Running head: ADVERSE EFFECTS OF HERBAL MEDICINES 1 Adverse Effects of Herbal Medicines in Cardiac Patients University of South Florida Alexsandra de Oliveira
ADVERSE EFFECTS OF HERBAL MEDICINES 2 Adverse Effects of Herbal Medicines in Cardiac Patients Heart disease is the number one cause of death in United States (Center forDisease Control and Prevention [CDC], 2011). In 2009, 26.8 million noninstitutionalizedadults were diagnosed with heart disease (CDC, 2011). The diagnosis of a cardiacdisease leads to a sequence of treatments that includes the prescription of one or moremedications to help manage the disease. Prescription medication is not the onlyresource used by cardiac patients to manage their disease. Gohar, Greenfield,Beevers, Lip, and Jolly (2008) found that complementary and alternative medicine(CAM) and home blood pressure devices are common self-care methods used byhypertensive patients along with the prescribed medication. CAM is widely used in the U.S with more than 15 million people using herbalmedicines (Tachjian, Maria & Jahangir, 2010). A clinical survey data revealed that 15%of patients taking allopathic medication also use herbal medicines (Bush et al., 2007).Research has also shown that the majority of patients do not tell their physicians aboutthe consumption of herbal medicines (Gardiner, Graham, Legedza, Eisenberg, &Phillips, 2006). The concomitant use of herbal medicines and allopathic medication canhave detrimental effects to cardiac patients. Gohar et al. (2008) found a significantassociation between CAM use and medication nonadherence among the femaleparticipants in their study. Nonadherence to medication in post cardiac infarctionpatients, for example, was associated to high risk of death (Ho et al., 2006). Cohen andErnst (2010) suggested that there are a large number of cardiac patients consumingherbal medicines that cause common and/or rare adverse effects.
ADVERSE EFFECTS OF HERBAL MEDICINES 3 Although herbal medicines have been used for centuries there is a lack ofscientific evidence about the risks and/or benefits of its use with today’s complexmedication regimen used to treat cardiac patients. The purpose of this literature reviewis to explore evidence-based literature related to the risks of the most commonly usedherbal medicines to cardiac patients taking allopathic medication. Research Question In cardiac patients, what are the potential adverse effects of herbal medicinewhen used in conjunction with the prescribed drug therapy? Relevance to Nursing Practice Nurses at all levels of care in a variety of settings including hospitals, cardiacrehabilitation services, and home care, are involved in assessing medicationmanagement. In this regard, nurses bear the responsibility not only to improve thepatient’s ability to manage their medication regimen, but also to ensure safety regardingpotential adverse effects. Therefore, nurse’s knowledge of scientific evidence about thepotential risks of herbal-drug interactions is desirable when providing medicationeducation and in assessing drug adherence. Review of the Literature Five studies were reviewed that describe potential adverse effects of theinteraction of herbal medicines and some of the most common prescribed cardiac drugtherapy. Mohammed, et al. (2008), sought to investigate possible interactions of herbalmedicines with warfarin in light of genetic variability. Garlic and cranberry were chosenfor this study because are widely consumed in the United States (Mohammed et al.,2008). The aim of the study was to investigate the possible effects of these two herbal
ADVERSE EFFECTS OF HERBAL MEDICINES 4medicines on the pharmacokinetics and pharmacodynamics of warfarin in subjects withtwo specific genotypes (Mohammed et al., 2008). Mohammed, et al. (2008) conducted an open-label, three-treatment,randomized crossover clinical trial included 12 healthy males with two known specificgenotypes, CYP2C9 and VKORC1. The garlic product utilized in this study wasselected based on the concentration of allicin per tablet (Mohammed et al., 2008).Allicin is the most important compound present in garlic involved in the antiplateleteffects (Mohammed et al., 2008). The cranberry concentrate juice was selected basedon the high concentration of anthocyanin and quercetin due the fact that only these twocompounds were equally found in all products analyzed for this study (Mohammed etal., 2008). Healthy male subjects were selected between the ages of 18 and 34 yearsold (Mohammed et al., 2008). A full medical history, physical