Herb–drug interactions

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chapter 5 Herb–drug interactions

INTRODUCTION

Complementary medicines such as herbal medicines are available through a variety of channels such as supermarkets, pharmacies, health-food stores, clinic rooms, internet sites and mail order companies. Many people self-select their products and do not receive professional advice about their safe and appropriate use.1,2 When using a complementary medicine, many do not discuss its use with their medical practitioner, either in the community or in the hospital setting.1,3–14 Importantly, people using complementary medicines tend to have poorer health than the general community15 and are not generally dissatisfied with conventional medicine but use complementary medicines as an adjunct to conventional medical care.1,4,16,17 This raises the possibility of dual care from both complementary and conventional practitioners and the concomitant use of herbs and pharmaceutical medicines. Widespread use, self-selection and poor disclosure suggest that many people feel sufficiently confident that over-the-counter (OTC) herbal medicines are beneficial and that their safety is assumed. This assumption is supported by several Australian studies.1,18

The assumed safety of herbal medicines is sometimes attributed to the fact that they are considered ‘natural’ and therefore inherently safe. This view is encouraged by some in the health-food industry and is too simplistic. Nature provides us with many examples of unsafe substances, such as the naturally occurring poisons hemlock, jimsonweed and oleander. Also, the concept of safety is a complex one and is ultimately determined by two main variables: ‘likelihood’ and ‘consequence’. For each individual and their particular circumstances, the concept of safety has to be redefined.

Australia’s risk-based regulatory process for therapeutic goods (including herbal medicines) provides some safeguard. Clinicians can feel reassured that OTC herbal medicines allocated an AUST L number have been produced according to the Code of Good Manufacturing Practice (GMP) and their ingredients assessed for safety. Alternatively, potentially unsafe herbal medicines have warning labels and may even be restricted from sale via the scheduling system, much like pharmaceutical medicines (more information about the regulation of herbal products can be found in Ch 4).

Despite this, it has become apparent over the past decade that some commonly used OTC herbal medicines are capable of causing significant drug interactions, which must be identified and managed to optimise patient safety. Open communication, familiarisation with the most commonly used complementary medicines and understanding the interaction mechanisms involved are vital first steps in promoting patient safety. This chapter provides an introduction to herb–drug interactions; detailed information about specific herb–drug interactions is beyond the scope of this chapter. Comprehensive drug–herb interaction charts and further information are available in Herbs and natural supplements—an evidence-based guide by Braun & Cohen.19

INTERACTIONS

Herbs contain a chemically complex cocktail of naturally occurring ingredients. In this way, they are very different from pharmaceutical medicines. The pharmacological effect of a herbal medicine is the end result of an interplay between various interactions. There are intra-herbal interactions between constituents, interactions between the herb and the vehicles it is mixed with during processing and manufacture, and then the final interaction between the product and person receiving it. Interactions can also occur between the foods, drugs and other herbal medicines being taken by that individual. As you can see, interactions are unavoidable and should not present any clinical problem unless they are unanticipated.

In medicine, a pharmacological interaction is an alteration of the usual predicted effect of one substance when used at the same time as another. Usually the term ‘interaction’ has a negative connotation when referring to therapeutic agents, as interactions can lead to adverse effects, drug toxicity or a loss of drug effect, and clinical outcomes can be difficult to predict. Interactions need not have negative outcomes; when manipulated skilfully they can be harnessed to produce beneficial outcomes, and managed or avoided to reduce harm. In clinical practice, this occurs every day.

THE MAIN INTERACTION MECHANISMS: OVERVIEW

Considering the great variation in physical properties and pharmacological effects of the numerous substances used as medicines, together with the variable nature of herbal medicines, a virtually endless number of interactions is possible. Interaction mechanisms can be broadly categorised as pharmacodynamic or pharmacokinetic interactions (Fig 5.1). Regardless of the interaction mechanism at work, there are three possible outcomes:

• increased therapeutic or adverse effects
• decreased therapeutic or adverse effects
• a unique response that does not occur when either agent is used alone.
image

FIGURE 5.1 The main classes of interactions

PHARMACOKINETIC INTERACTIONS

A pharmacokinetic interaction occurs when substance A alters the absorption, distribution, metabolism or excretion of substance B, causing a change in the amount and persistence of the available substance B at receptor sites or target tissues. The interaction causes a change in the strength or duration of effect, but not the type of effect.

