Medical Acupuncture
A Journal For Physicians By Physicians

Published by
The American Academy of
Medical Acupuncture

Fall / Winter 1998 / 1999 - Volume 10 / Number 2
"Aurum Nostrum Non Est Aurum Vulgi"

RECOGNITION AND PREVENTION OF
HERB-DRUG INTERACTIONS
By John K. Chen, Ph.D., La Puente, CA

ABSTRACT
     According to The Journal of the American Medical Association (JAMA), it is estimated that 15 million American adults in 1997, or 18.4% of all prescription drug-users, took prescription drugs concurrently with herbal remedies and/or vitamins (1). Even though herbal remedies are classified as dietary supplements, many of them possess strong medicinal properties and may adversely affect patients if used incorrectly. This article addresses the issue of potential herb-drug interactions for those who combine both prescription drugs and herbs, and the physicians who care for the patients. With some insight into pharmacology, one can foresee possible herb-drug interactions and utilize the necessary precautions to avoid such adverse reactions.

KEY WORDS
      Herbs, Chinese Herbs, Drugs, Interaction, Pharmacodynamic, Pharmacokinetic, Teratogenicity, Dosing

INTRODUCTION
      Countless patients are being simultaneously treated with Western and Oriental medicine. It is common for a patient to seek herbal treatment while taking several prescription medications. Safety has become a major issue. Patients want information about the simultaneous ingestion of herbs and prescription drugs, and their compatibility and possible interactions. Such specific questions are often difficult, if not impossible, to answer. Few studies published in Anglo-Saxon literature document the safety and effectiveness of combining herbs with prescription drugs. With some general insights in pharmacology, however, one can foresee possible interactions and exercise precautions to avoid incompatibilities.
     A "possible interaction" refers to the possibility that one substance may alter the bioavailability, or the clinical effectiveness of another substance, when two or more substances are given concurrently. The net result may be an increase or decrease in the effect of one or both substances. Most of the possible interactions may be classified in two major categories: pharmacokinetic and pharma-codynamic interactions (2,3).

I. PHARMACOKINETIC INTERACTION
     Pharmacokinetic interaction refers to the fluctuation in bioavailability of herb/drug molecules in the body as a result of changes in absorption, distribution, metabolism, and elimination (2,3).

ABSORPTION
     Absorption is the physical passage of herbs or drugs from the outside to the inside of the body. The majority of all absorption occurs in the intestines, where herbs or drugs must pass through the intestinal wall to enter the blood. Several mechanisms may interfere with the absorption of drugs through the intestines (4,5).
     The absorption of herbs may be adversely affected when the herbs are given together with some drugs, due to binding in the gastrointestinal tract. Drugs such as Questran (cholestyramine), Colestid (colestipol), and Carafate (sucralfate) may bind to certain herbs, forming an insoluble complex, and decrease absorption of both substances; the size of the insoluble complex is too large to pass through the intestinal wall (4,5,6).
     The absorption of herbs may be adversely affected when the herbs are given together with some drugs that change the pH of the stomach. Drugs such as antacids, Tagamet (cimetidine), Pepcid (famotidine), Axid (nizatidine), Zantac (ranitidine), and Prilosec (omeprazole) may neutralize, decrease, or inhibit the secretion of stomach acid (4,5). With the subsequent decrease of stomach acid, herbs may not be broken down properly, leading to poor absorption in the intestines. The drugs and herbs should be taken separately two hours apart to minimize this risk.
     Lastly, drugs which affect the GI motility may affect the absorption of herbs. GI motility is the rate at which the intestines contract to push contents from the stomach to the rectum. Slower GI motility cause the herbs to remain in the intestines for a longer period of time; there will be an increase in absorption. Conversely, faster Gl motility causes the herbs to stay in the intestines for a shorter period of time; resulting in a decrease in absorption. Drugs such as Reglan (metoclopramide) and Propulsid (cisapride) increase GI motility and possibly, decrease absorption of herbs; drugs such as Haldol (haloperidol) decrease GI motility and may increase absorption of herbs (4,5). Therefore, it may be necessary to decrease the dosage of herbs when the patient takes a drug that decreases the Gl motility and increases overall absorption; and increase the dosage of herbs when taking a drug that increases the GI motility and decreases overall absorption.

