herbdrug interaction article thomsen 6 march 2007

8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007

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Herb-Drug Interaction

By Michael Thomsen, Hanni Gennat and Dr Mathias Schmidt

Michael Thomsen

HerbResearch International

29 Macfarlane St

Sth. Hobart TAS 7004

Australia

Tel: 61 3 6223 5332

Fax: 61 3 6223 4842

Email: [email protected]

Introduction

Herbal products need to be assessed for safety and efficacy. A comprehensive safety

profile should also contain information about proven and potential interaction between

pharmaceutical preparations (i.e., drugs) and herbal preparations. A herb-drug interaction

can be defined as a pharmacologic or clinical response to the coadministration of a

traditional drug or pharmaceutical preparation and an herbal product. Concurrent use of

herbs may magnify or oppose the effect of the traditional drugs; some herb-drug

interactions may be clinically insignificant, others may have serious consequences. As

more practitioners prescribe, and more consumers choose to use, herbal preparations, the

possibility of a herb-drug interaction increases. Serious consideration of concomitant

medication needs to be given in order to promote the safe use herbal products within the

community.

The search for information relating to herb-drug interactions is a challenge for health

service researchers, educators and practitioners, and readily accessible information is

lacking. Unfortunately, the majority of information about herb-drug interactions comes

from theoretical suspicions, animal or in-vitro data and anecdotal case reports which

frequently lack pertinent information or are conflicting. Very little information is derived

from well-designed clinical studies and controlled trials. Thus, the relevance of such

information in terms of clinical relevance is questionable. An additional complication is


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that the documentation of herb-drug interactions is an evolving process, and will continue

to be as the use of herbal preparations increases. To guide practitioners through this

process, documentation of herb-drug interactions using consistent and reliable guidelines

and protocol are required. This will allow practitioners to consider an alternative

treatment that is unlikely to produce undesirable interaction.

Types of Herb-Drug Interactions

Drug metabolism can be divided into two categories: Phase I reactions (biotransformation

into polar metabolites) and Phase II reactions (conjugation). With respect to herb-drug

interaction, Phase I metabolism is more relevant as it can occur during drug absorption,

before the drug reaches the systemic circulation. This presystemic clearance (or first-pass

metabolism) determines the fraction of the oral dose that will reach the systemic

circulation (i.e., the fraction of the dose that is bioavailable). Cytochrome P450

(CYP450) is the major drug metabolizing enzyme system for Phase I reactions and is

found in the greatest concentrations in the liver and gut wall. The many fates of Phase 1

(P450) metabolites includes: inactivity; equal activity; greater activity; toxicity, or;

activation of a prodrug.

Humans have 17 families of CYP450 genes; 3 of these families are dedicated tometabolizing (i.e., CYP 1, 2 and 3). Drug metabolism (Phase I) is largely mediated by

CYP3A (~50%) and CYP2D6 (~30%), with CYP1A2, 2C9/10, 2C19 and 2E1 accounting

for approximately equal percentages of the remaining 20%. Clinically, the important

aspects of CYP450 drug metabolism to be considered are: induction, inhibition and

genetic polymorphism.

Inducer drugs can decrease the therapeutic levels of substrates by increasing the P450enzyme concentration, or increasing the rate of metabolism of the inducing drug, or other

drugs taken concurrently. An herb-drug interaction may result in increased inactivation of

protease inhibitors and decreased effectiveness of a HIV cocktail, if taken with St Johns

wort, via CYP3A4. Inhibitors can increase the potential for toxicity from substrates by

blocking P450 enzymes that metabolize other drugs, and increasing the serum


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concentration of a second drug. Pharmacogenetics concerns genetic polymorphisms that

exist for many drugs, which may explain some idiosyncratic reactions.(Agins 2006)

There are three basic types of drug interactions: 1. interactions that increase the toxicityof one or more drugs in the system; 2. interactions that diminish the therapeutic benefit of

one or more drugs in the system; 3. interactions that enhance, stimulate or complicate the

existing disease process. Herb-drug interactions primarily concern blood

coagulation/clotting, drug metabolism and the central nervous system. Interactions

between herbs and medications can be caused by either pharmacodynamic or

pharmacokinetic mechanisms.

Pharmacodynamic interactions can occur when a herbal product produces additive

(synergistic) or antagonist (competitive) activity in relation to a pharmaceutical drug with

no change in the plasma concentration of either herbal product or drug.(Boullata 2005),

i.e., the two drugs affect a common system. Pharmacodynamic interactions are related to

the pharmacologic activity of the interacting agents and can affect organ systems,

receptor sites, or enzymes. Although the pharmacodynamic interactions may be fairly

predictable based on the knowledge of the mechanisms of both substances, the strength of

the effect is unknown and there is therefore uncertainty about the clinical relevance. This

is further confounded by the fact that individual responses frequently occur.

