FROM NATWIJUKA ANDREW

1. BY
NATWIJUKA
ANDREW
15/BSU/BNS/016
10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
PHARMACOLOGY
(FIBRINOLYTICS)

2. Thrombolytic (Fibrinolytic) Drugs
10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 Thrombolytic drugs are used to dissolve (lyse) blood clots (thrombi). Blood
clots can occur in any vascular bed; however, when they occur in coronary,
cerebral or pulmonary vessels, they can be immediately life-threatening -
coronary thrombi are the cause of myocardial infarctions, cerebrovascular
thrombi produce strokes, and pulmonary thromboemboli can lead to
respiratory and cardiac failure. Therefore, it is important to rapidly diagnose
and treat blood clots

3. Mechanisms of Thrombolysis
10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 Thrombolytic drugs dissolve blood clots by activating plasminogen, which
forms a cleaved product called plasmin. Plasmin is a proteolytic enzyme that
is capable of breaking cross-links between fibrin molecules, which provide
the structural integrity of blood clots. Because of these actions, thrombolytic
drugs are also called "plasminogen activators" and "fibrinolytic drugs."
 There are three major classes of fibrinolytic drugs: tissue plasminogen
activator (tPA), streptokinase (SK), and urokinase (UK). While drugs in these
three classes all have the ability to effectively dissolve blood clots, they differ
in their detailed mechanisms in ways that alter their selectivity for fibrin
clots.

4. 10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 The figure below illustrates the fibrinolytic mechanisms for tPA and SK.
Derivatives of tPA are the most commonly used thrombolytic drugs,
especially for coronary and cerebral vascular clots, because of their relative
selectivity for activating fibrin-bound plasminogen. Tissue plasminogen
activator produces clot lysis through the following sequence:

5. 10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)

6. 10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 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

7. 10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 Plasmin is a protease that is capable of breaking apart fibrin molecules,
thereby dissolving the clot. However, it is important to note that plasmin also
breaks down other circulating proteins, including fibrinogen.
 But because of the relative fibrin specificity of tPA, clot dissolution occurs
with less breakdown of circulating fibrinogen than occurs with SK and UK.
Although tPA is relatively selective for clot-bound plasminogen, it still
activates circulating plasminogen thereby releasing plasmin, which can lead
to the breakdown of circulating fibrinogen and cause an unwanted systemic
fibrinolytic state.

8. 10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 SK is not a protease and has no enzymatic activity; however, it forms a
complex with plasminogen that releases plasmin. Unlike tPA, it does not bind
preferentially to clot-associated fibrin and therefore binds equally to
circulating and non-circulating plasminogen. Therefore, SK produces
significant fibrinogenolysis along with clot fibrinolysis.
 For this reason, tPA is generally preferred as a thrombolytic agent over SK,
especially when used for dissolving coronary and cerebral vascular thrombi.
Because SK is derived from streptococci, patients who have had recent
streptococci infections can require significantly higher doses of SK to
produce thrombolysis.

9. 10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 It is important to note that the efficacy of thrombolytic drugs depends on the
age of the clot. Older clots have more fibrin cross-linking and are more
compacted; therefore, older clots are more difficult to dissolve.
 For treating acute myocardial infarction, the thrombolytic drugs should
ideally be given within the first 2 hours. Beyond that time, the efficacy
diminishes and higher doses are generally required to achieve desired lysis

10. Specific Thrombolytic Drugs
Tissue Plasminogen Activators
10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 This family of thrombolytic drugs is used in acute myocardial infarction,
cerebrovascular thrombotic stroke and pulmonary embolism. For acute
myocardial infarctions, tissue plasminogen activators are generally preferred
over streptokinase.
 Alteplase (Activase®; rtPA) is a recombinant form of human tPA. It has a
short half-life (~5 min) and therefore is usually administered as an
intravenous bolus followed by an infusion
 Retaplase (Retavase®) is a genetically engineered, smaller derivative of
recombinant tPA that has increased potency and is faster acting than rtPA. It
is usually administered as IV bolus injections. It is used for acute myocardial
infarction and pulmonary embolism.

11. 10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 Tenecteplase (TNK-tPA) has a longer half-life and greater binding affinity for
fibrin than rtPA. Because of its longer half-life, it can be administered by IV
bolus. It is only approved for use in acute myocardial infarction

12. Streptokinase
10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 Streptokinase and anistreplase are used in acute myocardial infarction,
arterial and venous thrombosis, and pulmonary embolism. These compounds
are antigenic because they are derived from streptococci bacteria.
 Natural streptokinase (SK) is isolated and purified from streptococci bacteria.
Its lack of fibrin specificity makes it a less desirable thrombolytic drug than
tPA compounds because it produces more fibrinogenolysis.
 Anistreplase (Eminase®) is a complex of SK and plasminogen. It has more
fibrin specificity and has a longer activity than natural SK; however, it
ccauses considerable fibrinogenolysis

13. Urokinase
10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 Urokinase (Abbokinase®; UK) is sometimes referred to as urinary-type
plasminogen activator (uPA) because it is formed by kidneys and is found in
urine. It has limited clinical use because, like SK, it produces considerable
fibrinogenolysis; however, it is used for pulmonary embolism. One benefit
over SK is that UK is non-antigenic; however, this is offset by a much greater
cost.

14. Adverse Effects and Contraindications
10/1/2018 6:50:57 AMNATWIJUKA ANDREW NEWSON(NAN)
 Common adverse effects of all the thrombolytic drugs is bleeding
complications related to systemic fibrinogenolysis and lysis of normal
hemostatic plugs. The bleeding is often noted at a catheterization site,
although gastrointestinal and cerebral hemorrhages may occur. Therefore,
patients who have experienced trauma injury or who have a history of
cerebral hemorrhagic stroke are not usually administered thrombolytics. Re-
thrombosis can occur following thrombolysis, and therefore anticoagulants
such as heparin are usually co-administered, and continued after
thrombolytic therapy for a period of time.
