A Correct. When the VLPO is active and GABA is released to the TMN, the sleep promoter is on and the wake promoter is inhibited. Thus, inhibiting GABA activity can promote wakefulness.

B Incorrect. When the TMN is active and histamine is released to the cortex and the VLPO, the wake promoter is on and the sleep promoter is inhibited. Thus, inhibiting histamine activity can promote sleep, not wakefulness.

C Incorrect. The sleep/wake switch is also regulated by orexin neurons in the lateral hypothalamus, which stabilize wakefulness. Inhibition of orexin would therefore promote sleep, not wakefulness. In fact, a deficiency of orexin is an underlying cause of the extreme and sudden sleepiness seen in narcolepsy.

D and E Incorrect.

A and B Incorrect. Histamine 1, histamine 2, and histamine 3 are targets of both sleep- and wake-promoting agents including histamine releasers, antihistamines, and selective histamine antagonists.

C Incorrect. Serotonin 2C antagonism can be sedating and is one of the targets of some sleep agents, including trazodone and agomelatine.

D Correct. Eszopiclone is a positive allosteric modulator at GABA_A receptors. Eszopiclone primarily targets receptors containing the alpha 1 isoform and this is responsible for its effects on sleep.

E Incorrect. Although eszopiclone may target GABA A receptors that contain the alpha 2 and 3 isoforms, this is not its primary action nor is it related to the sleep effects. Instead, alpha 2 and 3 receptor subtypes are related to anxiolytic, muscle relaxant, and alcohol-potentiating factors.

A Incorrect. Hypnotics with ultra-long half-lives (greater than 24 hours: for example, flurazepam and quazepam) can cause drug accumulation with chronic use. This can cause impairment that has been associated with increased risk of falls, particularly in the elderly.

B Incorrect. Hypnotics with moderate half-lives (15–30 hours: estazolam, temazepam, most tricyclic antidepressants, mirtazapine, olanzapine) may not wear off until after the individual needs to awaken and thus may have “hangover” effects (sedation, memory problems). Given that the patient needs to drive early in the morning, this may not be the best option for her.

C Incorrect. Hypnotics with ultra-short half-lives (1–3 hours: zaleplon, triazolam, zolpidem, melatonin, ramelteon) can wear off before the individual needs to awaken and thus cause loss of sleep maintenance, which is already a problem for this patient.

D Correct. Hypnotics with half-lives that are short but not ultra-short (approximately 6 hours: zolpidem CR, eszopiclone, and perhaps low doses of trazodone or doxepin) may provide rapid onset of action and plasma levels above the minimally effective concentration only for the duration of a normal night’s sleep. Thus, of the answer choices, zolpidem CR may best treat the patient’s difficulties with sleep onset and maintenance while avoiding risks associated with agents with longer half-lives. The dose of zolpidem CR in eldery patients is 6.25 mg/night.

A and D Incorrect. Because this patient has developed tolerance to his current benzodiazepine, another benzodiazepine such as temazepam and chlordiazepoxide may not be the best choices.

B Incorrect. Ramelteon has not been reported to cause tolerance and can be used for sleep initiation; however, it is not necessarily used for sleep maintenance.

C Correct. Trazodone works by a serotonergic and histaminergic mechanism unique from estazolam and may be able both to induce sleep and suppress any mild withdrawal insomnia when estazolam is stopped. However, if severe insomnia results from estazolam discontinuation, a tapering of this may be necessary until rebound insomnia resolves, while adding trazodone.