Kaplan + Sadock's Synopsis of Psychiatry, 11e

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29.9 Benzodiazepines and Drugs Acting on GABA Receptors

medications) should be ruled out. Benzodiazepine use should be started at a low dosage, and the person should be instructed regarding the drug’s sedative properties and abuse potential. An estimated length of therapy should be decided at the begin- ning of therapy, and the need for continued therapy should be reevaluated at least monthly because of the problems associ- ated with long-term use. However, certain persons with anxiety disorders are unresponsive to treatments other than benzodiaz- epines in long-term use. Benzodiazepines are available in a wide range of formu- lations. Clonazepam is available in a wafer formulation that facilitates its use in patients who have trouble swallowing pills. Alprazolam is available in an extended-release form, which reduces the frequency of dosing. Some benzodiazepines are more potent than others in that one compound requires a rel- atively smaller dosage than another compound to achieve the same effect. For example, clonazepam requires 0.25 mg to achieve the same effect as 5 mg of diazepam; thus, clonazepam is considered a high-potency benzodiazepine. Conversely, oxaz- epam has an approximate dosage equivalence of 15 mg and is a low-potency drug. Zaleplon is available in 5- and 10-mg capsules. A single 10-mg dose is the usual adult dose. The dose can be increased to a maximum of 20 mg as tolerated. A single dose of zaleplon can be expected to provide 4 hours of sleep with minimal residual impairment. For persons older than age 65 years or persons with hepatic impairment, an initial dose of 5 mg is advised. Eszopiclone is available in 1-, 2-, and 3-mg tablets. The start- ing dose should not exceed 1 mg in patients with severe hepatic impairment or those taking potent CYP3A4 inhibitors. The rec- ommended dosing to improve sleep onset or maintenance is 2 or 3 mg for adult patients (ages 18 to 64 years) and 2 mg for older adult patients (ages 65 years and older). The 1-mg dose is for sleep onset in older adult patients whose primary complaint is difficulty falling asleep. Table 29.9-1 lists preparations and doses of medications dis- cussed in this chapter. R eferences Bahmad FM Jr, Venosa AR, Oliveira CA. Benzodiazepines and GABAergics in treating severe disabling tinnitus of predominantly cochlear origin. Int Tinnitus J. 2006; 12:140. Bannan N, Rooney S, O’Connor J. Zopiclone misuse: An update from Dublin. Drug Alcohol Rev. 2007;26:83. Brands B, Blake J, Marsh DC, Sproule B, Jeypalan R, Li S. The impact of ben- zodiazepine use on methadone maintenance treatment outcomes. J Addictive Disease. 2008; 27:37. Dubovsky SL. Benzodiazepine receptor agonists and antagonists. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol. 2. Philadelphia: Lippincott Williams & Wilkins: 2009:3044. Dell’osso B, Lader M. Do benzodiazepines still deserve a major role in the treat- ment of psychiatric disorders? A critical reappraisal. Eur Psychiatry. 2013; 28(1):7–20. Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Harmatz JS. Differences in pharmacodynamics but not pharmacokinetics between subjects with panic disorder and healthy subjects after treatment with a single dose of alprazolam. J Clin Psychopharmacol. 2000;20:338. Katsura M. Functional involvement of cerebral diazepam binding inhibitor (DBI) in the establishment of drug dependence. Nippon Yakurigaku Zasshi. 2001; 117:159. Korpi ER, Matilla MJ, Wisden W, Luddens H. GABA(A)-receptor subtypes: Clinical efficacy and selectivity of benzodiazepine site ligands. Ann Med. 1997; 29:275. Lemmer B. The sleep–wake cycle and sleeping pills. Physiol Behav. 2009;90:285. Najib J. Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treat- ment of transient and chronic insomnia. Clin Ther. 2006;28:490.

symptoms for 4 or more days. Tolerance does not develop to the sedative effects of zolpidem and zaleplon.

Drug Interactions The most common and potentially serious benzodiazepine receptor agonist interaction is excessive sedation and respira- tory depression occurring when benzodiazepines, zolpidem, or zaleplon are administered concomitantly with other CNS depressants, such as alcohol, barbiturates, tricyclic and tet- racyclic drugs, dopamine receptor antagonists, opioids, and antihistamines. Ataxia and dysarthria may be likely to occur when lithium, antipsychotics, and clonazepam are combined. The combination of benzodiazepines and clozapine (Clo- zaril) has been reported to cause delirium and should be avoided. Cimetidine (Tagamet), disulfiram (Antabuse), iso- niazid, estrogen, and oral contraceptives increase the plasma concentration of diazepam, chlordiazepoxide, clorazepate, and flurazepam. Cimetidine increases the plasma concen- trations of zaleplon. However, antacids may reduce the GI absorption of benzodiazepines. The plasma concentrations of triazolam and alprazolam are increased to potentially toxic concentrations by nefazodone (Serzone) and fluvoxamine (Luvox). The manufacturer of nefazodone recommends that the dosage of triazolam be lowered by 75 percent and the dosage of alprazolam be lowered by 50 percent when given concomitantly with nefazodone. Over-the-counter prepara- tions of kava plant, advertised as a “natural tranquilizer,” can potentiate the action of benzodiazepine receptor ago- nists through synergistic overactivation of GABA receptors. Carbamazepine can lower the plasma concentration of alpra- zolam. Antacids and food may decrease the plasma concen- trations of benzodiazepines, and smoking may increase the metabolism of benzodiazepines. Rifampin (Rifadin), phenyt- oin (Dilantin), carbamazepine, and phenobarbital (Solfoton, Luminal) significantly increase the metabolism of zaleplon. The benzodiazepines may increase the plasma concentrations of phenytoin and digoxin (Lanoxin). The SSRIs may prolong and exacerbate the severity of zolpidem-induced hallucina- tions. Deaths have been reported when parental lorazepam is given with parental olanzapine. The CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes. Coadmin- istration of 3 mg of eszopiclone to subjects receiving 400 mg of ketoconazole, a potent inhibitor of CYP3A4, resulted in a 2.2-fold increase in exposure to eszopiclone. Laboratory Interferences No known laboratory interferences are associated with the use of the benzodiazepines, zolpidem, and zaleplon. Dosage and Clinical Guidelines The clinical decision to treat an anxious person with a benzo- diazepine should be carefully considered. Medical causes of anxiety (e.g., thyroid dysfunction, caffeinism, and prescription