Bleeding Complications Associated with Herbal Supplements, Antiplatelet and Anticoagulant Medications

2007 Journal of Dental Hygiene Journal Special Supplement to Access magazine of Dental Hygiene

T HE A MERICAN D ENTAL H YGIENISTS’ASSOCIATION

An Examination of the Bleeding Complications Associated with Herbal Supplements, Antiplatelet and Anticoagulant Medications

• Introduction • Blood Clotting • Parenteral Anticoagulants • Oral Anticoagulants • Oral Antiplatelet Agents • NSAIDS • Herbal Supplements • Practice Considerations for Dental Professionals

This supplement is sponsored by Philips Sonicare. CEUs available online—see inside front cover. This special issue of the Journal of Dental Hygiene was funded by an educational grant sponsored by Philips Sonicare.

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Message

3 From the Editor of the Journal of Dental Hygiene Rebecca S. Wilder, RDH, BS, MS

Supplement An Examination of the Bleeding Complications Associated with Herbal Supplements, Antiplatelet and Anticoagulant Medications Ann Eshenaur Spolarich, RDH, PhD, and Leslie Andrews, RDH, MBA

4 Introduction

6 Blood Clotting

7 Parenteral Anticoagulants 7 Heparin 8 Low Molecular Weight Heparins 8 Antithrombotic Agents 8 Factor Xa Inhibitor

9 Oral Anticoagulants 9 Warfarin

11 Oral Antiplatelet Agents 11 Aspirin 12 Dipyridamole 12 Aspirin with dipyridamole 12 Clopidogrel 13 Cilostazole 13 Ticlopidine

13 NSAIDS

14 Herbal Supplements 15 Garlic Allium sativum 16 Ginkgo Ginkgo biloba 17 Ginseng Panax quinquefolius 18 Ginger Zingiber officinale 19 St John’s wort Hypericum perforatum L

21 Practice Considerations for Dental Professionals ■ STATEMENT OF PURPOSE The Journal of Dental Hygiene is the refereed, scientific publication of the American Dental Hygienists’ Association. It promotes the publication of Journal original research related to the profession, the education, and the practice of dental hygiene. The journal supports the development and dissemination of a dental hygiene body of knowledge through scientific inquiry in basic, applied, of and clinical research. Dental ■ EDITORIAL REVIEW BOARD Hygiene Celeste M. Abraham, DDS, MS Heather L. Jared, RDH, BS, MS Cynthia C. Amyot, BSDH, EdD Wendy Kerschbaum, RDH, MA, MPH Joanna Asadoorian, AAS, BScD, MSc Salme Lavigne, RDH, BA, MSDH special supplement Caren M. Barnes, RDH, BS, MS Jessica Y. Lee, DDS, MPH, PhD Phyllis L. Beemsterboer, RDH, MS, EdD Deborah S. Manne,RDH,RN,MSN,OCN Stephanie Bossenberger, RDH, MS Ann L. McCann, RDH, BS, MS Kimberly S. Bray, RDH, MS Stacy McCauley, RDH, MS Lorraine Brockmann, RDH, MS Gayle McCombs, RDH, MS Patricia Regener Campbell, RDH, MS Shannon Mitchell, RDH, MS Dan Caplan, DDS, PhD Tricia Moore, RDH, BSDH, MA, EdD EXECUTIVE DIRECTOR Barbara H. Connolly, PT, EdD, FAPTA Christine Nathe, RDH, MS Ann Battrell, RDH, BS, MSDH Valerie J. Cooke, RDH, MS, EdD Kathleen J. Newell, RDH, MA, PhD [email protected] MaryAnn Cugini, RDH, MHP Johanna Odrich, RDH, MS, DrPh Susan J. Daniel, AAS, BS, MS Pamela Overman, BSDH, MS, EdD DIRECTOR OF COMMUNICATIONS Michele Darby, BSDH, MS Vickie Overman, RDH, BS, MEd Catherine Davis, RDH, PhD. FIDSA Fotinos S. Panagakos, DMD, PhD, MEd Jeff Mitchell Connie Drisko, RDH, BS, DDS M. Elaine Parker, RDH, MS, PhD [email protected] Jacquelyn M. Dylla, DPT, PT Ceib Phillips, MPH, PhD Deborah E. Fleming, RDH, MS Marjorie Reveal, RDH, MS, MBA EDITOR EMERITUS Jane L. Forrest, BSDH, MS, EdD Kip Rowland, RDH, MS Mary Alice Gaston, RDH, MS Jacquelyn L. Fried, RDH, BA, MS Judith Skeleton, RDH, BS, MEd, PhD Mary George, RDH, BSDH, MEd Ann Eshenaur Spolarich, RDH, PhD EDITOR-IN-CHIEF Ellen Grimes, RDH, MA, MPA, EdD Sheryl L. Ernest Syme, RDH, MS Rebecca S. Wilder, RDH, BS, MS JoAnn R. Gurenlian, RDH, PhD Terri Tilliss, RDH, BS, MS, MA, PhD [email protected] Linda L. Hanlon, RDH, BS, MEd, PhD Nita Wallace, RDH, PhD Kitty Harkleroad, RDH, MS Karen B. Williams, RDH, PhD Harold A. Henson, RDH, MEd Charlotte J. Wyche, RDH, MS STAFF EDITOR Laura Jansen Howerton, RDH, MS Pamela Zarkowski, BSDH, MPH, JD Katie Barge Lisa F. Harper Mallonee,BSDH,MPH,RD/LD [email protected]

LAYOUT/DESIGN Jean Majeski ■ SUBSCRIPTIONS Paul R. Palmer The Journal of Dental Hygiene is published quarterly, online-only, by the American Dental Hygienists’ Association, 444 N. Michigan Avenue, Chicago, IL 60611. Copy- right 2007 by the American Dental Hygienists’ Association. Reproduction in whole or part without written permission is prohibited. Subscription rates for nonmembers are one year, $45; two years, $65; three years, $90; prepaid.

■ SUBMISSIONS

Please submit manuscripts for possible publication in the Journal of Dental Hygiene to Katie Barge at [email protected].

2 The Journal of Dental Hygiene Special supplement From the Editor-in-Chief of the Journal of Dental Hygiene

e are very excited to be based on evidence. This timely liter- contributed to the body of knowledge able to provide this CE ature review by 2 internationally rec- for our profession in numerous ways. W supplement to the Jour- ognized authors will provide an In addition, this supplement would nal of Dental Hygiene for our mem- overview of drugs and herbs that alter not be possible without the generous bers. The use of “natural” products bleeding and will suggest ways that support from Philips Sonicare. and supplements by the general pub- oral health care providers can assure lic is growing at an astounding rate. proper care and management of their Rebecca S. Wilder, RDH, MS Current estimates are that over 15 patients’ oral and overall health. The Editor-in-Chief, Journal of Dental Hygiene million Americans use various vita- publication will educate dental [email protected] mins and herbs in addition to their hygienists as they respond to patient prescription medications. Since these questions and plan treatment strate- P.S. This is the first print edition of supplements can be purchased over gies to improve patient care. the Journal of Dental Hygiene you the counter (OTC), many patients do I want to extend huge gratitude to have seen since 2004. If you like not consider them to be medications, Ann Eshenaur Spolarich, RDH, PhD, seeing the Journal of Dental Hygiene and therefore do not report them dur- and Leslie Andrews, RDH, MBA, for in print, please contact us at ing the medical history process. All their time in writing this supplement communications @adha.net and let oral health care providers need to be and for their extensive knowledge of us know that you enjoyed reading aware of the potential benefits and a subject that is difficult to decipher. this special print issue of the Journal disadvantages of these supplements Both of these authors have been ded- as a supplement to Access! in order to provide a level of care icated members of ADHA and have

about the authors

■ ANN ESHENAUR SPOLARICH, RDH, PHD, is a physiologist, practitioner, author, and consultant. She teaches pharmacology at the Arizona School of Dentistry and Oral Health and at the USC School of Dentistry.

■ LESLIE ANDREWS, RDH, MBA, is a former professional educator for Philips Oral Healthcare and is currently immediate past president of the Connecticut Dental Hygienists’ Association. She is a speaker and author on alternative medicine.

Special supplement The Journal of Dental Hygiene 3 Supplement

An Examination of the Bleeding Complications Associated with Herbal Supplements, Antiplatelet and Anticoagulant Medications

Ann Eshenaur Spolarich, RDH, PhD, and Leslie Andrews, RDH, MBA

Introduction Abstract Cardiovascular disease, including Dental professionals routinely treat patients taking prescription, nonpre- ischemic coronary heart disease, scription, and herbal medications that are known or have the potential to stroke, and peripheral vascular dis- alter bleeding. Prescription anticoagulant and antiplatelet medications, as ease, is the leading cause of death in well as over-the-counter drugs such as aspirin, are typically taken to reduce the United States.1 Stroke is the third the risk of thromboembolic events, including stroke. Herbal supplements leading cause of death, and is the pri- are widely used for a variety of indications, and both patients and health care practitioners are often unaware of the anticoagulant and antiplatelet mary cause of adult disability.2 Yearly, effects that occur as either predictable pharmacologic effects or adverse over 1 million Americans experience side effects of herbal medicines. In addition, patient use of these herbal new or recurrent myocardial infarc- supplements is usually undisclosed to health care providers. The purpose tion (MI) or fatal coronary heart dis- of this literature review is to examine the mechanisms of action of drugs ease. Most of these events occur in and herbs that alter bleeding, and to educate dental professionals as to the the elderly or in those with known risk proper care and management of patients using these medications. Deci- factors for cardiovascular disease.3 sion-making strategies, including interpretation of laboratory tests, and The age-adjusted mortality rate due when to discontinue the use of these medications are discussed. Patients to coronary heart disease, cerebrovas- undergoing routine dental and dental hygiene procedures do not need to cular disease and atherosclerotic dis- discontinue the use of anticoagulant and antiplatelet medications. However, ease is 194 per 100 000 cases, which alterations in drug use may be required for those patients undergoing inva- translates to more than 500 000 deaths sive surgical procedures. It is recommended that herbal supplements must 1 be discontinued 2 weeks prior to receiving invasive surgical procedures. per year. These leading causes of Dental practitioners must learn to weigh the risks of discontinuing drug ther- death correspond directly to chronic apy against the potential risks to patients, and implement risk reduction conditions experienced by many strategies to minimize adverse bleeding complications associated with patients, especially the elderly, who dental treatment. may live for decades with illnesses Keywords: Anticoagulants, Antiplatelet medications, Aspirin, Bleeding, that are typically controlled with med- 2,4 Clotting, Dental treatment, Garlic, Ginger, Ginkgo biloba, Ginseng, Herbal ication use. supplements, NSAIDS, Platelets, St. John’s wort, Warfarin Given these disease trends, dental professionals are seeing more patients taking anticoagulant and/or antiplatelet medications to prevent arte- an extremely rare event, even among tions against the potential risks asso- rial or venous thrombosis and stroke.5 patients at risk.6,7 ciated with altering the medications Controversy and confusion persist as Determining the proper manage- used to reduce significant cardiovas- to whether these medications actually ment strategy to safely treat patients cular risk.6 According to Little and pose a risk for significant postopera- taking anticoagulant and antiplatelet associates (2002), risk of “thrombo- tive bleeding following invasive den- medications must take into account sis is of greater overall clinical impor- tal procedures. However, excessive or the risk of thrombus formation in the tance in terms of morbidity and mor- life-threatening bleeding caused by patient. The clinician must weigh the tality than all of the hemorrhagic medication use in the dental office is risks of potential bleeding complica- disorders combined.”5