DISTRIBUTION
     After absorption, herbs or drugs need to be presented to the affected area to exert their effect. Distribution refers to the process in which herbs or drugs are carried and released to different parts of the body.
     Most drugs and herbs do not appear to have any clinically significant interactions affecting distribution, and can be safely taken together. Interactions occur during the distribution phase if the drug has a narrow range of safety index and is highly protein-bound. The anti-coagulant mediction, Coumadin (warfarin), is highly bound to protein, and has a very narrow range of safety index. Coumadin (warfarin) interacts with various drugs, vitamins, herbs, and foods via different mechanisms. Some known examples that interact with Coumadin include aspirin, ibuprofen, vitamin K, some types of tea, green leaf vegetables, etc. These items interact by either enhancing the drug's effectiveness and thus, leading to prolonged bleeding, or by decreasing its effectiveness and thus, increasing the risk of blood clots in the vessels. Both may be quite dangerous to thc patient (4,5). Patients who are taking Coumadin need to be exceedingly cautious when concurrently taking herbs. It is extremely difficult to predict whether an individual herb will interact with Coumadin (warfarin). Close observation of the patient's condition is the best precautionary measure. Signs of abnormal bleeding and/or braises may indicate that the dosage of herbs should be adjusted.

METABOLISM
     Most herbs and drugs are metabolized by the liver to inactive derivatives. The rate al which the liver metabolizes these herbs and drugs determines the length of time they stay active in the body. If the liver was induced to speed up its metabolism, herbs and drugs would be inactivated at a faster pace, and the overall effectiveness of ingested substances would be lower. Conversely, if the liver was induced to slow down its metabolism, herbs and drugs would be inactivated at a slower pace, and the overall effectiveness of the substances would be higher.
     Generally, drugs that induce liver metabolism do not exert an immediate effect; liver metabolism changes slowly over several weeks. Therefore, the effect of increased liver metabolism ' until weeks after the initiation of drug therapy. Examples Dilantin (phenytoin), Tegretol (carbamazepine), phenobarbitals, Rifampin. These drugs hasten liver metabolism(4,5). The then be inactivated faster, and their overall effectiveness may be low-ered. Under such circumstances, thc patient may need a hi. herbs to achieve the desired effectiveness.
     Antithetically, drugs that inhibit liver metabolism delay onset of action. The rate of liver metabolism may be impaired within a few days. Consequently, there is a higher risk herbs accumulating inside the body; the function of the liver to inactivate them is compromised. Drugs which slow or inhibit liver metabolism (4,5) include, but are not limited to, Tagamet (cimetidine), er thromycin, ethanol, Diflucan (fluconazole), Sporonox (itraconazole and Nizoral (ketoconazole). Thus, the herbs may be inactivated slowly, and the overall effectiveness may be prolonged. The dosage of herbs may need to be lowered to avoid unwanted side effects.

ELIMINATION
     The kidneys are also responsible for eliminating herbs and drugs from the body. Kidney damage would slow the rate of elimination leading to an accumulation of herbs and drugs. Important examples of drugs which can damage the kidneys include amphotericin B, methotrexate, tobramicin, and gentimicin (4,5). Safety precautions may deem it necessary to lower the dosage of herbs to avoid unnecessary and unwanted side effects.

SUMMARY OF PHARMACOKINETIC INTERACTIONS
     The pharmacokinetic interactions listed in this section include both theoretical and actual interactions. Though such interactions are possible, the extent and severity of each interaction will vary depending on the specific circumstances: dosage, sensitivity, body weight, and metabolic rate must be considered.

