The Issue Of The Interaction Between Medications And Dietary Supplements

Background

Potentially negative interactions between prescribed medications and dietary supplements, particularly herbal supplements, is a risk management consideration that has been mostly overlooked or disregarded within the mainstream medical community (Izzo & Ernst, 2009). In general terms, it presents as uncommon for physicians to question their patients about their use of dietary supplements prior to prescribing them a medication. This is due primarily to the majority of traditionally educated physicians adopting the attitude that supplement/drug interactions are of negligible concern, despite a girth of scientific evidence to the contrary. Some physicians however, especially those trained by the Institute for Functional Medicine (IFM), work with a certified Clinical Nutritionist on staff who monitors potentially negative herb/drug interactions. This problem therefore is of increasing concern, as Americans’ use of dietary supplements and herbs is on the rise in the past two decades and the dietary supplement business is, as of 2015, a 36.7 billion-dollar/year industry that is entirely unregulated by the FDA.

Discussion

The core thesis of this paper is that due to the widespread use of herbal supplements by the general public, every private practice, clinic, and hospital should incorporate herb/drug contraindications into their medication safety protocol. The first element required to so is the education of healthcare providers involved in the process of prescribing and dispensing medications and, ideally, cross-referencing possible negative interactions between the prescribed drugs and the herbs which the patient has been using. The crux of this argument is that the healthcare professionals themselves must first believe that a problem exists before that problem can be successfully addressed. A sobering example of the potentially dire consequences of failure to identify negative drug-herb interactions may be found in the tragic case of an 18-year-old woman named Libby Zion who died at New York Hospital on the morning of October 5, 1984 of complications relating to Serotonergic Syndrome. Libby presented with a history of depression and had been prescribed phenelzine by her physician. It was later learned that Libby had also been using herbal compounds, including high-dose St. Johns Wort (SJW). She was admitted to New York Hospital on the night of October 4, 1984. She was disoriented, agitated, febrile, and experiencing skeletal muscle spasms throughout her body. The attending ER physician did not identify Libby as presenting with Serotonergic Syndrome and her symptoms were documented as “of unknown origin”. She was administered an injection of meperidine, an opioid analgesic, to manage the spasms and to calm her. Libby’s body temperature rose to 107°F by 6:30 AM the next morning. Although emergency measures were taken to lower her temperature, Libby suffered cardiac arrest and died. It may be clearly deduced from this case history that numerous interventions could have potentially saved Libby’s life: her family physician could have asked her about her use of herbal supplements, and SJW specifically, prior to prescribing her an antidepressant medication that effects the serotonergic system. The attending physician at the ER could have diagnosed her with Serotonin Syndrome, instead of managing her relatively inconsequential outward symptoms such as spasms. Her family physician would have communicated to the attending physician that Libby was taking an SSRI. All these unfortunate oversights can be linked to lack of education of the physicians involved. This proposed comprehensive safety program is therefore devoted to the systematization and application of safety practices that have stood the test of time, applied to the prevention of adverse events related to negative drug-herb interactions.

Negative supplement/drug interactions are subdivided into two distinct categories, i.e. pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions are described in the literature as those that diminish or inhibit a drug’s pharmacologic action. An example of this would be the effect of garlic on blood concentrations of statin drugs. Pharmacodynamic interactions exert a direct pharmacologic action by the dietary supplement, one that is often in opposition to the intended effect of a given medication. A common example of this interaction would be the use of yohimbine by a hypertensive patient who has been prescribed a blood pressure medication, thus partly negating the positive effects of the drug on the patient’s blood pressure.

A few well-documented examples of negative herb-drug interactions include the following:

• Curcumin

Pharmacokinetic interaction that decreases levels of many antipsychotic and antidepressant medications. Curcumin also exerts a reverse pharmacokinetic action, in that it increases levels of Azuldine, which may necessitate a dosing adjustment by the prescribing physician.

• Black Cohosh

Pharmacokinetic interaction that may negatively impact the efficacy of amiodarone, fexofenadine, glyburide, and numerous statin medications.

• Echinacea

Pharmacokinetic inhibitory effect on drugs that are metabolized by the cytochrome CYP1A2 and CYP3A4 pathways, thereby affecting the metabolism of medications involving these enzymes, including various antipsychotic and antidepressant medications.

• Gingko Biloba

Pharmacodynamic effect of inhibiting platelet aggregation, increasing bleeding risk, and pharmacokinetic inhibitory impact on antiplatelet and anticoagulant medications. Recommendations are that patients taking warfarin concurrent with gingko biloba should have their INR monitored by their physician, or it may best to refrain altogether from the use of gingko biloba.

