MEDICINAL CHEMISTRY

of' streptokinase, urokinase and tissue plasminogen activator. The major reactions
involved in blood coagulation and fibrinolysis are shown in the figure 2.
Coagulation normally does not occur within an intact blood vessel. It is prevented by
several regulatory mechanisms requiring a normal vascular endothelium. Antithrombin, a
plasma protein, inhibits coagulation factors. Prostacyclin (PGI2), synthesized by
endothelial cells, inhibits platelet aggregation.
The drugs associated with phenomenon of blood coagulation may be discussed under
anticoagulants, antiplatelet drugs and haemostatics. A heparin antagonist is also discussed
under anticoagulants.
Anticoagulants are the drugs which prolong the coagulation time of blood. They are used
in the treatment and prophylaxis of thrombo-embolic occlusive vascular diseases such as
venous thrombosis, pulmonary embolism and cardiac infarction due to thrombosis of a
coronary artery. They are also used to prevent thrombosis after operation or from other
causes.
The retardation of coagulation may be accomplished by agents like heparin that acts
through its action on anti-thrombin to inhibit the activity of thrombin and activated factor
X. As heparin is not absorbed orally it is therefore, given parenterally. The other class of
drugs is anticoagulants which act by depressing the synthesis of vitamin K-dependent
coagulation factors.
Classification of Anticoagulants
A. Heparin (26) and its Derivatives
Heparin (named because of its abundance in liver) was discovered as a water-soluble
mucopolysaccharide by W. H. Howell in 1922. Heparin is a complex anionic linear
polysaccharide of mammalian origin with irregular sequence. It consists principally of
alternating D-glucuronic acid (or its epimer L-iduronic acid) and D-glucosamine
residues, most of which are sulphated. It may be described as a glucosaminoglycan. On
complete hydrolysis, heparin releases D-glucosamine, D-glucuronic acid, L-iduronic
acid, acetic acid and sulphuric acid. A pentasaccharide portion of heparin, which is
involved in binding with antithrombin, is shown below.
H
CH 2OSO 3 -
O H
O O
OH H
H NHAc
H
COO -
OH
O
H
H OH
O
H
CH 2OSO 3 -
-
OSO3 H
H
O H
H NHSO 3 -
O
H
H
O
COOH
OH
H H
H
H OSO 3 -
a b c d e
Heparin (26): (a = N-acetylglucosamine 6-O-sulphate; b = glucuronic acid; c = N-sulphated
glucosamine 3, 6-O-disulphate; d = iduronic acid 2-O-sulphate; e = N-sulphated glucosamine
6-O-sulphate)
O
H
CH 2OSO 3 -
H
OH
O H
H
H NHSO 3 -
O