Antiplatelet and fibrinolytics

ANTIPLATELET DRUGS& FIBRINOLYTICS

DR. K MUKHOPADHYAYASSISTANT PROFESSOR

ESI-PGIMSR

ANTITHROMBOTIC DRUGS

Fibrinolytics

REFLEX VASOCONSTRICTION

PRIMARY HEMOSTASIS

SECONDARY HEMOSTASIS

THROMBUS AND ANTITHROMBOTIC EVENTS

Platelet Adhesio

n

Platelet Aggregatio

n

Platelet Activatio

n

ANTI-PLATELETDRUGSMECHANISM

• COMPLETE INACTIVATION OF PLATELET COX-1 IS ACHIEVED WITH A DAILY ASPIRIN DOSE OF 75 MG.

HIGHER THE DOSE MORE EFFICACY ???

NO• AT HIGH DOSES (1 G/D), IT ALSO INHIBITS

COX-2 (RESPONSIBLE FOR SYNTHESIS OF PROSTACYCLIN, A POTENT INHIBITOR OF PLATELET AGGREGATION)

ASPIRIN

ADP RECEPTOR

P2Y1- induces a shape change and aggregation.

P2Y12 - inhibits adenylyl cyclase. So causes Platelet activation

- increases Adhesiveness of platelets

VORAPAXAR

P2Y12

P2Y1

TICLOPIDINE

A PRODRUG (ACTIVATED BY HEPATIC CYP) THAT INHIBITS THE P2Y12 RECEPTOR BY FORMING A DISULFIDE BRIDGE IN THE EXTRACELLULAR REGION OF THE RECEPTOR

SHORT T1/2 BUT LONG DURATION

NEUTROPENIA, FATAL AGRANULOCYTOSIS WITH THROMBOCYTOPENIA

CLOPIDOGREL

• IT IS AN IRREVERSIBLE INHIBITOR OF PLATELET P2Y12 RECEPTORS

• IT IS MORE POTENT AND HAS A MORE FAVORABLE TOXICITY PROFILE THAN TICLOPIDINE.

• GENETIC POLYMORPHISM CAN CAUSE RESISTANCE – CYP2C19

• THE USUAL DOSE IS 75 MG/DAY. LOADING DOSE MAY BE GIVEN

• THE COMBINATION OF CLOPIDOGREL PLUS ASPIRIN IS SUPERIOR TO ASPIRIN ALONE (TWO DRUGS ARE SYNERGISTIC)

PRASUGREL

• THIS ALSO IS A PRODRUG THAT REQUIRES METABOLIC ACTIVATION.

• HOWEVER, ITS ONSET OF ACTION IS MORE RAPID THAN THAT OF TICLOPIDINE OR CLOPIDOGREL.

• IT PRODUCES GREATER AND MORE PREDICTABLE INHIBITION OF ADP-INDUCED PLATELET AGGREGATION.

• RISK OF BLEEDING IS MORE AND CONTRAINDICATED IN PATIENTS WITH H/O CVA

GLYCOPROTEIN IIB/IIIA INHIBITORS

• GLYCOPROTEIN IIB/IIIA IS A PLATELET-SURFACE INTEGRIN.

• ABCIXIMAB, EPTIFIBATIDE, TIROFIBAN

ABCIXIMAB• IT IS IS THE FAB FRAGMENT OF A HUMANIZED

MONOCLONAL ANTIBODY DIRECTED AGAINST THE ΑIIB Β3 RECEPTOR.

• IT ALSO BINDS TO THE VITRONECTIN RECEPTOR (FACILITATES ADHESION) ON PLATELETS, VASCULAR ENDOTHELIAL CELLS, AND SMOOTH MUSCLE CELLS.

• PATIENTS UNDERGOING PERCUTANEOUS ANGIOPLASTY FOR CORONARY THROMBOSIS —

• TO PREVENT RESTENOSIS, RECURRENT MYOCARDIAL INFARCTION, AND DEATH (IN CONJUNCTION WITH ASPIRIN AND HEPARIN)

DIPYRIDAMOLEMOA

INCREASES CAMP LEVEL BY INHIBITING CYCLIC NUCLEOTIDE PHOSPHODIESTERASES ( INVOLVED IN METABOLISM OF CAMP)

DIPYRIDAMOLE IS A POTENT CORONARY VASODILATOR

NEWER ANTIPLATELET AGENTS

• CANGRELOR AND TICAGRELOR : DIRECT-ACTING REVERSIBLE P2Y12ANTAGONISTS.

THROMBIN RECEPTOR ANTAGONISTS• VORAPAXAR (SCH530348 ) AND

ATOPAXAR (E5555)

USE OF ANTIPLATELETS

•ACUTE CORONARY SYNDROME•CORONARY ARTERY DISEASE•CEREBRO VASSCULAR DISEASE• PROSTHETIC HEART VALVE• PERIPHERAL VASCULAR DISEASE

FIBRINOLYTIC DRUGS

Stable Angina

Acute Coronary Syndrome

Unstable Angina

NSTEMI

STEMI

Not relieved by nitrate Cardiac markers

+VeST Elevation = -Ve

Cardiac markers + Ve

ST Elevation = + Ve

Cardiac markers - Ve

ST Elevation = -Ve

FIBRINOLYSIS

Plasminogen activator inhibitors -1 and -2

Alpha 2-antiplasmin

FIBRINOLYTICS1. STREPTOKINASE.2. ANISTREPLASE.3. UROKINASE4. TISSUE PLASMINOGEN ACTIVATORS –• ALTEPLASE,• RETEPLASE,• TENECTEPLASE

ADVANTAGE OF ALTEPLASE OVER STREPTOKINASE• SPECIFICITY IS MORE – FIBRIN BOUND

PLASMINOGEN• LESS ANTIGENIC

ADVANTAGE OF TENECTEPLASE OVER ALTEPLASE

• LONGER HALF-LIFE –GIVEN AS BOLUS DOSE• RESISTANT TO PAI-1 INHIBITION

COMPARISON

USE OF FIBRINOLYTIC

•STEMI• ISCHAEMIC STROKE (ALTEPLASE)•PULMONARY EMBOLISM•DEEP VEIN THROMBOSIS

INHIBITORS OF FIBRINOLYSIS

• COMPETES FOR LYSINE BINDING SITES ON PLASMINOGEN AND PLASMIN, BLOCKING THE INTERACTION OF PLASMIN WITH FIBRIN.• AMINOCAPROIC ACID• TRANEXAMIC ACID

THANK YOU