posted
I wanted to post this so that those taking either Macrolides, a SSRI, a Benzo"s and possibly Rifampin.
Just two of these drugs taken at the same time can cause serious drug interactions that many mistake as herxes from lyme disease treatment.
You cannot hope that your doctor is familiar with these interaction because most are NOT.
To save someone from suffering as my daughter has from taking Biaxin XL, Lexapro and ocassionally Ambien, or Priosec. All of these drugs interat with one another and our best LLMD and Pharmacist were all unaware. Here is the Article. It is long but a must copy for future reference,
Cytochrome P450: New Nomenclature and Clinical Implications
MELANIE JOHNS CUPP, PHARM.D., and TIMOTHY S. TRACY, PH.D. West Virginia University School of Pharmacy, Morgantown, West Virginia
Many drug interactions are a result of inhibition or induction of cytochrome P450 enzymes (CYP450). The CYP3A subfamily is involved in many clinically significant
drug interactions, including those involving nonsedating antihistamines and cisapride, that may result in cardiac dysrhythmias.
CYP3A4 and CYP1A2 enzymes are involved in drug interactions involving theophylline.
CYP2D6 is responsible for the metabolism of many psychotherapeutic agents.
The protease inhibitors, which are used to treat patients infected with the human immunodeficiency virus, are metabolized by the CYP450 enzymes and consequently interact with a multitude of other medications.
By understanding the unique functions and characteristics of these enzymes, physicians may better anticipate and manage drug interactions and may predict or explain an individual's response to a particular therapeutic regimen.
The basic purpose of drug metabolism in the body is to make drugs more water soluble and thus more readily excreted in the urine or bile.
1,2 One common way of metabolizing drugs involves the alteration of functional groups on the parent molecule (e.g., oxidation) via the cytochrome P450 enzymes.
These enzymes are most predominant in the liver but can also be found in the intestines, lungs and other organs.3-6
These cytochrome P450 enzymes are designated by the letters "CYP" followed by an Arabic numeral, a letter and another Arabic numeral (e.g., CYP2D6).7 Each enzyme is termed an isoform since each derives from a different gene.
It should be noted, however, that structural similarity of enzymes cannot be used to predict which isoforms will be responsible for a drug's metabolism.
Drug interactions involving the cytochrome P450 isoforms generally result from one of two processes, enzyme inhibition or enzyme induction. Enzyme inhibition usually involves competition with another drug for the enzyme binding site.
This process usually begins with the first dose of the inhibitor,8,9 and onset and offset of inhibition correlate with the half-lives of the drugs involved.9 line
Until genetic tests for isoform expression become available, a physician can often anticipate drug interactions in a patient by knowing which medications inhibit or induce P450 enzymes.
SSRIs and cimetidine inhibit metabolism of tricyclic antidepressants, but the clinical significance of this finding depends on individual genetic variations and concomitant medications. line
Enzyme induction occurs when a drug stimulates the synthesis of more enzyme protein,9 enhancing the enzyme's metabolizing capacity.
It is somewhat difficult to predict the time course of enzyme induction because several factors, including drug half-lives and enzyme turnover, determine the time course of induction.
Cytochrome P450 Isoforms
CYP2D6
CYP2D6 has been studied extensively because it exhibits genetic polymorphism, meaning that distinct population differences are apparent in its expression or activity.
Approximately 7 to 10 percent of Caucasians are poor metabolizers of drugs metabolized by CYP2D6.10
Individuals with normal CYP2D6 activity are termed extensive metabolizers. Ethnic differences are indicated in this genetic polymorphism, since Asians and blacks are less likely than Caucasians to be poor metabolizers.
11,12 Poor metabolizers are at risk for drug accumulation and toxicity from drugs metabolized by this isoform.
