Pharmacokinetic Interactions
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.

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.

The absorption of herbs may be adversely affected when the herbs are given together with some drugs, due to binding in the G.I. 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 because the size of the insoluble complex is too big to pass through the intestinal wall.

The absorption of herbs may be adversely affected when the herbs are given together with some drugs which 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. With the subsequent decrease of stomach acid, herbs may not be broken down properly, leading to poor absorption in the intestines. To minimize the risk of interaction, it is best if the drugs and the herbs are taken separately by approximately two hours.

Lastly, drugs that affect the G.I. motility may affect the absorption of herbs. G.I. motility is the rate at which the intestines contract to push the content from the stomach to the rectum. Slower G.I. motility means the herbs stay in the intestines for a longer period of time and there will be an increase in absorption. Conversely, faster G.I. motility means the herbs stay in the intestines for a shorter period of time and there may be an decrease in absorption. Drugs such as Reglan (metoclopramide) and Propulsid (cisapride) increase G.I. motility and possibly decrease absorption of herbs; and drugs such as Haldol (haloperidol) decrease G.I. motility and may increase absorption of herbs. Therefore, it may be necessary to decrease the dosage of herbs when the patient takes a drug that decreases the G.I. motility and increases overall absorption; and increase the dosage of herbs when the patient takes a drug that increases the G.I. 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.

At the present time, 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. For example, Coumadin (warfarin) is an anti-coagulant medication which is very 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 (warfarin) include aspirin, ibuprofen, vitamin K, some types of tea, green leaf vegetables, etc. These items interact with Coumadin (warfarin) by either enhancing its effectiveness and thus leading to prolonged bleeding, or by decreasing its effectiveness and thus increasing the risk of blood clots in the vessels, both of which may be quite dangerous to the patient. This is why patients who are taking Coumadin (warfarin) need to be exceedingly cautious when taking herbs concurrently. Unfortunately, it is extremely difficult to predict whether an individual herb will interact with Coumadin (warfarin), because there are very few tests or experiments documenting such interactions. The best precautionary measure is close observation of the patient's condition. If the patient shows abnormal signs of bleeding and bruises, then the dosage of herbs may need to be adjusted and the patient's medical doctor should be contacted immediately.

Metabolism
Most herbs and drugs are metabolized by the liver to inactive derivatives. The rate at which the liver metabolizes these herbs and drugs determines the length of time these herbs or drugs stay active in the body. If the liver were 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. On the other hand, if the liver were 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.

In general, drugs that induce liver metabolism do not exert an immediate effect. The rate of liver metabolism changes slowly over several weeks. Therefore, the effect of increased liver metabolism is not seen until weeks after the initiation of drug therapy. Some examples include Dilantin (phenytoin), Tegretol (carbamazepine), phenobarbitals and rifampin. These drugs speed up liver metabolism. Therefore, the herbs may be inactivated faster and their overall effectiveness may be lower. Under such circumstances, the patient may need a higher dose of herbs to achieve the desired effectiveness.

On the other hand, drugs that inhibit liver metabolism have an immediate onset of action. The rate of liver metabolism may be greatly impaired within a few days. Therefore, there is a higher risk of herbs accumulating inside the body as the function of the liver to inactivate them is compromised. Examples of drugs that slow down or inhibit liver metabolism include, but are not limited to, Tagamet (cimetidine), erythromycin, ethanol, Diflucan (fluconazole), Sporonox (itraconazole) and Nizoral (ketoconazole). Therefore, the herbs may be inactivated more slowly and the overall effectiveness may be prolonged. In this case, one may need to lower the dosage of herbs to avoid unwanted side-effects.

Elimination
In addition to the liver, the kidney is also responsible for eliminating herbs and drugs from the body. If the kidney(s) were damaged, then the rate of elimination by the kidneys would be slowed down leading to an accumulation of herbs and drugs in the body. Important examples of drugs that damage the kidneys include amphotericin B, methotrexate, tobramicin and gentimicin. As a safety precaution, it may be necessary to lower the dose 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, such as dosage, sensitivity, body weight and metabolic rate.

