
Drug therapy to treat or prevent thrombosis or
thromboembolism, is extensively used because
such diseases are common as well as serious
Drugs affect haemostasis and thrombosis in three
distinct ways, by affecting:
1) Blood coagulation (fibrin formation)
2) Platelet function
3) Fibrin removal (fibrinolysis)
I. Anticoagulants
Blood coagulation



A sequential process of chemical reactions
involving clotting factors, phospholipids, and
calcium ions. This leads the blood to form solid
clots
Blood coagulation is considered as a series of
steps in which plasma inactive enzyme precursors
(proenzymes) are transformed into active
enzymes
Two main pathways have been described for
blood coagulation: the intrinsic and the extrinsic
pathways
Blood coagulation



Platelet activation and coagulation do not normally
occur within an intact blood vessel
Thrombosis is prevented by several regulatory
mechanisms that require a healthy vascular
endothelium
Under most circumstances, TF exposed at sites of
vessel wall injury initiates coagulation via the
extrinsic pathway
Blood coagulation

This results in a burst of thrombin (factor IIa)
generation
 Thrombin then converts fibrinogen to fibrin, which
reinforces the platelet aggregate and anchors it to
the vessel wall. In addition, because it serves as a
potent platelet agonist, thrombin also amplifies
platelet activation and aggregation

Later, as wound healing occurs, the platelet
aggregates and fibrin clots are degraded
Extrinsic
Pathway
Intrinsic
Pathway
TF
VII
XII
XI
IX
XIIa
X
TF-VIIa
XIa
IXa
Prothrombin
Xa
AT
Va
Thrombin
AT
Fibrinogen
Fibrin
Blood coagulation



Control of the coagulation system is regulated by
a series of protease inhibitors: protein C and S,
antithrombin III (ATIII), and tissue factor pathway
inhibitor (TFPI)
Antithrombin is a glycosylated, single-chain
polypeptide composed that is synthesized in the
liver
Antithrombin inhibits clotting factor proteases,
especially thrombin (IIa), IXa, and Xa, by forming
equimolar stable complexes with them
Anticoagulants



They inhibit the formation of fibrin by actions on
the coagulation phase
They do not lyse clots or affect the fibrinolytic
pathway
They can:
I.
Indirect thrombin inhibitors
II. Direct thrombin inhibitors
III. Oral direct factor Xa inhibitors
IV. Warfarin and other coumarin anticoagulants
Indirect and Direct thrombin inhibitors
Intrinsic Pathway
(surface contact)
Extrinsic Pathway
(tissue factor)
XIIa
VIIa
XIa
Heparin / LMWH
(AT-III dependent)
IXa
Xa
Direct antithrombin
Thrombin (IIa)
Thrombin-Fibrin clot
15
Indirect Thrombin Inhibitors


Agents: unfractionated heparin (UFH),
molecular-weight
heparin
(LMWH),
fondaparinux
lowand
The indirect thrombin inhibitors are so-named
because their antithrombotic effect is exerted by
their interaction with a separate protein,
antithrombin III (ATIII) and enhance its inactivation
of factor Xa
Heparin & LMWHs
 Two types of heparin are used clinically:
1.Older standard (unfractionated/
molecular weight) heparin
high
2.Newer type, called low-molecular-weight
heparin (LMWH), is derived from
unfractionated heparin
 The two classes are similar but not identical in
their actions and PKs
Heparin & LMWHs
I. Unfractionated heaprin
 A mixture of highly electronegative acidic
mucopolysaccharides found in the secretory
granules of mast cells
 Commonly extracted from porcine intestinal
mucosa or bovine lung
Heparin & LMWHs
II. Low molecular weight heprin (LMWH)
 Incude: enoxaparin, dalteparin,
and
tinzaparin
 Low-molecular-weight fragments produced
by chemical depolymerization and extraction
of standard heparin
 Advantages: greater bioavailability than
standard heparin, a longer-lasting effect, &
more predictable relationship between
anticoagulant response and dose
Heparin & LMWHs- MOA




Heparin, LMWHs, and fondaparinux have no
intrinsic anticoagulant activity
The active heparin molecules bind tightly to
antithrombin and cause a conformational change
in this inhibitor
The conformational change of antithrombin
exposes its active site for more rapid interaction
with the proteases (the activated clotting factors)
This conformational change accelerates the rate
of factor Xa inhibition by 1000-fold
Heparin & LMWHs- MOA