For example, one patient who suffered cardiotoxicity induced by desipramine (Norpramin) was found to be a poor metabolizer.13 Poor metabolizers of CYP2D6 substrates are at risk for postural hypotension and antipsychotic side effects such as oversedation,
because several antipsychotic agents are metabolized by CYP2D6.14 In a study of 45 elderly patients (five of whom were poor metabolizers) receiving perphenazine, side effects increased fivefold
in the poor metabolizers compared with the extensive metabolizers.15 Conversely, when formation of an active metabolite is essential for drug action, poor metabolizers of CYP2D6 can exhibit less response to drug therapy compared with extensive metabolizers.
Codeine is O-demethylated to morphine by CYP2D6, which accounts at least partially for its analgesic effect.16
Thus, poor metabolizers may have less response to codeine than other persons. The substrates and inhibitors of CYP2D6 are listed in Table 1.
Psychotherapeutic Agents. Many antidepressants are metabolized by CYP2D6, but other cytochrome P450 isoforms can also contribute to their metabolism (Tables 1 through 6).
The clinical importance of this "dual metabolism" will be illustrated later. With respect to drugs inhibiting CYP2D6, cimetidine (Tagamet), the selective serotonin reuptake inhibitors (SSRIs) and
some tricyclic antidepressants function as inhibitors of this P450 isoform.17-19 Of the antidepressants, paroxetine (Paxil) appears to have the greatest ability to inhibit the metabolism of CYP2D6 substrates.
This is followed by fluoxetine (Prozac) and norfluoxetine; sertraline (Zoloft) and desmethylsertraline; fluvoxamine (Luvox), nefazodone (Serzone) and venlafaxine (Effexor); clomipramine (Anafranil), and amitriptyline (Elavil).19
This ranking is based on in vitro data, however, and the choice of an antidepressant should be based on factors other than the propensity to inhibit CYP2D6. Although sertraline appears to be less likely than the other SSRIs to inhibit CYP2D6, inhibition may still occur at doses greater than 50 mg.
The clinical significance of the inhibition of tricyclics by SSRIs or cimetidine is subject to variation in enzyme activity between individuals, the degree to which the patient metabolizes and co-ingestion of other enzyme inhibitors.20
CYP3A
Inhibitors of CYP3A. Members of the CYP3A subfamily are the most abundant cytochrome enzymes in humans. They account for 30 percent of the cytochrome P450 enzymes in the liver21 and are also substantially expressed in the intestines.
Members of this subfamily are involved in many clinically important drug interactions.1 Substrates, inhibitors and inducers of CYP3A are listed in Table 2.
Nonsedating Antihistamines. High plasma concentrations of terfenadine (Seldane) and astemizole (Hismanal) have been associated with torsade de pointes, a life-threatening cardiac arrhythmia characterized by altered cardiac repolarization and a prolonged QT interval.22 Terfenadine is a prodrug that undergoes complete first-pass metabolism to an active
carboxymetabolite.23 It is therefore unusual to detect terfenadine in the plasma of patients who take this drug at the recommended dosage. Since it is terfenadine rather than its active metabolite that is cardiotoxic, arrhythmias occur when a build-up of parent terfenadine takes place.
This may occur when azole antifungal medications or macrolide antibiotics are taken concomitantly.22,24 To counteract this problem, fexofenadine (Allegra), the active metabolite of terfenadine, is now marketed as a noncardiotoxic alternative to terfenadine.
Like fexofenadine, loratadine (Claritin) does not appear to be cardiotoxic and thus is also a safe nonsedating antihistamine alternative.25
NOTE: Inhibitors will decrease metabolism of substrates and generally lead to increased drug effect (unless the substrate is a prodrug). Inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).