Absorption

Most absorption of orally administered medicines occurs in the small intestine, which has a larger surface area than the stomach and greater membrane permeability. If a slow-release dosage form is taken and it continues to release the drug for more than 6 hours, then absorption will also occur in the large intestine. The absorption of oral dose forms is influenced by differences in pH along the gastrointestinal tract, surface area per luminal volume, blood perfusion, the presence of bile and mucus, and the nature of epithelial membranes. Changes to gastrointestinal flora, transport systems, chelation and ion exchange also influence absorption. Ultimately, a change to any of these processes can alter the rate and/or extent of absorption.

A reduced rate of absorption can lead to a ‘sustained release’ effect, whereas a reduced extent of absorption is particularly problematic for drugs with a narrow therapeutic index (NTI). Gums and mucilages (such as guar gum and psyllium) are examples of substances known or thought to affect drug absorption. For example, a double-blind study found that guar gum slowed the absorption rate of digoxin but did not alter the extent of absorption, whereas penicillin absorption was both slowed and reduced.20 This brings into question the effects of other gums and highly mucilaginous herbal medicines such as Ulmus fulvus (slippery elm), Althea officinalis (marshmallow) and Plantago ovata (psyllium). Poorly lipid soluble, the mucilaginous content forms an additional physical barrier that needs to be traversed before the medicine can enter systemic circulation. Whether this will have clinically significant effects on the rate and/or extent of absorption of other medicines is uncertain and remains to be tested.

More research has been conducted on the way in which nutrients interact and alter the absorption of other medicines. The interactions between iron and mineral-based antacids are a useful example. Separating the intake of iron and the last antacid dose by at least 2 hours reduces the risk of interaction.19

Metabolism

Drug metabolism involves a wide range of chemical reactions, including oxidation, reduction, hydrolysis, hydration, conjugation, condensation and isomerisation. These processes largely determine the duration of a drug’s action, elimination and toxicity.

Metabolism can occur prior to and during absorption, thereby limiting the amount of drug reaching systemic circulation; however, most drug metabolism occurs in the liver in two apparent phases, known as phase 1 and phase 2.

Phase I reactions involve the formation of a new or modified functional group or a cleavage (oxidation, reduction, hydrolysis), whereas phase 2 reactions involve conjugation with an endogenous compound (e.g. glutathione, amino acids, sulfates, glycine). The metabolites produced after phase 1 metabolism are often chemically reactive and may even be more toxic or carcinogenic than the initial drug. A well-known example is paracetamol, whose phase 1 metabolite is chiefly responsible for its toxicity. Metabolites produced after phase 2 reactions are usually inactive.

Although there are many enzymes responsible for phase I reactions, the most important enzyme group is the cytochrome P-450 system (CYP). Many factors can interfere with CYP activity, such as the ingestion of environmental contaminants, certain food constituents, beverages, herbs and pharmaceutical medicines. Some of these factors induce CYP enzymes, whereas others have an inhibitory effect.

Enzyme inhibition is an immediate response, with effects seen rapidly.21 It can be reversible, quasi-reversible or irreversible. In practice, most inhibition is reversible, ceasing when use of the inhibitor agent is discontinued. The result of CYP enzyme inhibition is elevated serum levels of those drugs chiefly metabolised by the affected enzyme. Medicines with narrow therapeutic margins, such as digoxin, are of particular concern as small elevations in serum levels have the potential to produce toxic effects. In practice, enzyme inhibition is not always harmful and has been manipulated to raise serum drug levels without the need to increase the dose administered. The result has obvious cost advantages when expensive drugs are involved and has been used in some hospitals for medicines such as cyclosporin. Grapefruit is one example of a natural product having significant enzyme inhibition effects.

