Herbal Therapy Interactions with Immunosuppressive Agents
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Herbal Therapy Interactions with Immunosuppressive Agents

James E. Beaulieu, Pharm.D.
Clinical Pharmacist Specialist, Pharmacy Services,
Rhode Island Hospital and The Miriam Hospital
Lifespan, Providence, RI


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The immunosuppressive medications used to prevent allograft rejection after transplantation present a host of patient monitoring challenges for the pharmacist. Continuous monitoring is essential because of the potential for infection, malignancy, drug side effects, and drug­drug or drug­nutrient interactions. Immunosuppressive agents may also be used to treat other disease states, including rheumatoid arthritis, Crohn's disease, and lupus nephritis. Therefore, pharmacists will be called upon to provide pharmaceutical care to a diverse population of patients using immunosuppressive medicines.

Pharmacists must be ready to monitor and counsel transplant patients or other patients who are taking immunosuppressants concurrently with herbal products. The increased popularity of herbal medicines may place these patients at risk for an herbal­immunosuppressive interaction.1,2 In the transplant patient this could result in potentially devastating toxic side effects or the loss of the transplanted allograft. Some herbal medicines are also potential nephrotoxins. Renal transplant patients and other patients on a cyclosporine-based regimen (Sandimmune, Neoral) should especially avoid herbal medicines. The initial transplant patient assessment and continued follow-ups should include questions on the use of herbal therapies.

Unfortunately, little is known or reported on interactions of herbals with immunosuppressants. The herbal medications selected for this review have a reported interaction in the literature or have the potential to interact with immunosuppressants pharmacokinetically or pharmacodynamically.

Cytochrome P-450 and P-glycoprotein

Potential pharmacokinetic drug­drug and drug­nutrient interactions with cyclosporine, tacrolimus (Prograf) or sirolimus (Rapamune) that may pose a substantial clinical risk to the patient on immunosuppressants are well-known based on a growing wealth of knowledge about the cytochrome P450 (CYP) system. CYP3A represents the most abundant subfamily of enzymes within this system.3 It accounts for approximately 30% of all CYP content in the liver and as much as 70% in epithelial cells (enterocytes) of the small intestine. Major improvements in the scientific tools available to research this system allow the prediction of potential drug­immunosuppressive interactions.

 
There are at least 10 constituents, or groups of components that may contribute to the pharmacologic effect of St. John's wort on cyclosporine.
When predicting potential drug­immunosuppressive interactions, the role of the membrane transporter P-glycoprotein (PGP) must also be considered.4-6 PGP, a member of the superfamily of proteins known as the ATP-binding cassette, is capable of pumping a wide range of structurally diverse, lipophilic drugs out of cells, potentially acting as a defense mechanism. This glycoprotein is well recognized because of its contribution to multiple-drug resistance during cancer chemotherapy. PGP has been discovered in the liver, kidney (where it pumps drug out of the body into the urine), blood­brain and blood­testis barrier, lymphocytes, and the placenta.

  PGP has also been located in the enterocytes of the small and large intestine, where its role is to carry lipophilic molecules from the enterocyte back into the intestinal lumen for elimination. Many hydrophobic drugs are either metabolized by CYP3A or pumped back into the lumen by PGP after intestinal absorption and enterocyte uptake. Therefore, CYP3A and PGP, acting in tandem, may decrease the oral absorption and delivery of cyclosporine, tacrolimus or sirolimus.

Pharmacokinetic Immunosuppressive-Herbal Interactions

Cyclosporine/St. John's Wort: Case reports of St. John's wort (Hypericum perforatum) causing decreased serum levels of digoxin and indinavir were discussed previously in U.S. Pharmacist.1 Similar case reports of an interaction of St. John's wort with cyclosporine were documented in The Lancet.7 Both of these cyclosporine cases involved patients with stable heart transplant allografts who were maintained on a standard regimen of cyclosporine, azathioprine (Imuran) and corticosteroids. These cases are reviewed below.

* Case One: A 61-year-old patient was admitted for elective endomyocardial biopsy.7 The heart transplant had taken place 11 months earlier, and cyclosporine plasma levels were stable prior to being admitted for the biopsy. There were no signs of infection or hemodynamic compromise. The only patient complaint was a feeling of nonspecific fatigue. Three weeks prior to admission the patient started self-medicating with St. John's wort for mild depression. The biopsy revealed acute transplant rejection. A St. John's wort­cyclosporine interaction was suspected. St. John's wort was discontinued, the cyclosporine dose was increased and bolus corticosteroids were administered; however, this therapy was ineffective in reversing the acute rejection. A second biopsy performed seven days later showed prolonged rejection. Azathioprine was switched to mycophenolate mofetil (Cellcept) and intravenous antithymocyte globulin was given for 10 days. Cyclosporine plasma concentrations remained within therapeutic range after the patient stopped taking St. John's wort. Further episodes of rejection were not noted.

