Journal of Pharmacy Practice http://jpp.sagepub.com/
Patient Case: Impact of Smoking Cessation on International Normalized Ratio Shane D. Jordan, Mark D. Stone, Earnest Alexander, Joseph Haley and Albert McKee Journal of Pharmacy Practice published online 6 January 2014 DOI: 10.1177/0897190013516501 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2014/01/06/0897190013516501 A more recent version of this article was published on - Sep 23, 2014
Published by: http://www.sagepublications.com
On behalf of:
New York State Council of Health-system Pharmacists
Additional services and information for Journal of Pharmacy Practice can be found at: Email Alerts: http://jpp.sagepub.com/cgi/alerts Subscriptions: http://jpp.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
Version of Record - Sep 23, 2014 >> OnlineFirst Version of Record - Jan 6, 2014 What is This?
Downloaded from jpp.sagepub.com at GEORGIAN COURT UNIV on December 8, 2014
Review
Patient Case: Impact of Smoking Cessation on International Normalized Ratio
Journal of Pharmacy Practice 1-4 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190013516501 jpp.sagepub.com
Shane D. Jordan, PharmD, BCPS1, Mark D. Stone, PharmD2, Earnest Alexander, PharmD, FCCM1, Joseph Haley, BS, PharmD candidate1, and Albert McKee, BS, PharmD candidate1
Abstract Introduction: The concurrent use of cigarettes while on warfarin therapy is a common occurrence. Smoking cessation among patients on chronic warfarin therapy is suspected to reduce drug clearance that may require dose adjustments. This type of interaction is particularly important when dealing with narrow therapeutic medications, as is the case with warfarin. Our case describes a series of supratherapeutic international normalized ratios (INRs) due to smoking cessation while on concomitant warfarin therapy. Patient Case: A 51-year-old male presented to the anticoagulation clinic for management of his warfarin therapy for an acute deep vein thrombosis. After 2 months of stable, therapeutic INR levels, the patient abruptly decreased his smoking from 1 pack/day to one-half pack/day and then subsequently stopped smoking completely. The patient’s smoking cessation resulted in a major modification of his required weekly warfarin dose to maintain a therapeutic INR (a 39% dose reduction). Conclusion: This case exemplifies how certain lifestyle factors, such as smoking, can alter the pharmacokinetics of patients on chronic warfarin therapy. This is the first case to demonstrate a greater than 30% reduction in the weekly warfarin dose following smoking cessation. Keywords warfarin, smoking cessation, international normalized ratio
Introduction Warfarin is one of the most widely used oral anticoagulants around the world and after more than 60 years1 remains at the forefront of therapy for the prevention of thrombus formation and thromboembolic events in many settings. It is well established that warfarin has a narrow therapeutic index and is commonly impacted by multiple drug interactions. Patients on the medication must remain consistent in regard to both lifestyle and concomitant medication use. Smoking is just one lifestyle factor that can alter the metabolism of warfarin, since it has been theorized to induce several of the cytochrome P450 enzymes (ie, 1A1, 1A2, and 2E1) involved with the metabolism of warfarin.2 This case report describes a 51-year-old male who presented with an elevated international normalized ratio (INR) after smoking cessation, despite being stable on warfarin therapy for approximately 2 months.