4 The Journal of Dental Hygiene Special supplement The decision to alter the patient’s Understanding medication use supplements are available OTC, many medication regimen, by either lower- helps dental professionals anticipate patients do not include these products ing the dosage of or discontinuing the and prevent oral and systemic com- when listing medications on health his- medication prior to dental treatment, plications associated with adverse tory forms. For example, over 51% of is not supported by clinical studies in drug events.14 Drug-induced adverse patients scheduled to undergo surgical the literature.6,8,9 Yet, many dental cli- bleeding events can happen outside of procedures in a Colorado hospital were nicians continue to recommend med- the dental office, as well as during taking herbal medications, some of ication alteration as a management treatment. Assessing potential bleed- which may alter blood coagulation.18 strategy, with the belief that they are ing complications associated with Further, in a preanesthesia interview at promoting patient safety. Proposed medication and supplement use is a a university medical center, nearly 70% regimens are based on case reports, vital service that dental professionals of patients taking herbal medications opinions published in the literature, provide to their patients.14 Most dental did not report their usage.19 and habit, and are not supported by patients taking prescription medica- Several herbs contain substances clinical data.6,9 tions are aware of the bleeding risks that have coumarin, salicylate, or The justification for reducing or associated with their drugs, and in antiplatelet properties, such as garlic, withdrawing anticoagulant medica- fact, are monitored routinely to detect gingko, and ginseng.20 Although no tion prior to dental treatment can be alterations in coagulation before com- definitive studies have been per- dated back to a time when less than a plications arise. However, these same formed to show a direct cause and dozen case reports in the literature reported excessive bleeding following dental treatment in patients taking warfarin. However, it is important to note that during the timeframe when The decision to alter the patient’s those case studies were published, the medication regimen, by either lowering the prothrombin time test (PTT) was used to evaluate the effectiveness of dosage of or discontinuing the medication warfarin; but, testing was not yet prior to dental treatment, is not supported by standardized, and variations in clinical efficacy were bound to occur.6,10,11 clinical studies in the literature. Yet, many Today, standardized measures, such dental clinicians continue to recommend as the International Normalized Ratio (INR), are used to assess coagulation medication alteration as a management time in patients taking warfarin, and strategy, with the belief that they are guidelines for therapeutic ranges of anticoagulation have been estab- promoting patient safety. lished.12 These guidelines make it eas- ier for the clinician to predict the risks for bleeding in medicated dental patients. A variety of other medications can patients may not fully understand how effect of herbal use and bleeding com- contribute to bleeding complications their lifestyle, including diet, alcohol plications, the literature suggests that in dental patients, including nons- use, and the use of OTC medications, this is a phenomenon of increasing teroidal anti-inflammatory analgesics, can alter the bleeding effects of their concern due to the extreme popularity hormones, herbs, and dietary supple- prescription medications. and increasing use of these products. ments. It is critical that dental profes- In addition, dental professionals During January 2005, the National sionals conduct a pharmacologic his- must remember to ask their patients Institutes of Health (NIH) conducted a tory review as a component of a about the use of herbs, vitamins, and joint conference with the National comprehensive review of systems for dietary supplements when assessing Heart, Lung and Blood Institute all patients who present for oral health medication use. Surveys estimate (NHLBI), the Office of Dietary Sup- care. Assessing the patient’s prescrip- dietary supplement usage by 12% to plements (ODS), the NIH Clinical tion and over-the-counter (OTC) med- 24% of the general population.15 In Center (CC), the National Center of ication use provides important infor- addition, usage doubled for individuals Complementary and Alternative Med- mation about the patient’s current aged 65 years and older from 1999 to icine (NCCAM), the National Institute medical status, disease severity, com- 2002.16 Recent estimates suggest that of Neurological Disorders (NINDS), pliance with drug and treatment recover 15 million Americans take herbs, the NIH Foundation, and the Office of ommendations, and orientation to vitamins, or both, along with their pre- Rare Diseases (ORD) at the NIH that health and wellness.13 scription medications.17 Since these specifically addressed this issue as a

Special supplement The Journal of Dental Hygiene 5 public health concern. The conference only focus on garlic, gingko, ginseng, households, and found that 31% goal was to “increase our understand- ginger, and St John’s wort for several reported using 7 or more supple- ing of the potential for dietary supple- reasons. First, as indicated above, ments.25 These statistics may not ments to interfere with hemostasis and these herbs consistently rank high in reflect, and in fact may underesti- antithrombotic therapies.”15 sales, indicating predominant usage. mate, the growing use of combina- According to the Natural Medicines Second, the amount and quality of sci- tion products, or supplements that Comprehensive Database, approxi- entific evidence is more prevalent on contain multiple herbs as well as mately 180 dietary supplements have these botanicals as compared to other vitamins. Given these trends, it is the potential to interact with warfarin, herbs. highly likely that an individual is and more than 120 may interact with Health care professionals have an unknowingly taking several herbs aspirin, clopidogrel (Plavix®), or increasing responsibility to under- that have either anticoagulant or dipyridamole (Aggrenox®). The 2005 stand the rationale for use of these antiplatelet activity. Therefore, use NIH conference specifically identified herbal medications and their reported of dietary supplements has the poten- the following supplements as having effects on the body, given the large tial to a) cause a bleeding condition, this interaction potential: percentage of patients who take them. b) exacerbate an existing bleeding Unfortunately, it is challenging to condition, or c) alter the effective- • Anise locate accurate, consistent, and com- ness of other OTC and prescription • Dong Quai prehensive information pertaining to medications being taken concur- • Omega-3 fatty acids in fish oil herbal medications and their supposed rently. Obviously, the resulting com- • Ajoene in Garlic mechanisms of action. While the plications may be potentially serious. • Ginger knowledge base pertaining to herbs The purpose of this article is to • Ginkgo and other dietary supplements contin- assist dental professionals with under- • Vitamin E ues to grow, there are few studies that standing the mechanisms of action of • Fucus have determined conclusively how popular prescription and herbal med- • Danshen these products alter bleeding or inter- ications that alter bleeding. Drug and • St. John’s Wort act with other herbals and prescrip- herbal interactions will also be dis- • American Ginseng tion anti-thrombotic medications.23 cussed. Finally, practice management In addition, the following herbs Speculation and case reports from the considerations for medicated patients may affect blood clotting, which is literature have provided clues as to and strategies for risk reduction will dependent on vitamin K: the purported mechanisms of action; be presented to increase the dental however, relatively few clinical trials professional’s confidence in making • High dose vitamin E (specific have been conducted to formally treatment decisions for patients tak- dosage not indicated), a vitamin examine these issues. Further, case ing these medications. K antagonist reports in the literature sometimes fail • Alfalfa –high vitamin K content to take into account other herbals or • Coenzyme Q10 – dependent on drugs that the patient may have been vitamin K Blood Clotting taking. Therefore, it is difficult to Several of these listed herbs are credit the results of a case study to There are over 50 substances in the consistently among the top sellers. one definitive herbal action. blood that affect blood coagulation by Data from the Centers for Disease Clinicians encounter this same acting as either procoagulants or anti- Control and Prevention (CDC) in phenomenon with their own patients. coagulants. Normally, the anticoagu- 2002 included ginseng, ginkgo biloba, When asked, a patient may know a lant substances predominate, keeping and garlic as the dietary supplements product’s brand name, but cannot blood clots from forming. However, with the 2nd, 3rd, and 4th highest identify the multiple herbs that are when a blood vessel is ruptured, pro- sales, respectively. St John’s wort was contained within that same product. coagulant substances in the area of the 6th and ginger was 9th.21 The popu- Further, it is not unusual for a patient damaged vessel become activated and larity of herbs with anti-coagulation to take upwards of 7 individual override the effects of the anticoagu- potential was further validated by dietary supplements at the same time, lant substances, allowing a blood clot HerbalGram’s report of dietary sup- but often on an inconsistent basis. to form.26 plement sales in mainstream retail When the CDC last reported on When clotting poses risk to a stores in 2004. Garlic was the top dietary supplement usage (1988-94), patient, anticoagulant or antiplatelet seller with ginkgo at 4th, ginseng at 14.4% of respondents reported usage drug therapy is used to reduce the risk 7th, St John’s wort at 9th, and ginger of 3 or more supplements.24 The high- for thromboembolism. A thrombus is at 20th.22 Clearly, the popularity of est segment of users (22%) was an abnormal clot that forms in a blood these herbs has not waned. among those aged 40 years and older. vessel. When the velocity of the blood Of the 11 herbs highlighted during More recently, the Hartman Group, flowing past the clot breaks the clot the NIH conference, this article will a research firm, surveyed 43 000 U.S. free from its attachment to the vessel

6 The Journal of Dental Hygiene Special supplement wall, the free floating clot is referred to centrations to prevent intravascular When administered by intravenous as an embolus. Clots that originate on clotting.26 infusion or as a deep subcutaneous the left side of the heart on the arterial Heparin itself is not an anticoagu- injection, onset of action occurs any- side of the circulation clog arteries and lant; however, by binding to anti- where from 20 minutes to 30 min- arterioles that feed organs, resulting in thrombin III, it serves as a catalyst to utes.27,29 Response to heparin is varied ischemia and permanent damage to the enhance the inactivation of multiple and unpredictable; therefore, patients organ tissue. Clots that originate on the coagulation factors, including throm- receiving heparin are monitored with venous side of the circulation or on the bin. Heparin also prevents the con- an aPTT (activated partial thrombo- right side of the heart flow through the version of fibrinogen to fibrin, thus plastin time) test.5,27 pulmonary arteries to the lungs, result- inhibiting clot formation.5,26 Unfrac- Most patients receiving heparin will ing in pulmonary embolism (PE). Risk tionated heparin (Hep-Lock®, heparin be treated in the hospital setting, and for PE is high for patients who are sodium, heparin calcium) has been invasive dental procedures should be immobile or bedridden, as intravenous used in medicine since the 1920s, and avoided during active treatment. Den- clotting forms in the legs due to blood is used primarily in hospitalized tal emergencies in these hospitalized pooling in the lower extremities. This patients to treat thromboembolism and patients must be treated carefully and condition is known as deep vein throm- PE.27 High-dose therapy is used for conservatively.5 The most common bosis (DVT), a problem that can also DVT and PE, while low-dose therapy dental patients taking heparin seen out- occur in those traveling for long peri- is used preventively.5 side of the hospital setting are those ods of time sitting in a motor vehicle or Both warfarin (Coumadin®) and who are undergoing hemodialysis, airplane. heparin therapy are started on the first who receive heparin on an outpatient Dental hygienists should be aware day of treatment, and the overlap basis. As heparin has a half-life of 1 that circulating bacteria and bacterial allows for the 4 days to 5 days needed hour to 2 hours, its effects last for only endotoxins can also activate clotting for warfarin to take effect (see page a few hours after dialysis has been mechanisms, producing small but xx). Heparin inactivates existing coag- completed. It is safe for these patients numerous clots that plug blood ves- ulation factors relatively quickly, to receive invasive dental procedures sels in the periphery, depriving many while warfarin therapy blocks the syn- on the day following dialysis.5 tissues of oxygen and other essential nutrients.26 This is why patients who develop bacterial endocarditis are treated with anticoagulants as well as antibiotics: the antibiotics kill the There are over 50 substances in the blood causative bacteria, while the antico- that affect blood coagulation by acting as agulants help to prevent clotting and ischemia initiated by bacterial endo- either procoagulants or anticoagulants. toxins.