* Case Two: A 63-year-old heart transplant recipient was started on St. John's wort by his psychiatrist because of anxiety and depression, three weeks before being admitted for elective endomyocardial biopsy.7 Prior to admission, the patient had an event-free course with stable cyclosporine plasma levels; however, on admission, cyclosporine plasma levels had dropped below the therapeutic range. Physical examination and laboratory values did not reveal a cause of rejection. The endomyocardial biopsy, however, showed acute heart transplant rejection. Cyclosporine returned to normal concentrations after the St. John's wort was discontinued. Further episodes of rejection were not documented.

In both of these cases, the strong temporal relationship suggests that treatment with St. John's wort caused the acute rejection, due to a drop in plasma cyclosporine concentration. There are at least 10 different constituents or groups of components that may contribute to the pharmacologic effect of St. John's wort. One component, naphtodiantron, is a known inducer of CYP3A. In addition, it has been suggested that St. John's wort extract may induce PGP.8 Overall, the combination of these two pharmacokinetic interactions decreases the oral bioavailability of cyclosporine. The same interaction should be considered in patients taking tacrolimus or sirolimus.

Cyclosporine/Rosemary: Rosemary (Rosmarinus officinalis [Labiatae]) is used externally to improve circulation in hypotonic circulatory disorders, rheumatic conditions, eczema, and as a poultice for poorly healing wounds. Rosemary is taken orally for dyspeptic disorders, loss of appetite, liver and gallbladder complaints, and blood pressure problems.9 It inhibits the binding of doxorubicin (Adriamycin) and vincristine (Oncovin) to PGP, thereby increasing the intracellular accumulation of these chemotherapy agents.10 Rosemary may thus also increase cyclosporine plasma concentrations by increasing its oral bioavailability, through inhibition of PGP activity. Literature documentation or case reports of cyclosporine­rosemary interactions do not exist. However, a potential drug-herb interaction exists, and patients on cyclosporine-based regimens should be advised to avoid using rosemary for medicinal purposes.

A summary of the cyclosporine­St. John's wort and cyclosporine­rosemary interaction is provided in TABLE 1.

Table 1. Documented and Potential
Immunosuppressive­Herbal Interactions
Drug Herb Mechanism of Action Description of Interaction Counseling and Monitoring
Documented
Cyclosporine St. John's wort Induces CYP3A enzyme, increases drug metabolism
Induces PGP in gut, reduces drug absorption
cyclosporine drug levels Advise patients to avoid taking St. John's wort while on cyclosporine
Potential
Cyclosporine Rosemary Inhibits the binding of cyclosporine to PGP Potential in cyclosporine drug levels Advise patients to avoid using rosemary for medicinal purposes while on cyclosporine

Herbals with Purported Immunostimulating Effects

Pharmacists must also monitor the use of herbal medicines that have purported immunostimulating effects. Various agents have been recommended by herbalists as immunotonics or in patients with immunodeficiencies. In theory, these herbals may interact with immunosuppressants, possibly decreasing or offsetting the effects of the immunosuppressive regimen.1,2 Patients taking immunosuppressants should be counseled to avoid these immunostimulating herbs to prevent competing effects on the immune system. When considering the drug history of a patient, pharmacists should include questions on the use of echinacea, astragalus, ginseng, licorice root and alfalfa. Questions should also be asked on the use of zinc supplementation. It is important to keep in mind that these herbals may also be found in protein powders and other nutritional supplements. TABLE 2 summarizes information on immunostimulating herbs.

Echinacea: Echinacea (Echinacea purpurea) is used as an immune stimulant and lymphatic system antiseptic. It is also used for colds, cough, fever, bronchitis, tonsillitis, wound healing, asthma, glandular swelling, UTIs, and as a nasal decongestant.9 Given orally or parenterally, echinacea affects the immune system by increasing the number of white blood cells and activating the capacity for phagocytosis by human granulocytes. Other effects include increased production of T-helper cells and cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor alpha.2

Astragalus: Astragalus (Tragacanth) is used as a laxative because it stimulates stretching of the intestinal wall, resulting in increased peristalsis.9 Astragalus may also potentially stimulate T-cell activity.

Ginseng: Ginseng (Panax ginseng) is used to improve athletic ability because it increases stamina, and may possibly lower cholesterol.9 It is also used as an immune stimulant to potentially nourish major immune system glands in an unspecified manner.

