Antifibrinolytics and antiplatelet drugs

Dr.Rathnakar U.P
www.scribd.com
Blood coagulation
Two contrasting
properties of Blood

Remains fluid in circulation

Solidifies when vessels are injured
Blood Clotting [Pathophysiology]

Vascular Phase
 Platelet Phase
 Coagulation Phase
 Fibrinolytic Phase
 Platelet Phase
Ruptured atherosclerotic plaque

Exposure of Adhesion of platelets to thrombogenic surface

acidic
phospholipids

Coagulation
processes

thrombin

Activation of platelets

Linkage of adjacent platelets by fibrinogen[Adhesion]

Aggregation of platelets
 Intrinsic Pathway Extrinsic Pathway
Coagulation
Blood Vessel Injury Tissue Injury

XII XIIa Tissue Factor

Thromboplastin
XI XIa

IX IXa VIIa VII

X Xa X

Prothrombin Thrombin
Factors affected
By Heparin Fibrinogen Fribrin monomer
5 Vit. K dependent Factors Fibrin polymer
Affected by Oral Anticoagulants XIII
 Fibrin
Fibrinolysis [Insoluble]

PLASMINOG
PLASMIN
EN

Fibrin
[Soluble]
 Drugs used to
reduce clotting
1.
Anticoagulant
Parenteral Heparin Inactivation of clotting DVT
factors

Oral Warfarin Decrease synthesis of DVT

clotting factors
2.
Antiplatelet Aspirin Decrease platelet Prevent arterial
aggregation thrombosis
3.
Thrombolytic Streptokinase Fibinolysis Breakdown of
7 thrombi
 INTRINSIC
EXTRINSIC Factor
Streptokinase XIIA Fibrin
Urokinase Activators Kallikrein [Insoluble]
Rt-PA T-PA

PLASMINOGE PLASMIN
N

EACA α2Antiplasmin Fibrin

Tranexaemic acid α2Macroglobuli [Soluble]
Inhibitors n
Aprotinin
INTRINSIC
EXTRINSIC
8 Fibrinolytic system
Fibrinolytics[Thrombolytics]
1. Streptokinase
2. Urokinase
3. Prourokinase
4. Alteplase
5. Reteplace
6. Tenecteplase
7. Anisstreplace [Anisoylated purified
9
streptokinase activator complex]
 Source MOA Antigenic Route[i.v.] AD
[PA]
Alteplase Recombinant Fibrin specific No Bolus+infusion Les
[t-PA] [I gen]
Reteplase Recombinant As above No Bolus+Bolus Les
[r-PA] [II gen]

Tenecteplase Recombinant As above NO Bolus Les

Streptokinase Streptococci Plasminogen YES Infusion Hig

complex
Non-specific

Urokinase Human Directly acts, NO Bolus+infusion

urine/Recombinant [Not as
complex]

Prourokinase Recombinant Prodrug NO

Non specific

Anistreplase Synthetic No need to YES

Plasminogen+SK form complex
10
Non specific
Charecteristic Streptokinase Urokinase Alteplase

t1/2[Minutes] 15-25 15-20 4-8

Fibrin specificity Minimal Moderate Maximum

Plasminogen Indirect Direct Direct

Binding

Antigenicity Yes No NO

Dose 1.5 MU 3-4 MU 100mg

3L.i.v-10mts 15mg bolus

Administration 1.5MU i.v. 3L/h-12h 50mg-30mts
[MI] 35mg-60mts
General properties-Thrombolytic agents

 MOA-
All are activators of plasminogen
PK-
Administered by i.v. route
USE-
MI is the most important use
When-
To be given in the therapeutic window-6 hours
ADE
Some are highly antigenic
Hemorrhage is the most important complication
 Fibrinolytics-
Adverse effects

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 Streptokinase…
• Purified from culture broths of Group β-hemolytic streptococci.6
• Mechanism of action:
• Streptokinase has no enzymic activity.
• Forms an active complex with plasminogen.
• This enzymatically active complex converts uncomplexed
plasminogen to the active enzyme plasmin .

• Pharmacokinetics:
• Streptokinase therapy is instituted within 4-6 hours of a
myocardial infarction and is infused for 1 hour. Its half-life is less
than half an hour.
• On discontinuation of treatment, either heparin or oral
anticoagulants may be administered.
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 Streptokinase….

•
Therapeutic uses:
Acute myocardial infarction,
Acute pulmonary embolism,
Deep-vein thrombosis,
Arterial thrombosis [PVD],
Route
I.V.
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Streptokinase….
Adverse effects:
Bleeding
disorders,fever,allergic
reactions, and therapeutic
failure antistreptococcal
.antibodies in the patient
Repeat doses not effective
In the rare instance of life-
threatening hemorrhage,
aminocaproic acid may be
.administered
16
 Urokinase….

Isolated from human

Directly acts on plasminogen
Non-antigenic.
Adverse action profile same SK

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 Alteplase
 Alteplase (tPA) originally derived from cultured human
melanoma cells-now recombinant DNA technology.
 Mechanism of action: Alteplase has a low affinity for free
plasminogen in the plasma-rapidly activates plasminogen
that is bound to fibrin in a thrombus or a hemostatic plug.
 Fibrin selective-At low doses, it has the advantage of lysing
only fibrin, without unwanted degradation of other proteins-
fibrinogen.
 Streptokinase, which acts on free plasminogen and induces a
general fibrinolytic state. [Note: At therapeutic doses,
circulating plasminogen may be activated, resulting in
hemorrhage.]
……Alteplase
• Therapeutic uses:
• Myocardial infarction,Massive pulmonary embolism,
• Acute ischemic stroke. Alteplase seems to be superior to
streptokinase in dissolving older clots
• Pharmacokinetics: Alteplase has a very short half-life
(about 5 minutes)
• Ten percent of the total dose injected intravenously as a
bolus and the remaining drug is administered over 60
minutes.