Unfractionated heparin binds to antithrombin III
and induces a conformational change that
accelerates the interaction of antithrombin III with
the coagulation factors- most importantly,
thrombin (Factor IIa) and Factor Xa
To potentiate thrombin inhibition, heparin must
simultaneously bind to antithrombin and thrombin
 Only heparin chains composed of at least 18
saccharide units (molecular weight 5,400 Da) are
of sufficient length to perform this bridging
function
Heparin & LMWHs- MOA
 LMWHs complex with antithrombin III and
inactivate Factor Xa but have less effect on
thrombin. They are too short to bridge
antithrombin and thrombin together
Unfractionated Heparin
Thrombin (IIa)
(FXa)
AT
AT
LMWH
(FXa)
AT
Heparin and LMWHs-PKs

Heparin and LMWHs are not absorbed through
the GI mucosa and therefore must be given
parenterally
 Heparin is given by continuous intravenous
infusion, intermittent infusion every 4-6 hours, or
subcutaneous injection every 8-12 hours


Heparin has an immediate onset of action when
given intravenously
In contrast, there is considerable variation in the
bioavailability of heparin given subcutaneously,
and the onset of action is delayed 1-2 hours
Heparin and LMWHs- PKs
 LMWH are absorbed more uniformly after
subcutaneous injection
 The t1/2 of heparin in plasma depends on the
dose administered (t1/2 1-5 hours)
 LMWHs have longer biological half-lives than
heparin (t1/2 4-6 hours)
Heparin and LMWHs-PKs
 Heparin appears to be cleared and degraded
primarily by the reticuloendothelial system; a
small amount of undegraded heparin also
appears in the urine
 LMWHs are cleared almost exclusively by the
kidneys, the drugs can accumulate in patients
with renal impairment, which can lead to
bleeding
Comparison of the Features of Heparin,
LMWH, and Fondaparinux
Feature
Source
Molecular weight (Da)
Target
Bioavailability (%)
t1/2 (h)
Renal excretion
Antidote effect
Thrombocytopenia
Heparin
Biological
15,000
Xa and IIa
30
1
No
Complete
<5%
LMWH
Biological
5000
Xa
90
4
Yes
Partial
<1%
Fondaparinux
Synthetic
1500
Xa
100
17
Yes
None
<1%
Heparin and LMWHs
 Heparin is prescribed on a unit (IU) rather
than milligram basis
 The dose must be determined on an individual
basis
 Therapy routinely is monitored by the
activated partial thromboplastin time (aPTT or
PTT) & anti-Xa activity
Heparin and LMWHs

Heparin and LMWH are used during coronary
balloon angioplasty with or without stent
placement to prevent thrombosis
 In contrast to warfarin, heparin and LMWH do not
cross the placenta and have not been associated
with fetal malformations; therefore, these are the
drugs of choice for anticoagulation during
pregnancy
Adverse effects
1. Bleeding complications:


The chief complication of heparin therapy is
hemorrhage
Protamine sulfate is used routinely to reverse the
anticoagulant effect of heparin: protamine is a
highly basic peptide that combines with heparin
as an ion pair to form a stable complex devoid of
anticoagulant activity
Adverse effects
2.

Hypersensitivity reactions:
Include chills, fever, urticaria, or anaphylactic
shock
 Cause: heparin preparations are obtained from
porcine sources and, therefore, may be antigenic
3.
Osteoporosis: has been reported with long-term
(6 months or more) treatment
4.
Hypoaldosteronism is uncommon, but increases
with prolonged treatment
Adverse effects
5.

Heparin-induced thrombocytopenia (HIT):
It is a common abnormality among hospital
patients receiving heparin
 HIT (platelet count <150,000/mL or a 50%
decrease from the pretreatment value) occurs in
0.5% of medical patients 5-10 days after
initiation of therapy with heparin

The risk of HIT may be higher in individuals
treated with UFH of bovine origin compared with
porcine heparin and is lower in those treated
exclusively with LMWH
Adverse effects
5.