Ketoconazole (Nizoral), itraconazole (Sporanox) and fluconazole (Diflucan) inhibit CYP3A, although ketoconazole and itraconazole are more inhibiting than fluconazole.26 Based on in vitro and in vivo studies, ketoconazole and itraconazole markedly inhibit metabolism of terfenadine, causing changes in the QT interval.22,27
At dosages of 200 mg daily, fluconazole did not result in accumulation of parent terfenadine or changes in the QT interval.28 However, an interaction with terfenadine and fluconazole coadministration may occur in patients taking higher dosages of fluconazole or in patients with risk factors for ventricular arrhythmia.
These two drugs should be used together with caution.
In addition to the azole antifungal medications, the macrolide antibiotics can also inhibit terfenadine metabolism, resulting in the development of torsade de pointes.
Erythromycin and clarithromycin (Biaxin) have been shown to alter terfenadine metabolism, but this does not appear to occur with azithromycin (Zithromax).
29 Thus, a patient who is taking terfenadine and needs macrolide antibiotic therapy should be given azithromycin to avoid possible cardiac consequences.
The SSRIs are 28 to 775 times less potent as inhibitors of terfenadine metabolism than ketoconazole.30
With respect to ability to inhibit CYP3A, the following order of the SSRIs is observed: nefazodone is greater than fluvoxamine, and norfluoxetine is greater than fluoxetine, which is greater than sertraline, desmethylsertraline, paroxetine and venlafaxine.31
Several clinically important cardiac events have been reported in patients receiving fluoxetine or fluvoxamine with terfenadine or astemizole.30,32,33
The use of fluvoxamine or nefazodone with terfenadine or astemizole is contraindicated, and the U.S. Food and Drug Administration is currently considering requiring a contraindication against the use of other SSRIs with the nonsedating antihistamines.
30 The package insert for sertraline contains a warning against its use with terfenadine and astemizole.34 In patients who need to take an antidepressant and a nonsedating antihistamine concurrently, paroxetine, venlafaxine and tricyclic antidepressants may be safe options, since they inhibit CYP3A more weakly.35,36 Conversely, fexofenadine or loratadine, neither of which are associated with arrhythmias, could be prescribed, thus permitting more freedom in the choice of an antidepressant.
TABLE 2 Substrates, Inhibitors and Inducers of CYP3A line
�--Does not inhibit all CYP3A substrates; does not inhibit terfenadine metabolism.
NOTE: Inhibitors will decrease metabolism of substrates and generally lead to increased drug effect (unless the substrate is a prodrug).
Inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).
Cisapride. Serious ventricular arrhythmias have been reported in patients taking cisapride (Propulsid) and drugs that inhibit CYP3A, the isoform responsible for metabolism of cisapride.
37 Ketoconazole, fluconazole, itraconazole, metronidazole, erythromycin and clarithromycin have been associated with cisapride-induced torsade de pointes.37 Concurrent use of cisapride with fluoxetine, sertraline, fluvoxamine and nefazodone might be problematic because of CYP3A inhibition.38 line
Erythromycin, clarithromycin and ketoconazole inhibit CYP3A, causing build-up of drugs metabolized by the same enzyme.
Terfenadine and cisapride are examples of drugs that can rise to cardiotoxic levels. line
Theophylline. Erythromycin39 and clarithromycin40 (but not azithromycin41) decrease theophylline metabolism by inhibiting CYP3A.
The interaction between erythromycin and theophylline is most likely to occur in patients receiving higher dosages of erythromycin and increases with the duration of therapy.
Inducers of CYP3A. Because of the resurgence of tuberculosis in the United States, rifampin (Rifadin, Rimactane), an inducer of the CYP3A subfamily, is being prescribed more widely than in previous years. Of particular clinical relevance is the potential reduction of oral contraceptive efficacy by rifampin, since estradiol levels can be reduced by rifampin-mediated CYP3A induction.42
In addition to rifampin, potent glucocorticoids such as dexamethasone (Decadron) are also inducers of CYP3A, but lower-potency glucocorticoids, such as prednisolone, have minimal effect.43
TABLE 3 Substrates, Inhibitors and Inducers of CYP1A2 line
NOTE: Inhibitors will decrease metabolism of substrates and generally lead to increased drug effect (unless the substrate is a prodrug). Inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).
