Herb-Drug Interaction, Herbs, Counseling, Herbal Preparation INTRODUCTION Matter, Etc

International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 1, Supply 1, Nov.-Dec. 2009 Review Article

HERB-DRUG INTERACTIONS AND PATIENT COUNSELING MOHAMMAD YAHEYA MOHAMMAD ISMAIL* Dept. of Pharmacy, Higher College of Technology, P.O.Box 74 PC 133, Sultanate of Oman E mail: [email protected] (*Corresponding author)

ABSTRACT Millions of people today use herbal therapies along with prescription and non prescription medications. Although considered natural, many of these herbal therapies can interact with other medications, causing either potentially dangerous side effects and / or reduced benefits from the medication. Currently, there is very little information published on herb-drug interactions whilst the use of herbs is progressively growing across the world. As there is large belief that herbal medicines are safe to use, it needs to be understood that depending on the amount and potency of the pharmacologic principles contained in the herbal preparation, potential exists for herb-drug interaction to occur when the herbal product is consumed with the modern day medicine. It should be understood that herbal preparations contain active phytochemicals in varying proportions which have a tendency like any other active pharmacological substance to alter the enzymatic systems, transporters and / or the physiologic process. The intent of this review is to update on some imminent issues that may arise if the modern medicine is mixed with a suspecting herbal preparation. These situations may arise in our daily lives due to the lack of strict adherence to regular drug prescription practices, unabated use of over the counter drug products and / or self prescription practices. Health-care practitioners should caution patients against mixing herbs and pharmaceutical drugs. Keywords: Herb-Drug Interaction, Herbs, Counseling, Herbal Preparation INTRODUCTION matter, etc. Herbal drugs constitute only those Herbs have been used for medicinal purposes traditional medicines, which primarily use since the beginning of recorded time. medicinal plant preparation for therapy. Although most people believe that herbs are WHO estimates that about three quarters of harmless plants, about one third of our drugs world population currently use herbs and (including digitalis, morphine, atropine and other forms of traditional medicines to treat several chemotherapeutic agents) were developed their disease. Even as we entered into the new from plants. So, indeed, herbs can be potent century with its exciting prospect of gene products. Herbs can affect body functions; therapy, herbal medicines remain one of the therefore, when herbs are taken concurrently common forms of therapy available to the with drugs, interactions are possible. world population. The increasing awareness of herbal medicines Botanical medications have increased in is acknowledged by World Health popularity. In the United States, botanical Organization (WHO). WHO has recently products are now a $1.5 billion per year defined traditional medicine (including herbal industry. It is estimated that 60% to 70% of drugs) as comprising therapeutic practices the American population is taking botanical that have been in existence, almost for several products, but less than one third of these hundreds of years, before the development persons inform their medical practitioners of and spread of modern medicine and still in such use1. use today. The traditional preparations Today, our understanding of the interactions comprise medicinal plants, minerals, organic between drugs and herbs and between drugs