Herbs with a similar action to a drug should be used cautiously as additive effects may

occur, e.g., herbs with antiplatelet activity should be used with caution during

antiplatelet/anticoagulant drug therapy and perioperatively. Similarly, prescribing kava

(Piper methysticum) or valerian (Valeriana officinalis) with benzodiazepines due to

potential CNS depressive effects, herbal diuretics with pharmaceutical diuretics, or

antidepressants with St. Johns wort (Hypericum perforatum) should be undertaken with

caution, and monitoring of patients is essential.


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Antagonistic interactions occur when one drug compromises the effect of another. An

example is when a stimulant herb, such as guarana (Paullinia cupana) which contains a

high level of caffeine, is administered with a sedative-hypnotic or when immune

stimulating herbs such as astragalus (Astragalus membranaceus) or echinacea (Echinacea

sp.) are given with immunosuppressive drugs or when bitter herbs, e.g., gentian

(Gentiana lutea), is used with antacids to improve digestion. In addition, herbs with the

potential to cause organ toxicity may cause further risk of toxicity when drugs with

similar toxicity are administered concurrently, such as when the hepatotoxic herbal

comfrey (Symphytum officinale) is given with large and prolonged doses of

acetaminophen.(MacKinnon 2005)

Pharmacokinetic interactions occur when an herbal preparation changes the absorption

(via pH of stomach), distribution (via competition for protein binding), metabolism, or

excretion (one preparation slows the elimination of another) of a drug that results in

altered levels of the drug or its metabolites. Most of the current evidence of

pharmacokinetic drug interactions involves metabolizing enzymes and drug transporters

and most herb-drug interactions are related to metabolism by the CYP450 system or by

the effect of a herbal on the efflux drug transporter P-glycoprotein (PgP).(MacKinnon

2005) Most of the cases documented to date have concerned St. Johns wort.

In contrast, herbs such as cayenne (Capsicum spp.), coleus (Coleus forskohlii) or long

pepper (Piper longum) may increase drug absorption or availability and should be used

with caution. Absorption of drugs can be impaired when herbs that contain

hydrocolloidal fibers, gums, and mucilage are taken together. These herbals can bind to

drugs that can prevent absorption and, subsequently, reduce systemic

availability.(MacKinnon 2005) As an example, there have been case reports of reducedlithium serum concentrations taken concurrently with psyllium (Plantago ovata), which

inhibits the absorption of lithium.(Perlman 1990)Likewise, herbal laxatives such as aloe

latex (Aloe barbadensis), cascara (Rhamnus purshiana), rhubarb (Rheum palmatum), and

senna (Cassia spp.) can cause loss of fluids and potassium, and can potentially increase

the risk of toxicity with digoxin.(MacKinnon 2005)


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St Johns wort a cautionary tale

A detailed Medline search revealed a total of 32 drugs reported to interact with herbal

medicines in humans. These drugs include anticoagulants (warfarin, aspirin and

phenprocoumon), sedatives and antidepressants (midazolam, alprazolam and

amitriptyline), oral contraceptives, anti-HIV agents (indinavir, ritonavir and saquinavir),

cardiovascular drug (digoxin), immunosuppressants (cyclosporine and tacrolimus) and

anticancer drugs (imatinib and irinotecan). Most of them are substrates for CYP450s

and/or P-glycoprotein (PgP), many of which have narrow therapeutic indices.(Yang et al.

2006)

Most of these reports concerns the interaction with St. Johns wort. In the past 3 years,

more than 50 papers have been published regarding interactions between St. John's wort

and prescription drugs. Co-medication with St Johns wort has been documented as

decreasing plasma concentrations of a number of drugs, including amitriptyline,

cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam,

dextrometorphane, simvastatin, and oral contraceptives. This is not surprising as

sufficient evidence from interaction studies and case reports indicate that St Johns wort isa potent inducer of CYP450 enzymes (particularly CYP3A4) and/or PgP.(Madabushi et

al. 2006)

Recent studies could show that the degree of enzyme induction by St Johns wort

correlates strongly with the amount of hyperforin found in the product. Hyperforin is a

potent inductor of PgPs and CYP3A4.(Durr et al. 2000;Moore et al. 2000;Watkins et al.

2003;Wentworth et al. 2000) and in vitro studies suggest that this is the compound mostlyresponsible for triggering the interactions.


