Anti Coagulants
3rd Pharm D
Coagulants
 These are the substances which promote coagulation and are indicated in
haemorragic states.
 Classification :
1) vitamin K
K1 (fat soluble, from plants) :
phytonadione
K3
fat soluble :
menadione
water soluble : menadione sodium
2) miscellaneous :
fibrinogen
desmopressin
COAGULATION CASCADE
Vitamin k dependant factors have been encircled , factors in activated by heparin in red .
COAGULATION CASCADE:
 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 gets
converted to an active protease (activated factor). The protease zymogens involved in
coagulation include factor II (prothrombin). VII, IX, X, XI, and XII, and prekallikrein.
 In addition, there are nonenzymatic protein cofactors such as factor V and VIII.
 Thrombin cleaves factors V and VIII to yield activated factors (Va and VIIIa) that have at least
fifty times the coagulant activity of the precursor form.
 Factors Va and VIIIa have no enzymatic activity themselves but serve as cofactors that
increase the proteolytic efficiency of Xa and IXa, respectively
 In the process of coagulation fibrinogen, a soluble plasma protein, gets converted to
insoluble fibrin monomer by the action of thrombin (IIa) formed from its inert precursor
prothrombin (II). These smaller peptides unite end to end and side to side to form insoluble
strands of fibrin. These fibrins entangle blood cells and platelets to form the solid clot.
 The conversion of prothrombin to thrombin is achieved by activated factor X (Xa) in the presence of
Va, calcium ions and platelets or phospholipids.
 The formation of Xa may take place through two pathways. In the intrinsic pathway, clotting is initiated
when XII gets activated to XIIa. This is followed by activation of XI to XIa and IX to IXa. IXa then
converts X to Xa with the help of VIIIa, calcium ions and phospholipids.
 The extrinsic pathway initiates coagulation. In this pathway activation of factor X to Xa is by VIIa in the
presence of tissue factor and calcium ions.
 The Xa formed activates factor VII to VIIa and is sufficient to initiate coagulation in the presence of
tissue factor. Tissue factor, which is available at the site of injury, accelerates the activation of factor X
by VIIa (or VII), phospholipids and calcium ions
 It is likely that tissue factor plays a major role in haemostasis during injury. The activated VII can also
cause conversion of IX to IXa in the presence of tissue factor and calcium ions, supplementing the
process by intrinsic pathway.
 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.
Vitamin k:
 MOA: it acts as a cofactor at late stage in the synthesis by liver of
coagulation of protein ie, prothrombin, factors VII, IX ,X.
Anticoagulants
 These are the drugs used to reduce the coagulability of blood .
 They are classified as :
a)parentral anticoagulants:
*indirect thrombin inhibitors:
heparin,
low molecular weight heparin
*direct thrombin inhibitors:
lepirudin,
bivalirudin
b) oral anticoagulants:
* coumarine derivatives:
warfarin sodium
bishydroxycoumarine ( dicumarol)
* indandione derivative:
phenindione
*direct factor Xa inhibitors:
rivaroxaban
*oral direct thrombin inhibitor:
dabigatran etexilate
Why anticoagulants ?
 To reduce the coagulability of blood
 Blood clots – Thrombus
 Arterial Thrombosis:
 Adherence of platelets to arterial walls – “White” in color - Often associated with
MI, stroke and ischemia

Venous Thrombosis:
 Develops in areas of stagnated blood flow (deep vein thrombosis), “Red” in colorAssociated with Congestive Heart Failure, Cancer, Surgery
 Thrombus dislodge from arteries and veins and become an embolus
 Venous emboli can block arterioles in the lung and pulmonary
circulation
 Thromboembolism
HEPARIN:
 It is a mucopolysacharide containing 2 sulphated disaccharide units –
D-glucosamine–L-iduronic acid and D-glucosamine-D-glucuronic acid
 MOA:
it acts indirectly by activating plasma antithrombin III .
heparin-AT III complex binds to clotting factors (intrinsic clotting factors like Xa,
IIa, Ixa, XIIa, Xia , XIIIa)
inhibit conversion of fibrinogen to fibrin
Heparin mech of action
heparin
Antithrombin III
THROMBIN
it is the strongest organic acid present in the Body
 Present in mast cells of lungs, liver and intestinal mucosa
 Commercially - from Ox lung and Pig mucos
 Carries strong electro-negative charges
 Types - (i) Regular Heparin (MW 5000 to 30,000) – IV or SC
(ii) LMWH (MW 2000 to 6000) – mostly SC
 ADR :
Bleeding due to over dose
haematuria
thrombocytopenia
rash
urticaria
WARFARIN :
 MOA:
They act indirectly by interfering with the synthesis of vitamin k dependant clotting
factors in liver . They act as competitive antagonist of vitamin k and lower the plasma levels
of functional clotting factors
inhibit enzyme vit K epoxide reductase (VKOR)
interfere with regeneration of active form of vitamin k(cofactor for
carboxylase enzyme )
inhibit carboxylation and hence interferes with the ability of the clotting factor
to bind Ca2+ and to bind to phospholipid surfaces necessary for coagulation
 ADR:
Alopecia
dermatitis
diarrhoea
 Dosing: 10-15 mg
 Uses: Deep Vein Thrombosis, Pulmonary embolism and
atrial fibrillation
 Warfarin synthesis :
Indanedione:
Chemically it is a beta di ketone and is a very strong nucleophile.
Mode of Action of Indanedione: The action of indanedione is similar to coumarin
derivatives i. e., the synthesis of plasma prothrombin and other factors are
inhibited, thereby lengthening the prothrombin time.