151 and food is still in its infancy. Much research increases with the number of products is still required in herbal therapy to examine consumed e.g., for 2 products, the risk is 6%; individual plant constituents and to determine for 5 products, 50%; and for 8 or more how plants interact with drugs and food. products, 100%4. The mechanisms for drug Some researchers suggest that herb-drug interaction can be divided into two general interactions occur less often than predicted. If categories i.e. pharmacokinetics (absorption, an interaction between an herb and a drug distribution, metabolism, and excretion of a does occur, conventional drugs are usually drug) and pharmacodynamic interactions (the the culprits because they are more combined pharmacological effects of a drug). pharmacologically active2, 3. Pharmacokinetic interactions In this review an attempt has been made to Absorption update the most commonly occurring herb- Herbs that have hydrocolloidal carbohydrate drug interactions. components such as gums and mucilage are HERB-DRUG INTERACTIONS soluble in water but poorly absorbable; Many medicinal herbs and pharmaceutical examples include psyllium, rhubarb, flax- drugs are therapeutic at one dose and toxic at seed, marshmallow and aloe. These another. Interactions between herbs and drugs compounds bind to other drugs, particularly may increase or decrease the pharmacological when consumed in their whole or powdered or toxicological effects of either component. forms. For example, psyllium (an herb high in Synergistic therapeutic effects may mucilage) inhibits the absorption of lithium. complicate the dosing of long-term Rhubarb and aloe can cause diarrhea, which medications e.g., herbs traditionally used to reduces the action of drugs that have a narrow decrease glucose concentrations in diabetes therapeutic index (eg, digoxin, warfarin). In could theoretically precipitate hypoglycaemia order to prevent an herb from binding with if taken in combination with conventional drugs, the drug should be taken 1 hour before drugs. Because of the possible herb–drug or 2 hours after these herbal products. interactions, health care providers need to be Distribution aware of herb and supplement use by their Herbs such as meadowsweet and black patients 1. willow, which contain pain-reducing A drug interaction is defined as any salicylates, may displace highly protein- modification caused by another exogenous bound drugs such as warfarin and chemical (drug, herb or food) in the carbamazepine thus increasing the adverse diagnostic, therapeutic or other action of a effects of these drugs. These products should drug in or on the body. The possibilities of not be taken concurrently 2, 3. drug interaction are endless, because more Metabolism than 30000 over-the-counter products; more Liquorice (as an herb, not a sweetener) than 1000 unique chemical substances from decreases the metabolism of corticosteroids, which prescription drugs are produced; and leading to adverse and toxic effects from the hundreds of herbs, vitamins and minerals are buildup of corticosteroids. Recently, available. The risk for drug interactions researchers discovered that St. John’s wort

152 can induce hepatic microsomal enzymes in Many medicinal herbs contain anticoagulant the cytochrome P-450 system; thus, it coumarins (not all coumarins are increases the metabolism of drugs anticoagulant), which can also have additive metabolized in this system, such as digoxin effects when combined with pharmaceutical and theophylline, protease inhibitors and anticoagulants7. A Chinese herb, danshen cyclosporine. The drugs are thus rendered less (Salvia miltiorrhiza) has been associated with effective, so concurrent use of liquorice with three cases of profound anticoagulation in these drugs is not recommended 2, 3. patients on warfarin. Dong quai or danggui Pharmacodynamic interactions (Angelica sinensis, syn A. polymorpha), An example of a pharmacodynamic another Chinese herb, doubled prothrombin interaction is additive activity. For example, time (PT) and International Normalized Ratio the hypnotic activity of benzodiazepines is (INR) in a 46-year-old African-American increased by valerian and the anticoagulant woman, previously stabilized on warfarin, action of warfarin is enhanced by ginkgo and who had ingested dong quai for four weeks. possibly by many other herbs. It is best not to Laboratory values normalized within one take these products concurrently 3. month of discontinuing the herb8. In rabbits, INTERACTION RISKS IN SPECIFIC dong quai extract affected neither baseline PT PATIENT POPULATIONS nor warfarin pharmacokinetics9. Given the The following section reviews potential case reports, however, caution would dictate effects of dietary supplements in patients that patients avoid combining dong quai with taking anticoagulants, cardiovascular warfarin. medications, psychiatric medications, laxatives, In one poorly documented case report, the diabetic medications or medications for anticoagulant effect of warfarin was human immunodeficiency virus (HIV) potentiated by consuming an extract of the infection. green fruit of papaya (Carica papaya) 10. Patients receiving anticoagulants Green papayas, high in papain are commonly Warfarin and other coumarin anticoagulants consumed in Southeast Asia. Although interact with many drugs, foods and feverfew (Tanacetum parthenium) and ginger medicinal herbs. Both garlic (Allium sativum) (Zingiber officinale) often are invoked as and ginkgo (Ginkgo biloba) interfere with anticoagulant herbs in the literature, no cases platelet function in vitro and may increase the of bleeding problems have been linked to risk of bleeding when combined with these herbs. Although feverfew extracts and warfarin. Garlic inhibits platelet aggregation its sesquiterpene lactone constituents, notably and fibrinolytic activity in both patients with parthenolide, inhibit platelet aggregation by coronary artery disease and healthy subjects inhibiting serotonin release, neither bleeding and has been associated with postoperative episodes nor abnormal coagulation tests have bleeding and spontaneous spinal epidural been reported. Although ginger inhibits hematoma5,6. In ginkgo, the constituent platelet aggregation induced by arachidonic ginkgolides are potent antagonists of platelet acid, epinephrine, adenosine diphosphate and activating factor. collagen and a case report associated