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The content of hyperforin varies from plant to plant according to cultivation method and

harvesting time, however depending on the extraction method and processing hyperforin

can be concentrated in pharmaceutical extracts in varying amounts.(Wurglics et al. 2001)

Some German extracts are artificially enriched in hyperforin and tablet preparations

contain significant amounts, whereas normal extracts contain only traces of hyperforin.

There is reason to believe that traditional hypericum extracts which are low in hyperforin,

do not cause a significant reduction in serum levels of drugs metabolized through the PgP

and CYP450/3A4 systems. The level of interaction of St John's wort and digoxin varies

has been found to depend on the particular extract, especially the level of hyperforin.

(Mueller et al. 2004;Mueller et al. 2006) Products that contain insubstantial amounts of

hyperforin (


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Although the active compounds have not yet been identified, St Johns wort appears to be

efficacious in the treatment of mild to moderate depression. It is assumed that the overall

clinical effect is caused by synergies between several constituents.(Butterweck et al.

2003;Vandenbogaerde et al. 2000;Verotta 2003) In other words, for St. Johns wort, the

total extract is considered to be the active ingredient. Hence, full-spectrum extract of St.

Johns wort, with a low, un-enhanced level of hyperforin, is not only efficacious; it is also

less likely to cause significant drug interactions.

St Johns Wort is the most studied herb in terms of interaction with pharmaceutical

preparations. It should not be taken concurrently with other antidepressants, with

coumarin-type anticoagulants, the immunosuppressants cyclosporine and tacrolimus,

protease and reverse transcriptase inhibitors used in anti-HIV treatment or with certain

antineoplastic agents. Fortunately the use of these drugs, with the exception of warfarin,

is rare and in all cases, the use of St. Johns Wort can easily be avoided,(Schulz 2006)

particularly if better labelling of herbal products is instigated.

Several other herbs have been tested since it was established that certain preparations of

St. Johns wort induces CYPP450 and PgP. Most of them have not been found to have a

significant effect. Although milk thistle (Silybum marianum), echinacea (Echinacea spp.)

and goldenseal (Hydrastis canadensis) have been found to inhibit CYP P450 enzymes in

vitro, the effect on antiviral drugs concentrations for example, has been found to be

clinically insignificant.(Lee, Andrade, & Flexner 2006)

The Chinese herb schisandra (Schisandra chinensis) has been shown to have a strong

inhibitory effect on CYP3A4. A recent study evaluated the inhibitory effects of

schisandra fruit and shoseiryuto (a traditional Japanese herbal medicine containing eight

herbal medicines including schisandra fruit) on rat CYP3A activity in vitro, and the effect

of shoseiryuto on pharmacokinetics of nifedipine in rats, in comparison with those of

grapefruit juice, a well-characterized natural CYP3A inhibitor. Shoseiryuto and its herbal

constituents, schisandra fruit, ephedra herb and cinnamon bark exhibited in vitro

inhibitory effect of CYP3A. Although shoseiryuto inhibited rat CYP3A activity in vitro


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with a degree comparable to grapefruit juice, shoseiryuto did not significantly affect a

plasma concentration profile of nifedipine in rats as grapefruit juice did. These results

indicate that in vivo experiments using the extract of herbal medicine prepared with the

same dosage form as patients take are necessary to provide proper information about

herbdrug interaction.(Makino, Mizuno, & Mizukami 2006)

One clinical study examined the potential interaction between the drug digoxin and

hawthorn (Crataegus monogyna), a herbal extract used in the treatment of cardiovascular

disorders, and found that hawthorn had no effect on the pharmacokinetic profile of

digoxin.(Tankanow et al. 2003) Additionally, a randomized, placebo-controlled study

found that hawthorn was a beneficial adjunctive treatment in type 2 diabetic patients

taking prescription drugs without causing any adverse drug interactions. There was a

significant group difference in mean diastolic blood pressure reductions in the hawthorn

group compared to the placebo group. No herb-drug interaction was found and minor

health complaints were reduced from baseline in both groups. (Walker et al. 2006)

Saw palmetto (Serenoa repens)(Markowitz et al. 2003a) and ginkgo (Ginkgo

biloba)(Markowitz et al. 2003b) have been shown not to alter CYP450, 2D6 and 3A4 in

healthy volunteers, as assessed by the test drugs tested for each herb, dextromethorphan

(CYP2D6) and alprazolam (CYP3A4).

Herb-drug interaction reporting and evaluation

There is justified concern regarding potential herb-drug interactions. Any reporting of

adverse or beneficial effects must be subject to true scientific rigour; otherwise the true

nature of potential adverse events may be misleading and under reported.

