Fibrinolytics, antifibrinolytics and antiplatelet drugs

Dr.Rathnakar U.P
MD.DIH.PGDHM
www.scribd.com

Blood coagulation

Two contrasting properties of Blood

Remains fluid in circulation Solidifies when vessels are

injured Mechanism is complex and

Vascular Phase

Platelet Phase
Coagulation Phase Fibrinolytic Phase

1. Anticoagulant
Parenteral

Heparin

Inactivation of clotting factors

DVT

Oral

Warfarin

Decrease synthesis of clotting factors Decrease platelet aggregation

Fibinolysis

DVT
Prevent arterial thrombosis Breakdown of thrombi

2. Antiplatelet

Aspirin

3. Thrombolytic Streptokinase
4

EXTRINSIC Streptokina se Urokinase Rt-PA

Activators

INTRINSIC Factor XIIA Kallikrein T-PA

Fibrin [Insoluble]

PLASMINOGEN
[Circulating&Fibrin]

Activated to
PLASMIN

EACA Tranexaemic acid Aprotinin EXTRINSIC

5

Inhibitors

2Antiplasmin 2Macroglobul in INTRINSIC

Fibrin [Soluble]

Fibrinolytic system

Fibrinolytics

Streptokinase and Urokina

Alteplase Reteplase Tenecteplase Anisstreplace [Anisoylated purified streptokinase activator complex]

Source
Alteplase Reteplase Recombinant Recombinant

MOA [PA]
Fibrin specific As above

Antigen Route[i.v.] ic
No No i.v. i.v.

ADE
Less Less

Tenecteplas e Streptokina se

Recombinant Streptococci

As above Plasminoge n complex Non-specific

Destroyed by AB

NO YES

i.v. i.v.

Less High

Urokinase

Human urine/Recombinant

Directly acts, [Not as complex] Not Destroyed by AB No need to form

NO

i.v.

Less

7 Anistreplas e

Synthetic Plasminogen+SK

YES

i.v.

High

Charecteristi c
t1/2[Minutes]

Streptokinas e
30-80

Urokinase

Alteplase

15-20

4-8

Fibrin specificity

Minimal

Moderate

Maximum

Plasminogen Binding Antigenicity

Indirect

Direct

Direct

Yes

No

NO

Dose

1.5 MU

3-4 MU 3L.i.v-10mts 3L/h-12h

100mg 15mg bolus 50mg-30mts

Administration

1.5MU i.v.

General properties-Thrombolytic agents

MOAAll are activators of plasminogen PKAdministered by i.v. route USEMI is the most important use WhenTo be given in the therapeutic window-6

hours ADE Some are highly antigenic Hemorrhage is the most important

FibrinolyticsAdverse effects

10

Streptokinase

ADEs Bleeding Antigenic-Anaphylaxis, Rashes

Streptokinase.

Therapeutic uses: Acute myocardial infarction, Acute pulmonary embolism, Deep-vein thrombosis, Arterial thrombosis [PVD],

12

Urokinase.
Isolated from human? Directly acts on plasminogen Non-antigenic. Adverse action profile same SK
13

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.]

15

Anistreplase
Anisoylated plasminogen streptokinase

activator complex Anistreplase is a preformed complex of streptokinase and plasminogen and it is considered to be a prodrug.

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
AbsoluteContraindicatio

ns 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 menstruation]

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

Uses of Antifibrinolytics

ADEs Antifibrinolytics

Summary: Fibrinolytics

Antiplatelet drugs

Platelet-Adhesion-activation-aggregation

Vascular injury, von Willebrand factor binds to collagen in the exposed subendothelium at the site of injury. The other site of the rod-formed von Willebrand factor binds to the platelet receptor GPIb and platelets are thereby anchored to the site of the

Activation
5HT, ADP

Attach to nearby platelets and activate

TXA2

TXA2 [-]

ATP

cAMP

[+] DAG,IP3

[-]Aspirin

COX1

Arachidonic acid

[]Dipyridamole 5AMP
PGI2 Epoprostenol Receptors

Endothelium

Collagen+vW Factor

Aggregation

[-]Aspirin [GPIIb/IIIa ]Dipyridamole

Epoprostenol Fibrinoge n ADP P2Y1&P2Y12 Clopidogrel Abciximab-Eptifibatide-Tirofiban

GPIIb/IIIa

Aggregation Vasoconstrict TXA2 ion Atherosclero

Terutroban

Ticlopidine

The role of platelets

Platelet cox-1 inhibitor P2y12[Adenosine] receptor blockade

Aspirin Ticlopidine, Clopidogrel , Prasugrel, Elinogrel, Ticagrelor

GPIIb/IIIa antagonist
Phosphodiesterase inhibitor

Abciximab, Eptifibatide, Tirofiban

Dipyridamole, Pentoxifylline, Cilostazole

Thrombaxane A2 synthesis GR3219 inhibitor Natural platelet aggregation inhibitor PGI2 [Epoprosteno]l, nitric oxide

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 (810 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
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.1.

Platelet cox-1 inhibitor P2y12[Adenosine] receptor blockade

Aspirin Ticlopidine, Clopidogrel , Prasugrel, Elinogrel, Ticagrelor

GPIIb/IIIa antagonist
Phosphodiesterase inhibitor

Abciximab, Eptifibatide, Tirofiban

Dipyridamole, Pentoxifylline, Cilostazol

Thrombaxane A2 synthesis GR3219 inhibitor Natural patelet aggregation inhibitor PGI2 [Epoprosteno]l, nitric oxide

P2Y12 receptor antagonist

Drug interaction
Synergestic effect on platelet with aspirin

250mg twice daily orally

P2Y12 receptor antagonist

Clopidogrel
Closely related to ticlopidine 75mg once daily, orally

Less than

Platelet cox-1 inhibitor P2y12[Adenosine] receptor blockade

Aspirin Ticlopidine, Clopidogrel , Prasugrel, Elinogrel, Ticagrelor

GPIIb/IIIa antagonist
Phosphodiesterase inhibitor

Abciximab, Eptifibatide, Tirofiban

Dipyridamole, Pentoxifylline, Cilostazol

Thrombaxane A2 synthesis GR3219 inhibitor Natural patelet aggregation inhibitor PGI2 [Epoprosteno]l, nitric oxide

Glycoprotein IIb/ IIIa receptor antagonist

ABCIXIMAB:

A 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. i.v.infusion ADE: Bleeding, Thrombocytopinia, constipation

Indications for antiplatelet drugs

STEMI NON-STEMI
Acute ischemic event Percutaneous Coronary Interventions

Before During Procedure After MI Previous

Previous stroke PVD LL Arterial graft CABG Carotid endarterectomies AF

Acute ischemic stroke

High risk of vascular events

Revascularization procedures
Prosthetic valves

Usually with anticogulants

Summary: Antiplatelets