Case Report
medical history included a seizure disorder, hypertension, chronic back pain, chronic obstructive pulmonary disease, and transverse myelitis. The patient’s postdischarge medications included albuteral inhaler 1 puff every 4 hours as needed, cyclobenzaprine 10 mg 2 times daily as needed, lisinopril 20 mg daily, phenytoin 100 mg 3 times daily, tadalafil 5 mg once daily as needed, and warfarin as directed per pharmacotherapy clinic. No other medication changes were documented in the previous 6 months prior to start of the warfarin therapy, and all medications had been continued uninterrupted through inpatient admission. The patient had documented medication allergies to aspirin and chlorpromazine. During the patient’s initial visit to the clinic on July 25, 2011, the patient’s INR was subtherapeutic at 1.9 (goal of 2-3). Therefore, the weekly dose was subsequently increased from 30 mg up to 32 mg. The goal INR was finally reached at a weekly dose of 40 mg a month and a half later. However, after
1
A 51-year-old male was initiated on warfarin therapy, following a diagnosis of an acute deep vein thrombosis (DVT) in the inpatient setting. The patient elected to have his warfarin therapy managed with the affiliated hospital outpatient clinic, where anticoagulation services were provided primarily by a pharmacist. Concurrent
2
Tampa General Hospital, Department of Pharmacy Services, Tampa, FL, USA Bayfront Health, St. Petersburg, FL, USA
Corresponding Author: Shane D. Jordan, Tampa General Hospital, PO Box 1289, Tampa, FL 33601, USA. Email: [email protected]
Downloaded from jpp.sagepub.com at GEORGIAN COURT UNIV on December 8, 2014
2
Journal of Pharmacy Practice
Figure 1. Average daily warfarin dose compared to clinical visit international normalized ratios (INRs).
a few slight decreases in INR levels below goal range, due to possible hepatic induction of his long-term seizure medication (oral phenytoin capsules), the INR eventually stabilized on a weekly dose of 46 mg. After a series of stable INR values (approximately 9 months after warfarin initiation), the patient verbalized to the pharmacist that he recently reduced his smoking to half a pack a day (from 1 pack a day) and had plans of quitting completely in the near future. Three weeks after the initial smoking cessation strategy, a routine INR level was modestly supratherapeutic at 3.4. The patient reported no apparent signs or symptoms of bleeding and visual assessment did not reveal any findings consistent with bleeding. The patient was instructed to decrease his weekly warfarin dosage to 44 mg weekly and follow-up with the clinic in 2 weeks. Upon return to the clinic and with a stable INR (2.9), the patient verbalized that he was still following his smoking cessation strategy (half a pack a day). Over the course of 1 month, the patient’s INR fluctuated into supratherapeutic zones (Figure 1) until further reduction in dose to 38 mg weekly resulted in a stable INR reading of 2.5. Upon the patient’s next visit on September 17, 2012, the INR was 4 and the patient stated that he had stopped smoking completely 17 days prior. The patient had no apparent signs or symptoms of bleeding upon assessment. Over the next month, the patient’s INR continued to rise and finally peaked at 5.1 on October 15, 2012. It subsequently fell to 3.1 on October 29, 2012 (as seen in Figure 1) due to adjusting the dose down to 28 mg weekly. The patient was considered to be an accurate historian and was deemed credible in providing information over the course
of the clinic visits when the INR levels were not therapeutic. He stated multiple times during this period that he did not miss any doses or have any other medication changes. This included any herbal or over-the-counter products. The patient also stated he did not have any illnesses, gastrointestinal problems, or dietary changes during this period. Additionally, no other factors that could have altered the pharmacokinetics of warfarin were discovered in this patient. Overall, the patient went from a weekly warfarin dose of 46 mg while smoking 1 pack a day down to 28 mg a week after smoking cessation, which represents a 39% dose reduction needed to remain in therapeutic range. Of note, the extended duration of the patient’s anticoagulation was driven by the prescribing physician. The patient remains smoke free; no further changes or alterations in the INR have occurred.
