Antiplatelets, Anticoagulant,

Antithrombotic/Fibrinolytic
Dr. dr. Nicolaski Lumbuun, SpFK
Faculty of Medicine Universitas Pelita Harapan

Learning Objectives
To describe the role of Oral antiplatelets,
Antithrombotic-fibrinolytic, and rTPA
therapy.
To know the pharmacology of antiplatelet
medication, including the drug mechanism.
To know the pharmacology of anticoagulant
medication, including the drug mechanism.

Key-Words
Platelets >< Antiplatelets
Coagulation >< Anticoagulation
Thrombus >< Fibrinolytic

 Tissue Pathway Inhibitors

Vascular Injury
Exposure of collagen and vWF

Platelet adhesion and release

Platelet recruitment and activation

Platelet aggregation

Tissue factor exposure

Activation of coagulation
Thrombin generation
Fibrin formation

Platelet fibrin thrombus

III

Antiplatelet drugs
Effective in the arterial. Circulation coagulation process
have lack of effect.
Decrease platelet aggregation inhibit thrombus formation
Widely used in primary and secondary prevention of
cerebrovascular (occlusive stoke) or cardiovascular
disease & prevent end-stent thrombosis after PCI.
Sometimes used in peripheral arterial disease.

The most important antiplatelet drugs

Cyclooxygenase inhibitors
Aspirin (Cardioaspirin)
Adenosine diphosphate
(ADP) receptor inhibitors
Clopidogrel (Plavix)
Prasugrel
Ticagrelor
Ticlopidine (Ticlid)
Phosphodiesterase
inhibitors
Cilostazol (Pletaal)

Glycoprotein IIB/IIIA inhibitors (IV

use only)
Abciximab (ReoPro)
Eptifibatide (Integrilin)
Tirofiban (Aggrastat)
Adenosine reuptake inhibitors
Dipyridamole (Persantine)
Thromboxane inhibitors
Thromboxane synthase
inhibitors -> Picotamide
Thromboxane receptor
antagonists
Ifetroban, terutroban

Uses
1. Prevention of primary(?) or secondary occlusive stroke.
2. Prevention of myocardial infarction.
3. Following coronary artery bypass grafting (CABG) or
stenting (Percutaneous Coronary Intervention).
4. Following coronary artery angioplasty.
5. Prosthetic heart valves.
6. Chronic disseminated intravascular coagulation.
7. Prophylaxis of venous thrombosis.

Aspirin ( Acetylsalicylic Acid )

Mechanism of Action
Aspirin irreversibly acetylates the active site of cyclooxygenase, which
is required for the production of thromboxane A2, a powerful
promoter of platelet aggregation.

Indication :
Patients who survived a prior occlusive event (including MI, occlusive
stroke or transient ischemic attack, or other high risk categories
including unstable and stable angina, angioplasty, or CABG & PCI).
Aspirin, prevents ~25% of serious vascular events, including
significant reductions on MI, stroke, and CVD death.

Side effects
Peptic Ulcer, Increased incidence of GIT bleeding

ADP pathway inhibitors (Ticlopidine

& Clopidogrel)
Mechanism of Action
Inhibits binding of ADP to its platelet receptor by irreversibly
modifying the platelet ADP receptor.
Pharmacokinetics of ticlopidine

Given orally.

Extensively bound to plasma proteins.

Metabolized in the liver to give active metabolites.
Slow onset of action (3 - 5 days).
is taken twice ( 250 mg twice daily ).

Adverse Effects
Severe neutropenia, Bleeding (Prolong bleeding time), CYP450 inhibitors,
G.I.T : Diarrhoea, Nausea, Dyspepsia, Allergic Reactions.

Clopidogrel
Clopidogrel is more potent.
Less side effects ( less neutropenia).
Less Frequency of administration (75 mg once daily).
Bioavailability is unaffected by food.

Clinical Uses
Alternative prophylactic th/ to aspirin in secondary prevention
of stroke and myocardial infarction and unstable angina.

New Oral Antiplatelet Drugs

Adenosine Diphosphate-Receptor Antagonists
Prasugrel

Ticagrelor *

Thienopyridine
More rapid onset of action
than clopidogrel
Irreversible inhibitor of the
P2Y12 receptor

Cyclo-pentyl-triazo-pyrimidine
(CPTP)
More rapid onset of action
than clopidogrel
Reversible inhibitor of the
P2Y12 receptor

* Not approved by FDA

Dipyridamole
Phosphodiestrase inhibitor thus cAMP in the blood platelets
inhibition of platelet aggregation.
Uses
Taken orally.
Primary prophylaxis in patients with prosthetic heart values
(in combination with warfarin ).
Prophylactic therapy for angina pectoris in combination with
aspirin .
Disadvantages : Headache
Advantage : No excess risk of bleeding

Glycoprotein IIb/ IIIa receptor inhibitors

Is a receptor for fibronectin, fibrinogen, vitronectin
and von Willebrand factor.

