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.

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.