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During early 20th century, hemorrhagic diseases occurred in cattle that ate spoiled fodder (spoiled sweet clover silage). Chemists at Wisconsin Alumni Research Foundation extracted Bishydroxycoumarin responsible for this disease.

Afterwards warfarin was synthesized as coumarin derivative.

It was first used as Rodenticide

Afterwards during second half of 20th century, it was used as oral anticoagulant.


Mainly two chemical compounds are chosen for oral administration:

  1. Coumarin –commonly used like Warfarin
  2. Phenindione

Administered as racemic preparation, two enantiomers or isoforms exist:

1. S warfarin (levorotatory) 4 times more potent

2. R warfarin (dextrorotatory)

Mechanism of Action

Factor II, VII, IX, X are the glutamic acid residues and need to be carboxylated to alpha carboxy glutamic acid. This is required so that the Ca++ bridge with epithelium is formed.

During carboxylation, vitamin K is converted from reduced to oxidized form.

Oxidized form has to be converted back into reduced form, by vitamin K epoxide reductase for the reaction to continue.

Thus, reduced form is inhibited, and the process is suppressed.

The synthesis of factor II, VII, IX, X, protein C and S is suppressed, as no carboxylation occurs due to non-availability of reduced form of vitamin K.

The action of warfarin is delayed because of two reasons:

a. Delayed onset

Longer half life of about 40 hours, steady state is achieved after 2 days.

b. Anticoagulant effect

Already synthesized clotting factors are available in blood, warfarin effects can only be seen when new factors are synthesized.

As warfarin is given in racemic form, so S warfarin is 3-5 times potent than R warfarin.

Up till now no separate preparation has been prepared, and are given in combination.

Resistance to warfarin

Resistance to warfarin is genetic, due to mutation in epoxide reductase.

Administration & monitoring

Monitored by PTT and INR.

PT (Common and Extrinsic Pathway) – time taken for clotting of citrated plasma after addition of Ca+2 and standardized reference thromboplastin (12-14 s). Role of thromboplastin is not present in this clotting time as it is added from outside, so that only prothrombin is active.

Should be maintained at 2.5-3.5 times normal in warfarin therapy.

Different animal sources are used in different labs, due to differences in kits, various variations in prothrombin time are observed, and thus better method is introduced.

INR – International Normalized Ratio, which is the prothombin time ratio of a patient with reference value(2 – 3.5)

ISI is the international sensitivity index. Each thromboplastin is assigned a specific throboplastin number.

If INR is <1.5 there are more chances of thromboembolic phenomenon.

If INR is >4 there are more chances of bleeding.

Normal medicinal range is 2-3, while that for prosthetic heart valves is up to 3.5


Route of Administration

Most commonly orally, other routes include parenteral and rectal. After oral route, bioavailability is 100%.


Absorbed in GIT




Highly bound to plasma proteins (98-99%)

BBB & Placenta

Can cross BBB and placenta, thus not administered in pregnancy


Half life of S type is less than 25 hours.

Half life of R type is up to 50-60 hours.

On average, half life is 40 hours.


Metabolism is different for S and R types.

S type is metabolized by cytochrome P2C9

R type is metabolized by cytochrome P1A2, P3A4 and P2C19.


Excreted in urine.

Pharmacological Actions

1. Anticoagulant action –delayed onset (48hours) because clotting factors already present are not affected)

2. Also decreases synthesis of endogenous anticoagulants (protein C and S)

Clinical Uses

Prevention of thromboembolism

Not given in emergency, heparin is started, while warfarin is started as well. After 3-4 days, heparin is stopped, and then only warfarin is used.

Differences from heparin
Heparin Warfarin
Given in emergency Not given in emergency
Can be given in surgery Cannot be given in surgery
Can be given in pregnancy Cannot be given in pregnancy
Adverse Effects
1. Bleeding

If minor and patient is stable, only drug is discontinued, patient is monitored.

a. .Phytonadione (K1)

If INR is greater than 5, vitamin K preparation is given orally or I/V according to the need of patient. Action of this is only after 12-24 hours.

b. FFP

If INR is much higher, fresh frozen plasma is administered.

c. Different preparations of clotting factors are administered.

As inhibits clotting factors and protein C (half life 8 hours) and S (natural anticoagulant).

First natural anticoagulant is affected, and are not formed, but small thrombi are formed, especially patients deficient in protein C and protein S. There are greater chances of skin and tissue necrosis (fatty tissue necrosis).

2. Skin / Tissue necrosis

Occurs early in adults.

3. Teratogenicity

As warfarin can cross placental barrier, it is teratogenic and inhibits gamma carboxylation of proteins. In fetus bone and soft tissues are not properly formed.  Also hemorrhagic disorders occur in fetus.

4. As it decreases activity of protein C, it leads to cutaneous necrosis and infraction of breast fatty tissue, intestine and extremities (rare)

5. warfarin induced depression of protein C also leads to venous thrombosis

Warfarin Sensitivity – CYP2C9

Polymorphism occurs, less dose is required, as unable to metabolize at the natural rate (rate decreased)

Warfarin Resistance – VKORC1

Polymorphism occurs, leading to change in dose. In certain patients larger dose is required to produce therapeutic effects.

Dosing algorithms are prepared taking genotype, etc. in account, to calculate individualized dose.

Drug Interactions

Occur in two categories:

1. Pharmacokinetic

Mostly due to:

i. enzyme induction

ii. enzyme inhibition

iii. decreased PPB

1. Pyrazolone, Phenylbutazone and Sulfinpyrazone decrease metabolism of S-warfarin and displace albumin bound warfarin leading to increased warfarin and increased anticoagulant effects (increased risk of bleeding)

Effects include:

i. Augment hypoprothrombinemia

ii. Decrease platelet function

iii. May induce peptic ulcer disease

2. Barbiturates and Rifampicin (enzyme inducers) increase metabolism of warfarin, decreasing its effects.

3. Metronidazole, Trimethoprim-sulfamethoxazole (co-trimoxazole) and Fluconazole decrease metabolism of S-warfarin, increasing its effects.

4. Amiodarone, Disulfiram and Cimetidine decrease metabolism of both S and R warfarin, enhancing the effects.

5. Cholestyramine binds warfarin in intestine and decreases absorption and bioavailability.

Increased PT

Decreased PT













2. Pharmacodynamic

Mostly due to:

i. Synergism

ii. Competitive antagonism (vit. K)

iii. Altered physiologic control loop for vit. K (hereditary resistance to oral anticoagulants)

iv. Impaired hemostasis, decreased clotting factor synthesis as in hepatic disease

a. Aspirin (anti-platelet), hepatic disease and hyperthyroidism (increase turnover of clotting factors) increase warfarin effects.

b. Third generation cephalosporins eliminate bacteria in intestinal tract that produce vitamin K. Also decrease vitamin K like warfarin effects.

c. Vitamin K increases synthesis of clotting factors, decreasing the effect of warfarin.

d. Diuretics (Cholothalidone and Spironolactone) increase clotting factor concentration, decreasing effects.

e. Hereditary resistance decreases effects.

f. Hypothyroidism increases turn over of clotting factors.

Increased PT

Decreased PT


Aspirin (high doses)

Cephalosporins, third generation


Body Factors

Hepatic diseases




Vitamin K

Body Factors

Hereditary resistance


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