FIBRINOLYTICS, ANTI

FIBRINOLYTICS AND ANTI

PLATELETS

DR. B.K.BEZBARUAH
PROFESSOR
PHARMACOLOGY
GAUHATI MEDICAL COLLEGE
 What is Hemostasis ?
• Hemostasis refers to the physiologic process whereby bleeding is
halted, thus protecting the integrity of the vascular system after
tissue injury.

• It is responsible for minimizing blood loss.

• It is commonly referred to as stoppage of bleeding, however

coagulation is only one type of hemostatic process.
Functions of Hemostasis
– Maintain blood in a fluid state while circulating within the vascular
system

– Arrest bleeding at the site of injury by formation of hemostatic plug

– Ensure the removal of the hemostatic plug when healing is complete

Components of normal hemostasis include:

Blood vessels, Platelets, Coagulation factors and their inhibitors
and Fibrinolytic system
 Physiology of Thrombus formation
• The inner surface of blood vessels is lined with a single layer of
endothelial cells, that normally, acts to inhibit platelet activation
with the production of endothelial-ADPase, noradrenaline & PGI2.
ADPase clears away ADP , a platelet activator, from platelet
surface receptors.

• Endothelial cells also produce von Willebrandt's factor(vWF) ,

which helps them to adhere to collagen in the
basement membrane.
Normally neither collagen nor vWF pass into the bloodstream.
 Physiology of Thrombus formation
ENDOTHELIUM INJURED COLLAGEN EXPOSED

PLATELETS come into contact

with exposed COLLAGEN & vWF

PLATELETS ACTIVATED
 Thrombus formation
Thromboxane A2 Synthesisis
• Platelet activation initiates the Arachidonic acid pathway
to produce TxA2 which is involved in activating other
platelets.

Granule Secretion
Platelets contain 2 types of granules.
Activated platelets excrete the contents of these
granules into the surrounding blood.

• Dense granules (containing ADP or ATP, calcium and serotonin)

• α-granules (containing platelet factor 4, PDGF, fibronectin, B-

thromboglobulin, vWF, fibrinogen, and coagulation factors V and
XIII).
 Thrombus clot formation
Platelet adhesion to site of vascular injury

Platelet activation by
ADP, TxA2 , Collagen , 5HT & Thrombin

Expression of Glycoprotein IIb/IIIa receptors

Aggregation of platelets by cross linking reaction

due to fibrinogen binding to glycoprotein IIb/IIIa
receptors
FIBRINOLYTICS
 FIBRINOLYTICS (THROMBOLYTICS)

• Used to lyse the thrombin / clot to recanalise occluded

blood vessels (mainly the coronary artery)

• They are Curative rather than prophylactic

• Work by activating the natural fibrinolytic system

• Haemostatic plug at the site of injury of the blood vessel

is reinforced by fibrin deposition to form a thrombus.

• Once repair is over the fibrinolytic system is activated

to remove the fibrin
 Fibrinolytic pathway
Plasminogen
(profibrinolysis)

alfa-2-antiplasmin ------- ++++ tPA–vascular endo.

(tissue plasminogen activator)

Plasmin
(fibrinolysis-serine protease)

Fibrin (insoluble) Fibrin fragments

(soluble)

• Plasminogen circulates in the plasma & is bound to fibrin.

• The tPA selectively activates plasminogen bound to fibrin.

• The anti plasmins deactivate any plasmins that leaks , but are unable to
neutralise the one bound to fibrin because of same attachment site.
 CLASSIFICATION OF FIBRINOLYTICS
FIBRIN NON-SPECIFIC
• Streptokinase
• Anisoylated plasminogen streptokinase activator (APSAC)
• Urokinase

FIBRIN SPECIFIC
• Tissue plasminogen activator (rtPA or alteplase)
• Reteplase , Tenecteplase
• Recombinant prourokinase
• Recombinant single chain urokinase activator
 FIBRINOLYTICS
Characteristic Streptokinase Urokinase Alteplase

Plasma half life 15-25 15-20 4-8

(min)
Fibrin specificity Minimal Moderate Maximum

Plasminogen Indirect Direct Direct

binding
Potential for Yes No No
allergic reaction/
hypotension
Total dose 1.5 million units 3-4 million units 100mg
 STREPTOKINASE
• Produced by beta-haemolytic streptococci

• Not clot specific , acts on both bound and free plasminogen ,

depleting circulating fibrinogen & factor V & VIII.

• Streptokinase forms a complex in the plasma with plasminogen

to
form an activator complex. This complex then forms plasmin
from unbound plasminogen

• Given intravenously as soon as possible after the onset of a heart

attack to dissolve clots in the arteries of the heart wall. This
reduces the amount of damage to the heart muscle.
 Streptokinase (Adverse Reactions)
• Hypotension (sometimes severe) but less with rtPA

• Bleeding

• Respiratory depression

• Allergic reactions (eg, fever and shivering, urticaria,

itching)
• Nausea (rtPA),

• headache, musculoskeletal pain, anaphylactic and

anaphylactoid reactions, transient elevations of serum
transaminases; back pain
 ALTEPLASE (rt-PA)
• Produced by recombinant DNA technology

• Clot specific acting mainly on fibrin bound plasminogen

• Safer (NON ANTIGENIC)

• No depletion of circulating fibrinogen & factor V & VIII

• S/Effects : similar to streptokinase except more nausea &

no antigenic reactions

• Very expensive
RETEPLASE :
• Modified form of rt-PA ; Longer t1/2 (15-20 min)
• Less specific for fibrin bound plasminogen
• Administered as 2 bolus injections of 10 U each at 30 min

TENECTEPLASE :
• Mutant variant of rt-PA ; Long t1/2 (2 hrs)
• Higher fibrin specificity & increased resistance to
plasminogen activated inhibitor-1
• Single bolus inj. of 50mg over 5 sec

• Side effects : similar to alteplase ,very expensive

 ANISTREPLASE (ANISOLYTED PLASMINOGEN
STREPTOKINASE ACTIVATOR COMPLEX; APSAC):

• Complex of purified human plasminogen & bacterial

streptokinase in which the active site of plasminogen has
been protected by anisolyation (a process of acetylation)

• On administration , acyl group hydrolyzes , freeing the

activated streptokinase-proactivator complex

• More fibrin specific (compared to streptokinase)

• Half life is also more ( >90 min)
 How is over dose and toxicity of
fibrinolytic’s managed ?

ANTIFIBRINOLYTIC
These are drugs that act by blocking the conversion
of plasminogen to plasmin
 AMINOCAPROIC ACID
• Analogue of the amino acid Lysine
• Binds to the lysine binding site on Plasminogen &
prevents its combination with fibrin
• Uses :
– Overdose of fibrinolytics (Specific Antidote for
fibrinolytics)
– To prevent recurrence of subarachnoid & GI
hemorrhage
– In Traumatic & Surgical bleedings (prostatctomy, tooth
extraction in hemophiliacs)
– Abruptio placentae, PPH
 AMINOCAPROIC ACID

DOSE : 5g oral/i.v. then 1g every hourly till bleeding

stops

ADVERSE EFFECTS: Nausea, vomiting, abdominal pain,

and diarrhea,myopathy , intravascular thrombosis
Rapid i.v. injection may cause Hypotension ,
Bradycardia & Arrrhythmia
 TRANEXAMIC ACID
• MOA similar to ACA ; More potent (7 times)
• Dose : 500 mg TDS orally ; 0.5-1g TDS slow i.v. infusion

APROTININ
• Polypeptide isolated from bovine tissues with polyvalent
serine protease inhibitory activity ( trypsin,
chymotrypsin, kallikrein & plasmin are inhibited)
• Administered only i.v. ; t1/2 of 2hr