153 consumption of a marmalade containing 15% Specifically, patients receiving American raw ginger with inhibited platelet ginseng should be monitored when changing aggregation, clinical studies are reassuring11-13. products or even bottles of the same Case reports have shown interactions between product27. the anticoagulant warfarin (Coumadin) and Patients receiving cardiovascular St. John's wort, ginkgo, garlic and medications ginseng14,15. Studies have demonstrated that Of all the supplements used by patients who St. John's wort increases the metabolism of have cardiac disease, St. John's wort, used to warfarin, leading to diminished serum treat mood disorders, is associated with the levels16-19. However, the clinical response to most interactions. It decreases serum levels of the combination has not been quantified. verapamil and statins21,22,28. Blood pressure Ginkgo does not interact with warfarin or and lipid levels, respectively, should be aspirin directly, but has demonstrated monitored closely if a patient is taking one of antiplatelet activity20-21. In combination with these drugs and St. John's wort. nonsteroidal anti-inflammatory drugs, The suspected mechanisms of St. John's wort especially aspirin, ginkgo has been reported interactions are by the induction of to cause severe bleeding, including cytochrome P450 (CYP450) isoenzymes intracranial bleeding22-24. CYP3A4, CYP2C9, CYP1A2 and the Garlic has intrinsic antiplatelet activity. transport protein P-glycoprotein, leading to However, one clinical trial has demonstrated decreased concentration of medications18. In that garlic is safe and without any serious one study, St. John's wort decreased digoxin hemorrhagic risk for monitored patients blood levels by 25 percent, most likely by taking warfarin25. inducing the P-glycoprotein, which decreases A low-quality clinical study found no effect the bioavailability of digoxin29,30. Ginseng is of Asian ginseng (Panax ginseng) in another commonly used herb that has been combination with warfarin16. American reported to cause an increase in digoxin ginseng (Panax quinquefolius), a separate serum levels in a case report of one patient31. plant, decreases warfarin serum levels in Digoxin levels should be monitored in humans, resulting in less anticoagulation26. patients taking eleuthero or St. John's wort. Eleuthero (Eleutherococcus senticosus) has Consuming yohimbe (Pausinystalia yohimbe) not been studied; however, it contains a bark or extract increases the risk of constituent that inhibits platelet aggregation. hypertension. The constituent alkaloid, The narrow therapeutic index of warfarin and yohimbine (used conventionally to treat the serious consequences associated with erectile dysfunction), increases blood small changes, the anticoagulation status in pressure more in hypertensive than in patients taking dietary supplements should be normotensive subjects32. Hypertensive effects carefully monitored whenever they initiate or are potentiated when yohimbine is combined stop taking any supplement or when a new with tricyclic antidepressants33. bottle of the same product is used, untill the Foxglove (Digitalis purpurea) and other effect in the individual patient is known. herbs contain cardiac glycosides that could