examination and clinicallaboratory evaluation was utilized to classify the subjects as healthy (Mohammed et al.,2008). The subjects were tested for CYP2C9 or VKORC1 genotype, warfarin plasmaprotein binding, platelet aggregation and international normalized ratios (Mohammed etal., 2008). The activity of Factor II, Factor VII and Factor X of coagulation weremeasured after the consumption of warfarin alone and after warfarin and cranberry juiceextract ingestion (Mohammed et al., 2008). The 12 healthy male subjects were randomly assigned in three groups to receivea single dose of 25mg of warfarin either alone or after two weeks of pre-treatment withcranberry juice concentrate capsules or enteric-coated garlic tablets (Mohammed et al.,2008). Cranberry and garlic continued to be consumed for seven days after theadministration of warfarin. After a two week washout period the subjects were crossed
ADVERSE EFFECTS OF HERBAL MEDICINES 5over to receive the different treatment. The well-being and any adverse events wereassessed throughout this study. None of the subjects in this study presented majorbleeding or INR above four (Mohammed et al., 2008). The results of Mohammed et al. (2008) trial revealed two significant findings.First, the cranberry and warfarin treatment resulted in a 30% increase in the area underthe INR-time curve. Second, different genotypes react differently in response to thewarfarin and cranberry or warfarin and garlic interaction. The researchers concludedthat subjects with VKORC1 variant type (CT and TTalleles) were more susceptible tointeraction with warfarin and cranberry (Mohammed et al., 2008). Subjects with wild-type VKORC1 genotype are susceptible to warfarin with garlic interactions bydecreased of warfarin response (Mohammed et al., 2008). Although not statisticallysignificant, the researchers also found that there was a decrease in activity of all clottingfactors with the concomitant administration of warfarin and cranberry (Mohammed et al.,2008). This study presents two important limitations. First, the sample size for the twospecific genotypes was of only 12 subjects’ total. Second, the mean age of the subjectswas 23 years old. The small sample size might have yield the positive interactionswhich contradicts Mohammed, et al. (2008) literature review that no herb-druginteraction with warfarin was observed in previous research. The age of the subjects isan important factor when considering the applicability of this study in cardiac patients.Approximately 47% of Americans with cardiovascular disease are 60 years old or older(Lloyd-Jones et al. 2010). Therefore, further research is necessary including an agevariant to ensure the clinical relevance of the study for the majority of cardiac patients.
ADVERSE EFFECTS OF HERBAL MEDICINES 6 Paoletti et al. (2011) hypothesized that possible interactions of oralanticoagulants with herbal supplements represent a health risk for many individuals.Through a collection of spontaneous reports the researchers sought to identify all druginteractions between herbs and oral anticoagulants. The reports were extracted fromthe Italian National Institute of Health Database. Initially 379 reports of suspectedadverse reactions to natural products from April 2002 to December 2009 were collected.The reports with INR modification after herbal consumption were further analyzed toensure that individuals were previously stably anticoagulated (Paoletti et al., 2011).Cases with factors that could interfere with anticoagulant such as illnesses and vitaminK intake changes were excluded (Paoletti et al., 2011). The researchers identified 12reports, seven cases of INR reduction in patients treated with warfarin andacenocoumarol and five cases in which the INR increased (Paoletti et al., 2011).Among the reported cases of INR reduction due to herb-drug interaction was one caseof warfarin and home-made aloe preparation, one case of acenocoumarol and redginseng, one case of warfarin and yeast fermentation of papaya, one case of warfarinand papaya extract, one case of warfarin and bilberry concentrate juice, one case ofwarfarin and a supplement containing several vitamins and fish oil, and one case ofwarfarin and green tea (Paoletti et al., 2011). The researchers identified five cases ofINR increases involving the interaction of warfarin and arnica or boswellia-basedproducts. In one case arnica was used in a form of cream to myalgia and the patientpresented serious adverse effects with elevation of INR after one month of the use ofthe cream (Paoletti et al., 2011).
