Warfarin Part I

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Dear Bloggers let me bring you to a journey with a special drug I worked on when I was doing my Master Degree Research Project. This special drug is: WARFARIN which is named after The Wisconsin Alumni Research Foundation (WARF).

According to most online dictionaries and mainly to the more reliable online database (Wikipedia), Warfarin sodium or 3-(a-acetonylbenzyl)-4-hydroxycoumarin, where the formula is C19H15NaO4 is a colorless, crystalline and water-insoluble Coumarin common oral anticoagulant.[1] Warfarin is a racemic mixture of two enantiomers, R-warfarin and S-warfarin. The S-enantiomer is two to five times more potent than the R-enantiomer, and at steady state approximately two thirds of anticoagulant response is due to the S-enantiomer.[2] It is rapidly absorbed from the gastrointestinal tract, has high bioavailability,[3,4] and reaches maximal blood concentrations in healthy volunteers 90 minutes after oral administration.[5] Racemic warfarin has a half-life of 36 to 42 hours, circulates bound to plasma proteins (mainly albumin), and accumulates in the liver, where the 2 isomers are metabolically transformed by different pathways.[6]

Table 1: Pharmacokinetics of Warfarin

Stage

Specifications

Absorption

Rapid and complete

~ 100% bioavailability

Peak up to 4 hours

Half-life: R-warfarin ~29 hours, S-warfarin ~45 hours

Distribution

Extensively bound to plasma albumin

Volume of distribution similar between enantiomers

Metabolism

Extensively metabolized via Cytochrome P450 system

R-warfarin: 1A2, 3A4, 2C19

S-warfarin: 2C9 (major), 3A4 (minor)

Elimination

Metabolites excreted in urine

Warfarin is really a sensitive and common drug when we really care about the procedure of its administration but can also be really deadly if we find ourselves careless. It has both anticoagulant and antithrombotic activity. While the anticoagulant activity depends on the clearance of functional clotting factors from the systemic circulation, its antithrombotic effect are not reflected by the early changes in prothrombin time (PT).

With its narrow therapeutic window, warfarin is commonly used to anticoagulate patients for a variety of indications, both therapeutic (e.g., treating deep venous thrombosis, maintaining bypass graft patency) and prophylactic (e.g., preventing stroke in atrial fibrillation). [1]

O Barriers to the Use of Warfarin

Although, warfarin for being a common effective oral anticoagulant for many decades, many factors had always influenced its prescription. The decision to implement therapy with warfarin necessitates a close follow-up. Three general categories have been evaluated in terms of warfarin's prescription barriers, i.e., patient-, physician-, and health care system -related factors. [7-10]

O The Optimal Therapeutic Ranges

The optimal therapeutic ranges for oral anticoagulation in patients with warfarin therapy are varied depending on the risk of thrombus formation. From the American Heart Association / American College of Cardiology (AHA/ACC) recommendation and the Asian cardiology society, optimal INR range for different indications can be summarized as followed in the table 2

Table 2: Recommended Therapeutic Range for Warfarin Therapy

Indications

INR Range

Duration

Comments

Asia

US

Antiphospholipid Syndrome

No other risk factors

1.8-2.2

2.0-3.0

Lifetime

Higher range may be required

Additional risk factors

2.0-2.5

2.5-3.5

Atrial Fibrillation -Atrial Flutter

AF + Mitral Stenosis

1.8-2.2

2.0-3.0

Lifetime

AF+ Prosthetic valves

AF following Cardiac surgery lasting >48hrs

1.8-2.2

2.0-3.0

Several weeks

Duration depends on the presence of other risk factors

Cardioversion

1.8-2.2

2.0-3.0

3-4 weeks

Extend duration of AF reoccurs of others risk factors

Thromboembolism

1.8-2.2

2.0-3.0

3-6 weeks

Up to 35 days post surgery

for hip arthroplasty/fracture

Valular Disease

Aortic Valvuloplasty (AVP)

Mitral Valvuloplasty (MVP)

Tricuspid Valvuloplasty (TVP)

1.8-2.2

2.0-3.0

3-6 months

Any valve prolapsed + AF,

the duration is lifetime

Valve Replacement-Bioprosthetic

Aortic Valve Replacement(AVR)