Discussion Concomitant use of cigarettes with warfarin administration is hypothesized to have significant effects on the pharmacokinetics of warfarin in the body.3 The metabolism of warfarin is mediated through the hepatic cytochrome P450 system. Among the various P450 hepatic enzymes, CYP2D6, CYP3A4, CYP1A2, CYP2C9, CYP2E1, and CYP2A6 isoforms appear to have a significant role in hepatic drug metabolism.4,5 Based on these factors, warfarin has many drug interactions with substances that induce or inhibit these enzymes. The smoke from cigarettes contains at least 50 carcinogens, most notable are the polycyclic aromatic hydrocarbons, which
Downloaded from jpp.sagepub.com at GEORGIAN COURT UNIV on December 8, 2014
Jordan et al
3
result from the partial combustion of organic material.6 Theoretically, since polycyclic aromatic hydrocarbons can cause enzyme induction of CYP1A2, a potential interaction may occur between warfarin and carcinogens. Considering that CYP1A2 is a minor elimination pathway for warfarin, the extent of the interaction remains to be seen.7 Another potential mechanism for the interaction between warfarin and cigarette use is the content of phylloquinone in tobacco smoke. Tobacco has been estimated to contain 0.1 mol/kg phylloquinone that is approximately 10 to 30 times more than other green vegetable sources such as spinach.8 Furthermore, chronic use of cigarettes, resulting in the volatilization of phylloquinone, could contribute to increased vitamin K concentrations within fat stores, resulting in lower efficacy of warfarin. It is well established that chronic smoking can alter the metabolism of substances in the body. For example, Faber et al compared the conversion of caffeine to paraxanthine ratios as a marker for CYP1A2 activity in smokers.9 Caffeine was chosen for this study because it is metabolized mainly via CYP1A2. Upon smoking cessation, the CYP1A2 was no longer induced, which led to a 36.1% reduction in the clearance of caffeine. This study by Faber et al showed the importance of adjusting the doses of medications that are metabolized via CYP1A2 upon alteration of smoking habits. Bachmann et al showed that smoking causes an approximate 13% increase in clearance, 13% decrease in steady-state concentration, 23% decrease in half-life, and an 11% decrease in volume of distribution of warfarin with no effect on prothrombin time.10 Another study demonstrated that heavy smokers displayed a nearly 2-fold increase in the enzymatic activity of CYP1A2, as compared to nonsmokers.11 Other case reports have also demonstrated and corroborated our findings that upon smoking cessation a weekly warfarin dose reduction was necessary. Colucci et al discussed an 80-year-old white male who presented with supratherapeutic INRs stemming from smoking cessation while receiving chronic warfarin therapy.12 The patient was reported to be stable for 10 months on a warfarin dose of 35 mg weekly, while having maintained a smoking regimen of 1.5 to 2 packs/day for greater than 30 years. In the report, concomitant medications, alcohol use, liver function (aspartate amino transaminase), cardiovascular status, hemodynamics, and diet were deemed unchanged and discredited for INR shift. The patient’s warfarin dose per week stabilized 4 months post–smoking cessation, resulting in a net decrease of 14%. It was concluded that other causative factors could not be established and that smoking cessation was responsible for the patient’s elevated INR response. Evans et al also demonstrated similar findings in a case report where a 58-year-old man, on a stabilized warfarin regimen, was admitted to the emergency room for bacterial meningitis.13 After discharge, the patient completed smoking cessation. Upon follow-up, the patient’s INR proceeded to rise significantly. On consultation, it was determined that no other dietary or lifestyle changes had been made in addition to smoking cessation. After several adjustments, the patient was stabilized on a warfarin regimen 23% lower than the patient’s pre– smoking cessation regimen. The case report highlighted the
importance of potential interactions and monitoring smoking habits while on warfarin therapy.