There are several limitations to the current adverse event reporting system, including

limited availability of medical records for the reported adverse events, lack of product


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ingredient information for the substances involved in the adverse event, and limited

information on the product by the manufacturers.(MacKinnon 2005)

It is estimated that less than 40% of users of CAM disclose use to theirphysician.(MacKinnon 2005) However, the prevalence of clinically significant

interactions between herbals and medications is unknown. Additionally, patients may not

inform health care providers of suspected interactions, or they do not attribute the

reaction to the natural product. American authorities estimate that 50% of adult

Americans use at least one prescription medication and 7% of adults take 5 or more

prescription drugs. Among prescription drug users, 16% also take herbal

supplements.(Kaufman et al. 2002) In Australia, it is estimated that about 50% of patients

frequently use a combination of a CAM product and pharmaceutical drugs. Like in the

US, patients are reluctant to disclose the use of CAM products to mainstream health

professionals. The attitude of mainstream health professionals towards CAM and

patients relationship with their health professional influenced patients decisions to

discuss their CAM use with mainstream health professionals, especially during the initial

phase of trying a CAM preparation. The reasons given by patients for not disclosing

CAM use to their mainstream health professionals were anticipation of a negative

response, belief that CAM use is a patients own healthcare issue, and a perception that

disclosure of CAM use is not relevant.(Bensoussan & Lewith 2004)

All too often, analytical verification of the composition of herbal medicine(s) is not

conducted by the researchers reporting the drug-interaction. This is an important

consideration, given that the relative composition of herbal constituents varies greatly due

to agricultural, harvesting and post-harvesting processes and because there is no agreed

standardisation profile of St. Johns wort extracts. The botanical identity of medicinal

plant must be established, especially where the origin of particular plants is unknown ordifficult to control. On closer examination of undesired drug effects attributed to the

intake of herbal remedies, discrepancies regarding the listing of the single compounds are

frequently found. It is often found retrospectively that adverse effects attributed to a

certain plant were not likely to have been caused by the herbal preparation, but as the

result of an intentional or accidental substitution with other plants, or by a contamination


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of the listed components with; a more toxic plant, a toxin (e.g. mould toxins or heavy

metals), or even with a chemically defined drug.(Awang 1996;Corrigan D 2001;Fugh-

Berman 2000)

If there is no such identification of herbal preparations, the unsubstantiated correlation of

toxic effects with the wrong plant will, in the future, lead not only to erroneous scientific

citations, but also to unsubstantiated warnings for patients and practitioners and official

claims for the labeling of side effects or drug-interactions on packages and leaflets

demanded by the health authorities.

Consistency is required when reporting herb-drug interactions, to ensure that this process

is performed in the most scientifically rigorous way possible, in order to determine the

true effect. Without further pathophysiological or biochemical investigation into the

specific reaction, proper evaluation cannot take place, and a conclusion cannot be made

as to the exact mechanism of herb-drug interaction. When reporting herb-drug

interactions, information regarding the plant parts used, the extraction medium, the

amount of drug taken and the method of preparation should be provided. In addition other

causes including past medical history, the use of recreational drugs or dietary factors

should be thoroughly investigated and considered.

Currently, herbal products in the US are regulated by the Dietary Supplement Health and

Education Act (DSHEA) of 1994. Under DSHEA, information regarding herbal-drug

interactions is prohibited on the label. Currently, manufacturers of dietary supplements

are not required to follow good manufacturing practices (GMPs) for drugs, but are

required to abide by the regulations of GMPs for food. The FDA is currently finalizing its

rule for GMPs specific for dietary supplements.(MacKinnon 2005)

The Australian Therapeutic Goods Administration (TGA) recognizes the importance of

including potential drug interaction on the label, however, the warnings are generally


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non-specific. Consumers are advised to consult a health professional. Therapeutic

products are produced under pharmaceutical GMP in Australia.

Contaminants or undisclosed pharmaceuticals and intentional or unintentional herbsubstation may actually be responsible for suspected herbal-drug interactions. Testing of

the quality of more than 1,200 dietary supplement products by the independent laboratory

ConsumerLab found that one in four products lacked the labeled ingredients or had other

serious problems, such as unlisted ingredients or contaminants. This creates a problem

when evaluating the validity of herb-drug interactions.(MacKinnon 2005)

The lack of available clinical data for many herbal products also serves as a barrier for

post-marketing safety assessment of herbal products. The evidence of herb-drug

interactions is often based on presumed pharmacological activity, data derived from in

vitro orin vivo animal studies, or anecdotal single case reports and case series, and

making decisions on this type of data is inconclusive and inadequate. Clinical

investigations are needed to validate in vitro herb-drug interactions.(MacKinnon 2005)