Heparin-induced thrombocytopenia (HIT):
Patients who develop HIT are treated by
discontinuance of heparin and administration of
a direct thrombin inhibitor
Fondaparinux



Pentasaccharide anticoagulants that is purely
synthetically, derived with no variable biologic
activity (i.e. requires less monitoring than
heparin)
It selectively inhibits only Factor
selectively binding to antithrombin III
Xa,
by
Clinical uses in the prophylaxis of DVT that could
lead to PE in patients undergoing hip fracture
surgery, hip replacement surgery, and knee
replacement surgery
Fondaparinux

Fondaparinux is administered by subcutaneous
injection, reaches peak plasma levels in 2 hours,
and is excreted in the urine (t1/2 17 h)
 It should not be used in patients with renal failure


Fondaparinux can be given once a day at a fixed
dose without coagulation monitoring
Fondaparinux appears to be much less likely
than heparin or LMWH to trigger the syndrome of
heparin-induced thrombocytopenia
Oral direct factor Xa inhibitors
 Agents: rivaroxaban, apixaban, edoxaban,
betrixaban
 They inhibits factor Xa, in the final common
pathway of clotting
 Rivaroxaban is approved for the prevention
of VTE following hip or knee surgery & for
treating DVT or PE, and to reduce the risk of
recurrent DVT and PE following initial
treatment
 These drugs are administered as fixed doses
and do not require monitoring
Oral direct factor Xa inhibitors

They have a rapid onset of action and shorter
half-lives than warfarin
 They are excreted in part by the kidneys
 ADRs: predictable bleeding and nausea
Direct thrombin inhibotrs (DTIs)
1) Parenteral
direct thrombin inhibitor:
hirudin, bivalirudin, Lepirudin, argatroban
2) Oral direct thrombin inhibitors: dabigatren
etexilate mesylate

Exert their anticoagulant effect by directly
binding to the active site of thrombin,
thereby inhibiting thrombin's downstream
effects
Parenteral direct thrombin inhibitors

Clinical uses:
I.
Alternative to heparin primarily in patients
with heparin induced thrompocytopenia
II. Argatroban
and
pivalirudin:
during
percutaneous coronary interventions (PCI) in
patients who have or are at risk for
developing HIT


Are administered intravenously and the dose
being adjusted depending on the aPTT
They can cause bleeding or hypersensitivity
reactions (rash or fever)
Oral direct thrombin inhibitors



Dabigatran etexilate mesylate, is an orally active
direct thrombin inhibitor
It is licensed for prevention of VTE following hip
or knee replacement and to reduce risk of stroke
and systemic embolism with nonvalvular atrial
fibrillation
Advantages include: predictable PKs and
bioavailability, which allow for fixed dosing and
predictable anticoagulant response, and make
routine coagulation monitoring unnecessary
Oral direct thrombin inhibitors



Dabigatran does
interacting drugs
not
interact
with
P450-
It has a very rapid onset and offset of action
allow for immediate anticoagulation, thus
avoiding the need for overlap with additional
anticoagulant drugs
ADRs: bleeding
Vitamin K antagonists: warfarin

Are derivatives of 4-hydroxycoumarin or indan1,3-dione, and they resemble vitamin K
 Coumarin anticoagulants block the gammacarboxylation of several glutamate residues in
prothrombin and factors VII, IX, and X as well as
the endogenous anticoagulant proteins C and S

The blockade results in incomplete coagulation
factor molecules that are biologically inactive
Vitamin K antagonists- MOA

Unlike heparin, the anticoagulant effects of
warfarin are not observed until 8 to 12 hours after
drug administration, but peak effects may be
delayed for 72 to 96 hrs
Figure 1.4 Warfarin and the vitamin K cycle.
Clotting factors
II/VII/IX/X
(inactive form)
H H
N C
O
O
H H
N C
CH2
CHCOOH
COOH
CH 2
CH 2
COOH
Clotting factors
II/VII/IX/X
(active form)
γ-carboxylase
O
OH
CH3
Vitamin K
hydroquinone
R
CH 3
Vitamin K
Cycle
Vitamin K epoxide
R
OH
OH
Vitamin K reductase
O
Vitamin K epoxide reductase
(VKOR)
O
CH2
Warfarin
R
O
Vitamin K
Warfarin
Warfarin

