Update on Natural Product-Drug Interactions
Gayle Nicholas Scott, Pharm.D., FASCP, BCPS, CGP and Gary W. Elmer, PH.D.
Abstract and Introduction
AbstractThe interactions of natural products with drugs are discussed. Interactions between natural products and drugs are based on the same pharmacokinetic and pharmacodynamic principles as drug-drug interactions. Clinically important interactions appear to involve effects on drug metabolism via cytochrome P-450 isoenzymes, impairment of hepatic or renal function, and other possible mechanisms.
Natural products that have been reported to interact with drugs in humans include coenzyme Q10, dong quai, ephedra, Ginko biloba, ginseng, glucosamine sulfate, ipriflavone, melatonin, and St. John's wort. In many cases, more research is needed to confirm these interactions and to determine whether other natural products may also interact with drugs.
To effectively counsel patients about interactions involving natural products, pharmacists should be familiar with the most commonly used products and have access to information on more obscure products.
In view of the less than stringent provisions of the Dietary Supplement Health and Education Act, pharmacists should consult reliable, independent sources of information on natural products rather than rely on literature provided by manufactured to high quality-control standards.
Natural products can interact with drugs and with other natural products by the same mechanisms as drugs.IntroductionThe myth that natural products are completely safe is constantly promoted in advertising and creates a need for responsible public education. Although most clinicians can quickly debunk advertising myths with examples of toxic natural products, such as hemlock and cyanide, knowledge of the interactions of natural products with drugs may not be as prevalent.
In part because of the disappearance of pharmacognosy from the curricula of most pharmacy schools, the pharmacist who is well aware of a pseudoephedrine-caffeine interaction may not readily recognize the additive toxicity of ephedra (Ephedra sinesis) and guarana (Paullinia cupana).Since the passage in 1994 of the Dietary Supplement Health and Education Act (DSHEA), which allows natural products to be marketed with minimal FDA scrutiny, dietary supplement sales have grown from $8.8 billion (in 1994) to an estimated $15.7 billion in 2000.[1,2]
In a recent survey of medication use in the United States, 40% of respondents reported taking herbal supplements or vitamins on a daily basis, with higher rates among women, whites, and urban dwellers. The DSHEA does not require manufacturers to demonstrate the safety or efficacy of natural products in human trials before marketing. There are no specific requirements for including warnings about known or potential drug interactions on supplement labels, despite improved FDA requirements developed in response to findings by the Commission on Dietary Supplement Labels.[1,4]
Consumers need reliable information on interactions between these products and drugs. Pharmacists must be able to recognize such interactions, as well as interactions among natural products. Much of the available information about these interactions is theoretical or is gleaned from case reports, although clinical studies are slowly appearing in the literature.
This article discusses the interactions of natural products with drugs, sources of additional information on such interactions, and strategies for counseling people who use natural products. Natural products are defined here as herbs and supplements including amino acids, vitamins, minerals, and other products of natural origin.
Common Mechanisms of Natural Product-Drug Interactions
Interactions between natural products and drugs are based on the same pharmacokinetic and pharmacodynamic principles as drug-drug interactions. Natural products may affect the absorption of drugs and other natural products.
For example, herbs such as aloe leaf (Aloe vera), guar gum (Cyamposis tetragonolobus), senna (Senna alexandrina), and yellow dock (Rumex crispus), which are common ingredients in herbal weight-loss products, exert a laxative effect that may decrease intestinal transit time and reduce drug absorption. Zinc lozenges taken for the common cold can chelate fluoroquinolones and tetracyclines, resulting in lower serum antimicrobial levels.
St. John's wort (Hypericum perforatum) induces intestinal P-glycoprotein, which may decrease the absorption of common P-glycoprotein substrates, such as digoxin.Of interactions involving natural products, those that occur because of changes in volume of distribution are probably the least clinically important.
Theoretically, a drug with high plasma protein binding that has a small volume of distribution can be displaced by a natural product competing for the same binding sites. Because an increase in metabolism or excretion usually offsets higher serum drug levels, the clinical effect may be transient or may be meaningful only when drugs are added or discontinued.
Theoretically, aescin, a constituent of horse chestnut seed (Aesculus hippocastanum), might interfere with highly plasma proteinbound drugs, such as warfarin.[5,7] Natural product-drug interactions that involve distribution mechanisms have not been reported.Evidence for natural product- drug interactions in which effects on drug metabolism occur is growing.
Natural products, like drugs, can affect cytochrome P-450 (CYP) isozymes. The best-investigated metabolic interactions are those involving St. John's wort. Claimed to be effective for the treatment of mild to moderate depression, St. John's wort appears to be a potent inducer of isozyme CYP3A4.[6,8-13]
When given with substrates of CYP3A4, such as indinavir, St. John's wort reduces serum drug concentration and halflife. On the other hand, natural products can inhibit CYP isozymes.
For example, ipriflavone, a semisynthetic soy derivative, appears to inhibit CYP1A2 and CYP2C9. When given with theophylline, a CYP1A2 substrate, ipriflavone increases serum theophylline levels.Toxic herbs that impair hepatic or renal function, such as pennyroyal (Hedeoma pulegioides) and snakeroot (Aristolochia serpentaria), respectively, may decrease drug excretion.
Theoretically, the natriuretic effect of dandelion (Taraxacum officinale) might reduce the excretion of lithium.In addition to interacting pharmacokinetically with drugs or with other natural products, a natural product may interact pharmacodynamically. High-dose vitamin E (>1000 units per day) can enhance the anticoagulant effect of warfarin.
Many herbal weight-loss and "herbal speed" products rely on the pharmacodynamic interaction between ephedra and caffeine or caffeinecontaining herbs, such as cola nut (Cola acuminata), green tea (Camellia sinesis), guarana, and maté (Ilex paraguariensis).
The two primary alkaloids contained in ephedra, ephedrine and pseudoephedrine, have additive cardiovascular effects with caffeine. At higher doses, the ephedra- caffeine interaction has been cited as a cause of death.[15,16] In addition, ephedra or caffeine-containing herbs may antagonize the effects of antihypertensive medications.
The following, arranged alphabetically, is a list of popular botanical products and a discussion of actual or potential interactions that might occur if they are combined with conventional drugs.
Emphasis is placed on interactions that have been observed in humans.
Am J Health-Syst Pharm 59(4):339-347, 2002.
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