• Dose : 5 lac KIU (Kallikrein inactivator unit) followed by 2

lac KIU every 4hr as slow i.v. infusion
 ANTIPLATELET DRUGS
1.CYCLOOXYGENASE INHIBITORS (DECREASE ACTIVATION) Aspirin

2.ADENOSINE DIPHOSPHATE (ADP) RECEPTOR INHIBITORS (DECREASE

ACTIVATION)
Clopidogrel.Ticlopidine .Prasugrel

3.PHOSPHODIESTERASE INHIBITORS (DECREASE AGGREGATION)

Dipyridamole ,Persantine (adenosine reuptake inhibitors),
Pentoxyphylline ,Cilostazol

4.GLYCOPROTEIN IIB/IIIA INHIBITORS (INTRAVENOUS USE ONLY - DECREASE

AGGREGATION)
Abciximab ,Eptifibatide ,Tirofiban ,Defibrotide

5.PGE1 , PGI2 & THEIR ANALOGS

Iloprost , beraprost , limaprost , ciprostene , taprostene .

6.THROMBAXANE RECEPTOR BLOCKERS

Dazoxiben
CYCLOOXYGENASE(COX) INHIBITORS

ASPIRIN
•
ASPIRIN
IRREVERSIBLY inhibits COX1 & Thromboxane synthase in
platelets

• Aspirin acts as an Acetylating agent where an acetyl group is

covalently attached to a serine residue in the active site of the
COX enzyme .

• Low-dose (75-325 mg / day), long-term aspirin use irreversibly

blocks the formation of Thromboxane A2 in platelets, producing
an inhibitory effect on platelet aggregation

• Used Prophylatically in Coronary artery disease , post-MI & post-

stroke patients to lower risk of reinfarction

• Since platelets cannot synthesis new COX , this effect is

permanent for the lifespan of platelet (7-10 days)
ADENOSINE DIPHOSPHATE (ADP) RECEPTOR
INHIBITORS

TICLOPIDINE,CLOPIDOGREL,PRASUGREL

MOA :
Irreversible blockade of ADP receptor on
Platelet ↓↓↓ Activation of platelets
 TICLOPIDINE
• Prodrug , rapidly absorbed , highly Bioavailable
• Hit-and-run pharmacology : Short t1/2 (8hr) but a long
duration of action
• Cumulates in the body—peak antiplatelet effect is
produced after 8-10 days
• Dose : 250mg BD

• Uses : Stroke prevention (in pt. with H/o TIA ) , CABG,

Intermitent claudication, Unstable angina, MI
• Combined with Aspirin decrease chance of restenosis
after PTCA
CABG : Coronry artery Bypass grafting , PTCA : Percutaneous transluminal coronary angioplasty
 TICLOPIDINE
ADVERSE EFFECTS :
• Nausea, Dyspepsia , Diarrhoea (20%)
• Bleeding (5%)
• Neutropenia** (most serious – monitor CBC ) : STOP
therapy if cell count decrease

• Thrombotic thrombocytopenic purpura (remit on

stoppage of Rx)
Mortality : 18-57% in cases with TTP-HUS

• It has largely been Replaced by Clopidogrel

TTP-HUS : Thrombotic thrombocytopenic purpura hemolytic uremic syndrome

 CLOPIDOGREL
• Prodrug

• More potent , longer duration of action (7-10 days).

• Better A/E profile.

• Slow onset of action , so a loading-dose of 300-600 mg is usually

administered . Dose : 75 mg OD.
 CLOPIDOGREL
ADVERSE EFFECTS
• Severe neutropenia : Rare (Incidence: 1/2,000)

• Thrombotic thrombocytopenic purpura (TTP) : Very rare

(Incidence : 4/1,000,000 patients treated)