Parenteral thesis of new clotting factors by the Heparin may induce thrombocy- Anticoagulants liver. In older adults undergoing gen- topenia in up to 30% of users; how- eral surgery, prophylaxis with low- ever, for most affected patients, this Heparin dose unfractionated heparin (LDUH) adverse event is not clinically signif- or an intermittent pneumatic com- icant. However, heparin may induce Heparin is an endogenous sub- pression device, such as compression an immunologically-mediated throm- stance produced by many cells in the elastic stockings, is recommended to bocytopenia in 1% to 2 % of users that body, but is primarily made by mast prevent DVT and venous throm- causes a marked decrease in platelet cells found in the connective tissue boembolism (VTE).28 Heparin is also count, leading to thromboembolic surrounding capillaries in the body. used to prevent clot formation in complications, such as PE, skin necro- These mast cells continuously pro- catheters, shunts, pumps, and infusion sis, and gangrene.29 Daily platelet duce small quantities of heparin that machines (eg. dialysis machines).6 counts for the first week following the diffuses into the circulation. Standard heparin is comprised of initiation of drug therapy can help to Basophils in the blood also release an unfractionated heterogeneous mix- detect this condition. heparin into the plasma. The concen- ture of polysaccharide chains with Hemorrhage, including gingival tration of heparin in the blood is nor- mean molecular weights ranging from hemorrhage, is another risk associated mally very low, and only produces 12 000 to 16 000 daltons. Heparin is with heparin. This risk is increased by significant anticoagulant effects administered parenterally, usually by the use of other anticoagulant med- under specific circumstances. It is intravenous injection, which results in ications, thrombolytic agents and used medically in much higher con- an immediate anticoagulant effect.5,27,29 drugs that alter platelet function (see

Special supplement The Journal of Dental Hygiene 7 below). It is important to note that For patients undergoing orthopedic Antithrombotic Agents heparin is often used in conjunction surgery to the lower extremities, the with thrombolytics and during the ini- optimal duration of prophylaxis is There are 3 FDA approved tiation of warfarin therapy to assure unknown.28 Risk for DVT following antithrombotics that are used for the adequate anticoagulation. Certain surgery is related to the length of time prevention of postoperative deep vein cephalosporins and parenterally that the patient remains immobile and thrombosis (DVT), and for the treat- administered penicillins may also other risk factors; risk persists for up ment of heparin-induced thrombocy- increase risk for hemorrhage in to 2 months following total hip topenia and related thromboembolic heparinized patients.29 replacement surgery.28,34,35,36,37 Six ran- complications. These drugs are arga- domized double-blind controlled clin- troban (no brand name), danaparoid Low Molecular Weight Heparins ical trials demonstrated reduced risk (Orgaran®), and lepirudin (Refludan®). of total and proximal DVT by at least Argatroban is indicated for the pre- Low molecular weight heparins 50% for patients with total hip vention and treatment of thromboem- (LMWHs) are the preferred method replacement who received prophy- bolic complications in patients with for prophylaxis for elective hip laxis with either LDUH or LMWH for heparin-induced thrombocytopenia. replacement surgery, started preoper- 5 weeks beyond the hospital stay.30 This drug is a highly selective throm- atively or immediately after surgery, LMWHs can be provided on an bin inhibitor and binds reversibly to as these drugs have been found to be outpatient basis, and patients taking the active thrombin site of free and very effective in preventing asympto- these drugs have lower risks for hem- clot-associated thrombin. Drug admin- matic VTE.30 For elective knee orrhage and heparin-induced throm- istration is by IV, which produces an replacement or hip fracture surgery, bocytopenia, as compared to patients immediate onset of action. The drug LMWH or adjusted-dose warfarin taking heparin. Risks for bleeding inhibits fibrin formation, the activation may be used.28 Routine prophylaxis increase when the LMWHs are used of numerous clotting factors, and for VTE with LDUH or LMWH is with thrombolytic agents, oral antico- platelet aggregation.27,29 recommended for patients with agulants, and drugs that alter platelet Danaparoid (Orgaran®) is indicated ischemic stroke and impaired mobil- function, although they are frequently for the postoperative prevention of ity. These agents are also recom- used during initial therapy with oral DVT following elective hip replace- mended for patients with other risk anticoagulants to ensure proper anti- ment surgery. This drug prevents fibrin factors for VTE including immobil- coagulation. There are 3 FDA formation by inhibiting activated factor ity, cancer, heart failure, and severe approved LMWHs in the United X by antithrombin. It is administered lung disease.28 States: dalteparin (Fragmin®), enoxa- subcutaneously, with maximum effect LMWHs act in a similar manner to parin (Lovenox®), and tinzaparin occurring within 2 hours to 5 hours.27,29 standard heparin, by inhibiting acti- (Innohep• ).27,29 Enoxaparin is the most Lepirudin (Refludan®) is indicated vated factor X and thrombin; however, widely used LMWH, and has been for anticoagulation in patients with they produce a lesser effect on the shown to prevent ischemic complica- heparin-induced thrombocytopenia inhibition of thrombin.31,32,33 LMWHs tions associated with unstable angina and related thromboembolic compli- are formed by depolymerization of and non-Q wave myocardial infarc- cations, and has investigational use unfractionated heparin side chains, tion (MI).5,29,38 for the prevention of ischemic com- producing “smaller” heparin frag- Patients on LMWHs who present to plications associated with unstable ments, with mean molecular weights the dental office can usually receive angina. This drug is a highly specific ranging from 1000 daltons to 10 000 invasive dental treatment without any inhibitor of thrombin, and is adminis- daltons.27 modifications necessary to their med- tered by IV. All antithrombotic agents LMWHs are administered subcuta- ication regimen. Should excessive have a risk for hemorrhage, which is neously, and exhibit a better bio- bleeding be anticipated, as with oral or increased with concurrent use of oral availability than standard heparin, as periodontal surgery, a physician con- anticoagulants and drugs that alter they are less bound to plasma proteins, sultation is warranted to determine platelet function.27,29 endothelial cells and macrophages. whether the medication should be tem- They also have a longer half-life (2 porarily discontinued prior to per- Factor Xa Inhibitor hours to 4 hours) than heparin, and forming the dental procedure. Given dosage is based upon body weight. the short half-life of these drugs, high There is 1 antithrombotic agent in Because LMWHs produce a more pre- dose LMWH can be stopped for one this new class of medications called dictable anticoagulant response, labo- day on the day before the surgery; then, fondaparinux (Arixtra®). This drug is ratory monitoring during treatment is therapy is resumed following hemo- indicated for prevention of deep vein generally not necessary.5,27 Dental pro- stasis on the day of surgery. However, thrombosis (DVT) in patients under- fessionals do not need to order labora- the best option is to wait until LMWH going hip or knee replacement or hip tory testing for patients taking these therapy has been completed before fracture surgery. It may also be used drugs for routine dental care. attempting any elective dental surgery.5 for the treatment of acute pulmonary

8 The Journal of Dental Hygiene Special supplement embolism (PE) or for treatment of tors, resulting in a dangerous period of person’s response to warfarin, and acute DVT without PE. Fondaparinux hypercoagulation for a short period of could be used to determine the proper is a synthetic pentasaccharide that time. The anticoagulant effects of initial dose.40 inhibits activated factor X, which warfarin are not initially evident until inhibits thrombin formation. It is 8 hours to 12 hours after oral admin- administered subcutaneously, once istration, and given its 36 hour half- daily. Risk for hemorrhage is increased life, if may take up to 4-7 days of dos- The major when this drug is taken concurrently ing to reach the desired target complication of with oral anticoagulants, antiplatelet International Normalized Ratio (INR) drugs, non-steroidal anti-inflammatory value.29 For this reason, heparin ther- anticoagulation drugs (NSAIDS), salicylates, and apy (LDUH or LMWH) usually over- therapy is bleeding. thrombolytics.27,29 laps warfarin therapy for at least the first 2 days of oral anticoagulant ther- There is a positive apy to allow for the warfarin to take relationship between Oral Anticoagulants effect and to achieve an optimal therapeutic range of anticoagulation.28,39 the risk for Warfarin Heparin is discontinued after the INR hemorrhage and the has been in the therapeutic range for at Warfarin (Coumadin®, Jantoven™) least 2 measurements taken more than intensity of is an oral anticoagulant used for pre- 24 hours apart. anticoagulation. vention and treatment of VTE, PE, Despite its widespread use, physi- atrial fibrillation with risk of cians often find it difficult to prescribe embolism, and to prevent systemic warfarin, given its narrow therapeu- embolism after MI.29 Warfarin is also tic index. It may take weeks of clini- The major complication of antico- used for anticoagulation therapy in cal testing (via the INR) to find the agulation therapy is bleeding. There is patients with prosthetic heart valves. exact dose that results in the desired a positive relationship between the risk Coumarin derivatives work differently level of anticoagulation. Even small for hemorrhage and the intensity of than the other parenteral anticoagu- variations in dose can result in large anticoagulation.41 Patients on high- lants described above, by inhibiting clinical effects, including excess intensity warfarin therapy (INR>3.0) the synthesis of vitamin K- depend- bleeding (over-anticoagulation) or are at higher risk for hemorrhage as ent clotting factors. inadequate anticoagulation, which compared to warfarin therapy with an Several clotting factors are depend- places the patient at risk for develop- INR that falls between 2.0-3.0. The ent upon vitamin K for their synthesis ing clots. risk for intracranial hemorrhaging rises in the liver. Warfarin binds to the liver Individuals taking warfarin vary in dramatically with an INR>4.0.41,42 The microsomal enzyme vitamin K 2,3- their response to given doses of the major determinants of warfarin- epoxide reductase, and inhibits the drug. It is known that a variation in induced bleeding are the intensity of production of the reduced form of the gene that encodes the CYP2C9 anticoagulation, unique patient char- vitamin K. Reduced vitamin K is a liver enzyme that metabolizes war- acteristics, concurrent use of drugs that necessary cofactor in the gamma car- farin accounts for about 10% of the interfere with hemostasis (eg, aspirin), boxylation of the 4 vitamin K-depend- difference in response to the drug poorly controlled hypertension, and ent clotting factors: factors II, VII, IX, observed in warfarin users. Recently, the duration of drug therapy.41 Multiple X. Precursors to these 4 clotting fac- investigators have identified another large, randomized controlled clinical tors undergo vitamin K-dependent genetic variation in the VKORC1 trials support the use of combination modification to produce their active gene (vitamin K epoxide reductase), therapy with aspirin plus warfarin forms. By inhibiting the formation of which makes a protein that helps con- (INR 2.0-2.5) in high- risk patients reduced vitamin K, coumarins prevent trol clotting and is the target site of with atherosclerotic heart disease. the activation of these clotting factors. action of warfarin. By matching the Combination therapy increases the risk Thus, the clotting factors remain as genetic variations to the actual dose of both minor and major bleeding, but inactive molecules that cannot partic- taken by study subjects, the not intracranial bleeding in athero- ipate in the clotting process, thereby researchers found that individuals sclerotic patients. The most common stopping the formation of thrombin with particular variations in the bleeding complications include epis- and fibrin. VKORC1 gene generally took similar taxis (nosebleed), purpura (skin hem- Warfarin also depresses proteins C doses of warfarin. Study results sug- orrhages), gastrointestinal (GI) bleed- and S, which are endogenous antico- gested that variation in this one gene ing, hemoptysis (expectorating blood), agulants. Levels of these 2 proteins accounted for 25% of the overall vari- and hematuria (blood in urine).42,43,44 may be depressed by warfarin prior ance in warfarin dose. In the future, Unexpected elevations in the INR to depression of the other clotting fac- genetic testing could help to predict a increase concerns for adverse bleed-