Interpretation and evaluation of the data confounds the establishment of clear clinical

guidelines. How should the evidence be weighed? What is the degree of certainty about

the drug interaction? Is the interaction definite, probable, possible, conditional or

doubtful? And what is the clinical relevance? Is the effect representative of a consistent

effect, or is the interaction a conditional response, a rare response or idiosyncratic? And

is the dose of the drug and/or herb clinically relevant? In many instances, articles warn of

dangerous interaction without actually providing much in terms of proof of their

statements. In a recent review, Butterweck and colleagues demonstrated that beliefs about

herb-drug interactions are mainly theoretical considerations, and not clinically observed

facts.(Butterweck et al. 2004) Herb-drug interactions do occur but equally, alcohol,

cigarette smoking and common foods such as broccoli and grapefruit juice may causeinteractions.

Other examples include the use of feverfew (Tanacetum parthenium), which may

decrease platelet aggregation and therefore affect antithrombotic (e.g., aspirin) or

anticoagulant (e.g., warfarin) medications. Similarly, herbal preparations such as ginkgo


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may increase the risk of hypotension in patients taking antihypertensive drugs, due to the

addititive effect of lowering blood pressure. Alternately, licorice (Glycyrrhiza glabra)

and ginseng may decrease the effectiveness of antihypertensive drugs, due to the nature

of their constituents. Herbs such as valerian and kava are purported to increase CNS

depression in patients taking antipsychotics or antiepileptic medications.

Ginger (Zingiber officinale) is often cited as having antiplatelet activity, however, there is

no evidence of an interaction of ginger with warfarin.(Stenton, Bungard, & Ackman

2001;Vaes & Chyka 2000), and ginger has been shown not to alter prothrombin times in

pooled human plasma collected from male volunteers between the ages of 18-57

years.(Jones, Miederhoff, & Karnes 2001) A standardized ginger extract has been shown

to have no significant effect on coagulation parameters or on warfarin-induced changes in

blood coagulation in rats.(Weidner & Sigwart 2000) However, an interaction between

ginger and the anticoagulant drug phenprocoumon has been reported.(Kruth et al. 2004)

Since ginger does not posses anticoagulant activity, it is possible that the interaction was

caused by ginger having a pharmacokinetic effect on phenprocoumon as evidence by an

elevated international normalized ratio (INR) of up to 10 and episodes of epistaxis. The

INR returned to normal levels when the ginger tea was discontinued.

In a systematic review of published case reports, case series, and clinical trials of herb-

drug interactions found that out of 108 reported cases of suspected interactions, 69%

were unable to be evaluated, 19% deemed to be possible interactions and only 13% were

well documented using a 10-point scoring system. Eleven out of 14 cases involved

warfarin and 7 out of 11 involved St. Johns wort.(Fugh-Berman & Ernst 2001)

A recent report estimated that herb-anticancer drug interactions are responsible for

substantially more unexpected toxicities of chemotherapeutic drugs and possible under-

treatment seen in cancer patients and that the knowledge of induction of drug-

metabolizing has identified herb capable of causing interactions with anticancer drugs:kava, vitamin E, quercetin, ginseng, garlic, beta-carotene, and echinacea.(Meijerman,

Beijnen, & Schellens 2006) However, there are no any actual case reports or clinical

studies actuallyprovingthat these herbs are causing significant anti-cancer drug

interactions, therapeutic failure or increased toxicity. Again, the concerns are mainly

theoretical. On the contrary, there are in vivo and clinical reports suggesting that such


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natural compounds may reduce the toxicity of chemotherapeutic agents and/or enhance

their therapeutic effect.(HemaIswarya & Doble 2006;Kachnic et al. 1997;Kang et al.

2002;Kiyohara et al. 1995;Melchart et al. 2002;Sakamoto et al. 1991;Sugiyama et al.

1994;Sugiyama et al. 1995;Sugiyama, Ueda, & Ichio 1995)

In a recent article, Holden and colleagues(Holden, Joseph, & Williamson 2005),

identified echinacea and other herbs as dangerous for patients taking arthritis medication.

The authors state that devils claw (Harpagophytum procumbens), ginkgo (Ginkgo

biloba) and garlic (Allium sativum) may have antiplatelet or anticoagulant effects, which

could potentially exacerbate the risk of gastrointestinal bleeding from non-steroidal anti-

inflammatory drugs or corticosteroids, except one case report, which discusses a rare and

unusual event of excessive garlic ingestion causing a spontaneous spinal epidural

haematoma, which would not be considered typical. The other references were

experimental studies or theoretical discussions. The authors concluded that 11% of

patients were taking remedies that might interact with conventional drugs. This statement

is misleading, as the concomitant intake of herbs and conventional drugs is not equivalent

to observation or reporting of herb-drug interactions.

