COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY INTRODUCTION Haemostasis (arrest of blood loss) and blood coagulation involve complex interactions between the injured vessel wall, platelets and coagulation factors. A cascading series of proteolytic reactions is started by: (i) Contact activation of Hageman factor: intrinsic system, in which all factors needed for coagulation are present in plasma. This is slow and takes several minutes to activate factor X. (ii) Tissue thromboplastin: extrinsic system, needs a tissue factor, but activates factor X in seconds. The subsequent events are common in the two systems and result in polymerization of fibrinogen to form fibrin strands. Blood cells are trapped in the meshwork of fibrin strands producing clot. Two in vitro tests ‘activated partial thromboplastin time’ (aPTT) and ‘prothrombin time’ (PT) are employed for testing integrity of the intrinsic, extrinsic and common pathways of the coagulation cascade. The results are interpreted as: M.A.M. COLLEGE OF PHARMACY 1
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COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY
INTRODUCTION
Haemostasis (arrest of blood loss) and blood coagulation involve complex
interactions between the injured vessel wall, platelets and coagulation factors. A
cascading series of proteolytic reactions is started by:
(i) Contact activation of Hageman factor: intrinsic system, in which all factors needed for
coagulation are present in plasma. This is slow and takes several minutes to activate
factor X.
(ii) Tissue thromboplastin: extrinsic system, needs a tissue factor, but activates factor X in
seconds.
The subsequent events are common in the two systems and result in
polymerization of fibrinogen to form fibrin strands. Blood cells are trapped in the
meshwork of fibrin strands producing clot.
Two in vitro tests ‘activated partial thromboplastin time’ (aPTT) and
‘prothrombin time’ (PT) are employed for testing integrity of the intrinsic, extrinsic and
common pathways of the coagulation cascade. The results are interpreted as:
M.A.M. COLLEGE OF PHARMACY 1
COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY
Most clotting factors are proteins present in plasma in the inactive (zymogen)
form. By partial proteolysis they themselves become an active protease and activate the
next factor. In addition to its critical role in cleaving and polymerizing fibrinogen,
thrombin activates many upstream factors (especially f. XI, VIII and V) of the intrinsic
and common pathways—amplifying its own generation and continuation of clot
formation. It is also a potent activator of platelets.
On the other hand, factors like antithrombin, protein C, protein S,
antithromboplastin and the fibrinolysin system tend to oppose coagulation and lyse
formed clot. Thus, a check and balance system operates to maintain blood in a fluid state
while in circulation and allows rapid hemostasis following injury.
Roman Numerical Nomenclature of Blood-Clotting Factors and Some
Common Synonyms
M.A.M. COLLEGE OF PHARMACY 2
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The coagulation cascade. The vit. K dependent factors have been encircled,* Inactivated
by heparin a—activated form; Pl.Ph.—Platelet phospholipid; HMW—High molecular
weight.
COAGULANTS
These are substances which promote coagulation, and are indicated in
haemorrhagic states. Fresh whole blood or plasma provide all the factors needed for
coagulation and are the best therapy for deficiency of any clotting factor; also they act
immediately. Other drugs used to restore haemostasis are:
2. Severe hypertension, (risk of cerebral haemorrhage), threatened abortion, piles, g.i.
ulcers (risk of aggravated bleeding).
3. Subacute bacterial endocarditis (risk of embolism), large malignancies (risk of
bleeding in the central necrosed area of the tumour), tuberculosis (risk of hemoptysis).
4. Ocular and neurosurgery, lumbar puncture.
5. Chronic alcoholics, cirrhosis, renal failure.
6. Aspirin and other antiplatelet drugs should be used very cautiously during heparin
therapy.
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COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY
Low molecular weight (LMW) heparins
Heparin has been fractionated into LMW forms (MW 3000–7000) by different
techniques. LMW heparins have a different anticoagulant profile; selectively inhibit
factor Xa with little effect on IIa. They act only by inducing conformational change in
AT III and not by bringing together AT III and thrombin. As a result, LMW heparins
have smaller effect on aPTT and whole blood clotting time than unfractionated heparin
(UFH) relative to antifactor Xa activity. Also, they appear to have lesser antiplatelet
action—less interference with haemostasis. Thrombocytopenia is less frequent. A lower
incidence of haemorrhagic complications compared to UFH has been reported in some
studies, but not in others. However, major bleeding may be less frequent. The more
important advantages of LMW heparins are pharmacokinetic:
• Better subcutaneous bioavailability (70–90%) compared to UFH (20–30%): Variability
in response is minimized.
• Longer and more consistent mono exponential t½: once daily s.c. administration.