Pharmacodynamic Interactions
Pharmacodynamic refers to the study of how drugs actually behave inside the human body. Pharmacodynamic interactions refers 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 and prevent than pharmacokinetic interactions. Most of the pharmacodynamic interactions known now are documented through actual cases--as opposed to laboratory experiments. The best way to prevent pharmacodynamic interactions is to follow the patient closely and monitor all clinical responses including 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 antagonistic effect occurs when two drugs of similar properties show lessened or no clinical effect when given together.

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), such as the combination of Gypsum (Shi Gao) and Rhizoma Anemarrhenae (Zhi Mu) to clear "heat and purge" fire. The antagonistic effect is generally referred to as mutual counteraction (xiang wei), mutual suppression (xiang sha) or mutual antagonism (xiang wu), such as the combination of Semen Raphani (Lai Fu Zi) and Radix Ginseng (Ren Shen), in which the effect of the latter herb is decreased.

In addition, classic Chinese texts state numbers herb-to-herb interactions, such as the Eighteen Incompatibles (Shi Ba Fan) and Nineteen Counteractions (Shi Jiu Wei). Eighteen Incompatibles (Shi Ba Fan) is a classic list of eighteen herb-to-herb interactions. Nineteen Counteractions (Shi Jiu Wei) is a classic list of nineteen herbal combinations in which the herbs counteract each other. Combinations of such herbs will likely lead to adverse side-effects and/or toxic reactions.

The list of Eighteen Incompatibles (Shi Ba Fan) includes: Radix Glycyrrhizae (Gan Cao) is incompatible with Radix Euphorbiae Kansui (Gan Sui), Radix Euphorbiae seu Knoxiae (Da Ji), Flos Genkwa (Yuan Hua) and Herba Sargassum (Hai Zao); Rhizoma Aconiti (Wu Tou) is incompatible with Bulbus Fritillariae Cirrhosae (Chuan Bei Mu), Bulbus Fritillariae Thunbergii (Zhe Bei Mu), Fructus Trichosanthis (Gua Lou), Rhizoma Pinelliae (Ban Xia), Radix Ampelopsis (Bai Lian) and Rhizoma Bletillae (Bai Ji); Rhizoma et Radix Veratri (Li Lu) is incompatible with Radix Ginseng (Ren Shen), Radix Glehniae (Bei Sha Shen), Radix Adenophorae (Nan Sha Shen), Radix Sophorae Flavescentis (Ku Shen), Radix Salviae Miltiorrhizae (Dan Shen), Radix Scrophulariae (Xuan Shen), Radix Paeoniae Alba (Bai Shao), Radix Paeoniae Rubra (Chi Shao) and Herba Asari (Xi Xin).

The list of Nineteen Counteractions (Shi Jiu Wei) includes: Sulfur (Liu Huang) & Mirabilitum (Mang Xiao); Mercury (Shui Yin) & Arsenolite (Pi Shuang); Rhizoma Euphorbiae E. (Lang Du) & Lithargyrum (Mi Tuo Seng); Semen Crotonis (Ba Dou) & Semen Pharbitidis (Qian Niu Zi); Flos Caryphylli (Ding Xiang) & Radix Curcumae (Yu Jin); Nitrum (Ya Xiao) & Rhizoma Sparganii (Shan Ling); Cornu Rhinoceri (Xi Jiao) & Rz. Aconiti Kusnezoffii (Cao Wu); Cornu Rhinoceri (Xi Jiao) & Rhizoma Aconiti (Chuan Wu); Radix Ginseng (Ren Shen) & Rhizoma Trogopterorum (Wu Ling Zhi); and Cortex Cinnamomi (Rou Gui) & Hallositum Rubrum (Chi Shi Zhi).

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 as the desired effect becomes more unpredictable and harder to obtain with precision. The highest risk of clinically-significant interactions occurs between herbs and drugs that have sympathomimic effects, cardiovascular effects, diuretic effects, anti-coagulant effects and anti-diabetic effects.

Herbs with sympathomimic effects may interfere with anti-hypertensive 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 (Ma Huang) may interact with many other drugs and disease conditions and should always be used with caution in patients who have hypertension, seizures, diabetes, thyorid conditions, etc.