Conclusion Based on our case report, smoking may have the potential to significantly affect INR, which can necessitate more recurrent INR monitoring and possible warfarin dosage adjustment. Our case is the first to demonstrate the need for a greater than 30% weekly dose reduction in warfarin after smoking cessation. Smoking cessation reverses the induction, believed to be caused by the polyaromatic hydrocarbons, of CYP1A2. This case study reaffirms Faber’s position that medications that are metabolized via CYP1A2 should be closely monitored due to the possibility of supratherapeutic levels occurring upon smoking cessation. However, further research is needed in order to define a true cause and effect relationship between warfarin and smoking cessation. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Stahmann MA, Huebner CF, Link KP. Studies on the hemorrhagic sweet clover disease. Identification and synthesis of the hemorrhagic agent. J Biol Chem. 1941;138:513-527. 2. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007;64(18):1917-1921. 3. Nathisuwan S, Dilokthornsakul P, Chaiyakunapruk N, et al. Assessing evidence of interaction between smoking and warfarin: a systematic review and meta-analysis. Chest. 2011;139(5): 1130-1139. 4. Turkoski BB. Induction or inhibition: the complexity of cytochrome P450 enzymes and their impact on drug interactions. Orthop Nurs. 2002;21(3):68-73. 5. Correia MA. Drug biotransformation. Chapter 4. Basic & Clinical Pharmacology. New York: Lange Medical /McGraw-Hill; 2012. 6. Zevin S, Benowitz NL. Drug Interactions with Tobacco Smoking. Clinal Pharmacokinet. 1999;36(6):425-438. 7. Hoffmann D, Djordjevic MV, Hoffmann I. The changing cigarette. Prev Med. 1997;26(4):427-434. 8. Olson R, Shils ME, Olson JA, et al. Modern nutrition in health and disease. 8th ed. Volume 1. Philadelphia: Lea & Febiger; 1994:342-357. 9. Faber MS, Fuhr U. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharm Ther. 2004;76(2):178-184. 10. Bachmann K, Shapiro R, Fulton R, Carrol FT, Sullivan TJ. Smoking and warfarin disposition. Clin Pharmacol Ther. 1979;25(3): 309-315.
Downloaded from jpp.sagepub.com at GEORGIAN COURT UNIV on December 8, 2014
4
Journal of Pharmacy Practice
11. Terziivanov D, Bozhinova K, Dimitrova V, et al. Nonparametric expectation maximisation (NPEM) population pharmacokinetic analysis of caffeine disposition from sparse data in adult caucasians systemic caffeine clearance as a biomarker for cytochrome P450 1A2 activity. Clin Pharmacokinet. 2003;42(15):1393-1409.
12. Colucci VJ, Knapp JF. Increase in international normalized ratio associated with smoking cessation. Ann Pharmacother. 2001; 35(3):385-386. 13. Evans M, Lewis GM. Increase in international normalized ratio after smoking cessation in a patient receiving warfarin. Pharmacotherapy. 2005;25(11):1656-1659.
Downloaded from jpp.sagepub.com at GEORGIAN COURT UNIV on December 8, 2014
Patient Case: Impact of Smoking Cessation on International Normalized Ratio Shane D. Jordan, Mark D. Stone, Earnest Alexander, Joseph Haley and Albert McKee Journal of Pharmacy Practice published online 6 January 2014 DOI: 10.1177/0897190013516501 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2014/01/06/0897190013516501 A more recent version of this article was published on - Sep 23, 2014
Published by: http://www.sagepublications.com
On behalf of:
New York State Council of Health-system Pharmacists
Additional services and information for Journal of Pharmacy Practice can be found at: Email Alerts: http://jpp.sagepub.com/cgi/alerts Subscriptions: http://jpp.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
Version of Record - Sep 23, 2014 >> OnlineFirst Version of Record - Jan 6, 2014 What is This?
Downloaded from jpp.sagepub.com at GEORGIAN COURT UNIV on December 8, 2014
Review
Patient Case: Impact of Smoking Cessation on International Normalized Ratio
Journal of Pharmacy Practice 1-4 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190013516501 jpp.sagepub.com
Shane D. Jordan, PharmD, BCPS1, Mark D. Stone, PharmD2, Earnest Alexander, PharmD, FCCM1, Joseph Haley, BS, PharmD candidate1, and Albert McKee, BS, PharmD candidate1
Abstract Introduction: The concurrent use of cigarettes while on warfarin therapy is a common occurrence. Smoking cessation among patients on chronic warfarin therapy is suspected to reduce drug clearance that may require dose adjustments. This type of interaction is particularly important when dealing with narrow therapeutic medications, as is the case with warfarin. Our case describes a series of supratherapeutic international normalized ratios (INRs) due to smoking cessation while on concomitant warfarin therapy. Patient Case: A 51-year-old male presented to the anticoagulation clinic for management of his warfarin therapy for an acute deep vein thrombosis. After 2 months of stable, therapeutic INR levels, the patient abruptly decreased his smoking from 1 pack/day to one-half pack/day and then subsequently stopped smoking completely. The patient’s smoking cessation resulted in a major modification of his required weekly warfarin dose to maintain a therapeutic INR (a 39% dose reduction). Conclusion: This case exemplifies how certain lifestyle factors, such as smoking, can alter the pharmacokinetics of patients on chronic warfarin therapy. This is the first case to demonstrate a greater than 30% reduction in the weekly warfarin dose following smoking cessation. Keywords warfarin, smoking cessation, international normalized ratio
Introduction Warfarin is one of the most widely used oral anticoagulants around the world and after more than 60 years1 remains at the forefront of therapy for the prevention of thrombus formation and thromboembolic events in many settings. It is well established that warfarin has a narrow therapeutic index and is commonly impacted by multiple drug interactions. Patients on the medication must remain consistent in regard to both lifestyle and concomitant medication use. Smoking is just one lifestyle factor that can alter the metabolism of warfarin, since it has been theorized to induce several of the cytochrome P450 enzymes (ie, 1A1, 1A2, and 2E1) involved with the metabolism of warfarin.2 This case report describes a 51-year-old male who presented with an elevated international normalized ratio (INR) after smoking cessation, despite being stable on warfarin therapy for approximately 2 months.