Unlike enzyme inhibition, enzyme induction is a relatively slow process and results in reduced serum levels of the drugs chiefly metabolised by the affected CYP enzyme. Many different medicines and everyday substances have been found to be capable of inducing CYP enzymes—examples are broccoli, brussel sprouts, chargrilled meat, high-protein diets and alcohol.19

St John’s wort is a good example of a herbal substance capable of interacting with a variety of drugs through this mechanism. Clinical studies have confirmed that long-term administration of St John’s wort has significant CYP inducer activity, particularly CYP3A4.22–25 This is significant because CYP3A4 is responsible for the metabolism of many pharmaceutical drugs. Studies have isolated the hyperforin component as a potent ligand for the pregnane X receptor, which regulates expression of CYP3A4 mono-oxygenase. In this way, hyperforin increases the availability of CYP3A4, resulting in enzyme induction.26 Examples of CYP3A4 substrates are alprazolam, codeine, erythromycin and simvastatin. Importantly, low-hyperforin St John’s wort extracts such as Ze 117 do not significantly induce CYP3A4, 2D6, 2C9, 1A2 or 2C19, according to human pharmacokinetic studies.27–29 As such, the Ze 117 extract may present a safer treatment option for patients taking multiple drugs at the same time.

Excretion

Drug excretion occurs chiefly via the kidney but also to a lesser extent via the colon, saliva, sweat, breast milk and lungs. If a medicine is eliminated chiefly by one pathway, then alterations to that particular pathway can theoretically have a significant influence on its excretion. In the case of urinary excretion, factors that alter urinary pH are of prime importance. For example, the half-life of an acidic medicine, such as a salicylate, can be increased with the acidification of urine, such as with high-dose ascorbic acid ingestion, because less is eliminated.

PHARMACODYNAMIC INTERACTIONS

A pharmacodynamic interaction occurs when one substance alters the sensitivity or responsiveness of tissues to another substance. This type of interaction results in additive, synergistic or antagonistic drug effects. Pharmacodynamic interactions can also occur when therapeutic substances with overlapping side effects or toxicities are used together, leading to more serious side effects than when either substance is used alone. A good understanding of the pharmacological activity of the therapeutic substances involved can help to theoretically predict potential interactions and optimise therapy.

In practice, clinicians of every variety frequently use additive or synergistic pharmacodynamic interactions to improve clinical outcomes. For example, medical practitioners prescribe combination therapy to eradicate Helicobacter pylori infection or several antihypertensive agents at once if response to a single agent has not been satisfactory. Herbal medicine practitioners widely prescribe combinations of herbs with similar actions to strengthen clinical effects, and naturopaths may combine nutritional and herbal supplements in a similar way.

Although pharmacodynamic interactions involving herbal and pharmaceutical medicines have not been well investigated, it is easy to make theoretical predictions based on the known pharmacological actions of the medicines involved. For example, kava kava, a herbal central nervous system (CNS) sedative, could be reasonably assumed to interact with benzodiazepines, causing additive or synergistic sedative effects. Alternatively, the herbal CNS stimulant guarana may cause antagonistic effects when used together with benzodiazepines, so that less sedation results. Although predictions such as these are easy to make, this does not mean we can accurately predict the clinical significance of such interactions.

EVALUATING HERB INTERACTIONS

Most studies investigating herb–drug interactions have used in vitro testing of herbal constituents in microsomal systems, supersomes, cytosols, expressed enzymes or cell culture systems such as transfected cell lines, primary cultures of human hepatocytes and tumour-derived cells. There has also been some in vivo investigation in normal, transgenic and humanised animals and, increasingly, in humans. Although these studies are useful, they have limitations. Table 5.1 presents a summary of the limitations of different types of research. Most interaction studies conducted to date have focused on herbal constituents and their effects on cytochrome (CYP) enzymes and, increasingly, P-glycoprotein (P-gp), with few studies investigating effects on drug transport or phase 2 metabolism.

TABLE 5.1 Advantages and limitations of herb–drug interaction studies

Study type Advantages Limitations
In vitro
• Provides information about mechanisms
• Relatively simple to conduct compared with clinical studies
• Relatively cheap to conduct compared with clinical studies
• Relatively quick to conduct

• May use higher doses than can be achieved in clinical practice
• Does not account for poor bioavailability of the test compound
• May use one isolated constituent, whereas herbal extracts contain multiple constituents
• Does not account for human genetic polymorphism
In vivo using animal models
• Can address some of the issues relating to bioavailability
• Can produce results more quickly than clinical studies
• Can provide information when clinical studies cannot be conducted
• Species variations require different interpretation of results
• Selection of appropriate dosage can be difficult, and often very large doses are used
• Does not account for human genetic polymorphism
Clinical studies
• Provide the most relevant information and are the most definitive
• Most studies are conducted in healthy male subjects, but the most relevant results are obtained when conducted in the population who will be using the product
• Inter-product variability in constituent ratios means the tested product may not accurately represent the effects of other products
• Cannot differentiate between gut and liver effects (e.g. cytochromes)
• Does not provide information about mechanisms
• Costly to produce
• Time consuming
• May never be done, due to ethical reasons (e.g. safety studies in pregnancy)