The bioavailability of warfarin is nearly complete
when the drug is administered orally,
intravenously, or rectally
 Over 99% of warfarin is bound to plasma albumin,
which may contribute to its small volume of
distribution, its long half-life in plasma (36 hours),
and the lack of urinary excretion of unchanged
drug

S- warfarin is metabolized principally by CYP2C9
Warfarin


Warfarin is the most important oral anticoagulant
and is of the most commonly prescribed drugs
Clinical uses:
I.
Prevent the progression or recurrence of acute
DVT or PE after initial heparin treatment
II.
Prevention of VTE
gynecologic surgery
during
orthopaedic
or
III. Prophylactically, it is used in patients with acute
MI, prosthetic heart valves, or chronic atrial
fibrillation
Warfarin


The international normalized ratio (INR), as a
means of standardizing the PT results, is the most
recommended method for monitoring patients’
warfarin therapy
The goal of warfarin therapy is an INR of 2 to 3
for most indications and 2.5 to 3.5 in patients with
mechanical heart valves
Warfarin- ADRs
1. Bleeding disorders:
-
The principal untoward reaction caused by
warfarin treatment is hemorrhage
- Therefore, it is important to frequently monitor
and adjust the anticoagulant effect
-
Minor bleeding may be treated by withdrawal of
the drug and administration of oral vitamin K1
-
Severe bleeding requires that greater doses of
the vitamin be given intravenously
-
Whole blood, frozen plasma, or plasma
concentrates of the blood factors may also be
employed to arrest hemorrhaging
Warfarin- Drug & disease interactions

Warfarin has a narrow therapeutic window, and
interacts with other drugs, diet, and with disease
states
 These interactions can be broadly divided into:
I. Pharmacokinetic effects: mainly enzyme
induction, enzyme inhibition,
plasma protein binding
II.
and
reduced
Pharmacodynamic effects: vitamin K deficiency,
hepatic disease that impairs synthesis of the
clotting factors, and hypermetabolic states that
increase catabolism of the vitamin K-dependent
clotting factors
PK & PD Drug and Body Interactions with Oral Anticoagulants
Increased Prothrombin Time
PK
PD
Amiodarone
Drugs:
Cimetidine
Aspirin (high doses)
Disulfiram
Cephalosporins,
Metronidazole1
third-generation
Fluconazole1
Heparin
Phenylbutazone1
Body factors:
Sulfinpyrazone1
Hepatic disease
TrimethoprimHyperthyroidism
sulfamethoxazole
1Stereoselectively
Decreased Prothrombin Time
PK
PD
Barbiturates
Drugs:
Cholestyramine
Diuretics
Rifampin
Vitamin K
Body factors:
Hereditary resistance
Hypothyroidism
inhibits the oxidative metabolism of the S-warfarin enantiomorph of racemic warfarin
Warfarin
 Warfarin should never be used during
pregnancy, because its teratogenic and can
cause abortion and birth defects
 If anticoagulant therapy is needed during
pregnancy, heparin or LMWH may be
administered
II. Antiplatelet Drugs
Introduction



The vascular endothelial cell layer lining blood
vessels has an anticoagulant phenotype, and
circulating blood platelets and clotting factors do
not normally adhere to it to an appreciable extent
Following disruption of the endothelial lining and
exposure of blood to the subendothelial vessel
wall, platelets adhere to and virtually cover the
exposed collagen of the subendothelium
This triggers a complex series of chemical
reactions, resulting in platelet activation
Introduction

Activation of platelets results:
1) Activation
of thromboxane A2 synthesis, from
arachidonic acid within platelets, that causes platelets
to change shape, release their granules, and
aggregate
2) The release of platelet granules containing mediators,
such as ADP and serotonin (5-HT), which stimulate
aggregation
3) Conformational
change in the
IIb/IIIa receptor,
enabling it to bind fibrinogen, which cross-links
adjacent platelets, resulting in aggregation and
formation of a platelet plug
Platelet Aggregation Inhibitors