Licorice Root: Licorice root (Glycyrrhiza glabra) may stimulate the production of interferon.2 It is used as an antispasmodic and to promote healing of peptic ulcers by inhibiting gastric acid. Licorice is also used for colitis, diverticulitis, asthma, cough, bronchitis, eczema, and hypoglycemia.9

Alfalfa Sprouts: Patients may be using alfalfa sprouts (Medicago sativa) for arthritis, to improve thyroid function and to decrease cholesterol. It may also be used as a blood purifier, a diuretic, and an antiulcer and antidiabetic agent.9

Zinc: Although zinc is not considered an herbal product, patients may use zinc gluconate lozenges to prevent or treat the common cold. The mechanism of action of zinc is unknown; however, studies suggest that zinc may induce interferon production and prevent formation of viral capsid protein.2

Table 2. Herbals with Purported Immunostimulating Effects
Herb Purported Use Contraindications Adverse Reactions Drug Interactions/ Comments
Alfalfa
(Medicago sativa)
Arthritis, blood purifier, diuretic, antiulcer, cholesterol-lowering, anti-diabetic, improve thyroid function 1 Pancytopenia, SLE Contains vitamin K, can decrease INR with warfarin.
Do not exceed recommended dosage

Astragalus
(Tragacanth)

Laxative

Ileus, intestinal
obstruction, abdominal pain of unknown origin

Rare allergic reactions Take with adequate amounts of fluid.
Echinacea
(Echinacea purpurea)
Immune stimulant, lymphatic system antiseptic, colds, cough, fever Multiple sclerosis, HIV, tuberculosis, leukosis, collagenosis, pregnancy Fever, nausea, vomiting, allergic reactions Additive hepatotoxic effects with anabolic steroids, amiodarone, methotrexate, ketoconazole. Patients with renal impairment should not use for more than 10 days.
Ginseng
(Panax ginseng)
Stimulate immune system, improve athletic ability, increase stamina, possibly lower cholesterol Hypertension, pregnancy, hematologic disorders, renal failure, anticoagulant therapy, in infants Ginseng abuse syndrome with overuse, nervousness, hypertension, insomnia, tachycardia, dermatitis, fever, bleeding May increase clotting time with aspirin, dipyridamole, warfarin; avoid excessive caffeine; avoid with antidepressants; may increase toxicity of steroids

Herbal Medicines that are Potential Nephrotoxins

Medicines that may be nephrotoxic (e.g., aminoglycosides and amphotericin B) should be used cautiously or avoided in patients on immunosuppressants. This is especially important for renal transplant patients, because of the potential for additive nephrotoxicity with cyclosporine or tacrolimus. Herbal medicines may also be potential nephrotoxins (TABLE 3).9 Pharmacists must continuously monitor patients on immunosuppressants and educate them on potentially nephrotoxic herbals, such as Acorus calamus, birch bark, Ruta gravolens, Aristolochia clematitis, Stephania tetranda, and Magnoliae officinalis.

Acorus Calamus: A. calamus (calamus) has spasmolytic, carminative (antiflatulent), and sedative effects.9 It is used as a tea for dyspeptic disorders to stimulate appetite and digestion and may also be used for gastritis and ulcers. In addition, calamus may be used externally for its hyperemic effects in rheumatism, gum disease, and angina (it improves blood circulation). Even though it is a relatively safe herbal medicine when administered properly, patients should be counseled against using it long-term and exceeding recommended dosages.

Birch Bark and Birch Leaf: Birch bark and leaves (Betula species) have been used in folk medicine for centuries as blood purifiers, for gout and rheumatism, and for hair loss and dandruff.9 They are also used as flushing-out therapy in bacterial and inflammatory diseases of the urinary tract, and for kidney and bladder stones. Birch should not be used in patients with impaired cardiac or renal function or in patients with an aspirin sensitivity because it contains high amounts of methylsalicylate.

Ruta Graveolens: R. graveolens (Rue) has been used as a folk remedy for menstrual complaints, as a contraceptive and as an abortive agent.9

Aristolochia Clematitis: A. clematitis (birthwort) is used as an immunostimulant and in allergically induced gastrointestinal colic and cholecystitis.9 Pure aristolochic acid acts similarly to the gout medication colchicine. Birthwort is a highly toxic drug and should not be administered even in small doses. Acute intake of toxic doses leads to gastroenteritis, vomiting, spasms, and severe kidney damage. The United Kingdom Committee on Safety of Medications placed an emergency ban on the import, supply and sale of aristolochia on July 28, 1999.11 This ban resulted from case reports of end-stage renal disease caused by ingestion of a Chinese herbal remedy that contained aristolochia.12 The herbal preparations were from different sources and were prescribed for eczema.