PROBLEMS IN EXTRAPOLATING DATA

A review of the peer-reviewed literature reveals that there is a lack of clinical data and research regarding interactions between herbs and drugs, and it is apparent that much remains untested. Despite this, several OTC herbal medicines have demonstrated pharmacodynamic and pharmacokinetic interactions with drugs in clinical studies. One major concern is those herbal medicines that interact with transporters such as P-gp or cytochromes such as CYP3A4 which are responsible for the transport or metabolism respectively of many drugs commonly used in clinical practice.

In some instances, results obtained in vitro or with animal models about interactions do not accurately predict clinically significant effects in humans. This makes predicting the clinical significance of a possible interaction problematic, and a reliance on evidence other than clinical data is bound to lead to inaccuracies. To illustrate this point, the herbs Ginkgo biloba and saw palmetto will be used here as examples.

In vitro tests and/or tests with animal models have shown both CYP induction and inhibition for Ginkgo biloba.30–44 In contrast, four clinical studies have failed to identify a clinically significant effect on a variety of cytochromes. In one clinical study, Gurley and colleagues demonstrated that Ginkgo biloba had no significant effect on CYP1A2, CYP2D6 or CYP3A4 activity.45 Markowitz and colleagues also conducted a human study and found no significant effects on CYP2D6 or CYP3A4 activity.46 Two further clinical studies found no significant effect for Ginkgo biloba on CYP2C9 activity.47,48

In the case of saw palmetto, the herb has shown potent inhibition of CYP3A4, CYP2D6 and CYP2C9 in vitro,49 but no significant effect was observed on CYP2D6 or CYP3A4 activity in a clinical study by Markowitz et al.50 Gurley et al. also found no significant effect for saw palmetto on CYP1A2, CYP2D6, CYP2E1 or CYP3A4 activity in healthy subjects.51

To add to the complexity of the problem, in some instances researchers have tested individual herbal components or different forms of a herb, and found different effects on CYPs. For example, one study of different constituents of garlic used animal models and showed that diallyl sulfide (100 μmol/kg) slightly but significantly increased cytochrome CYP2E1 activity (1.6-fold vs control), whereas diallyl disulfide and diallyl trisulfide did not affect CYP2E1 activity or the hepatic total CYP level or CYP1A1/2 activity.52 The significance of these results in clinical practice is difficult to determine, as the overall effect on CYP activity will depend on the concentrations of these various constituents present in a garlic product. The example also highlights the general difficulty of extrapolating results for one herbal extract to another, as there may be significant chemical variations between batches of the same herbal product and between different products of the same herb produced by various manufacturers.

PUTTING THEORY INTO PRACTICE: CLINICAL CONSIDERATIONS

In clinical practice, not every patient who takes potentially interacting substances will experience an adverse effect. It is difficult, however, to predict which person is at greater risk. Some of the characteristics of both patients and drugs that appear to increase the risk of harmful interactions are:

• drugs with a narrow therapeutic index
• older and frailer patients
• patients with renal or hepatic disease
• patients already taking multiple medications
• multiple practitioners involved in patient care
• poor communication between patient and practitioner
• poor communication between complementary and medical practitioners
• use of products not manufactured under strict Code of GMP
• self-selection of OTC products without professional assistance.19

In addition, factors such as dose, timing of herbal intake, dosing regimen and route of drug administration are other influences.

METOPIA ALGORITHM

The METOPIA algorithm provides clinicians with a framework for making rational decisions about the possibility of a herb–drug interaction.19 The acronym METOPIA refers to:

• Medication and mechanisms

• Understanding the medicines involved is essential. For example, when drugs with a NTI are being used, extra care is required.
• An understanding of the pharmacokinetic parameters and pharmacodynamic effects of the medicines involved is fundamental to predicting the likelihood of a proposed interaction occurring. In the case of herbal medicines, this information might not be available and much will be speculative.