II. PHARMACODYNAMIC INTERACTIONS
     Pharmacodynamic refers to the study of how drugs actually behave inside the human body. Pharmacodynamic interactions refer to the fluctuation in bioavailability of ingested substances as a result of synergistic or antagonistic interactions between herb/drug molecules. Pharmacodynamic interactions are generally more difficult to predict aud prevent than pharmacokinetic interactions. Most of the pharmacodynamic interactions known are documented through actual cases, versus laboratory experiments. Preventing pharmacodynamic interactions is best achieved by following the patient closely and monitoring all clinical responses (signs, symptoms, and any abnormal reactions). Examples of pharmacodynamic interaction include additive and antagonistic interactions. An additive effect occurs when two drugs of similar properties show additive or exponential increase in clinical effects when given together. An antagonis-tic effect occurs when two drugs of similar properties show lessened or no clinical effect when given together (7).

HERB-TO-HERB INTERACTIONS
     Cases of pharmacodynamic interactions have also been documented in Oriental medicine. The additive effect is generally referred to as mutual accentuation (Xiang Xu), or mutual enhancement (Xiang Shi). An example is the combination of Gypsum (Shi Gao) and Rhizoma Anemarrhenae (Zhi Mu) to clear heat and purge lire. The antagonistic effect is generally referred to as mutual counteraction (Xiang Wei), mutual suppression (Xiang Sha), or mutual antagonism (Xiang Wu). The combination of Semen Raphani (Lai Fu Zi) and Radix Ginseng (Ren Shen), in which the effect of the latter herb is decreased, illustrates this effect (8).
     Additioually, classic Chinese texts state numerous herb-to-herb interactions, such as thc Eighteen Incompatibles (Shi Ba Fan), and Nineteen Counteractions (Shi Jiu Wet). Eighteen Incompatibles (Shi Ba Fan) is a classic list of 18 herb-to-herb interactions. Nineteen Counteractions (Shi Jiu Wet) is a classic list of 19 herbal combinations in which the herbs counteract each other. Combinations of such herbs are purported likely to lead to adverse side efi;ccts and/or toxic reactions (8).

THE EIGHTEEN INCOMPATIBLES (SHI BA FAN) INCLUDE:

1. Radix Glycyrrhizae (Gan Cae) is incompatible with Radix Euphorbiae Kansui (Gan Sui), Radix Euphorbiae seu Knoxiae (Da Ji), Flos Geukwa (Yuan Hua), and Herba Sargassum (Hat Zao).
2. RhizomaAconiti (Wu Tou) is incompatible with Bulbus Fritillariae Cirrhosac (Chuan Bet Mu), Bulbus Fritillariae Thunbergii (Zhe Bet Mu), Fructus Trichosanthis (Gua Leu), Rhizoma Pinelliac (Ban Xia), Radix Ampelopsis (Bat Lian), and Rhizoma Ble tillae (Bat Ji).
3. Rhizoma et Radix Veratri (Li Lu) is incompatible with Radix Ginseng (Ren Shen), Radix Glehniae (Bet Sha Shen), Radix Adenophorae (Nan Shit Shen), Radix Sophorae Flavescentis (Ku Shen), Radix Salviae Miltiorrhizac (Dan Shen), Radix Scrophulariae (Xuan Shen), Radix Paeoniae Alba (Bat Shao), Radix Paeoniac Rubra (Chi Shao), and Herba Asari [Xi Xin] (8).