Stephania Tetranda and Magnoliae Officinalis: Case reports have also been published regarding S. tetranda and M. officinalis.13 Two women under the age of 50 were diagnosed with a rapidly progressive fibrosing interstitial nephritis after starting a therapy for weight loss. Both women received the treatment from the same clinic and eventually required dialysis. The case reports prompted the authors of the article to perform an epidemiological survey. Upon analysis of the data, the authors discovered that the weight loss clinic had initially used the same slimming regimen for 15 years. No cases of renal dysfunction or renal failure had been reported on this old regimen; however, before the two reported cases, the clinic had changed to a new regimen that included the herbs in question. Other nephrotoxins or adulterants, such as diuretics or anti-inflammatory agents, were not found in the herbal treatment. In total, the survey identified nine young women on dialysis or with preterminal renal failure who had followed the same weight loss regimen.

 
Inquire about herbal use in an open, nonjudgmental fashion to provide an opportunity for patients to learn about the risks and benefits of these therapies.
The above cases outline the importance of advising and warning patients that some herbals may be found in combination products such as dietary aids or nutritional supplements. Herbal remedies may also contain nephrotoxic adulterants, such as mefenamic acid and phenylbutazone. Mefenamic acid has been found in Chinese herbal preparations known as "Chinese black balls." A 50-year-old woman, admitted to the hospital for a cholecystectomy, was noted to have a serum creatinine of 3 mg/dL.14 After a renal biopsy she was diagnosed with acute interstitial nephritis. The patient's medication list included Tung Shueh pills. She had taken eight pills daily for four weeks. Analysis of the Tung Shueh pills confirmed the presence of mefenamic acid (a nonsteroidal anti-inflammatory and antipyretic agent) and diazepam. The patient's renal function improved after a short course of hemodialysis. Many published case reports document renal function abnormalities associated with the use of mefenamic acid for osteoarthritis or musculoskeletal pain.15-19

Phenylbutazone has also been found as an illicit ingredient in herbal remedies. Renal toxicity associated with phenylbutazone has been well-documented; proteinuria, hematuria, anuria, oliguria, renal papillary necrosis and hypersensitivity-related renal dysfunction may occur during therapeutic use.20,21 Traditional Chinese herbals used to treat various forms of arthritis have been found to contain phenylbutazone.22 These formulations are readily available from Chinese medical halls and stipulate that the only active ingredients are Chinese herbs.

Table 3. Nephrotoxic Herbal Medicinals
Herb Purported Use Contraindications Adverse Reactions Comments
Acorus calamus
(Calamus)
Internal: gastritis, ulcers
External: rheumatism, gum disease, angina
1 Nephrotoxic, bloody diarrhea, dermatitis Used to make tea or put in bath water; avoid long-term use: do not exceed recommended dosage
Aristolochia clematitis
(Birthwort)
Stimulate immune system, allergically induced GI colic and cholecystitis 1 Gastroenteritis, renal failure, carcinogenic Highly toxic­ administration is prohibited; may be toxic as currently marketed
Birch bark, birch leaf
(Betula species)
Diuretic, UTI, renal calculi Aspirin sensitivity, impaired cardiac or renal function Hypersensitivity reactions Contains high amounts of methylsalicylate
Magnoliae officinalis Flatulent dyspepsia, cough, asthma 1 Mucous membrane irritation or numbness, dermal irritation, hypersensitivity, CNS stimulant or depressant Primary agent in Chinese herbal "Houpo;" may be nephrotoxic
Stephania
tetranda
Tetrandine has antiphagocytic, antioxidant, antitumor, analgesic, hypotensive, and antiplatelet effects 1 Other adverse effects unknown Contains 21 compounds (19 are alkaloids); may be nephrotoxic
Ruta graveolens
(Rue)
Antispasmodic, epilepsy, multiple sclerosis, Bell's Palsy, induce menstruation 1 Abortifacient, hepatotoxicity, photosensitizing Fatal outcomes reported with overdose; may be toxic as currently marketed

Role of the Pharmacist

It is the responsibility of the pharmacist to educate patients on the safe use of herbal products.23,24 The lack of scientific data on herbals makes it imperative for the pharmacist to take an active role, especially with patients on immunosuppressants. Pharmacists must keep an open dialogue with patients currently taking or contemplating the use of herbal medicines.

Because herbal medicines are not considered drugs by some individuals, they are frequently not listed by patients or mentioned during drug history interviews. Pharmacists recording patient drug histories should include questions on herbal medicines or dietary supplements. Pharmacists must inquire on the use of herbals in an open, nonjudgmental fashion to provide an opportunity for patients to learn about the risks and benefits of these alternative therapies. Patients should be asked the specific reasons for using the herbal medicine. Pharmacists should also review the patient's drug regimen to determine if herbal use is appropriate and not used to replace conventional therapies that may be more effective in the patient's disease state. During this review process, any herbal-related adverse events experienced by the patient should be reported to the institution's Pharmacy and Therapeutics Committee and, if warranted, to the FDA's MedWatch program.


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