we can know how fribinolytics work in our body and their mechanism , side effects .finally, we discuss about its importance in our heamostatic system

1. FIBRINOLYTICS
Presented By: A.HEMANTHBABU, B PHARM, MPHARM,
Department of Pharmacology
Advanced Pharmacology I

2. WHAT WE ARE GONNA DISCUSS 🗣🎙
• De
fi
nition
• Mechanism of action
• Drugs classi
fi
cation
• Laboratory studies
• Adverse e
ff
ects
• Drugs in pipeline
• References

3. DEFINITION :-)
It is a process of breakdown of
fi
brin in order to maintain homeastatis

4. • MECHANISIM OF FIBRINOLYSIS
• the mechanism by which the
fi
brin-speci
fi
c protease, plasmin, breaks down
fi
brin.
• The precursor form of the serine protease plasmin circulates in the bloodstream as
plasminogen in the
fi
brinolytic system, which is comparable to the coagulation
system in this aspect.
• PLASMINOGEN ACTIVATOR :-)
• Endothelial cells produce and release tissue plasminogen activator (t-PA ),which
turns plasminogen into plasmin, in response to damage (Figure 1).
• By proteolytically breaking down
fi
brin, plasmin remodels the thrombus and
prevents its growth.

5. • In order to give the
fi
brinolytic process clot speci
fi
city,
both plasminogen and plasmin have specialised protein
domains (kringles) that bind to exposed lysines on the
fi
brin clot.
• It should be underlined that only physiologic amounts
of t-PA are required to see this clot speci
fi
city.
• Clot speci
fi
city is lost and a systemic lytic state is
induced at the therapeutic levels of t-PA utilised in
thrombolytic therapy, which increases the risk of
bleeding.
• The plasminogen activator inhibitor (PAI), which inhibits
t-PA, is produced and released by endothelial cells.
• Additionally, plasminogen activator inhibitor 2
(antiplasmin) circulates in the blood at high
concentrations and, under physiological conditions, will
quickly inactivate any plasmin that is not clot-bound.

6. • However, therapeutic doses of plasminogen activators overwhelm this regulating
system.
• A pathological activation of the coagulation and
fi
brinolytic systems can send the
hemostatic system spinning out of control, resulting in widespread intravascular
clotting and haemorrhage.
• Disseminated intravascular coagulation, or DIC, can occur after signi
fi
cant tissue
damage, advanced malignancies, obstetric emergencies such abruptio placentae or
retained foetuses, or bacterial infections.
• . Addressing the underlying illness process is the goal of treating DIC; if this is not
achievable, DIC is frequently deadly.
• The therapeutic use of
fi
brinolytic system regulation. In order to treat thrombotic
disease i.e DIC ., increased
fi
brinolysis is a bene
fi
cial treatment.

7. • The
fi
brinolytic system is activated by the enzymes tissue plasminogen activator,
urokinase, and streptokinase (Figure 2). On the other hand, lowered
fi
brinolysis
lessens hemostatic failure-related bleeding and protects clots against lysis. A
clinically e
ff
ective inhibitor of
fi
brinolysis is aminocaproic acid. The oral
anticoagulant medications and heparin have no e
ff
ect on the
fi
brinolytic process.
•

10. RECOMBINANT TISSUE PLASMINOGEN ACTIVATORS :-
•This family of thrombolytic drugs is used in acute myocardial infarction,
cerebrovascular thrombotic stroke and pulmonary embolism
•Alteplase is a recombinant form of human tA.Moderately speci
fi
c for
fi
brin bound
plasminigen. It has a short half-life (~5 min) and therefore is usually administered as
slow iv infusion non antigenic. dis-Nausea ‚mild hypotension
•Retaplase is a genetically engineered, smaller derivative of recombinant tA. Longer
acting than rtPA. It is usually administered as IV bolus injections. but less speci
fi
c for
fi
brin bound plasminogen. It is used for acute myocardial infarction and pulmonary
embolism.
Dose- 10mg over 10min repeated after 30 min

11. •Tenecteplase (TNK-tPA) has a longer half-life and greater binding a
ffi
nity for
fi
brin
than rtPA Because of its longer half-life, it can be administered by IV bolus Single bolus
dose 0.5 mg/kg su
ffi
cient .
•Very expensive
•It is only approved for use in acute myocardial infarction STEMI"
•Cranial bleeding

12. Streptokinase
• 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 puri
fi
ed from streptococci bacteria. Its lack
of
fi
brin speci
fi
city makes it a less desirable thrombolytic drug than tPA compounds
because it produces more
fi
brinogenolysis.
• Anistreplase (Eminase®) is a complex of SK and plasminogen. It has more
fi
brin
speci
fi
city and has a longer activity than natural SK; however, it causes considerable
fi
brinogenolysis.
•Combines with circulating plasminogen-» forms activator complex- » proteolysis of
plasminogen->>Active plasmin
•Cheap, widely used in India