ADVERSE EFFECTS OF HERBAL MEDICINES 7 The researchers concluded that the cases analyzed confirmed the existence ofthe risk of herbal products and oral anticoagulants. However, the study is limitedbecause it was unable to identify if common factors such as age or herbal componentswere involved in the reported interactions. In addition, the applicability of this study toclinical practice is compromised because only one case of most herb-anticoagulantinteraction in the study was analyzed. Nevertheless, Paoletti et al. (2011) succeeded inopening the discussion of a variety of possible herbal interactions with oralanticoagulants based on reported INR results. Saw, Bahari, Ang, and Lim (2006) cross-sectional survey sought to determine theprevalence of herbal use possibly interfering with antiplatelet or anticoagulant therapy inmedical wards in a Malaysian hospital. The survey included 250 patients underantiplatelet or anticoagulant therapy in the cardiology, neurology, infectious andnephrology wards. Patients under the age of 18, pregnant women and patients unableto give consent were excluded from this study (Saw et al., 2006). A questionnaireincluding questions on socioeconomic background was developed to document the useof warfarin or aspirin with herbal medicines (Saw et al., 2006). The herbs that mostconcerned the researchers were ginseng, garlic and ginkgo. The population included inthe study consisted of 127 women and 123 men. Of this population 74.4% were in poorhealth conditions (Saw et al., 2006). Among the patients 42.2% reported taking herbalmedicine and 31% were taking ginseng, garlic or ginkgo for the past year (Saw et al.,2006). The survey showed that 40% of the patients were taking antiplatelet and /oranticoagulant for the past year (Saw et al., 2006).The survey also identified eightpossible interactions involving 50% garlic with aspirin, 37.5% warfarin with ginseng or
ADVERSE EFFECTS OF HERBAL MEDICINES 8ginkgo and 12.5% ginkgo with aspirin (Saw et al., 2006). The majority of theinteractions 62.5% were in patients older than 62 years of age (Saw et al., 2006). Themost common side-effects were headache 22.2% and dizziness 16.7% (Saw et al.,2006). Finally, the survey revealed that 90% of the patients did not inform theirhealthcare provider about the use of herbal medicines (Saw et al., 2006). Saw et al. (2006) concluded that these findings suggested potential health risksdue to herb-drug interaction for pre or post-operative patients and patients with clottingdisorders. The researchers also recognize that this survey presents limitations becauseother factors such as patient characteristics may also interfere in the effects of herb-drug interactions. Saw et al. (2006) findings are neither conclusive nor broadly applicable to cardiacpatients. The researchers associated symptoms such as headache and dizziness toherb-drug interaction based only on the review of the literature. However, most of theliterature on the subject of herb-drug interaction is based on isolated case reports.Therefore, further research is necessary to verify the applicability of these findings to alarger population of patients under anticoagulation or antiplatelet therapy. Gurley, Swain, Williams, Barone, and Battu, (2008) hypothesized that herbalmedicines can interact with drugs that are P-glycoprotein substrates and that thoseinteractions may be clinically observed. An open-label randomized research model wasused to test the effects of St. Johns wort and echinacea, two commonly used herbalsupplements, on the pharmacokinetic effect of digoxin which is a P-glycoproteinsubstrate. Clarithromycin and rifampin was used by the researchers as positive controlsfor digoxin induction and inhibition. The study subjects were 18 young adults which
ADVERSE EFFECTS OF HERBAL MEDICINES 9included nine females all in good health and were not under any form of medicationtherapy (Gurley et al., 2008). The participants were also told to avoid specific foods anddrinks that could interfere with the study. All subjects received all drugs in a randomsequence of supplementation phase first and then medication phase (Gurley et al.,2008). The supplementation phase which includes St. Johns wort or Echinacea lasted14 days. The medication phase with clarithromycin or rifampin was administered forseven days (Gurley et al., 2008). St. Johns wort was administered three times daily at300mg dosage, Echinacea three times daily at 2600 mg, clarithromycin wasadministered two times a day at 500 mg dosage and rifampin was administered twice aday at 300mg dosage(Gurley et al., 2008). Digoxin was always administered 24hbefore each supplementation or medication phase and on the last day of each therapy(Gurley et al., 2008). The results of this study showed that Echinacea had no significant effect on theblood concentration of digoxin when compared to the positive controls clarithromycinand rifampin. As a result no clinical effects were noticed (Gurley et al., 2008). Theadministration of St. Johns wort with digoxin resulted in a significant interaction. Theblood serum concentration of digoxin decreased 35% in the presence of St. John’s wort(Gurley et al., 2008). The concomitant administration of the positive control rifampinand digoxin also decreased the concentration of digoxin. Although this study includedequal amounts of gender participants the results did not showed a link between digoxin-herb interaction and gender. In regards to side effects two subjects had drowsinessduring the St. John’s wort phase (Gurley et al., 2008).