CYP1A2
CYP1A2 can be induced by exposure to polycyclic aromatic hydrocarbons, such as those found in charbroiled foods and cigarette smoke.44 This is the only P450 isoform affected by tobacco. Cigarette smoking can result in an increase of as much as threefold in CYP1A2 activity.44 Theophylline is metabolized in part by CYP1A2,45 which explains why smokers require higher doses of theophylline than nonsmokers.
Table 3 lists the substrates, inhibitors and inducers of CYP1A2.
Quinolones. Certain quinolone antibiotics can inhibit theophylline metabolism,46-48 although this effect is highly variable.
The interaction between enoxacin (Penetrex) or ciprofloxacin (Cipro) and theophylline47 is most significant in patients with plasma theophylline concentrations at the upper end of normal. Conversely, norfloxacin (Noroxin) and ofloxacin (Floxin) have little effect on theophylline concentrations,46 and lomefloxacin (Maxaquin) does not appear to alter the pharmacokinetics of theophylline.49
Since cimetidine is an inhibitor of CYP1A2,17 additive inhibition of theophylline metabolism occurs when cimetidine is combined with a fluoroquinolone.
CYP2E1
This isoform is inducible by ethanol and isoniazid and is responsible in part for the metabolism of acetaminophen.50 The product of acetaminophen's cytochrome P450 metabolism is a highly reactive intermediate that must be detoxified by conjugation with glutathione.
51 Patients with alcohol dependence may be at increased risk for acetaminophen hepatotoxicity because ethanol induction of CYP2E1 increases formation of this reactive intermediate, and glutathione concentrations are decreased in these patients.52
Cimetidine exhibits only moderate affinity for this isoform and produces no significant inhibition of the production of acetaminophen's toxic metabolite.17 Table 4 lists the substrates, inhibitors and inducers of CYP2E1.
CYP2C9
S-Warfarin. Warfarin is produced as a racemic mixture of R-warfarin and S-warfarin, but the predominance of pharmacologic activity resides in the S-enantiomer.53
Most metabolism of S-warfarin is by means of CYP2C9,54 and inhibition of this isoform results in several clinically important drug interactions.
Fluconazole, metronidazole, miconazole and amiodarone are a few examples of the many drugs that profoundly inhibit S-warfarin metabolism and produce marked increases in prothrombin time measurements.55-58
Interestingly, cimetidine, a very weak inhibitor of CYP2C9,17 has been shown to have very little effect on warfarin concentrations.59 The substrates, inhibitors and inducers of CYP2C9 are listed in Table 5.
TABLE 4
Substrates, Inhibitors and Inducers of CYP2E1 line
Substrates Acetaminophen (Tylenol) Ethanol
Inhibitors Disulfiram (Antabuse)
Inducers Ethanol Isoniazid (Laniazid)
NOTE: Inhibitors will decrease metabolism of substrates and generally lead to increased drug effect (unless the substrate is a prodrug).
Inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).
Phenytoin.
Phenytoin is primarily metabolized via CYP2C9,60 although CYP2C19 may also play a small role.61 As stated above, cimetidine is a weak inhibitor of CYP2C9.
It is most likely to cause clinically significant inhibition of phenytoin metabolism at cimetidine dosages greater than 1,200 mg in patients at the upper end of the phenytoin therapeutic range.
62 In patients with nonlinear metabolism of phenytoin at relatively low serum levels, the risk of interaction with cimetidine is increased. However, it is difficult to identify these patients in a clinical situation.
CYP2C19
Like CYP2D6, CYP2C19 has been shown to exhibit genetic polymorphism.
63,64 This enzyme is completely absent in 3 percent of Caucasians and 20 percent of Japanese. Drugs metabolized by this isoform include omeprazole (Prilosec),65 lansoprazole (Prevacid)66 and diazepam (Valium).
