Direct-acting anticoagulants like heparin work directly in the blood to inhibit coagulation factors. Heparin is extracted from pig intestines and bovine lungs. Indirect anticoagulants called oral anticoagulants or vitamin K antagonists inhibit coagulation factor synthesis in the liver. Coumarin derivatives like warfarin and dicoumarol are commonly used oral anticoagulants that act by inhibiting vitamin K and decreasing prothrombin synthesis. Warfarin is effective for treating deep vein thrombosis while dicoumarol has fallen out of favor due to side effects and unpredictable response. Anticoagulants must be closely monitored to prevent bleeding complications.

1. Anticoagulents
Pharm.D III Year

3. Coagulants
• Coagulants are the drugs that promote
coagulation and control bleeding.
• They are also called hemostatic agents and
indicated in haemorrhagic states.

8. Blood Coagulation
The phenomenon of blood coagulation is very complex.
Thrombin and several blood clotting factors present in
plasma and calcium ions are involved in the coagulation
The factors are precursor proteins or zymogens and at
each stage, a zymogen converted to an active protease
(activated factor).

12. Classification of coagulants

20. Anticoagulants
• Drugs that inhibit thrombus formation and prevent
coagulation or formation of new blood clots are called
Anticoagulants.
• Drugs that reduce aggregation of blood thrombocytes
are called Antiaggregants.
• Drugs that speed up lysis of already formed blood clots
are called Thrombolytics or Fibrinolytics.
• Drugs that facilitate reduction and stoppage of
bleeding are called Hemostatic Drugs.

21. Anticoagulants
• Coagulation and fibrinolytic processes are very
important protective physiological mechanisms of
the organism, and only a very fine regulatory
interaction between them provides the required
homeostatic condition of the vascular system.
• In normal conditions, microscopic blood clots are
often necessary for restoration of damaged areas
of vessels.

22. Process
• The process of blood clot formation and their
subsequent lysis is a very complex feature that
depends on a number of substances (coagulation
Factors-fibrinogen, Prothrombin, Tromoplastin,
Calcium, Antihemophylin Factor and others) that
exist in the plasma, blood cells, and to a lesser
degree in other tissues.

23. • Anticoagulants prevent the development of
the coagulation process of blood.
• Therapy using Anticoagulants is first and
foremost directed at preventing the formation
of clots in blood vessels.
• It is the main cause of death in
thromboembolic disease.

24. Thromboembolism
• Obstruction of a blood vessel by a blood clot
that has become dislodged from another site
in the circulation.

27. Classification of Anticoagulants
• Anticoagulants are subdivided into
• Direct-acting coagulants i.e. those that have an
effect on coagulation factors directly in the blood.
• Indirect-acting coagulants i.e. those that have an
effect on factors of synthesis or blood coagulation
in the liver.

28. On the other hand, anticoagulants are classified as
Parenteral and Oral Drugs.
Heparin is the only representative of parenteral
anticoagulants.
 Oral anticoagulants are made up of a number of
coumarin derivatives (Dicumarol, Ethylbiscumacetate,
Warfarin, Phenprocumon, Acenocumarol) and Indanone
(Fenidion, Anisindion).

29. Direct-acting anticoagulants
• Theses are called as parenteral anticoagulants.
• Heparin is one of the first types of direct-acting
anticoagulants.
• Heparin, a natural anticoagulant is formed in the
body.
• The source of commercial heparin is the mucous
membranes of Pig intestine and Ox lungs.
• Heparin is a mixture of natural sulfated
Mucopolysaccharides, which are generally found
in granules of mast cells.

30. Mast cells
• Mast cells are "Master Regulators" of the immune
system. They come from bone marrow and go into all
tissues of the body.
• Each mast cell contains secretory granules (storage sacs),
each containing powerful biologically active molecules
called mediators.
• Mast cells are well known for their role in allergic and
anaphylactic reactions, as well as their involvement in
acquired and innate immunity.