1.8-2.2

2.0-3.0

3-6 months

In the US the duration

is 3 months

Mitral Valve Replacement (MVR)

Tricuspid Valve replacement (TVR)

Valve Replacement-Mechanical

Aortic Valve Replacement(AVR)

1.8-2.2

2.0-3.0

Lifetime

Mitral Valve Replacement (MVR)

2.0-2.5

2.5-3.5

Tricuspid Valve replacement (TVR)

2.5-3.5

3.0-4.0

Pulmonary Hypertension (PH)

1.5-2.0

2.0-3.0

Lifetime

In my next blog, which I entitled Warfarin Part II, I will try stress out mainly three points: Warfarin interactions, its adverse Effect and Its Reversal.

But I want to point out that variability in anticoagulant response also results from inaccuracies in laboratory testing, patient noncompliance, and miscommunication between the patient and the healthcare provider.

Thank you and have a nice reading.

Blessings

This Blog Does Not Contain Any Plagiarized Material

References

[1] http://en.wikipedia.org/wiki/Warfarin

[2] Mc Evoy GK, ed. Warfarin sodium. In: AHFS drug information 2007. Bethesda, MD: American Society of Health-System Pharmacists 2007:1422-36.

[3] Breckenridge A. Oral anticoagulant drugs: pharmacokinetic aspects. Semin Hematol. 1978; 15:19-26.

[4] O'Reilly RA. Vitamin K and other oral anticoagulant drugs. Annu Rev Med. 1976; 27:245-261.

[5] Kelly JG, O'Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet. 1979; 4:1-15.

[6] O'Reilly RA. Warfarin metabolism and drug-drug interactions. In: Wessler S, Becker CG, Nemerson Y, eds. The New Dimensions of Warfarin Prophylaxis: Advances in Experimental Medicine and Biology. New York, NY: Plenum; 1986:205-212

[7] Beyth RJ, Antani MR, Covinsky KE, et al. Why isn't warfarin prescribed to patients with nonrheumatic atrial fibrillation? J Gen Intern Med.1996; 11:721-728.

[8] Monette J, Gurwitz JH, Rochon PA, Avorn J. Physician attitudes concerning warfarin for stroke prevention in atrial fibrillation: results of a survey of long-term care practitioners. J Am Geriatr Soc.1997; 45:1060-1065.

[9] Kutner M, Nixon G, Silverstone F. Physicians' attitudes toward oral anticoagulants and antiplatelet agents for stroke prevention in elderly patients with atrial fibrillation. Arch Intern Med. 1991; 151:1950-1953

[10] Rodgers H, Sudlow M, Dobson R, Kenny RA, Thomson RG. Warfarin anticoagulation in primary care: a regional survey of present practice and clinicians' views. Br J Gen Pract. 1997; 47:309-310.

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About the Author

Guy-Armel BOUNDA's picture

My name's Guy-Armel BOUNDA. I'm from Gabon (Middele Africa) and a Ph.D Candidate in China Pharmaceutical University.I am carrying out my Research Project in Nanjing Drum Tower Hospital, China .

Comments

Sravani kompella's picture

Hi , Can warfarin be administered in any other routes?

 
Guy-Armel BOUNDA's picture

Dear Sravani Thank you for your question. As you know Warfarin Sodium also known under brand names Coumadin, Jantoven, Marevan, Lawarin, and Waran, according to differents nations and states, is an oral anticoagulant. Mainly it's administered as a tablets (1mg, 2mg, 2.5mg, 5mg, 7.5mg, 10mg;and in China we have 2.5mg),but in few cases it can be administered as injection for intravenous use only and it is not recommended for intramuscular use. But to be administered as injection, it has to be supplied as a sterile, lyophilized powder, which, after reconstitution with 2.7 mL sterile Water for Injection, contains: Warfarin Sodium 2 mg/mL Sodium Phosphate, Dibasic, Heptahydrate 4.98 mg/mL Sodium Phosphate, Monobasic, Monohydrate 0.194 mg/mL Sodium Chloride 0.1 mg/mL Mannitol 38.0 mg/mL Sodium Hydroxide, as needed for pH adjustment to 8.1 to 8.3 Ref http://en.wikipedia.org/wiki/Warfarin http://www.rxlist.com/coumadin-drug.htm

