ANTICOAGULANTS,

THROMBOLYTICS AND
ANTIPLATELET DRUGS
Haemostasis is the arrest of blood loss from a
damaged vessel. This usually involves:

• localized vasoconstriction

• platelet adhesion and activation

• blood coagulation.
Sequence of Events in Homeostasis
 The formation of an unwanted clot within
the blood vessels is the most common
abnormality of homeostasis.
 Arterial thrombosis may result
in ischemic necrosis of the tissue supplied
by the artery.

An example is myocardial infarction due

to occlusion of the coronary arteries.
 Venous thrombosis may cause tissues
drained by the vein to become edematous
and inflamed.
BLOOD COAGULATION
The coagulation process that generates
thrombin consists of two interrelated pathways:

a. extrinsic pathway
b. intrinsic pathway
 The extrinsic system is initiated by the
activation of clotting factor VII, and the
release of tissue thromboplastin – a
phospholipid and protein mixture.
 The intrinsic system is triggered when blood
comes in contact with exposed collagen
fibres in the sub-endothelium of damaged
blood vessels.
Intrinsic pathway Extrinsic pathway
XII XIIa
XI XIa
IX
Ca2+ III
IXa Ca2+
PF-3 VIIa ← VII
Ca2+
VIII
X Xa X
Common Ca2+
pathway
PF-3
V XIII
Prothrombin Thrombin
(factor II)
XIIIa
Fibrinogen Fibrin
Stable fibrin
polymer
 Both systems activate factor X transforming
it into the active form Xa which then
converts prothrombin into thrombin.

 The final step in the pathway is the

conversion, by factor IIa, of fibrinogen
into fibrin.
ANTICOAGULANTS
 Two types of drugs are employed in
preventing blood coagulation, heparin and
the vitamin K antagonists.

 Their mechanisms of action

differ, as do their clinical uses.
Heparin
 Heparin is a rapidly- acting anticoagulant.

 Heparin occurs normally complexed to

histamine in mast cells.

 It is strongly acidic.
Mechanism of Action
 Heparin increases activity of antithrombin III
which inhibits activated serine proteases
such as IIa (thrombin) IXa, Xa, XIa, XIIa
and XIIIa, in the clotting cascade.
 Heparin forms a ternary complex with
antithrombin III and the clotting factors.

 The clotting factors are inactivated and

heparin is released from the complex.
 heparin also has a direct anticoagulant
activity as demonstrated by its effectiveness
in vitro.

 heparin releases lipoprotein lipase from

vascular beds – accelerates clearing of
lipoproteins from the plasma.
The anticoagulant effect of heparin is
immediate and maximal anticoagulation
occurs within minutes after direct intravenous
heparin injection.
Therapeutic uses
 preoperative prophylaxis against deep
vein thrombosis
 in acute myocardial infarction
 to prevent pulmonary embolism in patients
with established thrombosis
 to prevent clotting in extracorporeal
circulation devices.
 Heparin can be given either as a continuous
infusion or by intermittent injections.

 It can also be given as deep subcutaneous

injections.
 Heparin is taken up by the reticuloendothelial
system and undergoes hepatic degradation
to inactive products.

 Therefore it has a longer half-life in patients

with hepatic cirrhosis.
Adverse effects
b) Bleeding complications. Hemorrhage can
be controlled by giving protamine sulphate,
a basic substance. Protamine binds tightly to
and neutralizes the anticoagulant
effect of heparin.
Adverse effects (cont’d)
b) Hypersensitivity reactions (fever, anaphylaxis)
c) Thrombocytopenia
d) Osteoporosis with long term treatment
Warfarin
 Warfarin is a coumarin derivative.
Another example is dicoumarol.

 These anticoagulants act by antagonizing

Vit K which is essential for the synthesis
of a number of clotting factors including
Factors II, VII, IX.
 Unlike heparin, the anticoagulant effect of
warfarin and related compounds are not
observed until 8-12 hours after
drug administration.
 Warfarin is orally active – bioavailability is
100% after oral administration.

 It is extensively bound to plasma proteins

and can displace many other drugs from
this site.
Adverse effects
 bleeding
 hemorrhagic infarction in the breast,
intestine and fatty tissues
 Warfarin readily crosses the placenta and
can cause hemorrhage in the fetus.

 It is therefore contra- indicated in pregnancy.

Drug interactions
 there are a number of drugs that potentiate
the anticoagulant effect of warafarin such as
(acute alcohol intoxication, cimetidine,
& phenylbutazone), while others attenuate
the anticoagulant effect of warafarin
such as (chronic alcohol ingestion,
barbiturates & rifampicin)
THROMBOLYTIC DRUGS
 Fibrin clots are dissolved by the enzyme
plasmin.

 In vivo, inactive plasminogen is converted to

plasmin by tissue plasminogen activator
(tPA).
 Acute thromboembolic disease may be
treated by the administration of agents that
activate the conversion of plasminogen to
plasmin, a serine protease that hydrolyses
fibrin and thus dissolves clots.

Examples:-Streptokinase, urokinase and

tissue- type plasminogen activator (tPA).
Streptokinase
 Streptokinase is an extracellular protein
derived from streptococci.
Mechanism of action
 It binds to plasminogen and catalyzes the
conversion of plasminogen to active plasmin.

 It acts on both fibrin-bound and

circulating plasminogen.
Therapeutic uses
 In acute pulmonary embolism, deep vein
thrombosis, acute myocardial infarction,
arterial thrombosis and occluded
peripheral arteries.
 Pharmacokinetic
 Streptokinase therapy is instituted within
4 hours of a myocardial infarction and
continued for 1 to 3 days.

Adverse effects
• Bleeding disorders
• Hypersensitivity
Urokinase
 It was originally obtained from urine but
is now obtained from cultured kidney cells.

Mechanism of action
 Catalyzes the conversion of plasminogen
to plasmin. It acts on both fibrin-bound and
circulating plasminogen
Therapeutic uses
 In acute pulmonary embolism, deep vein
thrombosis, acute myocardial infarction,
arterial thrombosis and occluded
peripheral arteries.

 It is useful in patients sensitive to

streptokinase
Adverse effects
 Bleeding complications are the most
important side effects.
sue – type Plasminogen activato
an endogenous protease.
chanism of action
PA rapidly and preferentially activates
ibrin-bound plasminogen.
t has a shorter half-life than streptokinase
nd urokinase leading to limited systemic
dverse effects.
Therapeutic uses
 Myocardial infarction

Adverse effects
 Bleeding complications
ANTIPLATELET DRUGS
These include:

• Cyclooxygenase inhibitors – aspirin etc

They are used in unstable angina and
myocardial infarction
• Inhibitors of ADP receptor activity – eg
ticlopidine, clopidogrel
ADP receptor activation is negatively coupled
to adenyl cyclase. They are used in unstable
angina and in patients with transient ischaemic
attacks. Ticlopidine is suitable in patients who
cannot tolerate aspirin.
• Dipyridamole—coronary vasodilator.
It inhibits platelet phosphodiesterase activity.
It also inhibits synthesis of thromboxanes
and potentiate the effect of prostacyclin

• Dextran – inhibits platelet function and

fibrin polymerization
Coagulation Cascade