Holden and colleagues assume that with the UK drug legislation changes and the transfer

of uncontrolled food supplements into registered drugs, an overwhelming number of

adverse event reports will surface. While underreporting is likely from the uncontrolled

marketing of food supplements, the expectation of a flood of adverse effect reports seems

exaggerated. In countries such as Switzerland and Germany the herbs in question have

long been registered drugs, and subject to pharmacovigilance with little cause for

concern.

Evidence for Herbal-Drug Interactions

Serious herb-drug interactions are most likely to occur with drugs that have a narrow

therapeutic dosage index such as lithium, digoxin, theophylline and warfarin. Warfarin is

known to interact with many drugs and can result in potentially fatal consequences if


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bleeding complications arise or subtherapeutic levels occur. Herbs that decrease platelet

aggregation, inhibit platelet-activating factor, or contain salicylates may increase the risk

for bleeding. Interactions between warfarin and these herbs should be considered

theoretical at the moment,(MacKinnon 2005) however practitionersshould use these

herbs with caution when combined with antiplatelet or anticoagulant therapy.

Many herbs contain coumarins which has led many authors to warn against interaction

with warfarin. However, coumarins need be converted to dicoumarol to have any direct

anticoagulant activity. This conversion only occurs when the fresh plant is improperly

stored leading to the conversion of coumarins to dicoumerol by fungal activity. Some

herbs also contain appreciable amounts of vitamin K, and consumption may antagonize

warfarin therapy. Drinking significant amounts of green tea should be avoided in patients

receiving warfarin, although smaller amounts may not produce any appreciable clinical

reduction in INR values.(MacKinnon 2005)

Dong quai (Angelica sinensis) has been shown to affect the pharmacodynamics but not

the pharmacokinetics of warfarin in rabbits. The root extract did not increase prothrombin

time independently, but significantly lowered prothrombin time values 3 days after co-

treatment with single dose warfarin. Treatment with dong quai did not produce any

siginificant differences in steady state concentrations of warfarin.(Lo et al. 1995) It has

also been reported that a 46-year-old African-American woman with atrial fibrillation

stabilized on warfarin experienced a greater than 2-fold elevation in prothrombin time

and INR after taking dong gui concurrently for 4 weeks. No identifiable cause was

ascertained for the increase except dongquai. The patient's coagulation values returned to

acceptable levels 1 month after discontinuing the herb.(Page & Lawrence 1999) These

reports indicate that dong quai should be used caution in patients on chronic warfarintherapy.

In a randomized, placebo-controlled study in healthy young volunteers, American

ginseng (Panax quinquefolium) antagonized the effect of warfarin. The effect was overall

modest, but most subjects had a reduction in INR values warfarin area under the curve,


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with some individuals having substantial changes while taking American ginseng.(Yuan

et al. 2004) However, due to the quality of this study, the mechanism of the interaction

cannot be properly evaluated, thus making the significance of the results difficult to

assess.(Jiang, Blair, & McLachlan 2006)

The fruits and seeds of ginkgo have been used in traditional Chinese medicine for

millenia in the treatment of lung congestion. It is however the dried leaf extract which is

mainly used today, manufactured using acetone-water and subsequent purification steps

without addition of concentrates or isolated ingredients. The extract ratio is 35-67:1

(average 50:1). The extract contains 22-27% flavone glycosides and 5-7% terpene

lactones (ginkgolides and bilobalide) and a level of ginkgolic acids below 5 ppm. Ginkgo

is used mostly for memory impairment, dementia, tinnitus, and intermittent claudication.

Adverse effects of ginkgo are usually mild, transient, reversible, and include

gastrointestinal symptoms, headache, nausea and vomiting. Potentially serious adverse

effects are bleeding, including subdural haematoma.(Izzo & Ernst 2001)

Drug interaction of ginkgo with warfarin is widely suspected, primarily based on

extensive in vitro data,and the theoretical potential for a pharmacodynamic interaction.

