Psychosomatics 41:375-376, August 2000
© 2000 The Academy of Psychosomatic Medicine
Drug-Drug Interaction Update |
Consultation-Liaison Psychiatry Drug–Drug Interactions Update
Scott C. Armstrong, M.D.,
Kelly L. Cozza, M.D., and
Michael A. Cole, M.D., Guest Reviewer
Key Words: Drug-Drug Interactions
This edition of DDI Update will review reports about St. John's Wort (SJW) and the concerns about its interactions at cytochrome P450 3A4. We will also review the demise of cisapride, a strong reminder that postmarketing surveillance and the report of adverse drug reactions is a responsibility of us all.
Drug Interactions With Herbal Compounds
Consumer interest and use of alternative healthcare products have increased dramatically over the past few years, particularly the use of herbal supplements and extracts. Patients often self-medicate with herbs for therapeutic or preventive purposes based solely on the marketing of the product despite the lack of sound prospective research. Additionally, it is a common misconception that because a substance is "natural" that it must be safe. For these reasons, patients rarely report the use of herbal preparations to their physicians. Adding to this lack of communication, Physicians forget to ask about possible use of herbal therapies by their patients.
The literature is beginning to provide accounts of clinically important, even dangerous, interactions between herbs and prescription medications. One very popular product, St. John's Wort (SJW) (Hypericum perforatum)—an herb that has been shown to have antidepressant effects—has been identified to have significant herb-drug interactions (HDI). The two articles reviewed below focus on clinical complications seen with concomitant use of SJW and prescription medications. It is clear that both patients and physicians must increase their awareness of possible HDI with the use of SJW. If the hypothesis from these articles is correct—that SJW induces the cytochrome P450 3A4 enzyme—then many other medications may have reduced levels and decreased efficacy when used with SJW, because cytochrome P450 3A4 is involved in the oxidative metabolism in approximately 50% of all medications.—MAC and SCA
1. Piscitelli SC, Burstein AH, Chaitt D et al: Indinavir concentrations and St. John's Wort.
Lancet 2000; 355:547–548
The authors prospectively studied 8 healthy, human immunodeficiency virus (HIV)-negative volunteers. After 24 hours of treatment with indinavir alone, baseline pharmacokinetic profiles were established. The subjects then began a 14 day treatment with SJW (standardized extracts of 0.3% hypericin) of 300 mg 3 times a day during meals without indinavir. At the end of the Day 14, subjects were again given indinavir for 24 hours, and serum levels of indinavir were again measured to determine maximum plasma concentrations for 5 hours after the last dose of indinavir. Data were then extrapolated to an 8 hour model based on baseline kinetics.
The area under the concentration curve at 8 hours was significantly decreased by a mean of 57% after Day 14 treatment of SJW. Maximal serum concentrations were also significantly decreased. All study participants tolerated the medications, but some did experience side effects of nausea, circumoral paresthesias, and taste changes. Side effect intensity and duration were noted to be less after treatment with SJW. The authors implicate the induction of cytochrome P450 3A4 activity by SJW, but they admit that there is a possibility of a p-glycoprotein effect. The clinical implications of this modest, but significant study, are important. Subtherapeutic levels of antiretroviral medications can allow the HIV virus to become resistant to those medications. Viral resistance to medication can complicate the treatment of HIV infection or lead to failure and progression of disease.—MAC
2. Ruschitzka F, Meier PJ, Turina M, et al: Acute heart transplant rejection due to Saint John's Wort.
Lancet 2000; 355:548–549
The authors report two patients who were recipients of heart transplants. Their antirejection medications included corticosteroids, azathioprine, and cyclosporine. One patient was self-medicating with SJW, and the other had been prescribed SJW by a psychiatrist for depression and anxiety. Previously, both patients had stable serum concentrations of cyclosporine and no evidence of organ rejection. After treatment with SJW, both patients had significantly lower serum levels of cyclosporine and evidence of transplant rejection by endomyocardial biopsy. After stopping treatment with SJW, the serum cyclosporine concentrations returned to normal in both patients, and there were no further episodes of rejection. Although the evidence is extrapolated, the temporal relationship between the addition of SJW and rejection cannot be ignored. The authors of this report also implicate the induction of cytochrome P450 3A4, the enzyme known to metabolize cyclosporine. The authors also discuss the SJW extract and add that one part of the extract includes naphtodiantrons, compounds known to induce 3A4. The authors also note a suggestion in the literature that SJW may induce the intestinal activity of the p-glycoprotein drug transporter.—MAC