Case Report
medical history included a seizure disorder, hypertension, chronic back pain, chronic obstructive pulmonary disease, and transverse myelitis. The patient’s postdischarge medications included albuteral inhaler 1 puff every 4 hours as needed, cyclobenzaprine 10 mg 2 times daily as needed, lisinopril 20 mg daily, phenytoin 100 mg 3 times daily, tadalafil 5 mg once daily as needed, and warfarin as directed per pharmacotherapy clinic. No other medication changes were documented in the previous 6 months prior to start of the warfarin therapy, and all medications had been continued uninterrupted through inpatient admission. The patient had documented medication allergies to aspirin and chlorpromazine. During the patient’s initial visit to the clinic on July 25, 2011, the patient’s INR was subtherapeutic at 1.9 (goal of 2-3). Therefore, the weekly dose was subsequently increased from 30 mg up to 32 mg. The goal INR was finally reached at a weekly dose of 40 mg a month and a half later. However, after
1
A 51-year-old male was initiated on warfarin therapy, following a diagnosis of an acute deep vein thrombosis (DVT) in the inpatient setting. The patient elected to have his warfarin therapy managed with the affiliated hospital outpatient clinic, where anticoagulation services were provided primarily by a pharmacist. Concurrent
2
Tampa General Hospital, Department of Pharmacy Services, Tampa, FL, USA Bayfront Health, St. Petersburg, FL, USA
Corresponding Author: Shane D. Jordan, Tampa General Hospital, PO Box 1289, Tampa, FL 33601, USA. Email: [email protected]
Downloaded from jpp.sagepub.com at GEORGIAN COURT UNIV on December 8, 2014
2
Journal of Pharmacy Practice
Figure 1. Average daily warfarin dose compared to clinical visit international normalized ratios (INRs).