Platelets provide the initial hemostatic plug at
sites of vascular injury
They also participate in pathological thromboses
that lead to MI, stroke, and peripheral vascular
thromboses
These drugs decrease the formation or the action
of chemical signals that promote platelet
aggregation
These drugs act by discrete mechanisms, and
thus in combination their effects are additive or
even synergistic
Platelet Aggregation Inhibitors
 Antiplatelets include:
1) Aspirin and other NSAIDs
2) Glycoprotein IIb/IIIa receptor inhibitor
3) Antagonist of ADP receptors
4) Phosphodiesterase 3 inhibitors
Sites of Action of
Antiplatelet
Therapy on
Mechanisms of
Platelet Activation
and Aggregation
Copyright restrictions may apply.
Schulman, S. P. JAMA 2004;292:1875-1882.
Sites of Action of Antiplatelet Therapy
Clopidogrel
ADP Receptor (P2Y12)
Ticlopidine
ADP
Prasugrel
ADP
GP IIb/IIIa
receptor
Activation
Collagen
Thrombin
TXA2
COX
Fibrinogen
TXA2
Abciximab
Aspirin
Eptfibatide
Tirofiban
ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.
Adapted from Schafer AI. Am J Med. 1996;101:199-209.
Aspirin



It inhibits the synthesis of thromboxane A2 by
irreversible
acetylation
of
the
enzyme
cyclooxygenase-1 (COX-1)
Since platelets do not synthesize new proteins,
the action of aspirin on platelet cyclooxygenase is
permanent, lasting for the life of the platelet (7 to
10 days)
Repeated doses of aspirin produce a cumulative
effect on platelet function
Aspirin

Clinical uses:
1. Prophylactic treatment of transient cerebral
ischemia
2. To reduce the incidence of recurrent MI
3. To decrease mortality in pre- and postmyocardial infarct patients
 Aspirin is frequently used in combination with
other drugs having anticlotting properties (e.g.
heparin and clopedogril)

ADRs: increased incidence of hemorrhagic stroke
as well as GIT bleeding, especially at higher
doses
Ticlopidine, Clopidogrel, & Prasugrel


These drugs irreversibly block the ADP receptor
on platelets and thereby prevent ADP-mediated
platelet aggregation
Platelets contain two GPCRs for ADP:
1) P2Y1: couples to the Gq–PLC–IP3–Ca2+
pathway and induces a shape change and
aggregation
2) P2Y12 receptor couples to Gi and, when
activated by ADP, inhibits adenylyl cyclase,
resulting in lower levels of cyclic AMP and
thereby less cyclic AMP–dependent inhibition
of platelet activation
Ticlopidine, Clopidogrel, & Prasugrel inhibit the P2Y12
receptor
Clopidogrel
ADP Receptor (P2Y12)
Ticlopidine
ADP
Prasugrel
ADP
GP IIb/IIIa
receptor
Activation
Fibrinogen
Collagen
Thrombin
TXA2
COX
TXA2
ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.
Adapted from Schafer AI. Am J Med. 1996;101:199-209.
Ticlopidine, Clopidogrel, & Prasugrel
 Ticlopidine and clopidogrel arr effective in
preventing transient ischemic attacks (TIAs)
and ischemic strokes for patients with prior
cerebral thrombotic event
 Ticlopidine, clopidogrel, & prasugrel are used
in combination with aspirin following coronary
stent implantation to decrease the incidence
of stent thrombosis
Ticlopidine, Clopidogrel, & Prasugrel
 Clopidogrel is approved for prophylaxis of
thrombotic events in acute coronary syndrome
and for prevention of atherosclerotic events
following recent MI, stroke, or established
peripheral arterial disease
Ticlopidine, Clopidogrel, & Prasugrel
 Ticlopidine ADRs:
1.GIT: nausea, dyspepsia, and diarrhea
2.Hemorrhage
3.Leukopenia: detected by regular monitoring
of the WBC count during the first 3 months
of treatment
4.Thrombotic
(TTP)
thrombocytopenic
purpura
Ticlopidine, Clopidogrel, & Prasugrel
 Clopidogrel ADRs:
- Clopidogrel
has fewer ADRs than ticlopidine:
less frequent thrombocytopenia and leukopenia
- Clopidogrel is preferred over ticlopidine
 Prasugrel ADRs: the main side effect is
bleeding which can be fatal
Blockade of Platelet Glycoprotein IIb/IIIa
Receptors
 Agents: abciximab, eptfibatide, & tirofiban
 These drugs target the platelet IIb/IIIa
receptor complex
 By binding to GP IIb/IIIa, these drug reversibly
block the binding of fibrinogen and von
Willebrand factor; consequently, aggregation
does not occur
GP IIb/IIIa receptor
antagonist
Inhibition of platelet aggregation
GP IIb/IIIa receptors bound by
antagonists
Agonist
ADP, thrombin,
epinephrine, TXA2,
collagen, & others
Resting platelet
GP IIb/IIIa receptors in
unreceptive state
Fibrinogen
Activated platelet
GP IIb/IIIa receptors in
ligand-receptive state
Processes of Platelet Activation and
Aggregation and Inhibition of Platelet
Aggregation by Inhibitors of Glycoprotein
IIb/IIIa Receptors
Aggregation of platelets
GP IIb/IIIa receptors are bound to fibrinogen,
forming bridges between adjacent platelets
Blockade of Platelet Glycoprotein IIb/IIIa
Receptors
 These agents are administered parenterally
(IV)
 Clinical uses: to prevent restenosis after
coronary angioplasty and to decrease the
incidence
of
thrombotic
complications
associated with acute coronary syndromes
 Major ADRs: bleeding
III. Thrombolytic Drugs
Introduction