31. Synonyms
• Synonyms of this drug are Arteven, Hepalen,
Leparan, Liquemin, Panheprin, Vetren and
many others.

32. Direct-acting anticoagulants
• It is believed that heparin acts by neutralizing a
number of active blood coagulation factors, thus
disrupting the transformation of prothrombin into
thrombin.
• Heparin is used to prevent thrombus-formation in
myocardial infarctions, thrombosis and embolism,
for maintaining liquid conditions in the blood in
Artificial Blood Circulation and Hemodialysis.

34. Embolism
• An embolism is the lodging of an embolus,
which may be a blood clot, fat globule, gas
bubble or foreign material in the bloodstream.
• This can cause a blockage in a blood vessel.

35. Ideal Anticoagulant
• It should have rapid onset of action, wide
therapeutic index and long duration of action.
• Pharmacokinetic & Pharmacodynamic aspects of the
drug should be reproducible such that monitoring of
blood coagulation is not essential.
• Minimal adverse effects.
• Minimal interaction with drug and food & should
not result into any life-threatening complications.

36. • Heparin is a Mucopolysacharide extracted from
Porcine intestinal mucosa or Bovine lungs.
• It is a heterogenous mixture of straight, sulphated
and negatively charged Mucopolysacharide with
Mol wt ranging from 5-30 kDa.

37. Heparin
• Heparin is active only upon parenteral introduction.
• It is frequently used intravenously.
• Heparin is a heterogenic mixture of sulfonated
polysaccharides made from a repeating units of D-
glucosamine, D-glucuronic and L-iduronic acid.
• Commercial heparin is essentially a mixture of a
number of compounds with various chain lengths
and of molecular masses between 5000 and 30,000 .

38. Heparin
Heparin inhibits reactions that lead to the clotting of
blood and the formation of fibrin clots both in vitro
and in vivo.
Heparin acts at multiple sites in the normal
coagulation system.
Small amounts of heparin in combination with
antithrombin III (heparin cofactor) can inhibit
thrombosis by inactivating activated Factor X and
inhibiting the conversion of prothrombin to thrombin

39. Heparin
• Once active thrombosis has developed, larger
amounts of heparin can inhibit further coagulation
by inactivating thrombin and preventing the
conversion of fibrinogen to fibrin.
• Heparin also prevents the formation of a stable
fibrin clot in inhibiting the activation of the fibrin
stabilizing factor.

40. Thrombosis
The formation or presence of a blood clot in a
blood vessel.
The vessel may be any vein or artery as for
example, in a deep vein thrombosis or a coronary
(artery) thrombosis.
 The clot itself is termed a thrombus.

41. Heparin derivatives
• Attempts made towards decreasing the
unwanted side effects and to enhance
bioavailability resulted in a new class of heparin
derivatives with Fondaparinux being the
prototype for this class of agents.
• Fondaparinux is a synthetic, highly Sulphonated
Pentasaccharide available as sodium salt.

42. Adverse effects
• Bleeding is the most common adverse effect,
hence the patients must be closely monitored.
• Thrombocytopenia.

43. Thrombocytopenia
Thrombocytopenia is a condition in which you
have a Low Blood Platelet Count.
 Platelets (thrombocytes) are colorless blood
cells that help blood clot.
 Platelets stop bleeding by Clumping and
Forming Plugs in blood vessel injuries.

44. Indirect-acting or enteral
anticoagulants
• The most widely used anticoagulants in medicine
are structural derivatives of 4-hydroxycoumarin, a
compound that is isolated from sweet clover, and
that was a cause of fatal hemorrhagic diathesis in
flocks in the 1920s—the so-called ‘Sweet Clover
Disease.’

45. Coumarin derivatives
• Coumarin derivatives are an important class of
oral anticoagulants.
• They are the drug of choice for maintaining an
extended anticoagulant effect.
• Patients on therapy should be closely monitored.
• They exhibit longer duration of action.

46. Indirect acting or Oral anticoagulants
This class of agents are widely used for long-term
prophylaxis and are administered orally hence,
referred to as Oral anticoagulants.
They are effective only in-vivo and have longer
duration of action.
They are metabolized in liver and majority of
metabolites are eliminated in urine.