a few slight decreases in INR levels below goal range, due to possible hepatic induction of his long-term seizure medication (oral phenytoin capsules), the INR eventually stabilized on a weekly dose of 46 mg. After a series of stable INR values (approximately 9 months after warfarin initiation), the patient verbalized to the pharmacist that he recently reduced his smoking to half a pack a day (from 1 pack a day) and had plans of quitting completely in the near future. Three weeks after the initial smoking cessation strategy, a routine INR level was modestly supratherapeutic at 3.4. The patient reported no apparent signs or symptoms of bleeding and visual assessment did not reveal any findings consistent with bleeding. The patient was instructed to decrease his weekly warfarin dosage to 44 mg weekly and follow-up with the clinic in 2 weeks. Upon return to the clinic and with a stable INR (2.9), the patient verbalized that he was still following his smoking cessation strategy (half a pack a day). Over the course of 1 month, the patient’s INR fluctuated into supratherapeutic zones (Figure 1) until further reduction in dose to 38 mg weekly resulted in a stable INR reading of 2.5. Upon the patient’s next visit on September 17, 2012, the INR was 4 and the patient stated that he had stopped smoking completely 17 days prior. The patient had no apparent signs or symptoms of bleeding upon assessment. Over the next month, the patient’s INR continued to rise and finally peaked at 5.1 on October 15, 2012. It subsequently fell to 3.1 on October 29, 2012 (as seen in Figure 1) due to adjusting the dose down to 28 mg weekly. The patient was considered to be an accurate historian and was deemed credible in providing information over the course
of the clinic visits when the INR levels were not therapeutic. He stated multiple times during this period that he did not miss any doses or have any other medication changes. This included any herbal or over-the-counter products. The patient also stated he did not have any illnesses, gastrointestinal problems, or dietary changes during this period. Additionally, no other factors that could have altered the pharmacokinetics of warfarin were discovered in this patient. Overall, the patient went from a weekly warfarin dose of 46 mg while smoking 1 pack a day down to 28 mg a week after smoking cessation, which represents a 39% dose reduction needed to remain in therapeutic range. Of note, the extended duration of the patient’s anticoagulation was driven by the prescribing physician. The patient remains smoke free; no further changes or alterations in the INR have occurred.
Discussion Concomitant use of cigarettes with warfarin administration is hypothesized to have significant effects on the pharmacokinetics of warfarin in the body.3 The metabolism of warfarin is mediated through the hepatic cytochrome P450 system. Among the various P450 hepatic enzymes, CYP2D6, CYP3A4, CYP1A2, CYP2C9, CYP2E1, and CYP2A6 isoforms appear to have a significant role in hepatic drug metabolism.4,5 Based on these factors, warfarin has many drug interactions with substances that induce or inhibit these enzymes. The smoke from cigarettes contains at least 50 carcinogens, most notable are the polycyclic aromatic hydrocarbons, which
Downloaded from jpp.sagepub.com at GEORGIAN COURT UNIV on December 8, 2014
Jordan et al
3
result from the partial combustion of organic material.6 Theoretically, since polycyclic aromatic hydrocarbons can cause enzyme induction of CYP1A2, a potential interaction may occur between warfarin and carcinogens. Considering that CYP1A2 is a minor elimination pathway for warfarin, the extent of the interaction remains to be seen.7 Another potential mechanism for the interaction between warfarin and cigarette use is the content of phylloquinone in tobacco smoke. Tobacco has been estimated to contain 0.1 mol/kg phylloquinone that is approximately 10 to 30 times more than other green vegetable sources such as spinach.8 Furthermore, chronic use of cigarettes, resulting in the volatilization of phylloquinone, could contribute to increased vitamin K concentrations within fat stores, resulting in lower efficacy of warfarin. It is well established that chronic smoking can alter the metabolism of substances in the body. For example, Faber et al compared the conversion of caffeine to paraxanthine ratios as a marker for CYP1A2 activity in smokers.9 Caffeine was chosen for this study because it is metabolized mainly via CYP1A2. Upon smoking cessation, the CYP1A2 was no longer induced, which led to a 36.1% reduction in the clearance of caffeine. This study by Faber et al showed the importance of adjusting the doses of medications that are metabolized via CYP1A2 upon alteration of smoking habits. Bachmann et al showed that smoking causes an approximate 13% increase in clearance, 13% decrease in steady-state concentration, 23% decrease in half-life, and an 11% decrease in volume of distribution of warfarin with no effect on prothrombin time.10 Another study demonstrated that heavy smokers displayed a nearly 2-fold increase in the enzymatic activity of CYP1A2, as compared to nonsmokers.11 Other case reports have also demonstrated and corroborated our findings that upon smoking cessation a weekly warfarin dose reduction was necessary. Colucci et al discussed an 80-year-old white male who presented with supratherapeutic INRs stemming from smoking cessation while receiving chronic warfarin therapy.12 The patient was reported to be stable for 10 months on a warfarin dose of 35 mg weekly, while having maintained a smoking regimen of 1.5 to 2 packs/day for greater than 30 years. In the report, concomitant medications, alcohol use, liver function (aspartate amino transaminase), cardiovascular status, hemodynamics, and diet were deemed unchanged and discredited for INR shift. The patient’s warfarin dose per week stabilized 4 months post–smoking cessation, resulting in a net decrease of 14%. It was concluded that other causative factors could not be established and that smoking cessation was responsible for the patient’s elevated INR response. Evans et al also demonstrated similar findings in a case report where a 58-year-old man, on a stabilized warfarin regimen, was admitted to the emergency room for bacterial meningitis.13 After discharge, the patient completed smoking cessation. Upon follow-up, the patient’s INR proceeded to rise significantly. On consultation, it was determined that no other dietary or lifestyle changes had been made in addition to smoking cessation. After several adjustments, the patient was stabilized on a warfarin regimen 23% lower than the patient’s pre– smoking cessation regimen. The case report highlighted the
importance of potential interactions and monitoring smoking habits while on warfarin therapy.