Special supplement The Journal of Dental Hygiene 9 ing events. Frequent monitoring of informing their physicians may be anticoagulant effect of warfarin therapy, including the INR, is espe- inadvertently increasing their warfarin include antibiotics (cephalosporins, cially important in older adults, and requirements; sudden decreases in macrolides, metronidazole, quino- adjustments to the treatment regimen vitamin K intake then increases the lones, penicillins, tetracyclines), anal- are often necessary.45 When the INR risk for hemorrhagic events. gesics (acetaminophen, NSAIDS), is elevated, but no bleeding is present, Other factors that contribute to prednisone, and the systemic azole warfarin therapy can be reduced or alterations in anticoagulation effects antifungals (fluconazole, ketocona- stopped, which lowers the INR within include illness, fever, thyroid disease, zole, itraconazole).29,55,59 Single-dose 24 hours to 48 hours without return- biliary disease, liver disease, malab- antibiotic prophylaxis for the preven- ing it to baseline levels. In patients sorption syndromes, congestive heart tion of endocarditis and prosthetic with non-life-threatening bleeding, a failure, malignancy, and diarrhea.6,55 joint infection is not likely to alter the small dose of vitamin K1 (1-2.5 mg) Warfarin is also highly affected by effect of warfarin, although 3 case is administered orally or subcuta- medication use. In fact, more food reports have been reported in the lit- neously (SC). If urgent correction of and drug interactions have been erature describing elevations in INR the INR is needed, a larger dose of reported for warfarin than with any following prophylactic antibiotic vitamin K1 (2-4 mg) is given initially, other prescription medication.57Alco- use.60,61 Salicylates and NSAIDS with additional 1-2 mg doses given hol consumption has also been should be avoided in warfarin users, as needed. When the INR >9.0 and/or reported to increase bleeding in war- given their antiplatelet activity.60 All bleeding is life-threatening, warfarin farin users.55,58 dental professionals are encouraged therapy is stopped and large doses of Dental professionals should be to consult a drug reference guide prior vitamin K1 (3-5 mg orally; 5-10 mg aware that many commonly pre- to prescribing any medication to a SC) are given. Fresh frozen plasma scribed drugs used during dental treat- patient taking warfarin to ensure drug may also be given to replace the vita- ment have the potential to alter the compatibility and safety. Foods and min K-dependent clotting factors. Vit- effects of warfarin. The dental drugs herbs that alter warfarin activity are amin K1 may also be given by IV in that have been reported to enhance the summarized in Table I. life-threatening situations, but it must be administered slowly and carefully monitored, given the risk for anaphy- Table I. Foods and herbs that alter warfarin activity. laxis.46,47,48,49,50,51,52 Multiple factors can contribute to Alcohol Acute binge drinking increases PT/INR alterations in the INR. Poor compliance with warfarin therapy is the most Chronic daily drinking decreases PT/INR common reason for fluctuations in Foods rich in vitamin K Decreases effect of warfarin anticoagulation therapy.53 Switching Vitamin C Increases effect of warfarin between different brand names of Cranberry juice Increases effect of warfarin warfarin product formulations has been shown to contribute to major St. John’s wort Decreases serum levels of warfarin medical complications, and patients Alfalfa Decreases effect of warfarin due to large are advised not to switch brands once amount of vitamin K the desired therapeutic effect has been Coenzyme Q10 Decreases response to warfarin 29,54 achieved. Alterations in vitamin K Bromelain Avoid concurrent use: antiplatelet action intake, interference with intestinal Cat’s claw Avoid concurrent use: antiplatelet action bacterial synthesis of vitamin K, and impaired vitamin K absorption all Dong quai Avoid concurrent use: antiplatelet action cause significant fluctuations in Evening primrose Avoid concurrent use: antiplatelet action 55 response to warfarin. Many common Feverfew Avoid concurrent use: antiplatelet action foods, especially dark green leafy veg- Garlic Avoid concurrent use: antiplatelet action etables and 4 plant oils (soybean, canola, cottonseed, and olive) serve Green tea Avoid concurrent use: antiplatelet action as primary dietary sources for vitamin Ginseng Avoid concurrent use: antiplatelet action 56 K. Patients should maintain consis- Ginkgo Avoid concurrent use: antiplatelet action tency in their diet and meet the rec- Horse chestnut Avoid concurrent use: antiplatelet action ommended dietary allowance for vitamin K of 65 to 80 micrograms of Red clover Avoid concurrent use: antiplatelet action 56 phylloquinone per day. Patients who Source: Wynn RL, Meiller TF, Crossley HL. Drug Information Handbook for Dentistry. 10th ed., increase their intake of “heart- Hudson:Lexi-Comp, Inc. 2005. 29 healthy” green vegetables without

10 The Journal of Dental Hygiene Special supplement Oral Antiplatelet Agents Cell membrane phospholipids Aspirin ↓ Arachidonic Acid Aspirin was first used as an anal- ↓ gesic and antipyretic drug in 1899, and has quickly become the most Cyclooxygenase widely used drug in the history of ↓ 62 medicine. During the 1960s, the Prostaglandin G2 antiplatelet properties of aspirin were ↓ discovered.62 Since then, aspirin has become the most comprehensively Prostaglandin H2 studied and least expensive of all ______↓↓↓ antiplatelet medications.5 Aspirin Prostacyclin Prostaglandins Thromboxane A2 blocks the synthesis of thromboxane vasodilation, PGD2, PGE2, PGF2α vasoconstriction, A2 from arachidonic acid in platelets inhibits platelet aggregation vasodilation, edema promotes platelet aggregation by inhibiting the enzyme cyclooxygenase 1 (Figure 1). Thromboxane A2 Figure 1. The arachidonic acid cascade. is necessary for platelet aggregation and promotes blood clotting. The inhibitory effect of aspirin on the for- in this highest risk category exceeds inhibitory effect on prostaglandin syn- mation of this substance is irreversible the number of people who are already thesis, which stops the production of and lasts for the life of the platelet, taking the drug.62 Safety concerns, protective prostaglandins that coat the which is 7 days to 10 days. In fact, a including risks for hemorrhage and walls of the stomach that normally single dose of aspirin impairs platelet gastrointestinal (GI) ulceration and form a barrier between the hydrochlo- aggregation for up to 4 days, until new bleeding, are thought to limit the rec- ric acid and the gastric mucosa. Fur- platelets enter the circulation in suffi- ommendations of this drug by physi- ther, aspirin inhibits the synthesis of cient numbers to exert a thrombotic cians to their patients.62 However, many prostaglandins that protect the kidney. effect.63 patients choose to self-medicate with Notably, chronic aspirin use can lead Aspirin reduces mild to moderate aspirin, and may be unaware of its to kidney damage and renal failure. pain, inflammation, and fever.29 potential adverse effects. Hemorrhagic stroke is also a risk asso- Aspirin is also used for the primary In addition to data that supports the ciated with long-term aspirin use. A prevention of MI in patients at benefits of aspirin in patients with car- meta-analysis of 16 clinical trials increased risk, and for the secondary diovascular disease, data from 55 000 demonstrated an increased absolute prevention of ischemic cardiovascular individuals supports aspirin use for risk of 12 hemorrhagic stroke events events, such as stroke.62 Further, the prevention of first MI in healthy per 10 000 aspirin users.70 Although aspirin is used as an adjunctive ther- individuals, with an overall risk reduc- aspirin increases risk for adverse apy during revascularization proce- tion of 32%.66 Both the American bleeding events, the cardioprotective dures (eg, coronary bypass).29 Aspirin Heart Association (AHA) and the U.S. benefits of the drug outweigh these should be available in the dental office Preventive Services Task Force (USP- risks when used appropriately in at- as a pre-hospitalization drug for use in STF) have published guidelines for risk patient populations.62 patients experiencing MI. It is thought the use of aspirin for the primary pre- Many adverse events caused by that the fibrinolytic properties of vention of MI.3,67,68 aspirin are dose-related and are aspirin, given at an 81-325 mg dose, A meta-analysis of all available ran- extremely rare with low-dose therapy may help to reperfuse the ischemic domized, placebo-controlled clinical (81 mg per day). Bleeding risk myocardium.64 trials evaluating the effects of low-dose increases with concurrent use of other Despite the cardioprotective bene- aspirin therapy for secondary preven- medications that alter hemostasis, fits of this drug, aspirin is still under- tion revealed that aspirin reduces the including NSAIDS, warfarin, and alco- used by many at-risk populations.65 It is risk of death by approximately 20%. hol. Drinking more than 3 alcoholic important to note that although aspirin Further, aspirin also reduces the rela- beverages per day significantly is not approved for primary prevention tive risk for cardiovascular events (eg, increases risk for GI hemorrhage. of ischemic events, it may be possible MI) and cerebrovascular events Aspirin use should be discontinued if for people who are at an even higher (stroke) by 20% to 30%.69 patients develop tinnitus or hearing risk than those who have already expe- The most common adverse event loss. Caution should be used when rienced an adverse cardiovascular associated with aspirin use is GI ulcer- using aspirin in patients with bleeding event to benefit from the effects of ation and hemorrhage. These GI com- or platelet disorders, peptic ulcer dis- aspirin. The potential number of people plications are attributed to aspirin’s ease, and liver or kidney dysfunction.