154 have an additive effect with digitaloid cardiac (Cyamopsis tetragonolobus), psyllium glycosides34 but these are not commonly used (Plantago spp.), konjac (Amorphophallus medicinal herbs. The only reported case of an rivieri) and others, taken in sufficient quantity herb-drug interaction associated with digitalis can delay gastric emptying and reduce the proved to interfere between a preparation rate of absorption of carbohydrates and drugs, purported to contain Siberian ginseng including lithium, glibenclamide, lovastatin, (eleuthero) (Eleutherococcus senticosus) and tricyclics and digoxin41-45. Laxative herbs that the digoxin assay, causing spuriously elevated contain stimulant anthranoids, including digoxin levels 31. senna species (Cassia senna, C. acutifolia, Patients receiving psychiatric medications and C. angustifolia), Chinese rhubarb (Rheum St. John's wort may have an effect on officinale), cascara sagrada (Rhamnus serotonin levels. It has been associated with purshiana), frangula or alder buckthorn serotonin syndrome in patients also receiving (Rhamnus frangula), yellow dock (Rumex a selective serotonin reuptake inhibitor crispus) and aloe, the leaf exudate of Aloe (SSRI).35 St. John's wort should be tapered vera, can decrease the absorption of off when an SSRI is initiated36. Patients intestinally absorbed drugs due to an should be cautioned not to initiate St. John's increased rate of intestinal transit46. wort when receiving these drugs. Patients receiving diabetes medications St. John's wort decreases serum levels of Glucose control in both insulin-dependent psychiatric medications metabolized by the (type 1) and non-insulin dependent (type 2) CYP450 enzyme system. It has been shown diabetics can be affected by consumption of to affect serum levels of benzodiazepines and hypoglycemic herbs. tricyclic antidepressants, although these More than 400 plants have been traditionally changes may not result in a clinical effect37-39. used for their hypoglycemic action;47 of Patients taking bulk laxatives these, Aloe vera, syn. A. barbadensis, leaf Psyllium and related bulk-forming laxatives juice;48 the fruit of bitter melon/karela are dietary supplements often not considered (Momordica charantia) (found to improve to be medications by many patients. glucose tolerance without increasing insulin However, they can slow or diminish levels);49,50 and the seeds of fenugreek absorption of many drugs. Psyllium can (Trigonella foenum-graecum),51 are reduce carbamazepine absorption and serum commonly used herbs with documented levels40. Additionally, there is a case report hypoglycemic effects. Also, two clinical showing that psyllium decreased the studies with a water-soluble acidic fraction of absorption of lithium41. As a general rule, an ethanol extract of gurmar (Gymnema bulk laxatives such as psyllium should not be sylvestre) leaves have reportedly reduced taken at the same time as other medications; insulin requirements in both insulin- their use should be separated by several hours dependent and non-insulin-dependent to allow absorption to occur. diabetics, effects comparable to those Bulk-forming laxative herbs, such as the observed with Aloe vera juice and hydrocolloidal-fiber-containing guar gum glibenclamide.52-54 Antidiabetic effect of

155 fenugreek is attributed to intestinal effects of PATIENTS COUNSELING ABOUT the gum fiber (galactomannans), which also HERB-DRUG INTERACTIONS displays hypocholesterolemic activity 51. Use of herbal and dietary supplements is Ginseng has hypoglycemic activity in patients extremely common. In one US survey of with diabetes and this effect might be additive adults who regularly take prescription in patients taking oral hypoglycemics or medication, 18·4% reported the concurrent insulin. Chromium and psyllium also have use of at least one herbal product or high-dose hypoglycemic effects55-57. The effect of these vitamin (and 61·5% of those who used supplements is unpredictable in individuals unconventional therapies did not disclose and no specific changes in hypoglycemic such use to their physicians)62. A survey of doses are needed unless blood glucose 515 users of herbal remedies in the UK found changes occur. that 26% would consult their general While additive effects are certainly possible practitioner for a serious adverse drug when these herbs are combined with the reaction associated with a conventional over- hypoglycemic drugs, appropriate self- the counter medicine, but not for a similar monitoring by the patient and clear lines of reaction to a herbal remedy63. Patients may communication between the patient and not be forthcoming about the use of herbal health care practitioner should avert medicine even if it causes severe adverse problems. effects because they fear censure. Clinicians Patients receiving hiv medications must ask patients about their use of herbs in a Most antiretrovirals are metabolized via the non-judgmental, relaxed way. A disapproving CYP3A4 and P-glycoprotein systems. Dietary manner will ensure only that a patient will supplements that induce these systems may conceal further use. The patient should be decrease serum levels of the antiretrovirals. treated as a partner in watching out for St. John's wort is the dietary supplement with adverse reactions or interactions and should the most evidence of an effect on these be told about the lack of information on systems58. Limited clinical research has interactions and the need for open demonstrated reductions in antiretroviral communication about the use of herbal serum concentrations in patients taking garlic remedies. and vitamin C59, 60. Milk thistle, Echinacea Formulation, brand, dose and reason for use species, and goldenseal inhibit CYP450 of herbs should be documented on the enzymes in vitro, but not to a clinically patient’s charts and updated regularly. Any relevant effect58, 61. The effectiveness of HIV laxative or bulk-forming agents will speed therapy should be monitored in patients intestinal transit and thus may interfere with taking these supplements, particularly St. the absorption of almost any intestinally John's wort. Because of the risk of a absorbed drug64. The most popular stimulant dangerous interaction, patients taking laxative herbs are the anthranoid-containing antiretrovirals should be discouraged from senna (Cassia senna and C. angustifolia) and using St. John's wort. cascara sagrada (Rhamnus purshiana).