ADVERSE EFFECTS OF HERBAL MEDICINES 10 Gurley et al. (2008) study is of unique importance because it compared theresults of the herb-digoxin interaction to already documented digoxin interaction withrifampin and clarithromycin. This in turns produced a benchmark for evaluation of herb-digoxin interaction. The study also confirmed the researcher’s hypothesis that clinicalevents may be observed due to herb-drug interaction since two subjects during the St.John’s wort phase had drowsiness. However, a larger sample might be necessary toensure statistically significance. Another limitation is that no long term effects of theconcomitant administration of St. John’s wort and digoxin can be evaluated because thesupplementation phase only lasted 14 days. In summary, both the sample size and thelack of long term effects limit the applicability of these results to clinical practice. Werba et al. (2008) case report studied the effect of green tea on the simvastatintolerability. The authors’ literature review indicated that a patient’s adherence to statinsis directly affected by the most reported adverse effect of the drug; muscle cramps. Inthis case report the authors hypothesized that particular foods or fruit juices can alsointeract with statins and cause muscle cramps by increasing the bioavailability of thedrug (Werba et al., 2008). This case report involved a 61 year old male patient of whom a health historywas collected revealing a family history of coronary disease, hypertension andhypercholesterolemia but no family history of myopathy (Werba et al., 2008). Thesubject had been taking antihypertensive and cholesterol-lowering medications foreleven years (Werba et al., 2008). The cholesterol-lowering drug treatment had beenmodified between simvastatin, atorvastatin or rosuvastatin and eventually stopped bythe subject due to intense leg muscle cramps and pain (Werba et al., 2008). A physical
ADVERSE EFFECTS OF HERBAL MEDICINES 11examination of the subject revealed a minimal carotid atheroma upon ultrasonography(Werba et al., 2008). The subject was classified as generally healthy and physicallyactive. Upon nutritional history the researchers found that the patient typically drankthree cups of green tea each day to reinforce his health (Werba et al., 2008). The researchers accessed the bioavailability of simvastatin in order to study thepossible interaction of green tea and the drug by performing a kinetic study. The kineticstudy consisted of two parts. During the first part the subject took simvastatin 20mg/dfor five days and on the sixth day simvastatin was ingested fasting with a cup of greentea (Werba et al., 2008). During the second part the patient took the same simvastatin20mg/d for five days and on the sixth day simvastatin was ingested fasting with a cup ofwater (Werba et al., 2008). The patient’s plasma level of simvastatin lactone andsimvastatin acid were monitored for a month by a series of blood analysis (Werba et al.,2008). The results of the kinetic study showed that the levels of simvastatin lactone andsimvastatin acid were both higher during the concomitant ingestion of green tea andsimvastatin. In addition, the researchers reported that after stopping the green tea thepatient continued taking simvastatin 20mg/d with optimal tolerance for three months(Werba et al., 2008). The researchers concluded that due to the absence of intolerance during thewithdrawal of green tea and due to the blood results demonstrating high levels ofsimvastatin metabolites that the study suggested a clinically relevant green tea-statininteraction (Werba et al., 2008). In addition, Werba et al. (2008) suggested that uponmore investigation green tea should be considered an unexpected trigger for statintoxicity.
ADVERSE EFFECTS OF HERBAL MEDICINES 12 The main limitation of this study is that only one case was reported and analyzedwhich limits the applicability of the results to the overall population or even within thepopulation of cardiac patients. Another important limitation is that the subject’s level ofCYP450 3A4 the main enzyme that metabolizes simvastatin was not reported in thestudy. Werba et al. (2008) literature review stated that in healthy volunteers green teahad only minor effects on the activity of CYP450 3A4. Therefore, in reporting theactivity levels of this enzyme the authors would be able to narrow the cause of theirfindings to an herb-drug interaction rather than a possible individual geneticpredisposition of CYP450 to metabolize simvastatin faster when in the presence ofgreen tea. Nevertheless, in the face of lack of research addressing the topic of herb-druginteraction, the article is of unique value because it raises awareness among healthcare professionals about the subject. It also draws scientific conclusions based not onlyon laboratory inquiries but also based on clinical events. This intersection of methods isimportant for evidence-based nursing practices because it provides nurses with aclinical target to be observed when assessing medication history and/or drug adherencein cardiac patients. Application of the Literature to Practice The literature does not show conclusive findings in regards to specific adverseeffects of herb-drug interaction in cardiac drug therapy. However, it indicates that highrisk medications such as warfarin and digoxin have the greatest potential to interact withherbal medicines. The literature is consistent on the fact that the majority of patients donot tell their health care providers about the use of herbal medicines. In light of such
ADVERSE EFFECTS OF HERBAL MEDICINES 13knowledge nurses should include specific questions in their medication assessmentsuch as: Do you take any herbal supplements? In addition, nurses must be aware ofthe crucial role of educating cardiac patients about the potential risks of combiningherbal and allopathic medications. Conclusions There is a lack of research trials investigating the adverse effects cardiac drugtherapy when administrated with herbal medicines. Because heart disease is analarming problem in the United States all factors that may influence patient’s ability tocomply with the medication regimen must be addressed. Therefore further researchidentifying adverse effects of herb-drug interaction in a short and long term is of extremeimportance for cardiac patients. Until then, nurses must be aware of the most commonherb-cardiac drug interactions and educated patients on the possible risks of combiningherb and allopathic medication.
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