THE NINETEEN COUNTERACTIONS (SHI JIU WEI) INCLUDE:

1. Sulfur (Liu Huang) & Mirabilitum (Mang Xiao)
2. Mercury (Shut Yin) &Arsenolite (Pi Shuang)
3. Rhizoma Euphorbiae E. (Lang Du) & Lithargyrum (Mi Tuo Seng)
4. Semen Crotonis (Ba Dou) & Semen Pharbitidis (Qian Niu Zi)
5. Flos Caryphylli (Ding Xiang) & Radix Curcumae (Yu Jin)
6. Nitrum (Ya Xiao) & Rhizoma Sparganii (Shan Ling)
7. Comu Rhinoceri (Xi Jiao) & Rz. Aconiti Kusnezoffii (Cae Wu)
8. Cornu Rhinoceri (Xi Jiao) & RhizomaAconiti (Chuan Wu)
9. Radix Ginseng (Ren Shen) & RhizomaTrogopterorum (Wu Ling Zhi)
10. Cortex Cinnamomi (Rou Gui) & Hallositum Rubrum [Chi Shi Zhi] (8).

HERB-TO-DRUG INTERACTIONS
     Pharmacodynamic types of herb-to-drug interactions are best identified by analyzing the therapeutic effect of the herbs and drugs. Concurrent use of herbs and drugs with similar therapeutic actions will undoubtedly pose potential risk of herb-to-drug interactions. The increase in treatment effect interferes with optimal treatment outcome: the desired effect becomes more unpredictable and harder to obtain with precision. The highest risk of clinically-significant interactions occur between herbs and drugs that have sympathomimic effects, cardiovascular effects, diuretic effects, anti-coagulant effects, and anti-diabetic effects (9). Herbs with sympathomimic effects may interfere with anti-hyper-tensive and anti-seizure drugs. The classic example of an herb with sympathomimic effects is Herba Ephedrae (Ma Huang), which contains ephedrine, pseudoephedrine, norephedrine, and other ephedrine alkaloids. Herba Ephedrae may interact wilh many other drugs and disease conditions, and should always be used with caution in patients with hypertension, seizures, diabetes, thyroid conditions, etc. (9).
     Concomitant use of diuretic herbs and diuretic drugs may have additive or synergistic effects; hypertension may be more difficult to control and/or hypotensive episodes may result (9). The dosage of herbs and/or drugs must be adjusted to achieve optimal treatment out-come. Commonly-used diuretic herbs include Poria Cocos (Fu Ling), Polypori Umbellati (Zhu Ling), Semen Plantaginis (Che Qian Zi), and Alismatis Orientalis (Ze Xie).
     Herbs with anti-coagulant effects encompass herbs that have blood-activating and blood-stasis-removing functions. Such herbs may interfere with anti-coagulant drugs, such as Coumadin (warfarin), to prolong the bleeding time (9). Herbs that interfere with Coumadin (warfarin) include: Salviae Miltiorrhizae (Dan Shcn), Angelica Sinensis (Dang Gui), Ligustici Chuanxiong (Chuan Xiong), Persicae (Tao Ren), Carthamus Tinctorii (Hong Hua), and Hirudo seu Whitmania (Shut Zhi). The synergistic interaction between herbs and Coumadin (warfarin) may be advantageous for the patient; the dosage of both the herbs and drugs can be reduced without compromising clinical effectiveness. The reduction in dosage will also decrease the frequency and severity of side effects of the drugs. Optimal treatment, however, is directly dependent on careful titration of thc herb and drug, cooperation from the patient, aud communication between the physicians who prescribe thc herbs and drugs.
     Auti-diabetic herbs may interfere with anti-diabetic drugs by the enhancing hypoglycemic effects. The dosage of herbs and drugs must be carefully balanced to effectively control the blood glucose level without causing hyper- or hypoglycemia (9). Herbs with definite hypoglycemic effects comprise the following pairs of herbs: Anemarrhena Asphodeloidis (Zhi Mu) and Gypsum Fibrosum (Shi Gao), Scrophularia Ningpoensis (Xuan Shen) and Atractylodcs (Cang Zhu), and Dioscorea Oppositae (Shah Yao) and Astragalus Membranacei (Huang Qi).

