Chapter 11 Learning Objectives 

At the conclusion of this chapter, students will be able to:

Introduction 

Medical drugs, or medicines, are used to treat diseases, and to guarantee their safety and efficacy, they must be used in the appropriate way. Medicines usually contain active ingredients that react with the human metabolism in various ways, and certain dietary components frequently affect these properties of medicines. These so-called food-drug interactions occur when, for example, a dietary substance or food enhances, decreases or changes the activity of a drug. Typically, such interactions can be observed between drugs and foods (food-drug interactions) but also between drugs and herbs (herb-drug interactions) (White, 2010).

Food-drug interactions can be observed as a consequence of accidental misuse or insufficient knowledge on the substances involved in the interaction. In many cases, herbs, fruits, and alcohol can alter the efficacy of a given drug intervention with adverse consequences. In most cases, relevant food-drug interactions change the bioavailability of a medicine (White, 2010).

Drug-drug interactions are well known, and particular attention is given to detailing these interactions, for example, on drug instructions or clinical databases and guides. Traditionally, there has been less discussion about food-drug interactions, but this has been growing. This is an important area as oral drug dosing is common. Food-drug interactions may arise due to changes in drug kinetics, intestinal transport, metabolism and distribution. The effect of standard meals on drug intake is tested during clinical trials, and recommendations are given based on these studies. Research has tried to quantify this effect, but the food intake can vary once in clinical settings. Several reviews have discussed this issue, focusing on older adults (Raats, de Groot & van Asselt, 2017).

The food-drug interaction is a complex subject, and the interaction can be within the digestive system (e.g., uptake hindrance or binding to drug) or metabolic inhibition (e.g., liver enzymes) (Nakanishi & Tamai, 2015). Several factors play a part in these interactions. The patient’s condition is important, such as age, pre-existing conditions, organ malfunction and polypharmacy. Emerging evidence is demonstrating that the gastrointestinal microbiome also factors in complicating the interaction between drug and food absorption and metabolism. In the book ‘Gut Microbiota,’ this interaction is studied further, addressing topics such as gut microbiota throughout the lifespan, gut microbiota in health and disease, and genetic and environmental influences on gut microbiota. Further information on how the gut microbiome affects food-drug interactions can be found in this book:  Ishiguro, E., & Campbell, K. (2023). Gut microbiota: interactive effects on nutrition and health. Elsevier. 

Supplements are often concentrated components of food items, such as garlic oil, or herbal products. Both food and herbal supplements, even when taken in highly concentrated forms, are often considered safe by patients. The regulation landscape around supplements is different than food and medical drugs and is complex and not uniform worldwide, which can confuse consumers (Thakkar et al., 2020). The use of supplements is common with 12–45% of people using both drugs and supplements and 6–29% are at risk of harmful interactions (Boullata, 2013). The risk of interactions may occur with common drug categories (antithrombotic, antidepressants, antidiabetics and sedatives).

A further difficulty is that patients can use herbal medications without health care providers knowing. Patients may omit reporting supplements or the use of herbal products, assuming they are safe (e.g., the common use of St John’s Wort, Ginkgo Biloba, Garlic, Ginseng, Echinacea, Saw Palmetto, Evening Primrose and Ginger). Bioavailability is not always negatively affected, as iron supplementation can increase the bioavailability of tetracycline. It is therefore important that there is an open dialogue and understanding between health care providers and patients.

Milk can reduce the bioavailability of drugs such as antibiotics (e.g., tetracycline, doxycycline and penicillin). A small amount of milk, such as in tea or coffee, has shown up to 49% reduction in tetracycline bioavailability (Jung et al., 1997). Tetracycline and doxycycline are not solely affected by milk, as food products can reduce the bioavailability significantly (Meyer et al., 1989). Health professionals often know these effects, but with these commonly used products, patients may fail to understand the extent of the effect the food can have on drug efficacy. For example, a morning dose before breakfast may be difficult for those patients with the habit of starting the day with a meal and supplements. If the patient takes their medication afterwards, it is likely to lead to an unwanted effect (such as slower recovery). Provision of instructions for patients that are clear and outline the potential consequences may improve adherence to prescriptive instructions and, ultimately, patient outcomes.

Other popular common food products include grapefruit and cranberry juice. The interaction between grapefruit juice and drugs has been known for decades, but in recent years, the number of reported cases has increased (Baily, Dresser & Arnold, 2013). For instance grapefruit juice can increase the amount of active medication in the body by blocking the enzymes that metabolize the medication (U.S. Food and Drug Association, 2021). In other cases, it may block the absorption transporters of the drug and decrease the amount of active drug in the body (U.S. Food and Drug Association, 2021). The degree of interaction that occurs between grapefruit juice and medications varies by person and by medication (U.S. Food and Drug Association, 2021).  Other fruit juices can also affect drug potency (the amount needed for a response), increasing and decreasing bioavailability (de Morais et al., 2013). Cranberry juice is frequently recommended for H. pylori and urinary tract infections; however, care must be taken. Although cranberry juice is considered safe and administered in high doses. Griffiths et al. (2008) reported a fatal case of hemopericardium (blood in the heart pericardium) and gastrointestinal hemorrhage caused by an interaction between cranberry juice and enzymes responsible for warfarin clearance (Griffiths, Beddall & Pegler, 2008). In this case, the patient was on a recommended 300–400 mL of cranberry juice per day, 6 weeks prior to the incident.

