Anticoagulant classification and uses with mechanism of action

1. COAGULANTS AND
ANTI-COAGULANTS
3rd Pharm.D
PramodB Kumar

2. 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

4. COAGULATION CASCADE
Vitamin k dependant factors have been encircled , factors inactivated by heparin in red .

6. 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.

7. 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.

8. 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.

9. 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 calicum ions , supplementing the process by intrinsic pathway.

10. Vitamin k:

11.  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.

17. Menadione acts as a vitamin K analogue,
Acting as a cofactor in the synthesis of Factor II, VII, IX, X in
the liver.
The Vitamin K analogue is needed in the step of gamma
carboxylation of these factors which renders them capable of binding
ca ions to phospholipid surfaces which is essential for
the coagulation cascade

19. 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 color- Associated 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

21. ANTI COAGULANTS
 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: *direct factor Xa inhibitors:
warfarin sodium rivaroxaban
bishydroxycoumarine ( dicumarol) *oral direct thrombin inhibitor:
* indandione derivative: dabigatran etexilate
phenindione

22. HEPARIN  McLean, a medical student, discovered in 1916
that liver contains a powerful anticoagulant.
 Howell and Holt (1918) named it ‘heparin’
because it was obtained from liver.
 However, it could be used clinically only in 1937
when sufficient degree of purification was
achieved.
 Heparin is present in all tissues containing mast
cells; richest sources are lung, liver and intestinal
mucosa.
 Commercially it is produced from ox lung and pig
intestinal mucosa.

23. 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

24. 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

25. ADR :
Bleeding due to over dose
haematuria
thrombocytopenia
rash
urticaria

26. 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

27.  ADR:
Alopecia
dermatitis
diarrhoea
 Dosing: 10-15 mg
 Uses: Deep Vein
Thrombosis, Pulmonary
embolism and atrial
fibrillation

28.  Warfarin synthesis :

29. 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.
Indanedione: