warfarin pharmacology, blood thinner, anti-coagulant

1. Warfarin
Hani Hussain Alghamdi
R1 ( SBOMP )

2. Outline
Introduction FDA Approval
Mechanism and
Action
Pharmacodynamics
and
Pharmacokinetics
Adverse Effects Dosage
Drug Interactions Case Study

3. Warfarin
Warfarin: An anticoagulant drug
(brand names: Coumarin,
Panwarfin, Sofarin)
taken to prevent the blood from
clotting and to treat blood clots
and overly thick blood.
Warfarin is also used to reduce
the risk of clots causing strokes
or heart attacks.

4. History
University of Wisconsin
biochemistry professor Karl Paul
Link and his co-workers first
isolated dicoumarin, a molecule in
spoiled sweet clover that causes
cattle to hemorrhage and die. The
discovery led to the synthesis of
Dicumarol, the first anticoagulant
drug that could be taken orally. The
successor to Dicumarol was
Warfarin.
Warfarin is named after WARF, the
Wisconsin Alumni Research
Foundation, to which Professor Link
assigned the patent. Warfarin was
originally marketed as a rodenticide
(the rats bleed to death). Its
effectiveness in controlling rats and
mice led to great commercial
success. Warfarin has, in addition,
become the most widely prescribed
anticoagulant drug for people and
saved countless lives.

5. Warfarin
COUMADIN (crystalline warfarin sodium) is an anticoagulant which acts by
inhibiting vitamin K dependent coagulation factors.
Chemically, it is 3-(α-acetonylbenzyl)-4-hydroxycoumarin and is a racemic
mixture of the R- and S-enantiomers.
Crystalline warfarin sodium is an isopropanol clathrate.
The crystallization of warfarin sodium virtually eliminates trace impurities
present in amorphous warfarin.
Its empirical formula is C19H15NaO4.
Crystalline warfarin sodium occurs as a white, odorless, crystalline powder,
is discolored by light and is very soluble in water; freely soluble in alcohol;
very slightly soluble in chloroform and in ether.

6. Structure
• Chmeical formula: C19H1NaO4

7. FDA
It is a approved drug considered as an antithrombotic
agent (blood thinner), Vit K antagonist.
Trade names: Coumadin, others
License data: US FDA: Warfarin
Pregnancy category: AU: D , US: X (Contraindicated)
Routes of administration: By mouth or intravenous
ATC code: B01AA03 (WHO

8. Mechanism
and Action

9. Mechanism
and Action
Warfarin's main mechanism of action lies
in its ability to stop the synthesis of
vitamin K-dependent factors. It does so
by blocking the vitamin K epoxide
reductase (VKORC1) enzyme complex.
Since the enzyme can't work, it can't use
vitamin K to help make these vitamin K
dependent factors

10. Pharmacodynamics
and
Pharmacokinetics
Warfarin is essentially completely absorbed, with a
bioavailability achieving peak concentrations within 4
hours of administration.
Its volume of distribution is small, 0.14 L/kg, and is
limited by 99 percent protein binding, primarily to
albumin.
Commercially available warfarin products are equal,
racemic mixtures of the R and S enantiomers.
The S-warfarin enantiomer is five times more potent. It
is primarily metabolized by cytochrome P-450 (CYP)
2C9, and in part by CYP 2C19.
The less potent R-warfarin enantiomer is metabolized
by CYP 1A2 and CYP 3A4.

11. Pharmacodynamics
and
Pharmacokinetics
Its metabolism are inactive, and 92 % excreted in the
urine.
The half-life of warfarin is 36–42 hours; therefore, ≥4
days is required to achieve steady-state concentrations
of any given warfarin dose.
the chief pharmacodynamic effect of warfarin is
caused by its inhibition of factor II (thrombin).
The full effect of warfarin is therefore determined by
the half-life of factor II (60–72 hours), so complete
factor II inhibition can take 8 days or more to achieve

12. Adverse
Effects
Bleeding
The only common side effect of warfarin is bleeding.
All types of bleeding occur more commonly, but the
most severe ones are those involving the brain
(intracerebral hemorrhage/hemorrhagic stroke) and
the spinal cord.
Risk of bleeding is increased if the INR is out of range
(due to accidental or deliberate overdose or due to
interactions).

13. Adverse
Effects
Warfarin necrosis
A rare but serious complication which occurs more frequently shortly after
commencing treatment in patients with a deficiency of protein C.
Protein C is an innate anticoagulant that, requires vitamin K-dependent
carboxylation for its activity.
Since warfarin initially decreases protein C levels faster than the coagulation
factors, it can paradoxically increase the blood's tendency to coagulate
when treatment is first begun (many patients when starting on warfarin are
given heparin in parallel to combat this).
leading to massive thrombosis with skin necrosis and gangrene of limbs

14. Adverse
Effects
Purple toe syndrome
A rare complication that may occur early
during warfarin treatment (usually within 3
to 8 weeks) is purple toe syndrome.
This condition is thought to result from small
deposits of cholesterol breaking loose and
causing embolisms in blood vessels in the
skin of the feet, which causes a blueish
purple color and may be painful

15. Dosage
Forms and strengths
StrengthsFromGeneric name/
brand name
1mg, 2mg, 2.5mg,
3 mg 4mg, 5mg,
6mg, 7.5mg 10mg
Oral tabletWarfarin
1mg, 2mg, 2.5mg,
3 mg 4mg, 5mg,
6mg, 7.5mg 10mg
Oral tabletCoumadin
1mg, 2mg, 2.5mg,
3 mg 4mg, 5mg,
6mg, 7.5mg 10mg
Oral tabletjantoven

16. Dosage
Usual Adult Dose for Prevention of Thromboembolism in Atrial Fibrillation
Initial dose: 2 to 5 mg orally once a day
Maintenance dose: 2 to 10 mg orally once a day
Target INR: 2.5 (range: 2 to 3)
For patients with atrial fibrillation (AF) and prosthetic heart valves, target INR may
be increased depending on valve type, valve position, and patient factors.
Initial dose is influenced by age, race, body weight, gender, concomitant
medications, comorbidities, genetic variation, and possibly other factors.
Dosage and administration must be individualized according to the patient's INR
and condition being treated.

17. Dosage
Usual Adult Dose for Thromboembolic Stroke Prophylaxis
Initial dose: 2 to 5 mg orally once a day
Maintenance dose: 2 to 10 mg orally once a day
Target INR: 2.5 (range: 2 to 3)
For patients with atrial fibrillation (AF) and prosthetic heart valves,
target INR may be increased depending on valve type, valve position,
and patient factors.
Initial dose is influenced by age, race, body weight, gender,
concomitant medications, comorbidities, genetic variation, and
possibly other factors.
Dosage and administration must be individualized according to the
patient's INR and condition being treated.

18. Dosage
Usual Adult Dose for Myocardial Infarction/ and Prophylaxis
Initial dose: 2 to 5 mg orally once a day
Maintenance dose: 2 to 10 mg orally once a day
INR: 2 to 3
Duration of therapy: At least 3 months after myocardial infarction
Initial dose is influenced by age, race, body weight, gender, concomitant
medications, comorbidities, genetic variation, and possibly other factors.
Dosage and administration must be individualized according to the patient's
INR and condition being treated.

19. Dosage
Usual Adult Dose for Pulmonary Embolism First Event/ Recurrent
Event.
Initial dose: 2 to 5 mg orally once a day
Maintenance dose: 2 to 10 mg orally once a day
Target INR: 2.5 (range: 2 to 3)
Deep venous thrombosis (DVT) or pulmonary embolism (PE)
secondary to a reversible risk factor: 3 months
Unprovoked DVT or PE: At least 3 months; evaluate risk-benefit
ratio of long-term treatment after 3 months.
Two episodes of unprovoked DVT or PE: Indefinite; periodically
reassess risk-benefit ratio of continuing such treatment.

20. Dosage
Usual Adult Dose for Deep Vein Thrombosis First Event/
Recurrent Event/ Prophylaxis.
Initial dose: 2 to 5 mg orally once a day
Maintenance dose: 2 to 10 mg orally once a day
Target INR: 2.5 (range: 2 to 3)
Deep venous thrombosis (DVT) or pulmonary embolism (PE)
secondary to a reversible risk factor: 3 months
Unprovoked DVT or PE: At least 3 months; evaluate risk-benefit
ratio of long-term treatment after 3 months.
Two episodes of unprovoked DVT or PE: Indefinite; periodically
reassess risk-benefit ratio of continuing such treatment.

21. Dosage
Usual Pediatric Dose for
Thrombotic/Thromboembolic Disorder
Initial dose (if baseline INR is 1 to 1.3): 0.2 mg/kg
orally; subsequent dose adjustments should be
made to maintain an INR between 2 and 3.
Infants required an average of 0.33 mg/kg to
maintain an INR of 2 to 3.
Teenagers required an average of 0.09 mg/kg to
maintain an INR of 2 to 3.

22. Drug
interaction
ExamplesAssociated riskCategory
Factor Xa inhibitors such as:
apixaban, edoxaban
Direct thrombin inhibitors such
as: dabigatran
increased risk of bleedingAnticoagulants
P2Y12 platelet inhibitors such as:
Clopidogrel, Prasugrel, ticagrelor
increased risk of bleedingAntiplatelet drugs
SSRIs such as: Citalopram,
Fluoxetine
SNRIs such as: Duloxetine,
Venlafaxine
risk of bleeding is increased with
selective serotonin reuptake
inhibitors (SSRIs) and serotonin and
norepinephrine reuptake inhibitors
(SNRIs).
Antidepressants
Aspirin, diclofenac, ibuprofenincreased risk of bleedingNSAIDs
Antibiotics: azithromycin,
erythromycin
Antifungals: fluconazole,
ketoconazole
Some antibiotics & antifungals can
change how warfarin work on the
body
Antibiotics &
Antifungals
Garlic,
Ginseng
may increase the blood-thinning
effect
May increase the risk of blood clot
Herbal products

23. Case report

24. Clinical features

25. Thank you