Concomitant use of diuretic herbs and diuretic drugs may have additive or synergistic effects, making hypertension more difficult to control or hypotensive episodes more likely. The dosage of herbs and/or drugs must be adjusted to achieve optimal treatment outcome. 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 include 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. Herbs that interfere with Coumadin (warfarin) include Salviae Miltiorrhizae (Dan Shen), Angelica Sinensis (Dang Gui), Ligustici Chuanxiong (Chuan Xiong), Persicae (Tao Ren), Carthamus Tinctorii (Hong Hua) and Hirudo seu Whitmania (Shui Zhi). The synergistic interaction between herbs and Coumadin (warfarin) may be advantageous for the patient as the dosage of both the herbs and the 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 dependant on careful titration of the herb and drug, cooperation from the patient, and communication between the doctors who prescribe the herbs and the drugs.

Anti-diabetic herbs may interfere with anti-diabetic drugs by the enhancing hypoglycemic effects. The dosage of herbs and drugs must be balanced carefully to effectively control the blood glucose level without causing hyper- or hypo-glycemia. Herbs with definite hypoglycemic effects include the following pairs of herbs: Anemarrhena Asphodeloidis (Zhi Mu) and Gypsum Fibrosum (Shi Gao); Scrophularia Ningpoensis (Xuan Shen) and Atractylodes (Cang Zhu); and Dioscorea Oppositae (Shan 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 and thus leading to birth-defects or spontaneous abortion. Teratogenic herbs are classified into two categories: prohibited and use with caution.

Prohibited herbs are very potent and very toxic. The use of these herbs during pregnancy is prohibited to avoid possible harm to the fetus. Prohibited herbs include Semen Crotonis (Ba Dou), Semen Pharbitidis (Qian Niu Zi), Radix Euphorbiae (Da Ji), Mylabris (Ban Mao), Radix Phytolaccae (Shang Lu), Moschus (She Xiang), Rhizoma Sparganii (San Leng), Rhizoma Zedoariae (E Zhu), Hirudo seu Whitmania (Shui Zhi) and Tabanus (Meng Chong).

Herbs that should be used with caution are herbs that are pungent and warm in nature and have the functions to activate Qi, activate Blood circulation, and remove blood stasis. They are also very potent in nature and should be avoided during pregnancy whenever possible. The use of these herbs should be limited only to later stages of pregnancy and only when the benefits of using the herbs outweigh the risks. Herbs that should be used with caution include Semen Persicae (Tao Ren), Flos Carthami (Hong Hua), Rz. et Rx. Rhei (Da Huang), Fructus Aurantii (Zi Shi), Radix Aconiti (Fu Zhi), Rhizoma Zingiberis (Gan Jiang), and Cortex Cinnamomi (Rou Gui).

Conclusion
Historically, herbs and drugs have been two very different treatment modalities which have rarely, if ever, been used together. The line that separates herbs and drugs, however, has been blurred in recent decades with the increased accessibility to the lay public of different treatment modalities. It is not uncommon for one patient to seek care from several doctors for an ailment. As a result, a patient may easily be taking multiple drugs, herbs and vitamins concurrently. It becomes very difficult to predict whether the combination of all these medications will lead to unwanted side-effects and/or interactions. It is imprudent to assume that there will be no interactions. On the other hand, it is just as unwise to abandon treatment simply for the fear of possible interactions. The solution to this situation is in the understanding of drug-drug and drug-herb interactions. With understanding of these mechanisms, one can recognize potential interactions and take proper actions to prevent their occurrence.

 

John K. Chen, Ph.D., Pharm.D., OMD, L.Ac. is a recognized authority on western pharmacology and Chinese herbal medicine. He graduated from the University of Southern California (USC) School of Pharmacy and South Baylo University of Oriental Medicine. He also received extensive post-graduate training in China specializing in herbology and internal medicine. He currently teaches herbal medicine at USC, Chinese herbology at South Baylo University, and western pharmacology at Yo San University. He is the Chair of the Herbal Medicine Committee for the American Association of Oriental Medicine (AAOM) and an herbal consultant for the California Association of Acupuncture and Oriental Medicine (CAAOM). Dr. John Chen is the president and founder of Lotus Herbs, and is available for medical consultations through the Lotus Herbal Consultation Line. Tel: (626) 916-1070; Fax: (626) 917-7763; 1124 North Hacienda Blvd. La Puente, CA 91744. © Copyright 1998 All rights reserved. Written by Dr. John K. Chen, Ph.D., Pharm.D., OMD, L.Ac.