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Antihistamines

Dr. Armstrong is the Co-Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, OR, and Associate Clinical Professor of Psychiatry, Oregon Health Sciences University, Portland, OR. Dr. Cozza is the staff psychiatrist for the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, D.C., and Assistant Professor of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, MD. Drs. Armstrong and Cozza are co-authors, along with Dr. Jessica R. Oesterheld, of the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-glycoproteins, 2nd edition (American Psychiatric Publishing, Inc., 2003). Address correspondence to Dr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple St., Forest Grove, OR 97116; scott.armstrong{at}tuality.org (e-mail).
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

ABSTRACT

Antihistamines and their drug-drug interactions are reviewed in depth. The metabolism of "classic" or sedating antihistamines is coming to light through in vivo and in vitro studies. The polymorphic CYP 2D6 metabolic enzyme appears to be potently inhibited by many of these over-the-counter medications. The history of the discontinued "second-generation" antihistamines terfenadine and astemizole is reviewed to remind the reader why the understanding of the cytochrome P450 system became increasingly important when the cardiotoxicity of these drugs became apparent. The "third-generation" nonsedating antihistamines are also listed and compared. They have been exhaustively scrutinized for drug-drug interactions and cardiotoxicity, and they appear to have no serious drug-drug interactions at recommended doses.

Key Words: Drug-Drug Interactions

We have previously discussed in this column the drug-drug interactions associated with antihistamines.¹ Changes in the understanding of drug-drug interactions with antihistamines has occurred since that time. With antihistamines being among the most widely prescribed medications in the world,² and many now available over the counter, we decided to review once again the drug-drug interaction issues associated with them.

The "classic" or sedating antihistamines, with diphenhydramine (Benadryl® and others) as the prototype, are greatly effective but rife with side effects, most notably sedation. In fact, they are often found in over-the-counter sleeping aids, allergy remedies, and numerous multicompound preparations for "colds and flu." Finkle et al.³ indicated that 47% of people with allergies take over-the-counter medications that typically contain a first-generation antihistamine. The drug-drug interaction profiles of the classic drugs are just now being delineated. Some of the nonsedating antihistamines—those referred to as "second-generation" antihistamines—such as terfenadine (Seldane®) and astemizole (Hismanal®) were cardiotoxic in high concentrations. Most of these toxic antihistamines have been removed from the market. "Third-generation" nonsedating antihistamines, which are rapidly becoming available as over-the-counter drugs, offer better safety profiles and, for the most part, less sedation at recommended doses. We will review here what is known about each generation of antihistamines as they pertain to drug interactions (Table 1).

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TABLE 1. Antihistamines

First-Generation H₁ Receptor Blockers
The "first generation" antihistamines are lipophilic and fall into several distinct groups according to their chemical structure and metabolism. All of them are metabolized by the hepatic cytochrome P450 (CYP) oxidative enzymes. They are not substrates of p-glycoproteins,⁴ and this distinction may account for their predilection to cause sedation.

Metabolic differences or variability have been noticed between sexes, races, and species.⁵ Many classic antihistamines are metabolized at CYP 2D6, but all metabolic routes have not yet been delineated.⁵ Hamelin et al.⁶ studied the antihistamines diphenhydramine, chlorpheniramine, clemastine, perphenazine, hydroxyzine, and tripelennamine in vitro with human liver microsomes that were transfected with CYP 2D6 cDNA. All of these classic antihistamines inhibited the metabolism of the test 2D6 substrate. Sharma and Hamelin⁵ also reported that some may inhibit CYP 3A4 in vitro as well.

Lessard et al.⁷ studied 15 healthy men, nine with extensive (normal) CYP 2D6 metabolism and six with poor metabolism. They discovered that diphenhydramine alters the disposition of venlafaxine via CYP 2D6 inhibition. Diphenhydramine did not appear to be metabolized itself by CYP 2D6. The authors warn that several drugs with narrow therapeutic windows are dependent upon CYP 2D6 for metabolism, such as some tricyclic antidepressants, antiarrhythmics, beta-blockers, antipsychotics, and tramadol.

Hamelin et al.⁸ studied the metabolism of metoprolol in subjects with both extensive and poor CYP 2D6 metabolism while they were at steady-state concentrations of diphenhydramine or placebo. As expected, diphenhydramine had no effect on metoprolol metabolism or adverse hemodynamic effects in the subjects with genetic poor metabolism. In the normal functioning extensive metabolizers, diphenhydramine did decrease metoprolol's clearance and caused more pronounced and significant alterations of systolic blood pressure, longer duration in heart rate, and Doppler-derived aortic blood flow.

On the basis of these data, diphenhydramine appears to be a potent and competitive inhibitor of CYP 2D6. The fact that it is available over the counter and hidden in multiple cold remedies suggests that patients deserve a warning about the potential for worsened side effects and toxicities and should be monitored for such.