• Reteplase: is similar to Alteplase and can be used

19
as an alternative
20
Anistreplase

Anisoylated plasminogen streptokinase activator

complex
Anistreplase is a preformed complex of
streptokinase and plasminogen and it is considered
to be a prodrug.
Streptokinase must be released, and only
plasminogen to which it was associated will get
converted to plasmin.
Anistreplase
Anisoylated plasminogen streptokinase activator
complex
Anistreplase is a preformed complex of
streptokinase and plasminogen and it is considered
to be a prodrug.
Streptokinase must be released, and only
plasminogen to which it was associated will get
converted to plasmin.
Fibrinolytics-Indications
Acute MI
Acute Ischemic Stroke
Deep Vein Thrombosis
Pulmonary embolism
Peripheral arterial occlusion
Administration-STEMI-
Within 1 hr[golden hour]
Not useful after 6 hours of MI[Th.window]
Bleeding risk –same with all.
 Fibrinolytics-CI
AbsoluteContraindications
1. Prior ICH
2. Known Cerebral
vascular lesion
3. IC malignant neoplasm
4. Ischemic stroke-past 3
months
5. Aortic dissection
6. Active bleeding,bleeding
diatehsis[Not menses]
7. Closed head injury/facial
trauma-past 3 months
• Relative
Contraindications
• 1. Poorly controlled/sever
HTN
• 2. Major surgery-3 weeks
• 3. Recent internal
bleeding
• 4. SK/Anistreplase-h/o
allergy/prior admn.
• 5. Pregnancy
• 6. Active peptic ulcer
Anti-fibrinolyticws
MOA:
Occupy the binding sites of Plasminogen & Plasmin-
They can not bind to fibrin
1. Epsilon amino-caproic acid[EACA]
2. Tranexaemic acid.
3. Aprotinin
Indications
Overdosage of fibrinolytics
After surgery in hemophiliacs
Menorrhagia
Recurrent epistaxis
 Antiplatelets
Damaged vessel
Collagen wall Platelet
release activation
As
pir
in

TXA2 Release ADP release Thrombin

GPIIb
/IIIa
Anta
RECEPTOR
S P2Y1
2 an t a
PD
E-I Platelet
adhesion
 platelet inhibitors
Platelet cox-1 inhibitor Aspirin

P2y12[Adenosine] Ticlopidine, Clopidogrel ,

receptor blockade Prasugrel, Elinogrel, Ticagrelor

GPIIb/IIIa antagonist Abciximab, Eptifibatide, Tirofiban

Phosphodiesterase Dipyridamole, Pentoxifylline,

inhibitor Cilostazon

Thrombaxane A2 synthesis GR3219

inhibitor
Natural patelet PGI2 [Epoprosteno]l, nitric oxide
aggregation inhibitor
ASPIRIN
Mechanism of action:
Aspirin (acetylsalicylic acid)
irreversibly inhibits cyclooxygenase-1 in platelets

Blocks the formation of thromboxane A2 (TXA2; a

potent vasoconstrictor and platelet aggregant).

Only the parent form, acetylsalicylic acid, which has

any significant effect on platelet function.
Aspirin……
Platelets are unable to regenerate cyclooxygenase,
antithrombotic effect of aspirin remains for the
lifespan of the platelet (8–10 days).
After stopping aspirin therapy, normal haemostasis
may be regained when about 20% of platelets have
normal cyclooxygenase activity, daily aspirin intake
is recommended
Aspirin-ADE
Adverse effects

Dyspepsia

Erosive gastritis

Peptic ulcer with bleeding and perforation

Hepatic and renal toxicities

Increase in bleeding tendency

Aspirin-imp/points
1. Aspirin in low dose inhibits cox-1 of platelets in liver

2. Platelets have no nuclei-hence no regeneration

3. Inhibition irreversible [Other NSAIDs reversible]
4.Higher doses inhibit PGI2 in vessel wall
5. Low dose-can produce peptic ulceration and bleeding
6. Aspirin resistance-Failure to respond.-Genetic,
P2Y12 receptor blockers

P2Y12

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Ticlopidine (P2Y12 receptor blocker)
Adverse effects
Nausea diarrhoea vomiting, Severe
neutropenia, thrombocytopenia jaundice
bleeding,
Abdominal pain,, headache skin rashes
Drug interaction
Synergestic effect on platelet with aspirin
Clopidogrel (P2Y12 receptor blocker)
It is a theinopyridine derivative

Closely related to ticlopidine

Adverse effects
Lower frequency of neutropenia
thrombocytopenia, bonemarow toxicity
compared to ticlopidine
P2Y12 RECEPTOR BLOCKERS
Dosage and administration

Clopidogrel
75mg once daily
orally

Ticlopidine
250mg twice daily
orally
 Glycoprotein IIb/ IIIa
receptor antagonist
 ABCIXIMAB:
A hybrid murine human monoclonal antibody
MOA: Inhibition of this receptor blocks binding of
fibrin to platelets and platelet aggregation

USE: Used with Aspirin+Heparin during coronary

artery interventions.

ADE: Bleeding, Thrombocytopinia, constipatio

 Abciximab
Adverse effects

Bleeding

Thrombocytopenia

Constipation ileus and arrythmias can occur

37
 Indications for antiplatelet drugs
STEMI Acute ischemic event
NON-STEMI
Before

During Procedure PCI

After
Acute ischemic stroke

Previous MI
High risk of vascular events
Previous stroke
PVD
LL Arterial graft
CABG Revascularization procedures
Carotid endarterectomies
AF
Usually with anticogulants
Prosthetic valves