• Since aPTT/clotting times are not prolonged, laboratory monitoring is not needed; dose
is calculated on body weight basis. Most studies have found LMW heparins to be
equally efficacious to UFH. Indications of LMW heparins are:
1. Prophylaxis of deep vein thrombosis and pulmonary embolism in high-risk patients
undergoing surgery; stroke or other immobilized patients.
2. Treatment of established deep vein thrombosis.
3. Unstable angina.
4. To maintain patency of cannulae and shunts in dialysis patients, and in extracorporeal
circulation. A number of LMW heparins have been marketed. They differ in composition,
pharmacokinetics and dosage.
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COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY
A number of LMW heparins have been marketed. They differ in composition,
pharmacokinetics and dosage.
Enoxaparin,
Reviparin,
Nadroparin,
Dalteparin: for treatment of deep vein thrombosis
Pamparin: for unstable angina and prophylaxis of DVT;
Ardeparin
Fondaparinux:
Fondaparinux is a prototype of a novel class of anticoagulants with significant
advantages compared to their structurally related heparin. Based on the active site of the
heparins, fondaparinux is a synthetic, highly sulfonated pentasaccharide. The immediate
advantage of fondaparinux is that as a synthetic drug, its composition will not change,
which results in improved pharmacokinetics and a more selective anticoagulant action.
Mechanism of action
The development of fondaparinux, a synthetically derived pentasaccharide that
binds specifically to and activates antithrombin III, is a further refinement on the
mechanism of action of heparin. Fondaparinux and a related analogue, idraparinux, are
specific, indirect inhibitors of activated factor Xa via their activation of antithrombin.
Fondaparinux has strategically located sulfonates that bind to antithrombin. Fondaparinux
is structurally related to the antithrombotic binding site of heparin. Unlike heparin or
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COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY
LMWHs, however, these inhibitors have no effect on thrombin, because they lack the
longer saccharide chains required for binding to thrombin. The highly sulfated heparins
exhibit nonselective binding to a number of additional proteins, resulting in decreased
bioavailability and significant variation in activity.
Therapeutic application
Fondaparinux is the first selective factor Xa inhibitor that is approved for the
prophylaxis of DVT, which may occur in patients undergoing hip fracture surgery or hip
or knee replacement surgery. The most common side effect is major and minor bleeding,
and the patient must be carefully monitored. The drug is not to be used when spinal
anesthesia or spinal puncture is employed because of the potential for developing a blood
clot in the spine. Fondaparinux has not been reported to cause thrombocytopenia, a
condition seen with heparin (56,59,60). It is 100% bioavailable, with little or no protein
binding.
HEPARINOIDS
Heparan sulfate
It is a heparin-like natural substance found on cell surface and intercellular matrix
in many tissues. It is a less potent anticoagulant than heparin, but may have a more
favourable profile of action.
Danaparoid
It is a preparation containing mainly heparin sulfate, obtained from pig gut
mucosa, which is used in cases with heparin induced thrombocytopenia.
Lepirudin
This recombinant preparation of hirudin (a polypeptide anticoagulant secreted by
salivary glands of leech) acts by inhibiting thrombin directly. It is indicated in patients
with heparin induced thrombocytopenia.
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Ancrod
It is an enzyme obtained from Malayan pit viper venom. It degrades fibrinogen into an
unstable form of fibrin which is taken up by RE cells. Thus, fibrinogen gets depleted and
an apparent heparin like effect results. It is given only by slow infusion: 2 U/kg over 6
hours for deep vein thrombosis in patients who develop thrombocytopenia
or hypersensitivity reactions to heparin and require immediate anticoagulation.
Bivalirudin
Heparin antagonist Protamine Sulfate, USP.
Protamine sulfate has an anticoagulant effect, but if used in the proper amount, it
counteracts the action of heparin and is used as an antidote for the latter in cases of over
dosage. It is administered intravenously in a dose that depends on the circumstances.
M.A.M. COLLEGE OF PHARMACY 19
COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY
ORAL ANTICOAGULANTS
Action and mechanism
Warfarin and its congeners act as anticoagulants only in vivo, not in vitro. This is
so because they act indirectly by interfering with the synthesis of vit K dependent clotting
factors in liver. They apparently behave as competitive antagonists of vit K and reduce
the plasma levels of functional clotting factors in a dose-dependent manner. In fact, they
interfere with regeneration of the active hydroquinone form of vit K which carries out the
final step of γ carboxylating glutamate residues of prothrombin and factors VII, IX and
X. This carboxylation is essential for the ability of the clotting factors to bind Ca2+ and
to get bound to phospholipid surfaces, necessary for coagulation sequence to proceed.
Warfarin:
Warfarin, 3-(α-acetonylbenzyl)-4-hydroxycoumarin, is synthesized via Michael
reaction by attaching 4-hydroxycoumarin to benzalacetone in the presence of pyridine .