Garlic is traditionally used as a common food across many cultures but is also increasingly (self) prescribed as an alternative natural medicine supplement. Garlic has been studied extensively regarding its chemistry, pharmacology and clinical properties. The main research interests lie in the area of anticancer, antimicrobial and cardiovascular effects (Choo et al., 2020). The sulphur-containing compounds within garlic are considered responsible for the varied bioactive effects. Allicin is a precursor to several of these compounds; it is broken down enzymatically by allinase that is activated when garlic tissue is disrupted, cut or mashed. These unstable compounds are mostly found in fresh or freeze-dried garlic products. These compounds can cause an inhibition of CYP450 3A4 substrates—such as statin medications (e.g., atorvastatin, simvastatin) (Blalock et al., 2009).

Patients have traditionally taken garlic in hopes of a quicker recovery. In common folklore, blogs and healthcare websites, garlic has a reputation for helping with recovery from the common cold to cancer (Ansary et al., 2020); this is partially supported by evidence. Though garlic is considered food, a high dosage is commonly not recommended for older adults as there is evidence that garlic inhibits the effect of platelet activation, which in turn inhibits the mobilization of calcium stores. (Bradley, Organ & Lefer, 2016). Those that have slow blood clot formation or patients on anticoagulant, such as warfarin, should take care when taking garlic. In addition, several other herbal and natural products and foods interact with warfarin (Holbrook et al., 2005).

Herbal products such as ginkgo, St John’s wort, ginseng and valerian are among the more commonly used herbal supplements and may be taken with and instead of conventional medication. The actions of ginseng are described as ‘adaptogenic’—an action that can be both CNS depressant and stimulant and help to balance bodily functions. This may seem contradictory; however, studies of isolated compounds support traditional uses (Lim et al., 2018). Preparations are normally well tolerated, but caution is advised. An example of a drug interaction is an adverse effect with antiplatelets or anticoagulants (Lau et al., 2009, Peterson, Bergien & Staerk, 2021).

 Another example is the effect of St John’s wort on antidepressants. Hyperforin, a component of St John’s Wort, has an effect on the liver and the small intestine. St John’s wort can cause a significant decrease in drug plasma concentration, such as phenprocoumon (anticoagulant). Other drugs affected by hyperforin intake include simvastatin, nifedipine, digoxin, verapamil, dabigatran, rivaroxaban, apixaban and edoxaban (Mouly et al., 2017).

What makes herbal products challenging is that the chemical composition varies between producers, and it is difficult to predict their potency. Analytical study on different St John’s wort products in the USA showed that the concentration of hyperforin ranged from 0.01 to 1.89%, where many contained lower amount than suggested for antidepressant effect (de los Reyes & Koda, 2002).

Even the unpleasant smell of medication can reduce food intake. Further, drugs have the potential to negatively affect the absorption of vitamins or trace elements due to alterations in gastric acidity, diminishing nutrition assimilation, negatively impacting gut microbiota and leading to inflammation of the mucosa of the digestive tract (e.g. antacids, antibiotics, laxatives, anti-inflammatories, hypoglycemic drugs, lipid-lowering drugs, antidepressants, diuretics). When the negative action of drug therapy on nutrition status is likely to become clinically significant, the nutritional deficiency can be corrected with the use of dietary supplements (e.g. pyridoxine administered with isoniazid, an antibiotic used for the treatment of tuberculosis). Even though classic symptoms of nutrient deficiency syndromes are not often seen, nutrient insufficiencies can be still related to clinical manifestations. In several cases, the negative impact of a certain medication on nutrition status is acknowledged as adverse drug effects. For example, drug-induced osteomalacia is a result of some antiepileptic drugs negatively affecting vitamin D metabolism (Pascussi et al., 2005). Further, drug-induced hepatotoxicity and hyperammonemia (e.g., valproic acid, a drug to treat certain types of seizures) are thought to be a consequence of a lack of carnitine (Van Wouwe, 1995). It is still unclear what drug-nutrient interaction dietary supplementation is a feasible solution, and this is a field which needs more research in order to be able to recommend prophylactic nutrient supplementation. It should also be mentioned here that there are some drugs that are related to improvements in nutrient status (Drain et al., 2007). Older adults are likely to use medication that can impair hearing, vision, memory and mobility, resulting in a lack of compliance or wrong dosing (Van Zyl, 2011). This indirect drug action can then affect food intake by impairing the ability to buy and prepare food or to eat without assistance (Tawara et al., 1997).

Researchers have determined that 90% of all oral medications contain at least one ingredient capable of causing an adverse reaction (Reker et al., 2020). Inactive ingredients are broadly defined as any component of a drug product other than an active ingredient. These components are not intended or expected to have a direct biological or therapeutic effect but instead are added to alter the physical properties of an oral solid dosage form to facilitate absorption or to improve stability, taste, and appearance (Reker et al., 2020). Increasing numbers of clinical reports have seen adverse reactions triggered by an inactive ingredient in a medication (Reker et al., 2020). These are the most common symptoms in the form of an allergy or an intolerance to inactive ingredients. Intolerance to an inactive ingredient can cause symptoms through mechanisms such as malabsorption, which causes gastrointestinal symptoms (Reker et al., 2020).