Special supplement The Journal of Dental Hygiene 11 account the risks to the patient. If the decision is to discontinue aspirin, the A meta-analysis of all available patient should stop taking aspirin 10 days to 14 days prior to surgery to randomized, placebo-controlled clinical trials allow for the synthesis of new evaluating the effects of low-dose aspirin platelets.

therapy for secondary prevention revealed Dipyridamole that aspirin reduces the risk of death by Dipyridamole (Persantine®) stimu- approximately 20%. lates the release of prostacyclin or prostaglandin D2 (PGD2), inhibiting platelet aggregation and producing coronary vasodilation. The drug is primarily used to prevent angina pectoris, Other serious reactions include may be dose related; resistance is and to maintain the opening of the hypersensitivity reactions and idio- found more often during low-dose coronary arteries following bypass sur- syncratic reactions. therapy (< 100 mg daily) than at gery. This drug is often used in com- Patients who are sensitive to tar- higher doses (> 300 mg daily). Platelet bination with aspirin to prevent coro- trazine dyes, or who have nasal polyps aggregation studies of these individu- nary artery thrombosis, or with or asthma are more likely to be sensi- als reveal no biochemical activity of warfarin, to decrease the risk of throm- tive to aspirin. In patients with aspirin. Urinary concentrations of a bosis in patients with mechanical heart bronchial asthma, aspirin and other thromboxane metabolite (11-dehy- valves. It may also be used prophy- NSAIDS may precipitate a condition drothromboxane B2), a marker for lactically to prevent myocardial rein- known as aspirin-induced asthma aspirin resistance, may be used to farction.27,29 The drug is administered (AIA), a syndrome characterized by identify potential aspirin-resistant indi- orally and intravenously. aggressive and continuous inflamma- viduals. Patients who are aspirin resist- tory disease of the airways. AIA pro- ant should continue to take aspirin for Aspirin with dipyridamole gresses from the upper to lower respi- its anti-inflammatory effects, but may ratory tract and affects women more require additional antiplatelet thera- Combination aspirin with extended- than men, with an average age of onset pies for risk reduction.72,73 release dipyridamole is an antiplatelet at 30 years. Rhinorrhea and nasal con- Aspirin has many drug interactions, drug known as Aggrenox®. Aggrenox® gestion are the first symptoms, with and dental professionals should con- is used to reduce the risk of stroke in asthma and aspirin hypersensitivity sult a drug reference text prior to pre- patients who have had either transient developing 2 years to 15 years later. scribing any medications to patients brain ischemia or an ischemic stroke Once developed, aspirin intolerance taking this drug. For example, con- due to thrombosis. The drug contains remains throughout life.71 Further, current use of aspirin with NSAIDS 25 mg of aspirin and 200 mg of dipyri- patients who are allergic to NSAIDS may decrease the serum concentration damole. The aspirin inhibits platelet may not take aspirin or aspirin-con- of some NSAIDS.29 Dental profes- aggregation by inhibiting platelet taining products.29 sionals must remember that the effects cyclooxygenase and the generation of There is increasing concern about of this drug are irreversible; therefore, thromboxane A2. Dipyridamole stim- the number of individuals who exhibit additional bleeding will be evident ulates the release of prostacyclin, the aspirin resistance, also known as hypo- during any invasive procedure. There antagonist of thromboxane A2. The responsiveness, to the effects of is no evidence to support the discon- antithrombotic effects of this drug are aspirin. These individuals experience tinuation of low-dose aspirin therapy irreversible, given the aspirin compo- first MI or suffer a second adverse prior to dental procedures or dental nent of the drug.27,29 event while taking aspirin. For some surgery, as the risk for an adverse car- reason, aspirin therapy is not enough diovascular event outweighs the risk Clopidogrel to stop thrombotic activity. Three pos- for intraoperative and postoperative sible explanations have been offered bleeding in dental patients.8,29 Such Clopidogrel (Plavix®) inhibits to explain aspirin resistance: platelets bleeding can be managed locally with platelet aggregation by a different become activated by pathways not the use of hemostatic agents. However, mechanism than aspirin. This drug blocked by aspirin; patients require a a physician consultation is warranted inhibits the binding of ADP to its higher dose of aspirin to produce an to discuss whether patients who platelet receptors, which prevents the effect; or patients generate thrombox- require major surgery require an alter- binding of fibrogen between platelets, ane A2 despite aspirin therapy.72 Early ation in aspirin therapy. The decision reducing platelet adhesion and aggre- data suggests that aspirin resistance to discontinue therapy must take into gation. Clopidogrel also blocks the

12 The Journal of Dental Hygiene Special supplement amplification of platelet activation Cilostazole NSAIDS caused by released ADP. Plavix® is used as an antithrombotic for the pre- Cilostazole (Pletal®) is an oral Nonselective NSAIDS, such as vention of myocardial infarction, antiplatelet drug used to manage the ibuprofen, inhibit both cyclooxyge- stroke and vascular death in patients symptoms of peripheral vascular dis- nase1 and 2, and thus alter thrombox- with atherosclerosis. It is also pre- ease. This drug and its metabolites ane A2 synthesis and platelet aggre- scribed for the prevention of throm- inhibit phosphodiesterase III, which gation (Figure 1). However, unlike boembolic events following the place- increases cyclic adenosine monophos- aspirin, the effects of these drugs are ment of coronary stents. 27,29 phate (AMP), causing inhibition of reversible and last for a shorter period Plavix® was developed for use for platelet aggregation and vasodilation. of time, based upon the half-life of the patients who are unable to tolerate the Inhibiting phosphodiesterase III individual drug.27 When the drug is adverse gastrointestinal effects of increases cardiac contractility, atri- removed from the body, platelet func- aspirin, and has recently replaced oventricular (AV) nodal conduction, tion is restored. A recent study demon- ticlopidine (Ticlid®) as the drug of ventricular automaticity, heart rate, strated that platelet function returned choice for patients who are allergic or and coronary blood flow.29 to normal within 24 hours of discon- intolerant to aspirin.27 Evidence sup- The blood levels of cilostazole may tinuation of ibuprofen use in healthy ports that both clopidogrel and ticlo- be increased by erythromycin. In- individuals.76 Many professionals con- pidine are more effective than aspirin creased blood concentrations of this tinue to recommend discontinuing the in preventing stroke and other serious drug are observed with concurrent use use of NSAIDS at least 7 days prior to vascular events in high risk patients.74 of CYP3A4 inhibitors, including the surgery, when in fact, a much shorter Like aspirin, this drug produces irre- macrolide antibiotics and the systemic timeframe may suffice. Practitioners versible effects that last for the life of azole antifungals. Inhibition of should look up the half-life of the the platelet. Patients can receive rou- platelet aggregation caused by aspirin NSAID to determine how long it will tine dental procedures, including oral is potentiated with concurrent use of take for the drug to clear from the prophylaxis, without altering the dose cilostazole.29 body. of the drug.5,8 However, patients that are scheduled to undergo invasive sur- Ticlopidine gical procedures, including dental surgery, are advised to discontinue the Ticlopidine (Ticlid®) is an irre- Unlike aspirin, the drug for 7 days prior to surgery.5 Con- versible platelet aggregation inhibitor sultation with the patient’s physician used to reduce the risk for thrombotic effects of NSAIDS prior to discontinuing the drug is war- stroke. The other primary indication are reversible and ranted to ensure patient safety. for use is to reduce the incidence of Risk for hemorrhage is associated thrombotic complications in patients last for a shorter with this drug and bleeding may occur with coronary stents. Use of this drug period of time, based at any site, including the oral cavity. is typically reserved for patients who Risk for hemorrhage increases with are intolerant to aspirin, and for those upon the half-life of concurrent use of other drugs that alter whose aspirin therapy has failed. the individual hemostasis, including anticoagulants Ticlopidine has a mechanism of action and antiplatelet drugs. Avoid the use that is unique from other platelet drug.When the drug of herbs that demonstrate antiplatelet aggregation inhibitors. While the drug is removed from the activity (Table I). Concurrent use of inhibits adenosine diphosphate (ADP) clopidogrel with naproxen has platelet receptor fibrinogen binding body, platelet resulted in GI blood loss. Cases of (like Plavix®), this drug also signifi- function is restored. thrombotic thrombocytopenia purpura cantly increases bleeding time. The have been reported with use of this increase in bleeding time can be fur- drug, usually occurring within the first ther prolonged by the addition of 2 weeks of therapy.29 aspirin.29 The degree of platelet inhibition At high doses, clopidogrel may alter Ticlopidine has been associated with seems to vary among different nonse- the metabolism of some NSAIDS, life-threatening hematologic disorders, lective NSAIDS, but for most drugs, which can result in toxicity reactions. including neutropenia and thrombotic this effect does not appear to last Finally, CYP3A4 inhibitors, including thrombocytopenic purpura.75 Thus, use throughout the length of the dosing the macrolide antibiotics, may of clopidogrel has surpassed this drug period. For example, taking naproxen decrease the effects of clopidogrel. due to a better safety profile. Ticlopi- 500 mg twice daily inhibits platelet Dental patients who are prescribed dine use may increase the effect and aggregation throughout the dosing these antibiotics should be closely risk for toxicity of aspirin, anticoagu- period, versus ibuprofen, which monitored.29 lants, and NSAIDS.29 achieves adequate platelet inhibition

Special supplement The Journal of Dental Hygiene 13 at peak levels, but is not sustained, against vascular injury, causing these medications. In fact, use of any given the short half-life of the drug. increased prostacyclin synthesis, result- form of alternative medicine is not Further, data suggests that the ing in vasodilation and decreased disclosed to health care providers over antiplatelet effects of naproxen are platelet aggregation to facilitate blood 60% of the time.17 significant and comparable to those flow. Inhibition of the COX-2 enzyme A study in England documented that produced by aspirin, but are less with blocks these protective effects, and a significant number of patients may ibuprofen and diclofenac.77 This sug- because platelet thromboxane A2 is be co-ingesting herbal medicines with gests that naproxen may have greater unaffected, the balance of the equilib- warfarin. One thousand three hundred cardioprotective properties than other rium maintained between these 2 and sixty patients from 35 different NSAIDS. The variance in effect on prostanoids becomes disrupted. This medical practices were surveyed about platelet inhibition is among the many allows the influence of thromboxane the use of garlic, ginseng, ginkgo reasons why NSAIDS are not used for to predominate, increasing vasocon- biloba, feverfew, ginger, and St. John’s cardioprotective therapy. striction and clotting. This is the mech- wort. One hundred and nineteen A large epidemiologic study found anism thought to underlie the adverse patients (8.8% of the respondents) no evidence of cardioprotective effects hypertension and stroke events found reported taking one or more of these of traditional NSAIDS.78 Several stud- with long-term use of COX-2 inhibi- herbs. When asked if they had dis- ies concluded that current use of tors (eg, Vioxx®) cussed their herbal use with any health NSAIDS does not substantially reduce care professional, 92.2% reported that the risk of acute myocardial infarction they had not. The authors concluded (MI).79,80,81,82 Given the effects of Herbal Supplements that all general practitioners prescrib- naproxen, several investigations exam- ing warfarin should always ask about ined whether naproxen therapy could Physicians closely monitor patients the use of herbal medications. They reduce the risk for MI; study results taking prescription medications that also added that there are risks involved were inconclusive.80,81,83,84,85,86,87,88 There alter bleeding, because the effects of with any herbal preparations, and is also increasing evidence that con- these medications are known. Unfor- charged that physicians, as well as their current use of NSAIDS with aspirin tunately, patient use of OTC medica- patients, share a joint responsibility to may decrease the cardioprotective tions that alter bleeding, including the discuss potential herb-drug interac- effects of aspirin.89,90,91 use of dietary supplements, is not tions.94 Dental professionals are also A recent retrospective case-control supervised as closely, especially since well positioned to help patients under- analysis of 8688 case patients with many patients do not report taking stand the vital nature of this type of first-time acute MI revealed that current use of NSAIDS does not alter the risk of acute MI. Further, the risk for acute MI was higher among subjects who stopped taking NSAIDS within 2 months before the MI occurred. The authors hypothesize that current NSAID use does offer some protective effect, such as reducing MI risk related to chronic inflammation, but that this effect only occurs while the drug is being taken.92 Selective NSAIDS, known as the COX-2 inhibitors (eg, Celebrex®, Vioxx®, Bextra®), inhibit cyclooxygenase 2 without affecting cyclooxygenase 1. Thus, their effects predomi- nantly alter prostacyclin versus thromboxane A2 (Figure 1). Studies in healthy volunteers show that treatment with COX-2 inhibitors decreases systemic production of prostacyclin with no effects on platelet-derived thromboxane A2 synthesis.79,93 Expression of cyclooxygenase 2 is increased during ischemia, which is thought to be a protective mechanism

