Antiplatelet, Anticoagulant and

Thrombolytic Agents

Basic Pharmacology Block

PDNT/PMED.PMSC/PPHR -213
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 Objectives

1. Identify the classes of drugs used to prevent and treat

thrombotic disorders.
2. Recognize agents in the three classes (anticoagulants,
anti-platelets and Thrombolytics).
3. List the features and differences of drugs in each class.
4. Recognize the mechanisms of actions of agents in each
class.
5. List the side effects and contraindications of drugs in
each class.

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Significance of Blood Coagulation

• Hemostasis and thrombosis are related processes involving

the coagulation system.

• However physiological hemostasis is a protective response to

vascular injury to prevent excessive bleeding followed by a
series of changes i.e. vasoconstriction of blood vessels,
adhesion and activation of platelets and formation of fibrin
mesh.

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 Terminologies
• Thrombus i.e. clot so formed often obstructs blood vessels, leading to
pathologic complications.

• Fibrin is a fibrous, non-globular protein involved in the clotting of blood

• The broken piece of thrombus is called embolus, when the emboli is

formed in peripheral veins it is called deep venous thrombosis (DVT) and
obstruct blood flow in lungs causing pulmonary embolism.

• When embolus is formed in arteries it is called arterial thromboembolism.

• The stoppage of blood flow through a blood vessel or body part is called
hemostasis.

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 Terminologies
• Antiplatelet = Drugs which interfere with platelet functions

• Anticoagulants = Drugs used to reduce the coagulability of

blood

• Thrombolytic (Fibrinolytics) = Drugs used to lyse thrombin

clot (mainly therapeutic)

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Anticoagulant & Antiplatelet Agents

Drugs affect hemostasis and thrombosis in three different ways

influencing:

a. Blood coagulation i.e. conversion of liquid blood to a gel or

clot. The main event is the conversion of soluble fibrinogen to
insoluble fibrin by thrombin and the class of drug used is called
anticoagulants.

b. Platelet function i.e. inhibition of platelet aggregation, the

class of drug used is called antiplatelet agents.

c. Fibrin removal i.e. breakdown of fibrin threads, the class of

drug used is called fibrinolytic or thrombolytic agents.

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The Coagulation and Fibrinolytics Pathways

Kohler H and Grant P. N Engl J Med 2000;342:1792-1801

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 Antiplatelet Agents

Antiplatelet agents play an important role in preventing

atherosclerotic vascular disease and thrombosis through the
inhibition platelet aggregation.

They are classified on the basis of mechanism of action:

Ø Thromboxane A2 Synthesis Inhibitors

Ø Phosphodiesterase Inhibitors

Ø Adenosine diphosphate (ADP) Antagonists

Ø Glycoprotein Receptor Antagonists 8

 A. Thromboxane A2 Synthesis Inhibitors
• These drugs inhibit enzyme cyclooxygenase 1 (COX-1) required
for the synthesize thromboxane A2 a potent inducer of platelet
aggregation and vasoconstriction.

• Hence inhibit platelet aggregation e.g. aspirin.

• Inhibition of COX is irreversible and effect last for 7 to 10 days

till new platelets are formed.

• Dose as low as 75mg/day is enough to produce the effect.

• Aspirin and related medicines reduces the incidence of stroke and

MI in susceptible individuals.
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Prostaglandins main physiologic actions

Sanderson, S. et. al. Ann Intern Med 2005;142:370-380

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 B. Phosphodiesterase Inhibitors

• Dipyridamole inhibit enzyme phosphodiesterase.

• This inhibition increase cellular levels of cAMP, which ultimately

inhibit platelet aggregation, and inhibits thromboxane A2.

• It has been used in patients of transient ischemic attack or stroke

with effects similar to aspirin, however does not increase risk of
bleeding.

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C. Glycoprotein Receptor Antagonist

• Abciximab is murine monoclonal antibody that binds irreversibly

to GP IIb/IIIa receptors and prevent binding of fibrinogen.

• It can reduce platelet aggregation by more than 90%.

• It is given intravenously, mainly during and after coronary artery

procedures e.g. angioplasty.

• Eptifibatide is a synthetic inhibitor for GP IIb/IIIa receptors

• The main side effect for both drugs is bleeding

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D. Adenosine Diphosphate Antagonist
Ticlopidine & Clopidogrel:

Mechanism of action:
Irreversibly inhibit platelet activation by blocking adenosine
diphosphate receptors on the platelet membrane and they inhibit
GP IIb/IIIa receptors.

Therapeutic uses:
Decrease the incidence of thrombotic stroke (used for patients
who can not tolerate aspirin).

Adverse effects:
Most serious side effect of ticlopidine are neutropenia,
thrombocytopenia, aplastic anemia. Therefore clopidogrel is the
main agent currently.
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Sites of Action of Antiplatelet Drugs

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 Anticoagulants

• Anticoagulants are drugs that reduce clotting ability of

blood.

A. Heparin
The most common anticoagulants are heparin and warfarin.

• They are drugs of choice when a rapid anticoagulant effect is

required, due to immediate onset of action.

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 Anticoagulants
• LMWHs e.g. tinzaparin, enoxaparin, dalteparin and fondaparinux
are short fragments of heparin with a molecular weight from 1000
to 10000 Da, while the molecular weight of heparin is 15000 Da.