Manufacturer Removes Cisapride From the U.S. Market
3. Janssen Pharmaceuticals stops marketing cisapride in the U.S.
The U.S. Food and Drug Administration (FDA) Talk Paper T00–14, March 23, 2000, Rockville, MD
The FDA released the above talk paper in March 2000, stating that cisapride (Propulsid) will no longer be marketed in the United States after July 14, 2000. The prokinetic drug cisapride is a proton-pump inhibitor used for patients with upper gastrointestinal motility disorders. Cisapride has little effect on the metabolism of other drugs; it requires metabolism at cytochrome P450 3A4. The drug is very cardiotoxic. Under controlled conditions (i.e., without coadministration with potent inhibitors of cytochrome P450 3A4), cisapride is rapidly metabolized with few side effects or toxicities. At supratherapeutic serum levels, or when administered to patients with electrolyte abnormalities, cisapride may cause arrhythmias or torsades de pointes. As of December 1999, the FDA reported 341 reported heart rhythm abnormalities and 80 cisapride-related deaths. Most of the reported adverse events were associated with either coadministration of interacting drugs, or with underlying conditions known to increase the potential for cardiac arrhythmias with cisapride. Drugs that inhibit the metabolism of cisapride are those that are potent inhibitors at the cytochrome P450 3A4 enzyme. Some of those potent inhibitors include nefazodone (Serzone), itraconazole (Sporonox), ketoconazole (Nizoral), erythromycin, clarithromycin (Biaxin), ritonavir (Norvir), indinavir (Crixivan), quinupristin/dalfopristin, and grapefruit juice.
The demise of cisapride is a familiar one to those who remember the demise of the nonsedating antihistamines terfenadine (Seldane) and astemizole (Hismanal) which were cardiotoxic prodrugs (terfenadine's active metabolite, fexofenadine, is not cardiotoxic and is marketed as Allegra). All of these drugs went through multiple labeling revisions to include the "Black Box" warning we are all familiar with now. Importantly, no matter how the "Black Box" warnings were written, including mailings directly to providers by the manufacturers, adverse events continued to occur.
These three drugs highlight a few teaching points. Physicians must remember to report adverse drug reactions when they occur. One might suggest that there were many more adverse reactions to these drugs that were not detected or not reported. Adverse drug reactions may be reported to the manufacturer of the drug or to the FDA MedWatch Program at 1-800-FDA-0178. Physicians must also heed "Black Box" warnings and explain the potential for adverse events with coadministration of contraindicated medications to their patients. We tell our patients on cardiotoxic medications and drugs with narrow therapeutic windows that they need to contact us immediately if another provider prescribes any medication or if they are thinking about taking an over-the-counter drugs or herbal preparations. Although we receive many calls about drugs that are not a problem, the few serious adverse events that we prevent make these added precautions worthwhile.—KLC
FOOTNOTES
Dr. Armstrong is Medical Director, Willmar Regional Treatment Center, Willmar, Minnesota; Dr. Cozza is an HIV Psychiatrist at the Department of Medicine, Walter Reed Army Medical Center, Washington, DC; and Dr. Cole is a PGY-IV Med-Psych Resident, Walter Reed Army Medical Center, Washington, DC. Address correspondence to Dr. Armstrong, Willmar Regional Treatment Center, 1550 Hwy 71 N, Willmar, MN 56201; email Dr. Armstrong at scott.armstrong{at}state.mn.us
This article has been cited by other articles:
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S. C. Armstrong, K. L. Cozza, and E. A. Pimentel
Immunosuppressants
Psychosomatics,
October 1, 2002;
43(5):
424 - 427.
[Abstract]
[Full Text]
[PDF]
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