• Garlic

Garlic potentiates both pharmacokinetic and pharmacodynamic effects. Pharmacodynamic effects include urticaria, dermatitis, anaphylaxis, angioedema, and potential alterations of platelet function. Pharmacokinetic effects include enhancing the effect of anticoagulant medications such as warfarin, as well as anti-AIDS drugs, e.g. saquinavir. Garlic is also implicated with allergic reactions in some individuals. Garlic may also cause an undesirable increase in the pharmacological effect of specific anticoagulants such as fluindione and warfarin and, inversely, reduces the efficacy of some anti‐AIDS drugs. Additionally, garlic decreases concentrations of drugs in the P-gp group, which include colchicine, digoxin, doxorubicin, quinidine, rosuvastatin, and tacrolimus.

• American and Asian Ginseng

The pharmacokinetic and pharmacodynamic properties of American Ginseng and Asian Ginseng are distinct and need to be compartmentalized. American Ginseng has been shown to potentiate a 0.2-point drop in INR for patients on Warfarin. Asian Ginseng has been identified as inducing CYP3A4, decreasing the efficacy of numerous drugs, including statin medications, calcium channel blockers, HIV and chemotherapy agents, as well as certain antidepressants.

• Kava Kava

Kava Kava has been implicated in the inhibition of CYP2C9 and CYP2C19 enzymes, which are responsible for metabolizing NSAIDs, glipizide, rosiglitazone, warfarin, PPIs, phenytoin, clopidogrel, and angiotensin receptor blockers. Additionally, preoperative patients should be cautioned against the use of Kava Kava for at least five days prior to surgery, highlighting that anesthesiologists as well need to be educated on patients’ use of herbal supplements.

• Green Tea Extract

In vitro studies of Green Tea Extract have demonstrated an increase in simvastatin concentrations. Green tea extract has also been shown to inhibit the drug transporters OATP1A1 and OATP1A2, which are critical to the proper metabolism of statin drugs in general, as well as beta blockers, fluoroquinolones, imatinib, and antiretrovirals.

• Goldenseal

The pharmacokinetic actions of Goldenseal present as ubiquitous in respect to more than half of all prescribed medications, in that it significantly inhibits two important metabolic enzymes, CYP2D6 and CYP3A4, both of which are key to proper drug metabolism. Therefore, clinicians should caution their patients against the use of goldenseal, yet very few currently do so.

• St. John’s Wort

SJW is an especially egregious herb that is central to the point of this discussion. Its contraindications are potentially fatal, as illustrated by the previously delineated Libby Zion case. SJW has emerged as a potent inducer of P-gp and CYp3A4, causing a significant reduction in plasma levels of tacrolimus, cyclosporine, warfarin, protease inhibitors, theophylline, digoxin, and venlafaxine. Also, data indicate that use of St. John’s Wort with SSRIs, particularly in elderly populations, could cause dangerous Serotonergic Syndrome. Physicians should therefore be strongly urged to counsel their patients against the use of St. John’s Wort concurrent with most OTC and prescription drugs.

Safety Program Outline

Key to the success of the proposed comprehensive safety program in a clinic or hospital environment is contingent upon the active and enthusiastic involvement of all stakeholders:

1. Hospital Administrator and Board Members
2. Safety Officer
3. Department Managers
4. Physicians and Nurses
5. Lead Pharmacists
6. Certified Clinical Nutritionist.

The most integral stakeholder is of course the Clinical Nutritionist, in that this person would be responsible for identifying and preempting potential negative herb/drug interactions before they occur. This component of the safety program hinges on close collaboration between the Clinical Nutritionist and Pharmacist. Upstream to this consideration are the prescribing physicians at the frontline of care, who should be possessed of at least a modicum of education in respect to the most blatant examples of herb-drug contraindications, i.e. those defined herein.

Incident Reporting and Data Collection Plan

The two primary roles of a Safety Officer are incident prevention and incident reporting. Incident prevention is accomplished via the Safety Officer’s collaborative efforts alongside the Clinical Nutritionist. This may include chart reviews, analyses of patient interviews on herbal supplement use cross-referenced with medications they have been prescribed, and coordination with prescribing physicians. Incident reporting is the other side of this equation, such as when a patient has been identified as having suffered the effects of an adverse event linked to herb-drug interactions, e.g. Serotonin Syndrome. The Safety Officer then needs to initiate a Root Cause Analysis (RCA) and details of the event must be carefully documented. Subsequently, details need to be disseminated to stakeholders at periodic safety meetings organized by the Safety Officer. Safety protocol then needs to be established that will prevent the recurrence of a similar adverse event. This should be accomplished with the full cooperation and agreement of all stakeholders to ensure that the specific preemptive practices that are developed can be realistically implemented within the procedural domain of each department.

