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Herb-Drug Interactions

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Holistic practitioners are often confronted with difficult decisions regarding which treatments to use for complicated cases. It’s not uncommon to manage a pet taking multiple medications, herbal products and supplements – but how concerned should we be about potential interactions between all these substances?

Unfortunately, the literature can be confusing or even contradictory. This is due to the way adverse interactions are reported. Individual case reports can detail a specific case of suspected interaction. Clinical trials, in which the number of drugs and herbs combined are more closely controlled, may demonstrate adverse interactions. Experimental data and pharmacodynamics studies may also suggest potential interactions, at least theoretically. However, these various sources of information frequently contradict each other and can make it difficult for clinicians to know what is best when treating patients.

Herbal pharmacodynamics
Many drugs are metabolized in the liver and intestines via the cytochrome P450 enzyme pathway. Several enzymes are involved, including CYP2C19 and CYP2E1. Herbs and their metabolites are increasingly being discovered to modulate this pathway.1 Some herbs have also been shown to have different effects depending on the dosage. St. John’s wort can induce CYP2C19 at low concentrations but inhibit it at higher concentrations. Further problems arise with the lack of consistency in the preparation and quantities of active ingredients in herbal products from different vendors. Thus, the pharmacodynamic effect of any given preparation may be difficult to anticipate.

Many physicians and scientists are concerned about the effect herbs may have on drug metabolism and serum levels of certain frequently prescribed drugs. Induction of the cytochrome metabolism system may hasten metabolism and decrease a drug’s efficacy, while inhibition may result in high blood levels and toxicity.

Herbs that have been investigated for their effects on various cytochrome P450 pathway enzymes include Echinacea, garlic, ginkgo, ginseng, St. John’s wort and valerian, all of which have been found to have effects on one or several enzymes.

Garlic (Allium sativum)
This is a commonly used herb for hypercholesterolemia and prevention of arteriosclerosis in humans. In animals, it has been recommended as a treatment for cough, respiratory infections and hyperlipidemia and as an adjunct treatment for cancer for its antitumor and cytotoxic effects.

Many physicians recommend caution when taking this herb because of reports that garlic may infl uence platelet function and blood coagulation. There are also reports of possible interactions with anti-coagulants, especially warfarin. Two trials, however, demonstrated no change in pharmacokinetics or pharmacodynamics when garlic was combined with warfarin, suggesting that adequately monitored patients taking warfarin can safely take garlic.2,3

One case report described a possible interaction with chlorpropamide (sulfonylurea treatment for type 2 diabetes) and garlic in a diabetic patient who ate a curry containing garlic and karela.4 The report documented a decrease in the patient’s blood glucose level after eating the curry, but the hypoglycemic effect may have been the result of the additive effect of the two herbs. Additionally, one report may be insufficient to prove a causal relationship.

Garlic’s demonstrated effects on CYP2E1 do warrant caution when using it in combination with drugs metabolized by this enzyme.5 These drugs include theophylline, isofl urane and sevofl urane. Potential interactions with anti-coagulants remain questionable.

Ginkgo (Ginkgo biloba)
Herbalists commonly prescribe gingko for memory deficits and peripheral vascular disease in people. Indications for animals include treatment for cognitive dysfunction and cardiac disease in which hypercoagulability is a concern. Case reports have previously shown interactions between ginkgo and anticoagulant drugs or those with effects on platelets (such as aspirin and other NSAIDs).5 The patients experienced bleeding while concurrently taking these drugs and gingko. Recent trials have been unable to confi rm these effects when ginkgo was combined with several NSAIDs, thus it is questionable as to whether there is any true risk.5 Ginkgo may interfere with the CYP2C19 dependent pathway, thus altering drug metabolism of CYP2C19 substrates. There is one case report of an epileptic patient who experienced fatal seizures while taking valproic acid and phenytoin as well as several herbal supplements, including ginkgo.6 The patient’s serum concentration was found to be sub-therapeutic for both drugs, and interference of metabolism of the drugs from ginkgo was suspected. Because of this potential alteration of metabolism, care should be taken when combining ginkgo with any CYP2C19 substrate, which includes antidepressants, anticonvulsants (phenobarbital), propranolol and proton pump inhibitors (omeprazole).5 Asian ginseng (Panax ginseng) This is a frequently prescribed herb because it has many indications, including cancer prevention and improved mental and physical performance. Veterinary indications are numerous as well, including immune support, recovery from stress or illness, cancer prevention or adjunct treatment for cancer, and treatment for allergies (allergic skin disease) or brain injury. Ginseng has been shown to inhibit platelet aggregation, though one report demonstrated a patient taking warfarin with ginseng had a lowered international normalized ratio (INR).5 The INR is a measure of coagulation, and in this case, the patient’s lowered number demonstrated interference with anti-coagulation. This patient took several drugs concomitantly with ginseng, therefore, causation was not definitive. Further studies have been unable to confirm any interaction with warfarin. At this time, caution is warranted when combining ginseng with drugs known to have platelet effects, but there is no evidence that precludes the combination.

One report described a patient who co-administered the drug phenelzine (a MAOI class antidepressant) and ginseng.7 This patient experienced insomnia, headache and mania. In this case, causality was established after the patient inadvertently rechallenged herself, resulting in many of the same symptoms. While this may be an isolated case with a patient who has a particular sensitivity, clinicians should still be cautious when considering the combination of MAOIs, specifi cally phenelzine, with ginseng. Licorice (Glycyrrhiza glabra) Licorice is a common ingredient in many Chinese herbal formulas and a popular fl avoring for candy. Indications for humans include treatment for cough, bronchitis and gastric ulceration. Veterinary uses are very similar. Licorice has also been advocated as a treatment for Addison’s disease or to augment steroid treatment. In many Chinese herbal formulas, it is included as a harmonizing herb. A recent study demonstrated that co-administration of licorice with cortisone acetate in patients with Addison’s disease increased the serum levels of cortisol for several hours.8 Another study demonstrated elevated salivary levels of both dehydroepiandrosterone (DHEA) and deoxycorticosterone in healthy subjects given a confectionary containing licorice for one week.9 These reports

demonstrate licorice’s ability to alter circulating levels of several steroid precursors, and substantiate the claims that licorice has steroid-augmenting effects. As a result, licorice should be used judiciously with exogenous steroids. Valerian (Valeriana offi cinalis) People commonly take valerian to help with insomnia and anxiety. Pets with nervous or anxious behaviors are prescribed this herb, and valerian has also been recommended as an adjunct treatment for epilepsy. Valerian metabolites have been shown to modulate gamma-aminobutyric acid (GABA) receptors in rat brain stems.10 While there are no reports of interactions, it is suspected that valerian may potentiate the effect of certain sedatives and anesthetic agents. Benzodiazepines, such as valium and Xanax, are frequently used in veterinary behavior management, and concurrent use with valerian may result in increased sedation. Use before surgical procedures may cause unanticipated complications with anesthetic agents that utilize the GABA-ergic pathway.11 Caution should be used when combining valerian with any sedative or anxiolytic, and valerian usage should be stopped before any anesthetic procedure. More investigation on drug-herb interactions is needed at this time. While pharmacodynamic evidence has shown theoretical interactions, there is little evidence of these interactions occurring at the clinical level. This may be due to a lack of actual interaction or a lack of recognizing or reporting interactions. Case reports detailing potential herb-drug interactions do exist, but it is often diffi cult to fi rmly establish causation of the symptoms with herb-drug interaction.