47. • After discovering that coumarin is able to
suppress prothrombin synthesis, intense studies
in the area of coumarinic derivative synthesis
occurred, and as a result drugs, such as
Dicoumarol (bishydroxycoumarin), Ethyl
biscoumacetate, Warfarin, Phenprocoumon,
and Acenocumarol were introduced into
medicine.

48. • These factors are described as vitamin K-dependent
factors since their biosynthesis by hepatocytes is
partially linked with hepatic vitamin K metabolism.
• Oral anticoagulants are effective only in vivo because
their principal effect is suppression of synthesis of
prothrombin, proconvertin and other blood
coagulation factors in the liver.
• They are sometimes conventionally called vitamin K
antagonists.

49. 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.

50. Synthesis of Dicoumarol
• Dicoumarol
• 3,3′-methylene-bis(4-hydroxycoumarin) (24.1.8), is
synthesized from 4-hydroxycoumarin (24.1.7),
which is in turn synthesized from salicylic acid
methyl ester by cyclization to a chromone
derivative using sodium or sodium methoxide.

51. Synthesis of Dicoumarol
methyl ester of salicylic acid
4-hydroxycoumarin
cyclization
Dicoumarol
formaldehyde
Dehydration

52. Mechanism of action
• Dicoumarol is a prothrombopenic anticoagulant
and exhibits its action by inhibiting prothrombin
synthesis in liver.
• It decreases prothrombin synthesis by:-
a) Competing with vitamin K for transporting into
liver cells.
b) Competing with vitamin K at the site of synthesis
of vitamin K dependent clotting factors.

53. MOA of Dicoumarol
• In addition to inhibiting prothrombin,
Dicoumarol also inhibits the plasma levels of
other Vitamin K dependent clotting factors
such as VII, IX and X.
• Due to high incidence of GI effects and
inability to predict the response of the drug, it
is now replaced by Warfarin.

54. Uses
In traumatic injuries to blood vessels.
In the treatment of CHF and atrial fibrillation.

55. Adverse effects
• Bleeding from mucous membrane, skin and
GIT.
• GI side effects such as Nausea and Vomiting.

56. Warfarin
• Warfarin is used as an anticoagulant for
preventing and treating deep venous
thromboses and pulmonary embolism.
• Synonyms of this drug are Cumadin,
Panwarfin, Sofrain, Warnerin and others.

57. Synthesis of Warfarin
• Warfarin
• 3-(α-acetonylbenzyl)-4-hydroxycoumarin
(24.1.10), is synthesized via Michael reaction
by attaching 4-hydroxycoumarin (24.1.7) to
benzalacetone in the presence of pyridine
[14–19].

58. Synthesis of Warfarin
4-hydroxycoumarin
benzalacetone
pyridine
Warfarin

60. Mechanism of Action
of Warfarin
• Warfarin competitively inhibits the vitamin K
epoxide reductase complex 1 (VKORC1), an
essential enzyme for activating the vitamin K
available in the body.
• Through this mechanism, warfarin can deplete
functional vitamin K reserves and thereby reduce
the synthesis of active clotting factors.

63. SAR of Coumarin
4-hydroxy coumarin basic nucleus is essential for
the compound to exhibit anticoagulant activity.
Nonpolar substitution on C-3 is the basic
requirement for the compound to exhibit
anticoagulant activity.
C-3 is asymmetric and both the enantiomers(R
and S) differ widely in terms of potency,
metabolism, elimination and drug interaction.

64. • If the acidic 4-hydroxy proton is removed, the resulting oxyanion
can act as a nucleophile and attack the electrophililic carbonyl
carbon forming a hemiketal called cyclocoumarol, which is
neutral.
• Warfarin is a chiral compound.
• Though, the clinically utilized preparation is racemic, the
enantiomers are not equipotent.
• S-warfarin is 4-fold more potent than R-warfarin.

65. • 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.

66. Thrombophlebitis
• Thrombophlebitis is phlebitis (vein
inflammation) related to a thrombus (blood
clot).
• It occurs repeatedly in different locations.
• It occurs when a blood clot blocks one or more
veins, typically in legs.

67. Uses
• In prevention and treatment of venous
thromboembolism following administration of
heparin.
• To prevent venous thromboembolism in
patients undergoing orthopaedic or
gynaecological surgery