14 The Journal of Dental Hygiene Special supplement disclosure along with responsible prod- mnemonic can also be used to remem- Herbs with uct use. ber the herbs that are most likely to Table II. Both the desired and adverse interact with anticoagulant and anticoagulant/antiplatelet effects caused by prescription medi- antiplatelet agents. properties. cines are predictable, as they are man- It is important to note that other ufactured and tested according to herbal products have been implicated Alfalfa exacting standards. The effects of in causing adverse bleeding effects as Anise herbal phytotherapies, including well (Table II).29 However, this article Bilberry adverse reactions, are hard to foresee. will focus on 5 herbs that are widely Bladderwrack The FDA does not regulate herbal used and have some scientific evidence Bromelain product manufacturing, nor is safety to support the effects described here. Cat’s claw testing required, so it is challenging Celery to find documented safety and effi- Coleus cacy information. However, the pop- Garlic Allium sativum Cordyceps ularity of these products has dictated Dong quai the need for further study to gain a Recommended Dosage for general Evening primrose better understanding of how herbs use: Extract, aged: 4 ml daily; Fenugreek affect the body, and significant Fresh: 4 g daily; Oil: 10 mg daily Feverfew improvements in both herbal manu- Garlic* facturing and research have occurred Garlic is a perennial bulb with Ginger* in recent years. reported uses as an antilipidemic, Ginkgo biloba* Unlike prescription drugs, individ- antimicrobial, anti-asthmatic and anti- Ginseng* ual herbal preparations are often a inflammatory. The bulb contains aliin Grape Seed mixture of more than one active and degradation products such as Green tea ingredient. Thus, it is difficult to allicin, polysulfides, ajoenes, mer- Guarana determine which or how many con- captanes, thioglycosides, thiosulfi- Guggul stituents of the herbal product are nates, adenosine, and selenium.97 The Horse chestnut seed pharmacologically important. In addi- primary chemical components that Horseradish tion, comparable herbal products vary have been implicated in bleeding Horsetail rush in formulation, and their undefined include volatile oil and ajoene. The Licorice composition makes analysis of the antiplatelet effect of garlic has been Prickly ash active constituents extremely com- demonstrated by studying some of its Red Clover plex.95 This further confounds the pure isolated components on human Reishi understanding and utility of findings platelet aggregation. Ajoene appar- St. John’s wort* gleaned from research studies about ently functions as the chemical com- Sweet clover the effects of herbal drugs. ponent responsible for these effects.98 Turmeric Ciocon and colleagues have stated Ajoene is an unsaturated sulfoxide White willow “that certain herbals have been asso- disulfide and is a component of ciated with increased risk of bleeding allicin, a sulfinyl compound that gives *Herbs discussed within this article by inhibiting platelet function, platelet garlic its strong odor and flavor. Like Source: Wynn RL, Meiller TF, Crossley HL. aggregation and thromboxane synthe- aspirin, the effect of ajoene appears Drug Information Handbook for Dentistry. 10th sis, thrombin and thromboplastin to be irreversible, which lasts for the ed., Hudson:Lexi-Comp, Inc. 2005.29 mechanisms, and by those which contain coumarin-like effects, and salicylate-like effects.”96 They propose a mnemonic of a “Few G’s” to help health professionals remember a list The antiplatelet effect of herbs that are known to alter bleed- of garlic has been ing. The Few G’s include feverfew, plus ginkgo biloba, ginger, garlic and demonstrated by studying ginseng. They add that when the “g” some of its pure isolated is followed by a vowel (eg, ginkgo), the herb is associated with this components on human adverse effect. When an herb that platelet aggregation. starts with the letter “g” is followed by a consonant (eg, green tea), there is not a concern for bleeding.96 This

Special supplement The Journal of Dental Hygiene 15 life of the platelet, and may potentiate nolytic activity by the end of the sec- the effect of other platelet inhibitors.20 ond and third weeks.103 Several sulfur-containing compounds Case reports in the literature also isolated from garlic have also demon- suggest that ingesting garlic while tak- strated significant inhibition of human ing warfarin (Coumadin®) may result platelet aggregation.99 in over-anticoagulation. One case report Garlic oil exerts its effects on the documented that the INR of a previ- arachidonic acid pathway (Figure 1). ously stabilized patient on warfarin had Garlic interrupts the synthesis of more than doubled and that hematuria thromboxane, and stimulates the syn- occurred 8 weeks after commencement thesis of prostacyclin. By reducing of ingesting 3 garlic tablets a day.97 Izzo thromboxane and increasing prosta- and Ernst (2001) cite 2 case reports sug- cyclin, garlic decreases platelet gesting that the concomitant use of war- aggregation and increases bleeding. farin and garlic resulted in an increased Further, garlic inhibits platelet aggre- INR.95 It is evident that this popular gation in a dose-dependent fashion. herb has the potential to cause adverse Case reports support that both dietary bleeding effects. garlic and garlic supplements demonstrate these effects.100 Further, the constituents of garlic, particularly Ginkgo Ginkgo biloba Ginkgo holds alliin/allicin, also inhibit the produc- particular interest to tion and/or release of chemical medi- Recommended Dosage for general ators such as platelet-aggregating use: Standardized extract: 40 mg tid the baby boomer and factor and adenosine, which decreases platelet function.101 Interest- Ginkgo is a tree native to Asia and is geriatric populations ingly, many herbalists feel that the now also found in the United States. as its cerebral and best quality, most consistent, and The primary use of ginkgo is to pre- strongest source of allium sativum is vent decreased cerebral functioning vascular benefits the natural garlic clove itself. and peripheral vascular insufficiency continue to be Harenberg and colleagues (1988) associated with Alzheimer’s disease or studied the effects of dried garlic intake age-related dementia. Other reported researched. on blood coagulation, fibrinolysis, uses are summarized in Table III. platelet aggregation, serum cholesterol Components of ginkgo include levels and blood pressure in 20 patients flavonoids (ginkgo-flavones) and ter- penoids (ginkgolides and bilobalide). with hyperlipoproteinemia. During a The ginkgo leaf is processed and often 4-week study period, subjects received Additional standardized to 24% ginkgo flavong- 600 mg (200 mg bid) of dried garlic in Table III. lycosides and 6% trilactones (terpene a sugar-coated pill. After 4 weeks of indications for the lactones). The primary chemical com- garlic use, both fibrinogen and fib- use of ginkgo. ponent that has been implicated in rinopeptide A levels significantly bleeding is the terpene ginkgolides. decreased by 10%. Streptokinase-acti- antioxidant Ginkgolides, a terpene lactone, are vated plasminogen and fibrinopeptide peripheral artery disease potent and specific platelet activating B beta 15-42 significantly increased by circulatory problems factor (PAF) antagonists. Their effects 10%. Serum cholesterol levels signifi- depressive mood disorders are long lived and are rapidly estab- cantly decreased by 10%, and both sys- sexual dysfunction lished after oral dosing.104 Ginkgolide tolic and diastolic blood pressure (“herbal Viagra”) B, one component of ginkgo, inhibits decreased.102 asthma platelet activating factor by displac- In another in vivo study, 6 subjects glaucoma ing it from its receptor binding site, were given 5.0 g of crushed garlic menopausal symptoms resulting in reduced platelet aggrega- bulbs daily for a 3-week study period. multiple sclerosis tion.105 In laboratory tests, ginkgo Fasting blood samples were taken at headaches increases prothrombin time (PT), and baseline and at weekly intervals to tinnitus blood salicylate levels, and may assess the level of serum triglycerides. dizziness decrease platelet activity.106 Results showed that the addition of arthritis Ginkgo holds particular interest to garlic in the diet resulted in signifi- altitude sickness the baby boomer and geriatric popu- cantly lower levels of serum triglyc- intermittent claudication lations as its cerebral and vascular erides and an increase in blood fibri- benefits continue to be researched.

