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Delirium is a heterogeneous syndrome primarily characterized by fluctuations in attention and awareness. Sleep-wake disturbances are a common and significant feature of delirium and can manifest as circadian rhythm inversion, sleep fragmentation, and reduced rapid eye movement (REM) and slow-wave sleep. Some literature suggests that the relationship between sleep disruption and delirium is reciprocal wherein the two reinforce one another and may share an underlying etiology. As there are no FDA-approved medications for delirium or delirium-related sleep disturbances, management is primarily focused on addressing underlying medical concerns and promoting physiologic circadian patterns with non-pharmacological behavioral interventions. In practice, however, medications are often used, albeit with limited evidence to support their use. This literature review explores the pharmacology and pharmacokinetics of several medications with literature investigating their use in delirium: melatonin, ramelteon, dual orexin receptor antagonists (DORAs), and dexmedetomidine. Current evidence suggests a possible benefit of ramelteon or melatonin, dexmedetomidine for patients in the ICU setting, and DORAs as therapeutic options for the re-regulation of sleep-wake cycle disruption in delirium. We discuss pertinent pharmacokinetic and pharmacodynamic factors that may influence clinical decision-making regarding these interventions., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

The pharmacokinetics and pharmacodynamics of the benzodiazepine anxiolytic alprazolam (1 mg orally) were compared between young and elderly healthy volunteers. Eight young subjects (mean age 29.8 years) and eight elderly volunteers (mean age 68.4 years) received oral placebo and alprazolam (1.0 mg) in a randomized, double-blind, single-dose crossover study. In the elderly subjects, plasma concentrations were higher, although not significantly so, than in young volunteers 0.25, 0.5, and 0.75 hours after dosage. Apparent elimination half-life, time of maximum concentration, maximum concentration, volume of distribution, and apparent clearance were similar for the two groups. In both groups, alprazolam treatment (versus placebo) produced significant changes in typical benzodiazepine agonist effects, such as increased sedation and fatigue, reduced excitement, increased feelings of spaciness, and perception of thinking slowed. For some measures, the alprazolam-placebo difference was greater in young than in elderly subjects. In both groups, alprazolam significantly impaired performance on the digit-symbol substitution test (DSST). EEG studies indicated significant increases in relative beta amplitude (13-30 Hz range) after alprazolam compared to placebo. Percent DSST decrement and percent EEG change were highly correlated with plasma alprazolam concentrations for both groups. There were modest increases in alprazolam plasma concentration in the elderly compared to the younger group shortly after drug administration, but there was no evidence of increased sensitivity to the pharmacodynamic effects of alprazolam in the elderly.

Twelve healthy volunteers received oral placebo, 250 mg of caffeine, and 500 mg of caffeine in a randomized, double-blind, single-dose crossover study. Caffeine kinetics were nonlinear, with clearance significantly reduced and elimination half-life prolonged at the 500-mg compared to the 250-mg dose. The lower dose of caffeine produced more favorable subjective effects than the higher dose (elation, peacefulness, pleasantness), whereas unpleasant effects (tension, nervousness, anxiety, excitement, irritability, nausea, palpitations, restlessness) following the 500-mg dose exceeded those of the 250-mg dose. The lower dose of caffeine enhanced performance on the digit symbol substitution test and a tapping speed test compared to placebo; high-dose caffeine produced less performance enhancement than the lower dose. The plasma concentration versus response relationship revealed concentration-dependent increases in anxiety and improvements in cognitive and motor performance at low to intermediate concentrations. Both caffeine doses reduced electroencephalographic amplitude over the 4 Hz to 30 Hz spectrum, as well as in the alpha (8-11 Hz) and beta (12-30 Hz) ranges; however, effects were not dose-dependent. While favorable subjective and performance-enhancing stimulant effects occur at low to intermediate caffeine doses, the unfavorable subjective and somatic effects, as well as performance disruption, from high doses of caffeine may intrinsically limit the doses of caffeine used in the general population.

1. The relationship between plasma and brain caffeine and metabolite concentrations and behavioural stimulation was investigated over a 4 h time course. 2. CD-1 mice receiving single intraperitoneal doses of caffeine-sodium benzoate solution (caffeine doses: 0, 20, and 40 mg kg-1) were evaluated in an activity monitor, and their plasma and brain caffeine and metabolite concentrations were determined by high performance liquid chromatography (h.p.l.c.). 3. Kinetic variables for caffeine at low and high caffeine doses were: volume of distribution (Vd), 1.16 and 0.88 l kg-1; plasma elimination half-life (t1/2), 1.25 and 1.62 h; brain t1/2, 0.93 and 1.30 h; clearance, 0.64 and 0.38 l h-1 kg-1, respectively, with Vd and brain t1/2 differing significantly between the two caffeine doses. 4. Low-dose caffeine stimulated vertical behaviours significantly more than high-dose, during the first 150 min post-dosage; both doses stimulated vertical behaviours significantly more than vehicle treatment. 5. Low-dose and high-dose caffeine stimulated horizontal and stereotypic behaviours equivalently, during the first 150 min post-dosage; both doses stimulated these behaviours significantly more than vehicle. 6. Only later, 150 min post-dosage, did high-dose caffeine stimulate all behaviours significantly more than both low-dose and vehicle treatment; this occurred when caffeine concentrations had fallen to approximately 10 micrograms g-1 in the high-dose group. 7. The maximal stimulant effects of caffeine occurred in an intermediate concentration range, between 10-20 micrograms g-1, while lower and higher concentrations produced either no additional stimulation or decrements in activity.