Second-Generation H₁ Receptor Blockers
Drug interactions involving second-generation H₁ receptor antagonists (or nonsedating antihistamines) were one of the first-studied drug-drug interactions relating to the cytochrome P450 system. These antihistamines do not cross the blood-brain barrier because they are substrates of the p-glycoprotein efflux transporters.⁹ This property may be the reason that the drugs are less sedating, since the p-glycoproteins "pump" out the drugs before they can enter the CNS at the blood-brain barrier.⁴ They are also more H₁ selective than the older drugs, which also may result in less sedation as well as less weight gain and fewer other antihistaminic side effects. The first report of life-threatening cardiac arrhythmia associated with the use of terfenadine appeared in 1989, when a patient developed an arrhythmia after an intentional overdose.¹⁰ Monahan et al.¹¹ then followed with the first report of arrhythmia associated with terfenadine therapy. A woman taking terfenadine and cefaclor developed Candida vaginitis and treated herself with ketoconazole that she had remaining from treatment of a previous episode of vaginitis. She developed palpitations and later torsades de pointes even though she was taking standard doses of all medications. These case reports led to in vivo studies involving healthy volunteers, which clearly demonstrated that the potent CYP 3A4 inhibitor ketoconazole increases levels of unmetabolized terfenadine and is associated with QTc prolongation.^2,12

Terfenadine is a prodrug that undergoes a rapid and nearly complete first-pass hepatic biotransformation, producing the active metabolite at CYP 3A4. The parent or prodrug is cardiotoxic in overdose or when its first-pass metabolism is impaired by another compound at the same hepatic enzyme (in this case, CYP 3A4), causing prolongation of the QTc. Terfenadine seems to block potassium channels and to be as potent as quinidine in inhibiting the delayed rectifier potassium channel in cardiac tissue.¹² Carboxyterfenadine (fexofenadine), terfenadine's active metabolite, is not cardiotoxic and has no known hepatic metabolism (it is eliminated unchanged in the urine). The prodrug terfenadine has been voluntarily removed by the manufacturer from the U.S. market and has been replaced by fexofenadine (Allegra®).

Astemizole (which has also been taken off the U.S. market) and ebastine (available only in Europe at this time) are also arrhythmogenic at high doses. This effect may be heightened when either of these drugs is administered with potent inhibitors of CYP 3A4, including nefazodone, cyclosporine, cimetidine, some macrolide antibiotics, azole antifungals, antiretrovirals, selective serotonin reuptake inhibitors (SSRIs), and grapefruit juice.^2,12–14

Third-Generation H₁ Receptor Blockers
Fexofenadine has been found to be without the problems associated with terfenadine, even at 10 times the recommended dose. Fexofenadine is not metabolized, meaning that more than 95% of a dose can be found in urine and feces.¹⁵ Long-term post-marketing surveilliance supports its safety, as does a recent observational cohort study.¹⁶ Despite a negligible drug-drug interaction profile, the clinical response to fexofenadine varies widely among and within patients. Intensive study of efflux transporters as one of the elements responsible for this variability is underway at the time of this writing. P-glycoprotein efflux transporters have been described previously in this column.¹⁷ They are located on the luminal surface of epithelial cells in the gut, liver, kidney, testes, and the blood-brain barrier. P-glycoproteins may limit absorption and hence distribution of drugs that are substrates of p-glycoprotein. If a p-glycoprotein inhibiting substance is coadministered with a drug that is usually a substrate of (or "stopped" by) p-glycoprotein, the substrate drug will "gain admittance" to the gut, brain, testes, etc. Fexofenadine is considered a probe drug for p-glycoprotein because it is not metabolized and its bioavailability and clearance are dependent on p-glycoprotein gene expression. Wang et al.¹⁸ demonstrated that a single dose of St. John's wort (SJW) increased the concentration and decreased the clearance of fexofenadine, indicating inhibition of intestinal p-glycoprotein by SJW. Of interest is that chronic use of St. John's wort decreased plasma concentration of fexofenadine, meaning that St. John's wort may become a p-glycoprotein inducer or stimulator with chronic use. Rifampin is an inducer of intestinal p-glycoprotein, upregulating p-glycoprotein expression on the apical surface of intestinal cells. It has been found to increase the clearance of fexofenadine and reduce its bioavailability in healthy volunteers.¹⁵ The clinical implication of this effect on p-glycoprotein is that fexofenadine may lose effectiveness.