• Evidence available

• A review of the literature is required, to determine what evidence is available and its strengths and limitations. As illustrated, in vitro studies are poor indicators of the clinical significance of an anticipated interaction, but may be the only evidence available.

• Timing and dose—introducing which, when and for how long?

• For physicochemical interactions in particular, the scheduled administration times of the medicines are important.
• This step also includes considering the chronicity of use of the medicinal agents, as interaction mechanisms may only develop over several days or weeks (such as CYP induction) or may occur rapidly.

• Outcomes possible

• The time of onset and severity of the possible clinical consequence may be predicted from the available evidence, although in the case of herbal medicines, where much remains untested, this is likely to be speculative.

• Practitioner considerations

• The ability and willingness of the practitioner to monitor and manage a potential interaction that is clinically significant can depend on the practitioner and the patient’s setting. For example, in a hospital setting an interaction may be considered important if something needs to be done in order to relieve the patient’s symptoms, or if it will have a significant impact on critical therapy. Practitioners and nursing staff are in an ideal position to detect and manage interactions if necessary. In a community setting, general practitioners, pharmacists and CM practitioners are well placed to advise on interactions and ensure adequate patient self-monitoring.

• Individual considerations—these include:

• individual patient risk factors that may be present and may increase the likelihood of an adverse reaction
• the patient’s individual treatment preferences
• the patient’s ability to self-monitor a potential interaction and seek professional advice if they are concerned.

• Action required—having considered the previous steps to predict the ‘likelihood’ and ‘consequence’ of an interaction, five actions are possible:

• Avoid the new medicinal agent—a relatively high likelihood and/or severity of the consequence make it an unacceptable risk, so an alternative treatment should be considered.
• Avoid unless adequate medical monitoring is possible—a relatively high likelihood and/or severity of the consequence may be acceptable if professional help is available to manage the outcome and supervise treatment.
• Caution—the likelihood of an adverse effect is relatively lower and/or a more minor consequence is possible than the previous level, making it an acceptable risk if the patient is made aware of the possibility and seeks professional advice if concerned.
• Observe—there is a relatively low likelihood and/or negligible clinical consequence of a predicted interaction, making it an acceptable risk.
• Prescribe—there is a relatively high likelihood of a beneficial consequence, making the interaction clinically useful.

If you suspect an interaction, what are the next steps?

1. Case reporting

• A detailed case report should be written, to alert authorities to the possible interaction.
• All suspected adverse reactions should be reported to the relevant authority(ies):

image the local government agency responsible for post-marketing surveillance and collecting adverse drug reaction case reports (in Australia this is the Adverse Drug Reactions Advisory Committee (ADRAC)—reporting is confidential, open to everyone and can be done online, www.tga.gov.au)
image local herbal and natural medicine associations
image the relevant product manufacturer—in some countries, manufacturers keep their own records and are obligated to inform the relevant government authorities; they may also need to recall suspected faulty products
image the prescriber—if applicable.

2. Analysis of the medicine

• Ask the patient to bring in a sample of the medicine. If an interaction involving a herbal or natural medicine is highly likely, then it must be authenticated and botanically verified, and analysed for the presence of contaminants. These essential steps will establish whether the interaction is due to an intrinsic property of the medicine itself and therefore reproducible, or due to extrinsic factors such as poor manufacturing processes.

CONCLUSION

The evidence on the safety of herbal medicines is incomplete, complex and confusing. As with pharmaceutical medicines, their use is associated with both risks and benefits. As more people take herbal medicines, the pressure increases on healthcare professionals such as doctors, pharmacists, naturopaths and herbalists to be well informed about the subject, and on researchers to fill the many and somewhat embarrassing gaps in our current knowledge. It could be argued that failing to do (and fund) this work constitutes the true risk associated with herbal medicines.

RESOURCES

Adverse Drug Reactions Advisory Committee (ADRAC). http://www.tga.gov.au.

Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 3rd edn. Sydney: Elsevier, 2009.

Brinker F. Herb contraindications and drug interactions. 3rd edn. USA: Eclectic Medical Publications, 2001.

Bone K, Mills S. The essential guide to herbal safety. Sydney: Elsevier, 2005.

Natural Standard. http://www.naturalstandard.com/.

Natural Medicines Comprehensive Database. http://www.naturaldatabase.com/(S(frcdl52p5bn02uqyb2buvg33))/home.aspx.

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