TERATOGENIC HERBS
     Teratogenic herbs are known to have the tendency or likelihood of causing danger or harm to the fetus during pregnancy, leading to birth defects or spontaneous abortion. Teratogenic herbs are classified into two categories: prohibited, and, "prescribe with caution."
     Prohibited herbs are very potent and toxic. The use of these herbs during pregnancy is prohibited to avoid possible harm to the fetus. Prohibited herbs include:

1. Semen Crotonis (Ba Dou)
2. Semen Pharbitidis (Qian Niu Zi)
3. Radix Euphorbiae (Da Ji)
4. Mvlabris (Ban Mao)
5. Radix Phytolaccae (Shang Lu)
6. Moschus (She Xiang)
7. Rhizoma Sparganii (San Leng)
8. Rhizoma Zedoariae (EZhu)
9. Hirudo seu Whitmania (Shui Zhi)
10. Tabanus (Meng Chong)

     Herbs that should be prescribed with caution are pungent and warm in nature, and function to activate Qi, activate blood circula-tion, and remove blood stasis. These herbs are also very potent in nature, and should be avoided during pregnancy. Their use should be limited only to later stages of pregnancy, and only when the benefit outweigh the risk. Herbs which should be prescribed with caution are:

1. Semen Persicae (Tao Ren)
2. Flos Carthami (Hong Hua)
3. Rz. et Rx. Rhei (Da Huang)
4. Fructus Aurantii (Zi Shi)
5. Radix Aconiti (Fu Zhi)
6. Rhizoma Zingiberis (Gan Jiang)
7. Cortex Cin namomi (Rou Gui)

CONCLUSION
     Historically, herbs and drugs were rarely prescribed together. Patients now commonly seek care from several physicians for the same ailment. The result is that a patient may be concurrently using multiple drugs, herbs, and vitamins. The difficulty lies in predicting the unwanted side effects, and/or interactions, of these medications. Itl is imprudent to assume that no interactions will occur. The solution to this dilemma lies in understanding drug-drug and drug-herb interactions, and to utilize appropriate measures to prevent their occurrence.

REFERENCES

1. Eisenberg DM, et al. Trends in alternative medicine use in the United States, 1990-1997. JAMA 1998.
2. Berkow R, Fletcher AJ. The Merck manual of diagnosis and thera-py, 16th edition. Merck Research Laboratories, 1992.
3. Fauci AS, et al. Harrison's principles of internal medicine, 14th edition. McGraw-Hill Health Professions Division, 1998.
4. Hansten PD. Understanding drug-drug interactions. Science and Medicine Jan-Feb 1998; 16-25.
5. Hasten PD. Chapter 3 drug interactions in Applied Therapeutics. Applied Therapeutics, lnc 1993.
6. Segal S, Kaminski S. Drug-nutrient interactions. American Druggist July 1996; 42-49.
7. Kalant H, Roschlau W. Principles of medical pharmacology, 6th edition. Oxford University Press 1998.
8. Bensky D, Gamble A. Chinese herbal medicine material medica revised edition. Eastland Press 1986.
9. D'Arcy PF. Adverse reactions and interactions with herbal medi-cine part 2 drug interactions. Adverse Drug React. Toxicol Rev 1993. Oxford University Press 12(3), 147-162.

AUTHOR INFORMATION
Dr. John Chen is the President and founder of Lotus Herbs (La Puente, California), which offers health care practitioners Chinese herbal products and medical consultation. Dr. Chen has doctorates in Western pharmacology and Oriental medicine. He is an Assistant Professor of Herbal Medicine at USC, and Professor of Western Pharmacology at Yo San University of Traditional Chinese Medicine, Santa Monica, California.

John K. Chen, Ph.D., Pharm. D., O.M.D., L.Ac.
1124 N. Hacienda Blvd.
La Puente, California 91744
Phone: 626-916-1070 · Fax: 626-917-7763 · Email: LotusHerbs@aol.com

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