Psychiatry - November 2008 - (Page 35)

potential to interfere with the activity of anticholinergic medications, may act synergistically with other cholinomimetic drugs, and should be prescribed with care in patients with a history of asthma or obstructive pulmonary disease.19–22 Similar to other cholinomimetics, ChEIs may induce or exacerbate extrapyramidal symptoms.20,21 Finally, although all ChEIs have the same molecular target, chemically they are sufficiently different to possess different pharmacokinetic and pharmacodynamic properties. Thus, major enzymes involved in metabolic processing of donepezil and galantamine are the CYP 450 isoenzymes 2D6 and 3A4. No clinical trials have investigated the effects of donepezil on the clearance of drugs metabolized by those two enzymes, but a study conducted in healthy volunteers showed that ketoconazole, an inhibitor of CYP 450 3A4, reduced donepezil clearance.19 Similarly, drugs that are potent inhibitors of the CYP 450 isoenzymes 2D6 and 3A4 (ketoconazole, paroxetine, amitriptyline, fluoxetine, fluvoxamine, and quinidine) have been shown to reduce clearance of galantamine.22 On the other hand, rivastigmine is primarily metabolized by esterases, undergoes only minimal modification by CYP 450 isoenzymes, and has no known metabolic drug-drug interactions.20,21 Clearance of all three ChEIs is decreased in patients with moderate to severe hepatic impairment; moderate to severe renal impairment is associated with a decreased clearance of galantamine and rivastigmine, but not of donepezil.19–22 These subtle differences in metabolism and clearance should be kept in mind when making prescribing decisions and when monitoring patients for adverse reactions. Memantine. Since memantine does not inhibit AChE, its use is not associated with cholinomimetic tolerability issues, and gastrointestinal AEs are rare. The three most common AEs associated with memantine use are confusion, dizziness, and headache, with only headache occurring at a frequency twice the one observed among the placebo-treated patients. In a 24week pivotal trial of memantine involving patients with moderate to severe AD patients who were already taking stable doses of donepezil,29 the rates of AEs in patients treated with both drugs were mostly similar to those observed in patients treated with donepezil alone. In addition, in the group treated with memantine and donepezil compared to the placebodonepezil group, fewer patients experienced certain gastrointestinal AEs (diarrhea, fecal incontinence); however, statistical analyses of tolerability were not performed in this study and further studies would need to be performed to determine whether adding memantine actually improves tolerability to ChEIs. Similar to cholinesterase inhibitors, memantine requires a gradual titration (achieved in 5-mg weekly increments) before reaching the recommended dose of 20mg/day. Memantine undergoes minimal hepatic metabolism, which makes interactions with the inhibitors of CYP 450 enzymes unlikely.18 The drug is primarily excreted in urine, largely as the unmetabolized parent compound. The clearance of memantine is diminished in individuals with moderate to severe renal impairment, and dosage adjustment is recommended in patients with severe renal impairment.18 Pharmacokinetic studies demonstrate that dosage adjustment is not necessary in patients with mild to moderate hepatic impairment, but caution should be used when prescribing memantine to patients with severe hepatic impairment, as metabolism in this patient population has not been studied.18 The principal limitation of our report is the fact that there were no head-to-head comparisons of the four drugs within a single controlled trial. We attempted to make our approach more objective by (1) limiting data sources to the AE data from PI documents only, thus using only the material that was selected by the manufacturers or FDA, and (2) performing an odds ratio analysis for each AE in order to indicate which ones were significantly more likely to occur during active treatment. The analysis was not weighted (i.e., it did not take into account differences in the number of patients reported for each drug), a consideration that should be kept in mind when comparing the statistical significance of odds ratios calculated from data sets with different numbers of patients (lower numbers of patients are associated with larger confidence intervals). Thus, the odds ratios calculated for this study, while useful for making general comparisons within each study, should be used with caution when comparing trials. It also should be noted that each PI document reports data in a slightly different format. Finally, the PI documents typically do not reference or provide details about the trials that are compiled in the data tables. The authors took the information contained therein as being representative of the most accurate data for each drug. CONCLUSION Since patients with AD are typically frail, have several comorbid conditions, and take multiple medications, physicians should be aware of the tolerability and safety profiles of the currently prescribed antidementia drugs. Direct, head-tohead clinical trials would be an ideal method for assessing differences in tolerability and efficacy between AD medications; unfortunately, such trials have not been performed and are not likely to be sponsored by the drug manufacturers. This study sought to overcome the lack of direct-comparison trials by analyzing the data presented by each company in its own PI material; however, caution should be exercised when comparing values obtained from different trials or trial groups. [NOVEMBER] Psychiatry 2008 35

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Psychiatry - November 2008 Editor's Message Editorial Advisory Board Contents PsychRx Letters to the Editor Measuring Adverse Events in Psychiatry Nonsuicidal Self Injury in Adolescents Relative Tolerability of Alzheimer's Disease Treatments Biracial Identity Development and Recommendations in Therapy Depression and Cardiovascular Disease: Just an Urban Legend? Three Risk Management Basics Journal Watch Classified Advertising Information for Authors

Psychiatry - November 2008

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