16 The Journal of Dental Hygiene Special supplement Whereas earlier and better known otherwise healthy older patient self- 2000.113 With the increasing interest in research focused on older and cogni- medicating with fatal consequences. both alternative medicine and tradi- tively impaired individuals, a recent A 40-year-old woman was admit- tional Chinese medicine, the use of review in Herbalgram provided a ted to the hospital with an acute sub- ginseng will continue to be strong by comprehensive report of its successes dural hematoma with no history of a large segment of the population. with “healthy and cognitively intact head trauma, falls, alcohol abuse, or The word Panax is derived from the adults.” Both short- and long-term bleeding disorders. Her hematoma Greek word for panacea, as the herb is studies resulted in positive benefits of was evacuated via burr holes, yet her considered a cure-all, ie, good for all ginkgo in the improvement of blood results, especially the INR, parts of the body. In fact, the plant itself processes such as memory, attention, were difficult to stabilize. After treat- resembles a human figure. According and speed of processing.107 ment and questioning, it was revealed to Chinese sages, ginseng replenishes Case reports document dangerous that she had been taking 40 mg of vital energy, increases production of bleeding episodes following the regu- ginkgo twice daily for the past 2 vital body fluids, and promotes health lar use of ginkgo: intracranial bleed- months to “assist her while studying.” and longevity. This is the concept of a ing (4 cases), spontaneous hyphema Disturbingly, her family continued to tonic or adaptogen, which our culture (hemorrhage within the anterior give her the herb while in the hospital, has little understanding of. chamber of the eye) (1 case), and stating that they were “just herbs.” Standardized ginseng extracts con- postoperative bleeding after chole- Once the herb was discontinued, the tain 5% ginsenosides, an aglycone cystectomy (1 case).96 One of these blood results returned to normal.97 chemical component believed to act reports occurred when a 70-year-old Clearly, ginkgo has tremendous as a stimulant. Ginsenosides act on man presented with bleeding from the potential for causing bleeding com- the hypothalamus-pituitary-adrenal iris into the anterior chamber of the plications, and with its broad range of cortex axis, stimulating the secretion eye just 1 week after beginning a self- claimed benefits, the use of this herb of adrenocorticotropic hormone prescribed regimen of a concentrated is attractive to many. With a growing (ACTH), which increases production ginkgo extract twice daily. He was geriatric population and baby boomers of the adrenal hormones (eg, cortisol, also taking 325 mg of aspirin daily wishing to preserve cognitive func- sex hormones, aldosterone). Thus, and had done so for 3 years. It is inter- tion, it is safe to expect use of this ginseng produces central nervous sys- esting to note that when he discontin- herb to increase. tem (CNS) stimulating effects, estro- ued taking the ginkgo, but not the gen-like effects, and elevates blood aspirin, the bleeding resolved. There Ginseng Panax quinquefolius pressure.29 Ginseng is also thought to was no recurrence of bleeding 3 Panax ginseng restore and strengthen the body’s months later.108 immune response, and promotes Another case is a 61-year-old man Recommended dosage for general growth of normal cells.104 who developed subarachnoid hemor- use: Capsules: 200-500 mg extract The ginsenosides are also believed rhage after consuming 40 mg of daily; Powdered root: 1-4 g daily; to have the potential to inhibit platelet- ginkgo 3 or 4 times per day for more standardized extract: 200-500 mg activating factor.106 Ginseng has been than 6 months. No other medication daily; Tincture: 1-2 ml extract daily reported to inhibit platelet-activating was used. The patient’s bleeding time (1:1 dilution) factor (PAF), platelet aggregation, increased to 6 minutes but normalized thrombin and thromboplastin, and can to 3 minutes within 4 months after dis- Ginseng is one of the most popular, cause further bleeding when combined continuing the ginkgo.109 well-known, and valued herbs world- with aspirin, heparin, warfarin, and non- A systematic review by Izzo and wide. Panax Ginseng has been used steroidal anti-inflammatory drugs.114,115 Ernst discusses 2 case reports docu- medicinally in Asia for more than There are only a few kinds of menting that patients taking warfarin 5000 years and, in China, it is more “true” ginsengs in the botanical genus and aspirin had experienced severe highly valued than gold.111 The Chi- Panax. There are other plants that are spontaneous bleeding after self-pre- nese believe that ginseng can fight in the ginseng family, but they are scribing ginkgo at recommended cancer, slow aging, protect one against more distantly related to ginseng doses.95 A fatal intracerebral mass heart attack and other sudden ill- botanically, such as eleuthero or bleeding was reported in a 71-year-old nesses, strengthen digestion, and Siberian Ginseng. These other gin- man who had taken ginkgo in con- reduce high blood pressure, among sengs affect the body in similar ways. junction with ibuprofen. He was pre- numerous other benefits.112 The Asian They are not as powerful as “true” viously in excellent health. He had population is significant in the United ginsengs, but they are less costly. True 1 been taking ginkgo for 2 /2 years for States. According to the US Census ginsengs in the Panax category self-reported dizziness and had added 2000, almost 12 million Asians are include: Oriental, Chinese, Korean ibuprofen 600 mg daily for osteoarthri- living in the United States, and the and American ginseng.112 tis of the hip just 4 weeks prior to his Asian population increased faster than The effects of ginseng are sup- death.110 This is a good example of an the total population between 1990 and ported by hundreds of laboratory

Special supplement The Journal of Dental Hygiene 17 some postmenopausal symptoms. After using the cream, she experienced 2 episodes of spotting and her follicle- stimulating hormone (FSH) dropped significantly. After one month of discontinuing the product, the bleeding Ginseng produces stopped and her FSH returned to pre- central nervous system (CNS) vious levels. The authors concluded that ginseng appeared to have an estro- stimulating effects, gen-like effect on genital tissues. 118 estrogen-like effects, With its broad range of claimed benefits from increased physical endurance and elevates to improved ability to cope with stress, blood pressure. it seems reasonable to expect that all ginsengs will continue to be a popular choice in an increasingly fast-paced society.

Ginger Zingiber officinale

Recommended dosage for general use: Dried ginger capsules: 1 g/day; Dried root equivalent: 500mg bid- qid; Fluid extract: 0.7-2ml/day (1:2 experiments, but there are very few INR returned to therapeutic level (3.3) 2 dilution); Tablets/caps: 500 mg bid- controlled human studies.112 Two labo- weeks after he stopped using ginseng.116 qid; Tincture: 1.7-5 ml/day (1:5 ratory studies assessed the potential for Ginseng possesses a paradoxical dilution) ginseng to cause bleeding. Chung and effect. Despite ginseng’s anticoagu- colleagues (1987) examined the effect lant potential, it has been noted to Ginger is primarily used to relieve of a ginkgolide mixture (BN 52063) in decrease the effectiveness of warfarin. motion and morning sickness, and antagonizing skin and platelet Yuan and colleagues (2004) con- preliminary research documents its responses to PAF in human subjects. ducted a study with 20 healthy volun- efficacy in decreasing pain and The ginkgolide significantly inhibited teers to assess this potential drug-herb inflammation associated with arthritis PAF-induced platelet aggregation in interaction. Subjects had no medical and other joint disorders.106 Tradi- platelet-rich plasma (p< 0.001). The conditions requiring warfarin, nor had tionally, in herbal folklore, ginger is researchers concluded that the BN they taken warfarin or ginseng. Dur- best known for settling upset stom- 52063 “seems to be an antagonist of ing the 4-week study period, all of the PAF in man.”105 volunteers were given warfarin. Dur- There is some research to suggest ing the second week, the researchers that Oriental ginseng (Ginsana) may randomly assigned each volunteer antagonize the anticoagulant effects of either a placebo or ginseng, taken in warfarin. In 1 case report, the INR of a addition to the warfarin. Subjects had 47-year-old man who had been receiv- their blood clotting times tested using ing warfarin for 9 months (7.5 mg every the INR. Results of the study revealed Tuesday and 5 mg on all other days) to that the subjects taking ginseng had prevent thrombotic complications asso- lower blood levels of warfarin, thus ciated with a mechanical heart valve compromising anticoagulation.117 was stabilized at 3.9 – 4.0. The patient As previously stated, ginseng began taking Oriental ginseng, and increases the production of adrenal within 2 weeks, his INR fell to 1.5. The hormones, including the sex hormones, patient denied any other changes in his leading to estrogen-like effects. There medication regimen, including the use is a case report of postmenopausal of other nonprescription or herbal prod- bleeding that was attributed to the use ucts, diet, alcohol consumption, or other of topical ginseng. A 44-year-old lifestyle factors that may have affected woman used a ginseng face cream his response to warfarin. The patient’s from China in the hopes of relieving

18 The Journal of Dental Hygiene Special supplement achs. The major constituents of gin- St John’s wort Hypericum perfora- clotting. The reduced anticoagulation ger are pungent principles (gingerol, tum L effect of warfarin is likely caused by shogaol, zingerone), volatile oils (bis- Recommended Dosage for general induction of the liver enzyme abolene, zingiberene, zingiberol), and use: 300 mg hypericum extract, cytochrome P450 2C9, which proteolytic enzymes. Many people standardized to 0.3% hypericin, tid increases the metabolism of warfarin, consider ginger to be a root, but it is thus decreasing its effect.124 None of actually a rhizome. Zingiber comes St John’s wort is a popular herb the patients in these studies developed from the Sanskrit word for ginger, used to manage mild to moderate thromboembolic complications, but singabera, meaning “shaped like a depression. Depression is a silent the decrease in INR was thought to be horn.”119 health threat and statistics from the clinically significant. The INR The research on ginger is mixed NIH indicate the highest risk is among returned to target values either after and limited to a few case reports, middle-aged adults, aged 45 years to the warfarin dose was increased or the small scale in vivo studies and some 64 years.123 Depression is considered St John’s wort was withdrawn. in vitro studies. In one laboratory test, to be of epidemic proportion among The induction reaction of hepatic aqueous ginger extract reduced adolescents in the United States, and cytochrome P450 has been attributed platelet thromboxane and also inhib- is more common in women. This herb to the hypericum extracts from St. ited platelet aggregation.120 In a small is one of few herbs with a significant John’s wort, which may double the study of 8 healthy male volunteers, body of research to support its effi- metabolic activity of the liver, and thus subjects ingested either 2 grams of cacy. Given its popularity and numer- reduce the effects of many drugs.125 For dried ginger in capsule form or a ous adverse effects, there are signifi- example, use of St John’s wort (900 mg placebo. Bleeding time, platelet cant risks associated with undisclosed per day of hypericum extract LI160) count, thromboelastography, and usage among patients. resulted in a significant decrease of whole blood platelet aggregometry St John’s wort has had a colorful digoxin when compared to placebo in were performed before, 3 hours, and history. Ancient Europeans believed it subject taking 0.25 mg of digoxin per 24 hours after ingestion. It was con- had magical protective powers against day.126 Digoxin is a drug that is used for cluded that the effect of ginger on disease and evil. Ancient herbalists the treatment of congestive heart failure thromboxane synthetase activity was from Hippocrates to Dioscorides val- and various types of arrhythmias.29 It is dose dependent and only occurs with ued St John’s wort not only for the easy to see that the adverse metabolic fresh ginger, and that up to 2 grams of treatment of “melancholia” and other effects of this herb can cause many sig- dried ginger is unlikely to cause emotional disorders, but also for burns, platelet dysfunction when used ther- wounds (especially those involving apeutically. Data obtained from case nerve injuries), neuralgia or nerve reports and studies with very small pain, inflammation, ulcers, and more. sample sizes (eg, N=7) suggest that Today, it is used as an antidepressant. ginger’s antiplatelet effect exists with The major constituents of the herb raw ginger only. For example, in one include: hypericin, hyperforin, pseudo- case report, an unspecified amount of hypericin, flavonoids, xanthones, and marmalade with 15% raw ginger was essential oils. consumed leading to inhibition of A meta-analysis of 23 randomized platelet aggregation. One week after European clinical investigations discontinuing ginger, platelet func- involving a total of 1757 patients con- tion was described as spontaneously cluded that standardized St. John’s returning to normal.121 It is important wort extract was significantly more to note that these are very small sam- effective than placebo and just as ple populations, and additional study effective as standard antidepressant is needed to further define the effects medications in the treatment of mild of ginger on platelet function. or moderate depression.119 Since 1998, Despite the lack of substantial evi- 7 case reports were received by the dence, ginger continues to be included Medical Products Agency (MPA) in in published literature reviews that Sweden that demonstrated a reduced detail the ability of herbal therapies anticoagulant effect of warfarin to increase clotting time either alone (decreased INR) associated with the or together with another herb or pre- concomitant use of St John’s wort. scription drug.96,114,122 Further, as one This is the opposite of the other herbal of the “few G’s,” health care profes- interactions previously discussed, and sionals need to be aware of the poten- is actually more dangerous, as the tial for adverse bleeding events. effect would be to potentially increase

Special supplement The Journal of Dental Hygiene 19 Resources for Dental Professionals National Center for Complementary and Pubmed - screened for alternative medicine Alternative Medicine www.nlm.nih.gov/nccam/camonpubmed.html Division of National Institutes of Health Clearinghouse P.O. Box 8218 RxList Alternatives Silver Spring, MD 20907-8218 www.rxlist.com Phone: 888-644-6226 FAX: 301-495-4957 WebMD http://nccam.nih.gov www.webmd.com

Food and Drug Administration 5800 Fishers Lane BROCHURES Rockville, MD 20857 Phone: 202-205-5124 American Society of Anesthesiologists Medwatch: 800-332-1088 to report adverse drug Phone: 847-825-5586 events “What You Show Know About Herbal Use and www.fda.gov Anesthesia” www.cfsan.fda.gov “What You Should Know About Your Patient’s Use of Herbal Medicine” www.asahq.org Websites