Conclusion Based on our case report, smoking may have the potential to significantly affect INR, which can necessitate more recurrent INR monitoring and possible warfarin dosage adjustment. Our case is the first to demonstrate the need for a greater than 30% weekly dose reduction in warfarin after smoking cessation. Smoking cessation reverses the induction, believed to be caused by the polyaromatic hydrocarbons, of CYP1A2. This case study reaffirms Faber’s position that medications that are metabolized via CYP1A2 should be closely monitored due to the possibility of supratherapeutic levels occurring upon smoking cessation. However, further research is needed in order to define a true cause and effect relationship between warfarin and smoking cessation. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Stahmann MA, Huebner CF, Link KP. Studies on the hemorrhagic sweet clover disease. Identification and synthesis of the hemorrhagic agent. J Biol Chem. 1941;138:513-527. 2. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007;64(18):1917-1921. 3. Nathisuwan S, Dilokthornsakul P, Chaiyakunapruk N, et al. Assessing evidence of interaction between smoking and warfarin: a systematic review and meta-analysis. Chest. 2011;139(5): 1130-1139. 4. Turkoski BB. Induction or inhibition: the complexity of cytochrome P450 enzymes and their impact on drug interactions. Orthop Nurs. 2002;21(3):68-73. 5. Correia MA. Drug biotransformation. Chapter 4. Basic & Clinical Pharmacology. New York: Lange Medical /McGraw-Hill; 2012. 6. Zevin S, Benowitz NL. Drug Interactions with Tobacco Smoking. Clinal Pharmacokinet. 1999;36(6):425-438. 7. Hoffmann D, Djordjevic MV, Hoffmann I. The changing cigarette. Prev Med. 1997;26(4):427-434. 8. Olson R, Shils ME, Olson JA, et al. Modern nutrition in health and disease. 8th ed. Volume 1. Philadelphia: Lea & Febiger; 1994:342-357. 9. Faber MS, Fuhr U. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharm Ther. 2004;76(2):178-184. 10. Bachmann K, Shapiro R, Fulton R, Carrol FT, Sullivan TJ. Smoking and warfarin disposition. Clin Pharmacol Ther. 1979;25(3): 309-315.
Downloaded from jpp.sagepub.com at GEORGIAN COURT UNIV on December 8, 2014
4
Journal of Pharmacy Practice
11. Terziivanov D, Bozhinova K, Dimitrova V, et al. Nonparametric expectation maximisation (NPEM) population pharmacokinetic analysis of caffeine disposition from sparse data in adult caucasians systemic caffeine clearance as a biomarker for cytochrome P450 1A2 activity. Clin Pharmacokinet. 2003;42(15):1393-1409.
12. Colucci VJ, Knapp JF. Increase in international normalized ratio associated with smoking cessation. Ann Pharmacother. 2001; 35(3):385-386. 13. Evans M, Lewis GM. Increase in international normalized ratio after smoking cessation in a patient receiving warfarin. Pharmacotherapy. 2005;25(11):1656-1659.
Downloaded from jpp.sagepub.com at GEORGIAN COURT UNIV on December 8, 2014