Strategies for Involvement of Senior Leadership and Frontline Personnel

Senior leadership, including the Hospital Administrator, and all frontline personnel, need to be educated on the very real need for incorporating the prevention of herb-drug adverse events into their existing safety program. The author proposes, based on analyses of successful safety programs, that the fundamental approach required to get “buy in” from key personnel is by putting a human face on the problem. This could be accomplished by presenting case histories of specific patients in the system who were harmed by herb-drug contraindications, such as the Libby Zion case. This would be a potentially far more effective approach than merely presenting graphs or charts in a PowerPoint presentation.

Staff Training and Education of Committee Members

The Safety Officer in collaboration with the Clinical Nutritionist and Department Managers should develop and distribute educational materials in the form of quick reference guides that prescribers and pharmacists can use to easily identify potential herb-drug interactions, as well as key staff such as pharmacists and nurses who dispense medications. Herb-drug interactions and updates relating to new findings should also be disseminated at periodic safety meetings, such as when new drugs are cleared by the FDA or new research data uncovers previously unknown herb-drug contraindications. Quality control of this process needs to be the responsibility of the Clinical Nutritionist, under supervision by the Safety Officer reporting directly to the Hospital Administrator. Interdepartmental cooperation is also key to successful implementation, as a patient who had been taking a herbal supplement may have been treated with a specific medication in the ICU, then treated with a different drug in the CCU. It is critical to this process to maintain clearly defined roles and accountability both upstream and downstream. The ultimate objective of a comprehensive safety program is the well-being of the patient. Hence a punitive approach is generally unproductive for addressing this safety concern, relative to appropriate education of staff. Simply because negative herb-drug interactions are less common in a clinical setting does not render this problem any less important than any other source of potential harm.

Evidence-Based Practice for Identifying Herb-Drug Contraindications

Numerous resources are available to the clinician to clearly identify potential sources of adverse events stemming from negative herb-drug interactions. There is certainly a vast unexplored “gray area” inherent to this discussion, in that herbs in general have not been well-studied by the mainstream medical community, nor has the FDA approved any herb for the treatment or prevention of any disease. However, a few herbs such as those identified in this paper have a substantial body of evidence in support of their potential adverse effects, hence they should serve as the focal point for evidence-based practice in respect to this issue. The pharmacokinetic and pharmacodynamic effects of some herbs are quite powerful and comparable in some cases to the effects of prescription medications. It is therefore incumbent upon the healthcare professional to conscientiously screen their patients for use of herbal supplements and potential adverse effects, in the same context as physicians’ concerns regarding the possible side effects of prescription drugs.

Conclusion

Data strongly suggest the importance of physicians initiating an active dialogue on the use of dietary supplements, especially herbs, with patients taking OTC and prescription medications. This is also applicable to a clinical or hospital setting. Even when a patient is not conscious and unable to be interviewed about their supplement use, their family members giving consent for treatment should be questioned about the aforesaid. A recent Harris Poll revealed that 86% of Americans use dietary supplements, yet only about 30% voluntarily inform their physicians on their use. Naturally, most patients do not expect their physicians to be well-educated on dietary supplements, but they prefer that their doctor should be the one to initiate a conversation on supplement use. It is also important for clinicians to stay current on emerging data from in vitro and in vivo studies on herb-drug interactions, knowledge which ideally should be disseminated to clinicians by a certified Clinical Nutritionist. Older resources may provide misleading or antiquated data that are no longer applicable in clinical practice, as well as the additional consideration that hundreds of new medications are cleared by the FDA each year, many with as-yet-unknown herb-drug interactions. A few examples of reliable sources of continuously updated data on herb-drug interactions include the Natural Medicines Database, the Allied and Complementary Medicine Database, the National Institute of Health’s Office of Dietary Supplements, and of course PubMed. One final practical consideration in this discussion is that it may behoove physicians in private practice, as well as clinics and hospitals, to add a licensed Clinical Nutritionist to their frontline personnel, since the majority of physicians in our modern era are already overburdened by time constraints and a patient load that may prohibit them from personally monitoring potentially negative herb-drug interactions.