During plug formation, the fibrinolytic pathway is
locally activated
 Plasminogen is enzymatically processed to
plasmin (fibrinolysin) by plasminogen activators in
the tissue

Plasmin is a relatively nonspecific protease; it
digests fibrin clots and other plasma proteins,
including several coagulation factors
Plasminogen
Plasmin
Thrombin
Fibrinogen
degradation
products
Lytic state
Fibrinogen
Fibrin
Fibrin
degradation
products
Clot
dissolution
Thromoblytic/Fibrinolytic Drugs
 Fibrinolytic agents include:
1) Tissue plasminogen activator: alteplase,
erteplase, and tenecteplase
2) Streptokinase
3) Urokinases
 Either directly or indirectly lyse thrombi by
catalyzing the formation of the serine
protease plasmin from its precursor zymogen,
plasminogen
Plasminogen
Fibrinolytic Agents
Plasmin
Thrombin
Fibrinogen
degradation
products
Lytic state
Fibrinogen
Fibrin
Fibrin
degradation
products
Clot
dissolution
Streptokinase

Protein synthesized by streptococci that combines
with the proactivator plasminogen
 It forms an active one-to-one complex with
plasminogen

This enzymatically active complex catalyzes the
conversion of uncomplexed plasminogen to the
active enzyme plasmin (fibrin plug hydrolysis)
Plasminogen
Streptokinase
Plasmiogen
(proactivator)
Plasmin
Thrombin
Fibrinogen
degradation
products
Lytic state
Fibrinogen
Fibrin
Fibrin
degradation
products
Clot
dissolution
Streptokinase



Uses: PE, DVT, acute MI, arterial thrombosis, and
occluded access shunts
The greatest benefit of appears to be achieved by
early administration (within 4 hrs)
Since the advent of newer agents, streptokinase
is rarely used clinically for fibrinolysis. It currently
is not marketed in the U.S.
Streptokinase- ADRs
1.
Bleeding disorders:

Aminocaproic acid inhibits streptokinaseplasminogen activator complex formation and
can be used in the rare instances of lifethreatening hemorrhage
Streptokinase-ADRs
2.
Hypersensitivty (rash, fever, anaphylaxis)

Foreign protein and is antigenic

Circulating antibodies against streptokinase
are likely to be present in most patients

Esp. individuals who have had a streptococcal
infections (antistreptococcal antibodies)

Antibodies can combine with streptokinase
and neutralize its fibrinolytic properties
Anistreplase (anisoylated plasminogen
streptokinase activator complex)
 Pro-drug consists of a complex of purified
human
plasminogen
and
bacterial
streptokinase that has been acylated to
protect the enzyme's active site
 When
administered,
the
acyl
group
spontaneously
hydrolyzes,
freeing
the
activated streptokinase-plasminogen complex
Anistreplase (anisoylated plasminogen
streptokinase activator complex)
 Advatnages:
1. Rapid IV injection
2. Greater clot selectivity (ie, more activity on
plasminogen associated with clots than on
free plasminogen in the blood)
3. More thrombolytic activity