 

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Sravani kompella's picture

Very well explained sir
Siriki Praveen Kumar's picture

Hi, good blog... why only "oral warfarin" ? can you state few patient related factors in monitoring the dose of warfarin? thank you

Regards,

S. Praveen Kumar.

sirikipraveen11@gmail.com

Pharma warriors

Guy-Armel BOUNDA's picture

Dear Praveen Kumar, Thank you for your questions. As the patient related factors in monitoring the dose of Warfarin, we have the main factors which is the age. It's perceived as an embolic risk, because the more the age increases the more it's seen as a factors which need to be watch due to the relationship between the pharmacodynamics and pharmacokinetics of this drug in those elder patients. We know also that cocomittant disease in a patient can be seen as a patient related factors to administrate Warfarin. For exemple physicians are more enthusiastic about and more aggresive with anticoagulation therapy in patients with history of stroke. Thanx

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SS Md Shafi's picture

hi... nice blog...

what is the protein binding capacity if warfarin..??

shafi ..

Guy-Armel BOUNDA's picture

Thank you sir for commenting on my blog. Sorry your question is incomplete, would you mind to elaborate it again? Thank you

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SS Md Shafi's picture

dear pettho sir.....

warfarin binds with the protiens in blood almost above 90 percent of total drug(WARFARIN) . that means only below 10 percent of the total drug (WARFARIN)is in the FREE FORM in blood.

shafi ..

K Rajakrishna's picture

Dear sir the information is very well presented. Can you please provide the information about the mechanism of action of both S and R form of warfarin.
Guy-Armel BOUNDA's picture

As I already point out, Warfarin is a racemic mixture of two enantiomers: R-warfarin and S-warfarin. The S-enantiomer is two to five times more potent than the R-enantiomer, and at steady state approximately two thirds of anticoagulant response is due to the S-enantiomer.[a] It is rapidly absorbed from the gastrointestinal tract, has high bioavailability, [b, c] and reaches maximal blood concentrations in healthy volunteers 90 minutes after oral administration.[d]

Warfarin in human is mainly metabolized to a series of monohydroxylated metabolites. Warfarin metabolism is isomer-specific via hepatic cytochrome P450 enzyme system, including the isoenzymes CYP1A2, 2C8, 2C9, 2C18, 2C19 and 3A4. [e] While the S-warfarin is primarily metabolized by CYP2C9 (and in small degree by CYP3A4) and is eliminated in bile, the R-warfarin, in contrast, is primarily metabolized by CYP1A2 and CYP3A4 and is excreted in urine as inactive metabolites.

References:

[a]. Mc Evoy GK, ed. Warfarin sodium. In: AHFS drug information 2007. Bethesda, MD: American Society of Health-System Pharmacists 2007:1422-36.

[b]. Breckenridge A. Oral anticoagulant drugs: pharmacokinetic aspects. Semin Hematol. 1978; 15:19-26.

[c]. O'Reilly RA. Vitamin K and other oral anticoagulant drugs. Annu Rev Med. 1976; 27:245-261.

[d]. Kelly JG, O'Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet. 1979; 4:1-15.

[e]. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73:67-74.

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K Rajakrishna's picture

respected sir, you have very nicely and impressively explained my query by representing pictorially and being on to the point. thank you for taking pain in answering my query. thank you sir.
Guy-Armel BOUNDA's picture

Thank you sir, it was my pleasure. Be blessed

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Navya Sai's picture

Hi sir, Blog is informative.Why WARFARIN is not recommended for intramuscular route?

Regards,

Navya sai

Guy-Armel BOUNDA's picture

Dear Navya Sai Thank you for the question. It's really a good question to be asked. Right now i don't have the full answer on this one but i know that Warfarin can go through alternative i.V route for those who can not have the drug through the oral route. And it's even recorded that "it's should be administered as a slow bolus injection over 1 to 2 min into a peripheral vein", and there are very strict condition during the preparation of this injection, because this vial should containt the same dose as the oral drug. But i promise you that i will keep looking for the reasons why Warfarin can not be given through i.m Ref: http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Mon...(General%20Monographs-%20C)/COUMADIN.html

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Gangadhar Hari's picture

Very Informative blog sir..

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