13. Disadvantages
•Activates both circulating &
fi
brin bound plasminogen Depletion of circulating plasminogen
->bleeding
•Antistreptococcal Abs from past infections inactivate considerable fraction of initial dose,
loading dose needed
•Repeat doses less e
ff
ective due to neutralisation by Abs
USES
Acute myocardial infarction - 7.5 to 15 IU; I.V over 1 hr period • Deep vein thrombosis,
Pulmonary embolism

14. Adverse e
ff
ects
Bleeding, hypotension, allergic reactions, fever, arrhythmias
Contraindications
Recent trauma, surgery, abortion, stroke, severe hypertension, peptic ulcer, bleeding
disorders
Urokinase
•Urokinase, a protease enzyme that activates plasminogen directly, is obtained from tissue
culture of human kidney cells
•It has limited clinical use because, like SK, it produces considerable
fi
brinogenolysis;
however, it is used for pulmonary embolism.
• One bene
fi
t over SK is that UK is non-antigenic; however, this is o
ff
set by a much greater
cost

15. •Rapid acting, more potent
•Superior in dissolving old clotsShort half life 4-8 min
•Nausea, mild hypotension, fever may occur.
•For MI: 2.21U+-
USES
•Acute myocardial infarction
•Deep vein thrombosis
•Pulmonary embolism
•Peripheral arterial occlusion
•Ischemic Stroke

16. LABARATORY STUDIES :-)
Development of an in vitro model to study clot lysis activity of thrombolytic drugs
Thrombolytic drugs are widely used for the management of cerebral venous
sinus thrombosis patients. Several in vitro models have been developed to study clot
lytic activity of thrombolytic drugs, but all of these have certain limitations.
There is need of an appropriate model to check the clot lytic e
ffi
cacy of thrombolytic
drugs. In the present study, an attempt has been made to design and develop a new
model system to study clot lysis in a simpli
fi
ed and easy way using a thrombolytic
drug, streptokinase.

17. A clear, visual representation of clot lysis is shown in
fi
gure no.1
1. When 100 μl water was added to the control clot negligible clot lysis was observed.
Whereas, tubes to which di
ff
erent dilutions of streptokinase was added, signi
fi
cant clot
lysis could be visually seen. Percent clot lysis obtained after treating clots with
streptokinase and control group is shown in
fi
gure
2. Maximum clot lysis was observed when undiluted streptokinase (100 μl) was added to
the clots. With water 2.55% weight di
ff
erence was seen. Though undiluted streptokinase
(30,000 I.U.) showed maximum clot lysis (p = 0.004) but another three dilutions (22,500
I.U., 15,000 I.U., 7,500 I.U.) of streptokinase also showed approximately same percent of
clot lysis (p < 0.05). The mean clot lysis % of streptokinase with all di
ff
erent concentration
was found to di
ff
er signi
fi
cantly when compared with water (i.e, p < 0.05 for all the
concentrations of streptokinase).

18. Clot-lysis of blood samples of normal subjects (positive and negative control). Tube no.
1 is a control clot (negative control) to which water was added. No clot lysis was observed in
tube no.1; a black arrow indicates the intact clot. Tube no. 2–5 (positive control) was lysed
by four di
ff
erent concentrations of streptokinase with decreasing order. After dissolution of
the clots, tubes were inverted and
fl
uid (blue arrow) along with the remnants of clots (red
arrow) could be clearly seen

19. WHAT HAPPENS 👀🤔
What are the risks or complications of thrombolytic therapy?
Bleeding may occur from your IV puncture wounds or other recent injury sites. Spontaneous bleeding can also
develop in the following ways:
• Nosebleeds.
• Blood in your pee (urine).
• Blood in your poop (stool).
• Heavy vaginal bleeding.
• Brain bleed, which is rare.
• Major bleeding in the brain
• Kidney damage in patients with kidney disease
• Severe hypertension (high blood pressure)
• Severe blood loss or internal bleeding
• Bruising or bleeding at the site of thrombolysis
• Damage to the blood vessels
• Fragments of the clot may migrate to other vessels and cause obstruction
• Increased risk of bleeding in pregnant woman, elderly people, and people with bleeding disorders
• Increased risk for infection
• Allergic reactions

20. • As we know streptokinase, urokinase
are majorly used for
fi
brinolytic
therapy in addition to we have
fallowing drugs which shows
fi
brinolytic activity
DRUGS IN PIPELINE

21. REFERENCES :
• Basic and clinical pharmacology by G.KATZUNG
• Development of an in vitro model to study clot lysis activity of thrombolytic drugs
(doi: 10.1186/1477-9560-4-14 : Pub med )
• Daigrams(gifs) from https://makeagif.com/i/rOGT4W
• For further kind queries refer https://go.drugbank.com/drugs/DB00086
(streptokinase)
• Slideshare [slideshare id=230141900&doc=
fi
brinolytics-200312093025]