Ginkgo has also been found to significantly decrease platelet aggregation in healthy

subject and in type 2 diabetics taking ginkgo.(Kudolo, Dorsey, & Blodgett 2002)

However, controlled in vivo studies using EGb761, the most widely investigated

standardized extract ofGinkgo biloba, have found no significant independent effect on

platelet function and coagulation(Bal Dit, Caplain, & Drouet 2003) or additive effects on

coagulation parameters in patients receiving warfarin.(Engelsen, Nielsen, & Hansen

2003)

Furthermore, a recent study investigating herb-drug interactions with warfarin found very

little evidence of significant interaction. Serum warfarin concentration and response

(prothrombin complex activity) data from healthy subjects who received a single warfarin

dose (25 mg) and either St John's wort, Asian ginseng (Panax ginseng), ginkgo, or ginger

were examined. Coadministration of St John's wort significantly increased warfarin


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clearance, whereas treatment with Asian ginseng produced only a moderate increase in

warfarin clearance. Ginkgo and ginger did not affect the pharmacokinetics of warfarin in

healthy subjects. None of the herbs studied had a direct effect on warfarin

pharmacodynamics.(Jiang, Blair, & McLachlan 2006) The discrepancy between the in

vitro data and the lack of an interaction based on in vivo studies is likely to be a

consequence of the pharmacokinetics of the ginkgo constituents.

A few rare case reports suggest a possible connection between ginkgo and excessive

bleeding. A 78-year-old woman who had been taking warfarin for five years after

coronary bypass surgery suffered a left parietal haemorrhage after using a ginkgo product

for two months.(Matthews, Jr. 1998) No change was noted in her prothrombin time. The

intracerebral bleeding was attributed to the antiplatelet effects of ginkgo. However,

patients should be cautioned about potential interactions of ginkgo and drugs with

antiplatelet or anticoagulant effects.

In another reported case, a 33-year-old woman was diagnosed with bilateral subdural

hematomas after almost two years of ingesting ginkgo, in a dosage of 60 mg twice daily.

Her other medications were acetaminophen and an ergotamine-caffeine preparation,

which she used briefly. While she was taking ginkgo, her bleeding times were 15 and 9.5

minutes. Within 35 days after she stopped taking the ginkgo product, her bleeding times

were normal (3 to 9 minutes).(Rowin & Lewis 1996)

Herb-drug interaction in perspective

There is justified concern regarding potential herb-drug interactions. While there are

many articles discussing potential herb-drug interactions, there are very few actual cases.

Perhaps herb-drug interactions are under-reported. Perhaps they are actually quite rare

events. More clinical studies are needed to establish the clinical relevance and

significance of suspected herb-drug interactions.


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It seems prudent to be vigilant when prescribing herbal preparations for patients taking

any prescription medications, particularly the elderly, patients with impaired renal or

liver function, or taking critical drugs, (e.g., anti-HIV drugs, chemotherapy), and in

patients on drugs with a narrow therapeutic window (e.g., anti-rejection drugs, digoxin,

lithium and warfarin) and in patients suffering from serious and chronic diseases.

Additionally, clinical medical and natural practitioners alike, should be aware of common

pitfalls, including failure to: consider the effects of dose on the outcome of the

interaction; appreciate the time-course of drug interactions; consider the effects of

sequence of administration and; consider the pharmaceutical, herbal or dietary habits of

the patients. Practitioners should also be aware of making assumptions regarding: similar

magnitude of drug interactions among patients; separating doses to circumvent absorption

interactions, and: routes of administration interacting in the same way. On a practical

note, always recognize the potential for interactions at the level of metabolism when

prescribing. It may also be advantageous to include the patients family medical history,

and to update their drug history on a continual basis.(Agins 2006)

Any reporting of adverse or beneficial effects, however, must be subject to true scientific

rigour; otherwise the true nature of potential adverse events may be misleading and under

reported.

The following herb-drug interaction table outlines the most common and important herb-

drug interactions. It is not a complete reference and should be used as a guide only.

Drug Interaction Chart

Drug Sample

Trade name

Botanical

name

Common

name

Interaction

Alprazolam

(benzodiazapines)

Xanax Piper

methysticum

Kava GABA receptor

stimulation

Avoid. Co-

prescription

may increase

sedation.

Aspirin Aspro,

Solprin,

Astrix, Cartia

Ginkgo biloba Ginkgo Decreased platelet

aggregation

Avoid. Co-

prescription

may increase


18/29

bruising and

bleeding.

Betablockers and

other hypotensive

medication

Enalapril,

Peridopril,

Atenolol,

amlodipine

Glycyrrhiza

glabra

Liquorice Long-term use may

elevate blood

pressure

Avoid.

Carbamazepine Tegretol Hypericum

perforatum

St. Johns wort St. Johns wort

may decrease

serum levels.

Avoid.

Carbimazole

(antithyroid

medication)

Neo-

mercazole

Fucus

vesiculosus

Bladderwrack Bladderwrack

contains iodine.

Avoid.

Cortisone,

prednisolone

Cortate,

Presolone,

Solone

Glycyrrhiza

glabra

Liquorice May decrease

metabolism and

therefore potentiate

the effect.

Use with

caution.

Hypericum

perforatum


decreases serum

level.

Avoid.