• Hemorrhage - The incidence of hemorrhage may be increased by

the co-administration of aspirin.
– Gastrointestinal Hemorrhage (Incidence: 2.0%)
– Cerebral Hemorrhage (Incidence: 0.1 to 0.4%)
– Use of non-steroidal anti-inflammatory drugs is discouraged in
those taking clopidogrel due to increased risk of digestive
tract hemorrhage
 CLOPIDOGREL
Uses :
• Unstable angina or NSTEMI(Non ST elevated
myocardial ischemia): with Aspirin
• STEMI(ST elevated myocardial ischemia)
• Recent MI or Stroke
• Peripheral arterial disease
 PRASUGREL
• Introduced in July 2009
• Prodrug, Rapid onset of action , More potent (than
ticlopidine & clopidogrel)
• Dose : 60 mg loading dose, then 10 mg daily

• ↑↑ Bleeding risk : C/I in patients with H/o TIA or

stroke
• Caution is required : if used in pt <60 kg & in renal
impairement

• CYP2C19 polymorphisms less important ; may be a

reasonable alternative to clopidogrel in such cases
GLYCOPROTEIN IIB/IIIA
INHIBITORS
(intravenous use only)
ABCIXIMAB
EPTIFIBATIDE
TIROFIBAN
DEFIBROTIDE
 GP IIB/IIIA INHIBITORS
ADVERSE EFFECTS

• Bleeding : main risk

• Thrombocytopenia : a rare but known serious

risk
Abciximab : 2% , Eptifibatide : 0.5-1%
(Abciximab-induced thrombocytopenia can
typically be treated with transfusion of platelets)

• Allergic reactions : with Abciximab

USES OF GLYCOPROTEIN IIB/IIIA
INHIBITORS:

Unstable angina
Non Q wave MI
Angioplastic coronary intervention
PHOSPHODIESTERASE INHIBITORS

DIPYRIDAMOLE
(Adenosine Reuptake Inhibitor)

CILOSTAZOL
 ADENOSINE
• Adenosine plays an important role in biochemical processes, such
as energy transfer, as adenosine triphosphate (ATP) and
adenosine diphosphate (ADP) - as well as in signal transduction
as cyclic adenosine monophosphate, cAMP

• Function of adenosine is primarily that of cytoprotection

preventing tissue damage during instances of hypoxia, ischemia,
and seizure activity
 DIPYRIDAMOLE
MECHANISM OF ACTION
It inhibits the cellular reuptake of adenosine into platelets,
red blood cells and endothelial cells leading to increased
extracellular concentrations of adenosine.

It also inhibits the enzyme adenosine deaminase which normally

breaks down adenosine into inosine. This inhibition leads to
further increased levels of extracellular adenosine resulting in
vasodilation.

Dipyridamole also inhibits the enzyme phosphodiesterase- 5 (PDE 5)

which normally breaks down cGMP & blocks uptake of adenosine
to increase cAMP of vessel wall & platelets which potentiates PGI2
& interfers with aggregation.

This results in added benefit when given together with NO or statins.

 DIPYRIDAMOLE
OVERDOSE
– Dipyridamole overdose can be treated with
aminophylline and reverses its hemodynamic
effects (vasodilation).

USES
• Transient ischemic attacks
• Dipyridamole + warfarin decrease risk of
thromboembolism in patients with prosthetic heart
valves.
 CILOSTAZOL
• Is used in the alleviation of the symptom of
intermittent claudication in individuals with
peripheral vascular disease.
– dose is 100 mg twice a day. The effects may take as
much as 3 months to be evident.

• Cilostazol is a selective cAMP phosphodiesterase inhibitor.

It
inhibits platelet aggregation and is a direct arterial
vasodilator. Its
main effects are dilation of the arteries supplying blood to
the legs
and decreasing platelet coagulation.
 CILOSTAZOL
ADVERSE EFFECTS
• headache (the most common), diarrhea, abnormal stools,
increased
heart rate, and palpitations

INTERACTIONS
• Cilostazol is metabolized by CYP3A4 and CYP2C19
• Drugs that inhibit CYP3A4, such as itraconazole, erythromycin,
ketoconazole,
and diltiazem are known to interact with cilostazol.
• The proton pump inhibitor omeprazole, a potent inhibitor of
CYP2C19,
increases exposure to the active metabolite of cilostazol.
Thank You