67 However, clinical examples of excessive or adverse drug effects in people who are CYP2C19-deficient are lacking. Table 6 lists the substrates and inhibitors of CYP2C19.
TABLE 5
Substrates, Inhibitors and Inducers of CYP2C9 line
NOTE: Inhibitors will decrease metabolism of substrates and generally lead to increased drug effect (unless the substrate is a prodrug). Inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).
NOTE: Inhibitors will decrease metabolism of substrates and generally lead to increased drug effect (unless the substrate is a prodrug). Inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).
Illustrative Case 2
A 47-year-old man recently diagnosed with HIV infection visited his physician with flushing, dizziness and swelling of the feet and ankles. He had been taking sustained-release nifedipine for treatment of hypertension for about three years. Approximately two weeks earlier, his physician had prescribed a combination of lamivudine, zidovudine and the protease inhibitor ritonavir.
The HIV-1 protease inhibitors ritonavir, indinavir, saquinavir and nelfinavir all inhibit the CYP3A subfamily of enzymes, thus increasing the serum levels of other drugs that are metabolized by this pathway, including nifedipine. It is likely that the addition of ritonavir to this patient's medical regimen resulted in an increase in the serum level of nifedipine and the subsequent symptoms of flushing and dizziness. Of the currently available protease inhibitors, ritonavir, because of its ability to both inhibit and induce CYP450 enzymes, is associated with the most drug-drug interactions.68
Final Comment
Physicians who become familiar with the role of the various cytochrome P450 enzymes in drug metabolism can often predict the consequences of drug interactions and explain patients' responses to medication regimens. Although tests for isoform expression are not widely available, it is conceivable that such testing may become standard practice in the future, given the clinical importance of isoform deficiencies. In the future, testing may help to identify individuals at risk for drug interactions and adverse events.
The Authors
MELANIE JOHNS CUPP, PHARM.D., is a clinical assistant professor at West Virginia University School of Pharmacy and a drug information specialist at West Virginia Drug Information Center, both in Morgantown. She earned her pharmacy degree at West Virginia University School of Pharmacy and completed a hospital pharmacy practice residency at West Virginia University Hospitals.
TIMOTHY S. TRACY, PH.D., is an assistant professor of clinical pharmacology in the Department of Basic Pharmaceutical Sciences at the West Virginia University School of Pharmacy. He earned a Ph.D. in pharmacy from Purdue University, Lafayette, Ind., and completed a postdoctoral fellowship in clinical pharmacology at the Indiana University School of Medicine, Indianapolis.
Address correspondence to Melanie Johns Cupp, Pharm.D., West Virginia University School of Pharmacy, 1124 HSN, P.O. Box 9550, Morgantown, WV 26506-9550. Reprints are not available from the authors.
Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.
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Posts: 677 | From USA | Registered: Aug 2002
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liz28
Unregistered
posted
Auntybiotic,
While I've never taken SSRIs, I wanted you to know rifampin put me into remission in seven weeks, after being sick five years. There's probably a few more herxes coming up, but you were right, it's a miracle drug. Please wish your mother all the best of health.
robi
Frequent Contributor (1K+ posts)
Member # 5547
posted
Aunty ..... thanks for posting this article ....... is there a short summary ...... i cannot get through all of that.
Thanks, robi
-------------------- Now, since I put reality on the back burner, my days are jam-packed and fun-filled. ..........lily tomlin as 'trudy' Posts: 2503 | From here | Registered: Apr 2004
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Thanks so much for posting the article. I couldn't quite grasp what it means to me right now though. I'm taking levaquin and diflucan (and zith, plaq, nystatin, & mepron), and my LLMD wants me to start taking Paxil. Would you (or anybody else) know if I should just abstain?
Thanks!
Posts: 449 | From Vermont | Registered: Nov 2004
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