156 Dried exudate from the aloe vera (Aloe may potentiate the action of corticosteroids, barbadensis) leaf (not gel) also contains and betel nuts have pronounced cholinergic anthranoids and is used as a laxative. Aloe effects. There are doubtless many as yet vera gel, found within the leaves, is used undiscovered interactions. topically for burns and cuts and is sometimes CONCLUSION recommended by herbalists for internal All drugs with a narrow therapeutic index ingestion to treat ulcers and other disorders. may either have increased adverse effects or The gel (or juice made from the gel) does not be less effective when used in conjunction contain anthranoids, but some oral with herbal products. More research is preparations are contaminated by the laxative required to define the interactions. When leaf. Less commonly used anthranoid- adverse reactions are experienced with drug containing plants are frangula (Rhamnus therapy, patients must always be queried as to frangula), yellow dock (Rumex crispus) and their intake of herbal products e.g., what they Chinese rhubarb (Rheum officinale). Patients are taking in pills and tincture form, what they with clotting disorders, those awaiting are drinking as teas, and what food they are surgery or those on anticoagulant therapy eating65, 66. should be warned against the concurrent use Patients taking drugs with a narrow of ginkgo, danshen, dong quai, papaya or therapeutic index (cyclosporine, digoxin, garlic. Although the combined use of hypoglycemic agents, lithium, phenytoin, anticoagulants with these herbs should be procainamide, theophylline, tricyclic discouraged, patients who insist on the antidepressants and warfarin) should be combination should have their bleeding times discouraged from using herbal products.2, 65 monitored (most of these herbs interfere with Concurrent use of herbs may mimic, magnify, platelet function, not the coagulation cascade or oppose the effect of drugs. Plausible cases and thus will not affect prothrombin time, of herb-drug interactions include bleeding partial thromboplastin time, or international when warfarin is combined with ginkgo normalised ratio [INR]). Many other herbs (Ginkgo biloba), garlic (Allium sativum), also contain anticoagulant substances; as a dong quai (Angelica sinensis) or danshen precaution, patients on warfarin should have (Salvia miltiorrhiza); mild serotonin an INR measurement within a week of syndrome in patients who mix St John’s wort starting any herbal treatment. Patients on (Hypericum perforatum) with serotonin- serotonin-reuptake inhibitors, cyclosporin, reuptake inhibitors; decreased bioavailability digoxin, phenprocoumon or any critical of digoxin, theophylline, cyclosporin, and chronic medication should avoid St John’s phenprocoumon when these drugs are wort; those on phenelzine should avoid combined with St John’s wort; induction of ginseng and those on tricyclic antidepressants mania in depressed patients who mix should avoid yohimbine. Patients taking antidepressants and Panax ginseng; phenytoin should avoid Ayurvedic herbal exacerbation of extrapyramidal effects with mixtures for seizures. Liquorice (a very neuroleptic drugs and betel nut (Areca common ingredient in Chinese herb mixtures) catechu); increased risk of hypertension when

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