1. Abciximab
a monoclonal antibody that inhibits glycoprotein

IIb/ IIIa
receptor.
Inhibits all the pathways of platelet activation (Final
common pathway).
Given I.V. infusion
Uses : adjuncts to heparin and aspirin for prevention of
cardiac ischemic complications.
Side effect is immunogenicity

2. Tirofiban & Eptifibatide

Eptifibatide (peptide)
Tirofiban (non-peptide)
are synthetic mimetics of arginine-glycine-aspartic
sequence of fibrinogen
inhibits glycoprotein IIb/ IIIa receptor at site that
interacts with arginine-glycine-aspartic sequence of
fibrinogen (by occupancy of the receptor) fibrinogen like
mimetic agent
Given I.V.
Uses : Acute coronary syndromes to decrease incidence of
thrombotic complications

Recent Issue of Antiplatelets

Adverse events :
Un-tolerate of ADE of Aspirin GI symptom, bleeding
Unacceptable risk of bone marrow toxicity Ticlopidine

Antiplatelet Drug Resistance :

Resistance of Aspirin, Clopidogrel & Glycoprotein
IIB/IIIA inhibitors
The issue is whether it is clinically important to routinely
screen patients for antiplatelet drug resistance.

ANTI COAGULANTS
Indirect Thrombin
Inhibitors

Unfractionated Heparin
LMWH Enoxaparin,
dalteparin

Fondaparinaux
Rivaroxiban (1st oral factor
Xa inhibitor)

Direct Thrombin
Inhibitors

Hirudin Lepirudin
Bivalirudin
Argatroban
Melagatran
Ximelagatran (oral)
Dabigatran (oral)

Indications For Antithrombotic Therapy

Venous thromboembolic disease
Deep venous thrombosis (DVT)
Pulmonary embolism (PE)
Primary prophylaxis of DVT or PE
Arterial thromboembolic disease
Prosthetic heart valves
Mitral valve disease, especially with atrial fibrillation
Congestive cardiomyopathies, especially with atrial fibrillation
Atrial fibrillation
Mural cardiac thrombi
Transient ischemic attacks
Stroke in evolution
Disseminated intravascular coagulation
Maintenance of patency of vascular grafts, shunts, bypasses

Heparin
Preventing the formation of clots and extension of existing
clots within the blood.
Does not break down clots that have already formed
(unlike tissue plasminogen activator), it allows the body's
natural clot lysis mechanisms to work normally to break
down clots that have already formed.
Antidote of heparin intoxication : protamine sulphate

Anticoagulant Properties of Heparin

1.

Activation anti-thrombin III Inhibits the thrombinmediated conversion of fibrinogen to fibrin

2.

Inhibits the aggregation of platelets by thrombin

3.

Inhibits activation of fibrin stabilizing enzyme

4.

Inhibits activated factors XII, XI, IX, X and II

Unfractionated Heparin
High Dose
Treatment of venous/arterial thrombi
Requires monitoring
IV- 5,000 Units bolus, then 30,000-35,000 units/24 hrs
80 Units/kg bolus, then 18 Units/kg/hr to maintain aPTT in
therapeutic range
Low Dose
Surgical Prophylaxis
5,000 Units SC 2 hr pre-op
5,000 Units SC every 12 hours
Medical Prophylaxis
5,000 Units SC every 12 hours
No monitoring required

FIBRINOLYTICS

Streptokinase
Urokinase
Anistreplase
t-PA
Reteplase
tenecteplase

Thrombolytic Agents = Fibrinolytic drugs

Dissolve blood clots by activating

plasminogen, which forms a
cleaved product called plasmin.

Plasmin is a proteolytic enzyme

that is capable of breaking crosslinks between fibrin molecules,
which provide the structural
integrity of blood clots.
Tissue plasminogen activator produces
clot lysis through :
1.
tPA binds to fibrin on the surface
of the clot
2.
Activates fibrin-bound plasminogen
3.
Plasmin is cleaved from the
plasminogen associated with the
fibrin
4.
Fibrin molecules are broken apart
by the plasmin and the clot
dissolves

Anisolated
Plasminogen
Streptokinase
Activator Complex

Keep in mind about Streptokinase

Is a bacterial product, the body has the ability to build
up an immunity to it.
Recommended that this medication should not be used
again after four days from the first administration, as it
may not be as effective and can also cause an allergic
reaction.
For this reason, it is usually given only for a person's
first heart attack. Further thrombotic events could be
treated with Tissue plasminogen activator (tPA).
Overdose of streptokinase or tPA can be treated
with aminocaproic acid.

Take Home Message

Take Home Message

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