Anxiolytic agents and ethnic variations: Benzodiazepines

Benzodiazepines comprise the most frequently prescribed subclass of antianxiety agents. These agents, first introduced in the early 1960s, quickly replaced the use of barbiturates as the pharmacological approach to anxiety. The popularity of these agents can be attributed to their generally quick onset of action and wider safety margin in overdose compared to the barbiturates. However, the potential of these agents to elicit physical dependence also quickly became apparent. In addition to the frequent use of these agents as anxiolytics, benzodiazepines are also commonly used for muscle tension, insomnia, status epilepticus (diazepam), myoclonic epilepsy (clonazepam), preoperative anesthesia, and alcohol withdrawal. Importantly, Ativan (lorazepam) is often used in the emergency room and inpatient setting to manage acute agitation in patients. Controlled studies involving Asians and Caucasians demonstrated significant pharmacokinetic differences involving use of the benzodiazepines (Ghoneim et al. 1981; Kumana et al. 1987). The volume of distribution of diazepam in these studies was found to be lower, and both serum diazepam and desmethyldiazepam levels were higher in Asian than in white physically and psychiatrically healthy volunteers. These differences became statistically insignificant, however, after controlling for ethnic differences in skinfold thickness and the ratio of actual to ideal body weight, suggesting that ethnic differences may be secondary to differences in the percentage of body fat.

Lin et al. (1988) studied plasma alprazolam concentrations in 14 American-born Asian, 14 foreign-born Asian, and 14 Caucasian healthy male volunteers. Both Asian groups had greater AUCs and peak plasma concentrations and lower total plasma clearance than did the Caucasian group, after both oral and intravenous administration of alprazolam. Pharmacodynamically, the onlysignificant difference was that foreign-born Asians experienced more sedation compared with both Caucasian and American-born Asian subjects. In a more recent study, Ajir et al. (1997) also reported that Asians had higher maximum serum concentrations, larger AUCs, and lower clearance of both adinazolam and its major active metabolite than did their Caucasian and African American counterparts. Together, the findings support the concept that Asian patients require smaller doses of adinazolam than do Caucasian patients to achieve similar levels of the parent drug and its metabolite.

Similar to Asians, African Americans have been found to have slower clearance of the benzodiazepines. Furthermore, many studies have reported that African Americans have greater cognitive effects and more anxiety reduction from the benzodiazepines when compared to Caucasians on the same dose of medications. In a study by Ajir et al. (1997), African Americans were found to have increased clearance of adinazolam. However, the AUC of its metabolite N-desmethyladinazolam was found to be higher in African Americans and may be responsible for the larger drug effects on African Americans in terms of adverse effects such as slower psychomotor performance, despite the higher metabolic capacity for adinazolam in this ethnic group.

In terms of the ethnic response to benzodiazepines in Hispanics, studies have implicated the important role of dietary effect. When Mexican subjects were fed a corn-rich diet, the metabolism of nifedipine by 3A4 appears to be reduced (Palma-Aguirre et al. 1994). Many studies suggest that the flavonoid quercetin is effective at inhibiting the intestinal agglomeration of CYP3A4. Corn is rich in quercetin and is a dietary staple for Hispanics. Importantly, many benzodiazepines such as alprazolam, midazolam, and triazolam are all metabolized by CYP3A4, and their use in Hispanics should be downwardly adjusted with caution to take into account the dietary effect on CYP3A4 activity. Similar considerations may apply for citrus-loving Hispanics, since flavonoid naringin found in grapefruit juice is a powerful inhibitor of CYP3A4.