Cetirizine (Zyrtec®) is the carboxylic acid metabolite of hydroxyzine. With regard to cetirizine, there are no reports in the literature of QTc prolongation or hepatic metabolism. In studies in which healthy volunteers were administered cetirizine at three times the recommended dose, no effect on QTc was found. Cetirizine is a racemic mix of R and S enantiomers. Levocetirizine, the S enantiomer of racemic cetirizine, seems to have a smaller volume of distribution than cetirizine, providing for better safety and efficacy. There are no reports of cardiotoxicity or drug interactions to date.¹⁹

Loratadine (Claritin® or Alavert®) is hepatically metabolized at CYP 3A4 and CYP 2D6. Its safety profile has been the subject of much professional debate. Initially, loratadine was believed to not be associated with QTc prolongation at high doses, even in in vivo drug interaction studies involving potent 3A4 inhibitors such as erythromycin.^2,12,13 The package insert does state that 3A4 inhibitors can increase levels of loratadine, but that CYP 2D6 takes over when this occurs. The package insert does not mention that the drug may affect the QTc.²⁰ Abernethy et al.²¹ studied healthy volunteers who received nefazodone (a potent 3A4 inhibitor) 300 mg every 12 hours (a high dose, but it is the recommended maximum dose by the manufacturer) with terfenadine (60 mg b.i.d.), loratadine (20 mg/day), or placebo. For comparison, each of the three drugs was also used alone. Blood levels of parent compounds and metabolites were measured, as were ECGs in each permutation. As expected, terfenadine's levels were increased, and the average QTc increased 42.4 msec when used with nefazodone. The concomitant use of nefazodone with loratadine yielded an average increase of the QTc of 21.6 msec, nearly one-half that seen with terfenadine. For comparison, this change in QTc for the loratadine-nefazodone combination is similar to the change noted when ziprasidone (Geodon®) is used alone.²² Abernethy et al. astutely point out that loratadine is often used at doses higher than 20 mg/day and that this study had only healthy volunteers. It is surprising that one of the coauthors of Abernethy et al.'s report later wrote a letter to the journal's editor suggesting that the method of obtaining and recording ECGs was somewhat misleading, listing four areas of questions about the ECGs and statistical manipulation of the determined QTc.²³

In contrast, Kosoglou et al.²⁴ report that co-administration of loratadine with the potent 3A4 inhibitor ketoconazole significantly increased plasma concentration of loratadine and its major metabolite desloratadine without significantly affecting QTc in healthy volunteers. Co-administration of the potent 3A4 and 2D6 inhibitor cimetidine (Tagamet® and others) and loratadine significantly increased loratadine plasma concentrations, but not desloratadine, and also resulted in no significant alterations of the QTc. They concluded that although there was a drug-drug interaction, there were no significant QTc changes in healthy adult volunteers. Since both ketoconazole and nefazodone are p-glycoprotein inhibitors, the different outcomes of the two studies on QTc cannot be explained simply by efflux transport mechanisms. Watchfulness may be appropriate when loratadine is co-administered with potent CYP 3A4 and CYP 2D6 inhibitors or with p-glycoprotein inhibitors. Further study is needed, especially since loratadine is now available over the counter. Loratadine may also be an inhibitor of p-glycoprotein, causing an increase in ATPase activity above basal levels (inhibiting the ATP-binding transporters) in vitro but is less potent than verapamil and cyclosporine.²⁵

Desloratadine (Clarinex®) is the orally active major metabolite of loratadine and is now available in the United States. Desloratadine is 15 times more potent than loratadine at the H₁ receptor and seems to have a more rapid onset of action.²⁶ Despite these findings, there may be no clinical advantage over loratadine.²⁷ Desloratadine is reported to have no adverse cardiac effects in healthy volunteers, even at 10 times the recommended dosage. Like loratadine, desloratadine does not inhibit nor induce other medications via the cytochrome P450 system. No clinically significant cytochrome P450-mediated drug interactions, including QTc alterations, have been reported to date.^28,29 Co-administration with ketoconazole and erythromycin did increase the area under the curve and C_max of desloratadine to a small extent.³⁰ Desloratadine does not seem to have any inhibitory effects on p-glycoprotein.^25,31

Summary

Most first-generation antihistamines—most of which are available as over-the-counter preparations—are inhibitors of CYP 2D6 and may alter the metabolism of drugs dependent upon CYP 2D6 such as venlafaxine, tricyclic antidepressants, some antipsychotics, beta blockers, antiarrhythmics, and tramadol. The second-generation antihistamines have a known potential for cardiotoxicity and include terfenadine, astemizole, and ebastine. If used in an overdose or administered with other compounds that inhibit CYP 3A4 enzymes, these drugs could lead to palpitations, syncope, or fatal arrhythmias. Because of this problem, only ebastine remains available, but not in the U.S. market. The third-generation antihistamines include fexofenadine, loratadine, desloratadine, and cetirizine. None of these drugs appears to affect the QTc directly, although there is some controversy about loratadine's effects on the QTc when used in combination with potent CYP 2D6 or 3A4 inhibitors. More studies are needed to be conclusive regarding loratadine's effects on QTc. Second- and third-generation antihistamines are generally less sedating, and this property may be due to the fact that they are p-glycoprotein substrates and that the drugs are effluxed out of the CNS. However, if p-glycoprotein is inhibited or induced by other drugs, decreased efficacy or enhanced side effects of second- or third-generation antihistamines may result. None of the second- or third-generation antihistamines are inhibitors or inducers of the cytochrome P450 system. Inhibition by other drugs of CYP 2D6 or 3A4 with concomitant use of second- or third-generation antihistamines generally does not lead to serious side effects, primarily because of their wide safety margin.

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