American Botanical Council (publishes Herbalgram) JOURNALS AND NEWSLETTERS www.herbalgram.org Herbalgram - The Journal of the American Botanical American Holistic Medical Association Council and the Herb Research Foundation www.holisticmedicine.org published quarterly ($50/year = four issues) phone: 703-556-9728 Phone: 800-373-7105 www.herbalgram.org Consumer Labs - Independent testing on herbs/supplements Self Healing - Andrew Weil, MD newsletter www.consumerlab.com Phone: 1-800-523-3296 www.drweilselfhealing.com Food and Nutrition Information Center www.nal.usda.gov/fnic BOOKS HerbMed www.herbmed.org 1. LaValle J Krinsky D, Hawkins E, Pelton, R, Willis, N. Natural Therapeutics Pocket Guide. 2nd ed. Herb Research Foundation Hudson: Lexi-Comp, Inc., 2003. www.herbs.org 2. Skidmore-Roth L. Mosby’s Handbook of Herbs and Natural Supplements. 3rd ed. Littleton: Mosby, Lexi-Comp, Incorporated 2006. Drug Information Handbook for Dentistry (text) 3. Wynn RL, Meiller T, Crossley HL. Drug Information Lexi-Interact (electronic) Handbook for Dentistry, 11th ed. Hudson: Lexi- Dental Lexi-Drugs (electronic) Comp Inc., 2006. www.lexi.com 4. Brinker F. Herb Contraindications and Drug Inter- actions. 3rd ed. Sandy: Eclectic Medical Publica- Medline tions, 2002. www.nlm.nih.gov/databases/databases_medline.html 5. Hobbs C. Herbal Remedies for Dummies. Foster City: IDG Books Worldwide,1998. Medline Plus www.nlm.nih.gov/medlineplus/herbalmedicine.html JOURNAL FULL ISSUES AND ARTICLES Mosby Mosby’s 2007 Dental Drug Consult (text) • The Journal of the American Medical Association - www.elsevierhealth.com Volume 280, No. 18 - November 11, 1998. Entire issue devoted to comprehensive alternative medi- Pubmed cine research and editorials. www.pubmed.gov • Ang-Lee M Moss J Yuan CS Herbal Medicines and Perioperative Care JAMA July 2001 286;2:208-16. nificant complications in patients with patient’s response to warfarin. Fluctu- versions of reference guides should be heart disease. ations in the patient’s INR may be seen replaced on an annual basis, as the field The National Center for Comple- for several days, even weeks, following continuously evolves and changes. The mentary and Alternative Medicine is illness, dietary, or medication changes. advantages to electronic databases studying the effects of St John’s wort It is essential to ask all patients taking include speed of access to and the for a wide spectrum of mood disor- warfarin about the results of their most immediate availability of a vast quan- ders. Positive research findings will recent INR. A follow-up with the tity of information, and access to the likely lead to renewed interest in this patient’s physician may be warranted. most current drug data. Suggested re- herbal remedy. At every appointment, patients sources for dental professionals are listed should provide a list of all of the med- at the end of this paper. (Please see ications and herbs that they take, Resources for Dental Professionals.) Practice Considerations including dosing schedules. This med- Dental professionals should also for Dental Professionals ication list should be documented in observe their patients for physical the treatment record at every appoint- manifestations of bleeding complica- The most important risk reduction ment. Follow-up questioning of the tions. Signs of altered bleeding may strategy implemented by dental profes- patient is conducted as a component of include excessive or diffuse bruising, sionals is the completion of a compre- the comprehensive health history to petechial hemorrhaging, prolonged hensive health history for every patient ensure that this list is accurate and bleeding following dental procedures, on a regular basis. The review of sys- complete. It is important to note that and spontaneous gingival bleeding. tems allows for the discovery of sys- many patients think of some herbs as Patients may report bruising easily or temic conditions that alter bleeding, or merely popular cooking ingredients noticing an increase in bleeding with that require the use of drugs that alter (eg, garlic and ginger) and/or that these toothbrushing and flossing. Bruising bleeding. Systemic causes of bleeding plant-derived substances are all natural, is frequently observed in elderly include liver disease, kidney disease, and must therefore be “safe” health patients taking antiplatelet and anti- chronic alcoholism, bone marrow sup- products for ingestion. For this reason, coagulant medications, who also pression, blood dyscrasias, Vitamin K patients must often be prompted to dis- demonstrate epithelial thinning as a deficiency, and inherited coagu- close the use of herbal medications. normal part of aging. Clinical signs lopathies.127,128 As most clotting factors Remember that many herbal prepara- from observation and symptoms are formed by the liver, liver disease tions contain multiple herbs within one described by the patient should be can greatly affect bleeding tendencies. supplement and that patients may not documented in the treatment record. Dental patients may present with liver always know what herbs they are con- Whenever there is doubt as to the disease caused by a variety of conditions, suming in these products. While clearly patient’s safety and/or the stability of most commonly alcoholism, cirrhosis, herbs provide substantive and benefi- his current medical status, the patient’s and/or infections, such as hepatitis. cial health properties, consuming herbs physician should be contacted. The Intestinal bacteria continually pro- on a regular basis from either supple- dental professional must be prepared duce Vitamin K, thus, a deficiency is ment use or cooking can potentially to discuss the nature of the concern and rarely seen in a normal person due to alter bleeding. proposed dental treatment with asso- an absence of Vitamin K from the diet. It is imperative that dental profes- ciated or potential risks, then request Exceptions are those with gastroin- sionals have access to a good drug ref- any information needed to safely pro- testinal diseases that result in poor fat erence guide, either as a chairside ref- ceed with treatment. Results from absorption, as Vitamin K is fat-soluble erence text or in the form of an recent, relevant laboratory tests should and is absorbed into the blood along electronic database, to assist with com- be obtained for the treatment record. with dietary fats. One of the most pleting an accurate medication list. Copies of any test results ordered by common causes of Vitamin K defi- Many popular dental drug resources the dentist that are required prior to ini- ciency is failure of the liver to secrete also contain information on herbal tiating dental treatment should be for- bile into the gastrointestinal tract, as medications, although dental profes- warded to the patient’s physician as lack of bile prevents fat digestion and sionals may find it helpful to also have needed. Conversations with the absorption, thus reducing Vitamin K a resource that is strictly devoted to patient’s physician must be docu- absorption as well.26 herbal supplements. Resources provide mented in the treatment record. Dental professionals should remem- valuable information about drug dos- As previously discussed, few anti- ber to question patients about recent ing, common side effects, drug inter- coagulant and antiplatelet medications illnesses, changes in health behaviors, actions, and precautions for treating require discontinuation prior to routine or modifications to their diets. Intesti- patients using these medications. Den- dental treatment. Exceptions have been nal viruses that cause vomiting or diar- tal professionals should look up all previously noted elsewhere in this rhea, changes in the intake of green medications that a patient is taking paper. However, discontinuation may leafy vegetables, or the use of medica- prior to prescribing other medications be required prior to invasive dental sur- tions can dramatically alter the to ensure safety and compatibility. Text gery. Herbal supplements should

Special supplement The Journal of Dental Hygiene 21 always be discontinued prior to any type of surgery, including dental sur- It is essential that gery. Different herbs possess specific safety windows that range from 24 dental professionals have access to hours (ephedra) to 7 days to 14 days local hemostatic agents for use in (garlic and ginseng) prior to undergo- the operatory. ing surgery.20 Patients taking herbal supplements that possess anticoagulant and/or antiplatelet properties should be (2003) for a review of hemostatic teach patients that gingival bleeding is advised to discontinue use at least 2 agents used in dentistry.129 Invasive not “normal,” as so many patients mis- weeks prior to having a surgical pro- procedures should be performed with takenly believe, so that gingival bleed- cedure until more is definitively known as minimal trauma to the tissues as ing as a complication of medication about the potential for bleeding com- possible. Careful post-surgical moni- therapy can be quickly and accurately plications.6,29 This 2 week to 3 week toring is advised.6 identified. safety window is suggested by the To determine whether increased gin- Dental hygienists possess an American Society of Anesthesiologists gival bleeding is caused by a medica- important role in educating patients (ASA).20 It is important to note that the tion side effect, or is a manifestation of about bleeding effects that may affect safety window also takes into account gingival disease, a thorough oral exam- the oral cavity and the provision of other herbal side effects that may ination should be performed at each oral health care services. Patients increase surgical risk, such as the abil- visit. Patients should be taught proper should be taught about the importance ity to recover from general anesthesia. oral hygiene techniques to decrease eti- of accurately reporting their medica- A discussion of these and other effects ologic bacteria that cause gingival tion and herbal use, compliance with is beyond the scope of this paper. The inflammation. Manual plaque removal their medication regimens, and rou- reader is referred to Ang-Lee et al may be improved through the use of tine monitoring with blood tests as (2001) for a detailed discussion of power-assisted toothbrushes, floss aids, prescribed by their physicians. Patient these considerations and oral irrigators. Chemotherapeutic education may also include dispelling Despite careful planning and pre- agents that exhibit antimicrobial prop- myths about the need to discontinue cautions, the potential for an unex- erties are useful adjuncts to kill residual medication use prior to undergoing pected bleeding event always exists organisms that brushing and flossing routine oral care. Many patients dis- for patients taking these medications. may leave behind. Broad- spectrum continue their medications on their Therefore, it is essential that dental antimicrobial agents, such as chlorhex- own, without consulting their physi- professionals have access to local idine, essential oil mouthrinse, and tri- cians or dental professionals, because hemostatic agents for use in the oper- closan toothpaste, have demonstrated they are worried about a bleeding atory. There are a variety of pharma- efficacy in reducing supragingival complication. It is important to edu- cologic agents that are available for plaque and gingivitis, and resultant gin- cate patients about how bleeding is this purpose; however, a complete dis- gival bleeding. Improving oral hygiene adequately managed in the oral health cussion about these products is reduces gingival inflammation, thus care setting, provide reassurance, and beyond the scope of this paper. The eliminating the primary etiologic factor how, if needed, their medications reader is referred to Burrell and Glick for gingival bleeding. It is important to should be discontinued.

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New ProResults brush head with broader sweeping motion and contour fit bristles for increased tooth coverage

Clinically proven to significantly improve gum health in only 2 weeks4

Simplicity is more than a brush, it’s superior oral health. Introducing FlexCare. Our most advanced sonic technology combined with the new ProResults brush head now makes brushing more effective for you and your patients. To order your new FlexCare trial unit, contact your Sonicare representative at 1-800-676-SONIC (7664). www.sonicare.com

the sonic toothbrush *In vitro †Compared with Oral-B Triumph ‡ Compared with Sonicare Elite References: 1. Schaeken M, Sturm D, Master A, Jenkins W, Schmitt P. Data on file, 2007. 2. Milleman J, Putt MS, Sturm M, Master A, Jenkins W, Schmitt P, Hefti AF. Data on file, 2007. 3. De Jager M, Nelson R, Schmitt P, Moore M, Putt MS, Kunzelmann KH, Nyamaa I, Garcia-Godoy F, Garcia-Godoy C. Data on file 2007. 4. Holt J, Sturm D, Master A, Jenkins W, Schmitt P, Hefti AF. Data on file, 2007.