Echinacea spp. Echinacea Opposite activity. Avoid.

Cyclosporin and

other

immunosuppressive

drugs

Neoral,

Cicloral,

Cysporin

Andrographis

paniculata

Andrographis Opposite activity. Avoid.

Hypericum

perforatum


decreases serum

level.

Avoid.

Crataegus spp. Hawthorn May increase

cardiac effects of

digoxin (possibly

without increasing

the toxicity).

Use with

caution.

Monitor

digoxin

dosage.

Digoxin Lanoxin,

Sigmaxin

Glycyrrhiza

glabra

Liquorice Potassium

depletion may

increase digoxin

toxicity

Avoid.

Haloperidol Serenace Ginkgo biloba Ginkgo May potentiate

effect of

heloperidol.

Use with

caution.

HIV Protease Indinavir Hypericum St. Johns wort St. Johns wort Avoid.


19/29

inhibitors and non-

nucleoside

transcriptase

inhibitors

perforatum decreases serum

indinavir.

Imatinib mesylate Glivec

(anticancer

drug)

Hypericum

perforatum


may increase

metabolism of

imatinib

Avoid.

Levodopa Madopa,

Sinemet

Piper

methysticum

Kava Kava may decrease

the effectiveness of

levodopa, because

of dopamine

antagonism.

Avoid. May

reduce the

effectiveness

of levodopa in

the treatment

of

symptoms of

Parkinsons

disease.

Oral contraceptives Diane-35 Hypericum

perforatum


decreases serum

levels.

Clinical

significance

unknown.

Phenprocoumon Anticoagulant Hypericum

perforatum


decreases serum

phenprocoumon.

Avoid.

Phenelzine

monoamine

oxidase inhibitor

Nardil Panax ginseng Korean

ginseng

Inhibits cAMP

phosphodiesterase

activity

Avoid.

Concomitant

use may result

in manic-like

symptoms

Selective Serotonin

Reuptake Inhibitors

Prozac Hypericum

perforatum

St. Johns wort Similar action. Avoid.

Sodium valproate Epilim,

Valpro

Ginkgo biloba Ginkgo Ginkgo has been

shown to reduce

the effects of

sodium valproate

in mice.

Avoid.

Theophylline Nuelin Hypericum

perforatum


decreases serum

theophylline.

Use with

caution.


20/29

Glycyrrhiza

glabra

Liquourice Increase in

potassium

excretion.

Avoid.Thiazide

(potassium

depleting diuretic)

Accuretic,

Amizide

Cassia senna

and other

laxative herbs

Senna and

other laxative

herbs

May cause further

potassium

depletion.

Avoid.

Thyroxine sodium Eutroxsig,

Oroxine

Lycopus spp. Bugleweed Interaction

unknown.

Avoid

Angelica

sinensis

Dong quai May decrease

platelet

aggregation.

Use with

caution.

Patients should

be monitored

for

prothrombin

and INR

values.

Allium sativa Garlic May decrease

platelet

aggregation.

Use with

caution.

Patients should

be monitored

for

prothrombin

and INR

values.

Cucurma longa Turmeric May decrease

platelet

aggregation.

Use with

caution.

Patients should

be monitored

for

prothrombin

and INR

values.

Warfarin Coumadin,

Marevan

Coleus

forskolhii

Coleus May decrease

platelet

aggregation.

Use with

caution.

Patients should

be monitored

for

prothrombin

and INR

values.


21/29

Ginkgo biloba Ginkgo May decrease

platelet

aggregation.

Use with

caution.

Patients should

be monitored

for

prothrombin

and INR

values.

Hypericum

perforatum

St. Johns wort May increase pro-

thrombin time and

international

normlized ratio

(INR) values.

Avoid.

Panax ginseng Korean

ginseng

May decrease

plateletaggregation.

May increase pro-

thrombin time and

international

normlized ratio

(INR) values.

Use with

caution.Patients should

be monitored

for

prothrombin

and INR

values.

Salix spp. Willow bark May decrease

platelet

aggregation.

Use with

caution.

Patients should

be monitored

for

prothrombin

and INR

values.

Salvia

miltiorrhiza

Dan Shen May decrease

platelet

aggregation.

Use with

caution.

Patients should

be monitored

forprothrombin

and INR

values.


22/29

Vaccinium

myrtillus

Bilberry May decrease

platelet

aggregation.

Use with

caution.

Patients should

be monitored

for

prothrombin

and INR

values.

Zingiber

officinale

Ginger May decrease

platelet

aggregation.

Use with

caution.

Patients should

be monitored

for

prothrombin

and INR

values.

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herbdrug interaction article thomsen 6 march 2007

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