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COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY
Warfarin is used as an anticoagulant for preventing and treating deep venous thrombosis
and pulmonary embolism. Synonyms of this drug are cumadin, panwarfin, sofrain,
warnerin, and others.
Dicoumarol:
Dicoumarol, 3,3′-methylene-bis(4-hydroxycoumarin), is synthesized from 4-
hydroxycoumarine, which is in turn synthesized from salicylic acid methyl ester by
cyclization to a chromone derivative using sodium or sodium methoxide; or from o-
oxyacetophenone by reacting it with diethylcarbonate in the presence of sodium ethoxide.
Condensation of the resulting 4-hydroxycoumarin with formaldehyde as a phenol
component gives dicoumarol .
This drug is used for preventing and treating thrombosis, thrombophlebitis, thromboemolium, and for preventing thrombo-formation in post-operational periods. Synonyms of this drug are bishydroxycoumarin, dicumol, cromolyn, and others.
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COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY
Ethyl biscoumacetate:
Ethyl biscoumacetate, the ethyl ester of bis-(4-hydroxy-3-coumarinyl)-acetic acid,
is synthesized analogously from 4-hydroxycoumarine, but using ethylglyoxylate, its
semiacetal or glyoxylic acid instead of formaldehyde. This drug is used for the same
indications as dicoumarin. Synonyms of this drug are neodicoumarin, ethyldicourmarol,
tremexan, dicumacyl, and others.
Acenocoumarin:
Acenocoumarin, 3-(α-acetonyl-p-nitrobenzyl)-4-hydroxycoumarin , is synthesized
by a scheme completely analogous to making warfarin, but using p-nitrobenzalacetone.
It is used for the same indications for preventing and treating thrombosis and
pulmonary embolism. A synonym of this drug is sintrom.
Phenprocoumon:
Phenprocoumon, 3-(α-ethylbenzyl)-4-hydroxycoumarin, is synthesized by
acylating sodium salts of diethyl ester (1-phenylpropyl)butyric acid with acetylsalicylic
acid chloride, which forms the compound, which upon reaction with sodium ethoxide
cyclizes to 3-(α-ethylbenzyl)-2-carboethoxy-4-hydroxycoumarin. Alkaline hydrolysis of
this product and further decarboxylation gives phenprocoumon.
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COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY
Phenprocoumon is used for the same indications as all of the forementioned
drugs. Synonyms of this drug are marcoumar and liquamar.
Phenindione:
Phenindione, 3-phenylindan-1,3-dion, is synthesized in two ways. The first
consists of condensating benzaldehyde with phthalide in the presence of sodium ethoxide.
Evidently, the resulting phenylmethylenphthalide rearranges under the reaction
conditions to give the desired phenindione. The second method consists of condensation
of phenylacetic acid with phthalic anhydride, forming phenylmethylenphthalide, which
rearranges further in the presence of sodium ethoxide to phenindione.
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COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY
Like coumarin derivatives, phenindione, a compound of the indandione class, acts
by altering biosynthesis of coagulant proteins in the liver. It is used for preventing and
treating thrombosis, thrombophlebitis, and thromboembolism. However, because of a
number of side effects such as polyurea, polydipsia, tachycardia, and others, it is rarely
used in practical medicine. Synonyms of this drug are pindone, bindan, gevulin, indan,
phenyline, and rectadione.
Anisindione:
Anisindione, 3-(p-methoxyphenyl)indan-1,3-dion, differs from phenidione only in the
presence of a p-methoxy group in the phenyl ring, and it is synthesized in the same
manner as phenindione, but by using p-methoxybenzaldehyde or p-methoxyphenylacetic
acid.
It is used for the same indications as phenindione. Synonyms of this drug are
unidone and miradon.
Adverse effects
Bleeding as a result of extension of the desired pharmacological action is the most
important problem: ecchymosis, epistaxis, hematuria, bleeding in the g.i.t. Intracranial or
other internal haemorrhages may be fatal. This is more likely if therapy is not properly
monitored or interacting drugs/contraindications are present.
Contraindications
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COAGULANTS AND ANTICOAGULANTS MEDICINAL CHEMISTRY
All contraindications to heparin apply to these drugs as well. Factors which
enhance the effect of oral anticoagulants should also be taken into consideration. Oral
anticoagulants should not be used during pregnancy. Warfarin given in early pregnancy
increases birth defects, especially skeletal abnormalities: foetal warfarin syndrome—
hypoplasia of nose, eye socket, hand bones, and growth retardation. Given later in
pregnancy, it can cause CNS defects, foetal haemorrhage, foetal death and accentuates