• Heparin and all other LMWHs are biologically derived from

animals tissues where as fondaparinux is the synthetic analogue
of heparin.

• Heparin must be given parenterally either subcutaneous or

intravenously.

• Intramuscular heparin is contraindicated because of hematoma

formation.

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 Mechanism of Action

• Heparin binds to anti-thrombin III and induces

conformational changes that accelerate the
interaction of antithrombin III with the
coagulation factors. Heparin also catalyzes the
inhibition of thrombin by heparin cofactor II and
Xa a circulatory inhibitor.

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 Drug Targets

• Low Molecular Weight Heparin

(LMWH)

• Unfractionated heparin(UFH)
Anticoagulants: Pharmacokinetics
• Heparin is not absorbed from the GIT therefore is given
intravenously or subcutaneously.

• Produce an immediate action on intravenous administration,

but onset is delayed up to 60 min when given subcutaneously.

• Warfarin is absorbed rapidly and completely from the gut

after oral or rectal administration.

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Anticoagulant Test and Antidote

HEPARIN
• APTT (activated partial thromboplastin time)
• Antidote-Protamine sulfate

WARFARIN
• INR (international normalized ratio)
• Antidote- Vitamin K

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 Adverse Effects of Heparin
Main adverse effects are :
1. Bleeding
2. Thrombocytopenia
3. Osteoporosis and diminished renal function may occur
following use of LMWH longer than three months.
4. Others

• Alopecia may occur in 0.5% patients after 5 to 10 days of therapy.

• Hypersensitive reactions e.g. chills, fever, bronchospasm,
urticaria and anaphylactic reactions, since obtained from bovine
lungs and porcine intestine.
• Hypoaldosteronism, since inhibits aldosterone synthesis.
• Hyperkalaemia
• Spontaneous fractures when used for 6 months or more.
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 Advantages of LMWHs
LMWHs have some advantages over heparin therapy:
• Better bioavailability following subcutaneous injection.

• Longer duration of action, reducing repeated administrations.

• Predictable plasma levels without frequent APTT monitoring.

• Lower risk of bleeding and osteoporosis.

• Lower incidence of thrombocytopenia.

** LMWH is contraindicated in renal failure patient, while unfractionated

heparin is used.
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Therapeutic uses of Heparin and
LMWHs

• Prevention and treatment of venous thrombosis and

pulmonary embolism

• Prevention of thrombosis after myocardial infarction (MI)

• Treatment of patients with unstable angina and MI.

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 Drug Interactions

• Heparin should be carefully used with drugs causing

changes in coagulation status or platelet function e.g.
aspirin, phenylbutazone, dipyridamole, warfarin, etc.

• It may antagonize the actions of corticosteroids, insulin or

ACTH.

• Heparin may increase plasma levels of diazepam.

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 B. Warfarin

Mechanism of Action:
• Warfarin acts as vitamin K antagonists. Inhibit activation of
vitamin K by blocking enzyme vitamin K epoxide reductase.

• Thus inhibit the formation of clotting factors II, VII, IX and X,

whose synthesis depends on the availability of vitamin K.

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 Adverse Effects: Warfarin

• Major adverse effect is hemorrhage. Bleeding in the intestine

and brain can be troublesome.

• Other adverse effects are allergic reactions, GIT disturbances

and teratogenicity, since crosses the placenta therefore is not
given in the first months of pregnancy and also in the later
stages of pregnancy..

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 Drug Interactions: Warfarin

• Enzyme inhibitors e.g. cimetidine and ciprofloxacin

increase plasma levels of warfarin.

• Aspirin and other NSAIDs can increase the risk of

bleeding, partly by their effect on thromboxane synthesis.

• Enzyme inducers e.g. rifampicin and griseofulvin increase

the metabolism of warfarin.

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 Comparison

HEPARIN
• Parenteral
• Immediate onset
• Duration of action 4-6 hrs
• Activity in vitro & in vivo
• Activate AT-III that Blocks
action of factor X & II
• Antagonist - protamine
sulfate
• Monitor APTT
WARFARIN
• Oral
• Delayed onset of action
• 3-6 days
• Only in vivo
• Inhibits Vit K reductase and
synthesis of clotting factors
• Antagonist is Vit K
• Monitor PT/INR

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 C. Lepirudin and Bivalirudin

• These drugs are direct inhibitors of thrombin and

have been approved to provide intravenous
anticoagulation in patients with heparin induced
thrombocytopenia.

• No antagonists for these drugs are available.

Adverse effects:
Bleeding and hypersensitivity reaction.

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 Thrombolytic Drugs
Thrombolytic therapy cause rapid lysis of already formed clots.
Mechanism of action:
Fibrinolysis is initiated by activation of the proenzyme plasminogen
into plasmin. Plasmin catalyzes the degradation of fibrin.
A. Alteplase (tpA): second generation.
Previously known as tissue-type plasminogen activator.

B. Streptokinase and Urokinase: first generation.

Treatment of myocardial infarction, pulmonary embolism and acute
ischemic stroke.
Adverse effects:
Bleeding including gastrointestinal and cerebral hemorrhages.

* Several studies shown that fibrinolytic drugs reduce mortality if

given within 12 hours of the onset of symptoms. 30