Midazolam drug administration

Fig. 18.6. Midazolam administration with and without grapefruit juice (CFJ) treatment [41]. Midazolam (15 mg tablet) was administered to eight male subjects (average body weight 82 kg) before and after consumption of two glasses (200 mL each) of CFJ, 1 h before drug administration. QMPRPIus was used to estimate human effective permeability (12 x 10 4 cm s 1), pure aqueous water...

Benzodiazepines have been shown to impair divided attention.119 Two groups of investigators reported that oxazepam (7.5 to 50 mg)123 and alprazolam (0.5 mg)162 impaired performance on a test that required subjects to divide their attention between a central tracking task and responding to stimuli in the peripheral visual field. Using a similar test of divided attention, Moskowitz et al.145 found that 30 mg flurazepam and 15 mg midazolam impaired performance the day after drug administration. 

Few studies have examined the effects of benzodiazepines on other cognitive abilities. Rusted et al.170 reported that 5 and 10 mg diazepam impaired performance on a logical reasoning test, but had no effect on a mental rotation task. Judd et al.178 found that 30 mg flurazepam, but not 15 mg midazolam, impaired arithmetic (addition) abilities the day after drug administration. In contrast, flurazepam had no effect on reading comprehension. 

Drug administration route Intranasal midazolam is used widely and successfully as pre-medication, particularly in children, avoiding first-pass metabolism and increasing systemic availability [29" ]. 

Research in rodents has provided evidence of solvent withdrawal. Continuous exposure to toluene for 4 days and subsequent cessation produced an increase in handling-induced convulsions for at least 2 hours after cessation (Wiley et al. 2003). A similar pattern of trichloroethane administration to rodents produced pronounced withdrawal, which was worsened by the administration of the proconvulsant drug pentylenetetrazole and attenuated by reexposure to 2,000 ppm of toluene or the administration of alcohol, pentobarbital, or midazolam (Evans and Balster 1993). 

Most BZs are completely absorbed from the gastrointestinal (GI) tract. The one exception is clorazepate, a pro-drug that undergoes acid hydrolysis in the stomach and is decarboxylated to form N-desmethyl-diazepam, which is then completely absorbed into the bloodstream (Bellantuono et ak, 1980 Hobbs et ak, 1996 Chouinard et ak, 1999). In contrast, most BZs, with the exception of lorazepam and midazolam, are not consistently absorbed from intramuscular injection (Chouinard et ak, 1999). Lorazepam is available as a sublingual form that reaches clinical effect at the same rate as an oral dose. In general, intravenous administration is used only for anesthesia or for the acute management of seizures. When BZs are given via this route, the onset of action is almost immediate (Chouinard et ak, 1999). 

Recovery is sufficiently rapid with most intravenous drugs to permit their use for short ambulatory (outpatient) surgical procedures. In the case of propofol, recovery times are similar to those seen with sevoflurane and desflurane. Although most intravenous anesthetics lack antinociceptive (analgesic) properties, their potency is adequate for short superficial surgical procedures when combined with nitrous oxide or local anesthetics, or both. Adjunctive use of potent opioids (eg, fentanyl, sufentanil or remifentanil see Chapter 31) contributes to improved cardiovascular stability, enhanced sedation, and perioperative analgesia. However, opioid compounds also enhance the ventilatory depressant effects of the intravenous agents and increase postoperative emesis. Benzodiazepines (eg, midazolam, diazepam) have a slower onset and slower recovery than the barbiturates or propofol and are rarely used for induction of anesthesia. However, preanesthetic administration of benzodiazepines (eg, midazolam) can be used to provide anxiolysis, sedation, and amnesia when used as part of an inhalational, intravenous, or balanced anesthetic technique. 

Diazepam, lorazepam, and midazolam are used for preanesthetic medication and as adjuvants during surgical procedures performed under local anesthesia. As a result of their sedative, anxiolytic, and amnestic properties, and their ability to control acute agitation, these compounds are considered to be the drugs of choice for premedication. (The basic pharmacology of benzodiazepines is discussed in Chapter 22.) Diazepam and lorazepam are not water-soluble, and their intravenous use necessitates nonaqueous vehicles, which cause pain and local irritation. Midazolam is water-soluble and is the benzodiazepine of choice for parenteral administration. It is important that the drug becomes lipid-soluble at physiologic pH and can readily cross the blood-brain barrier to produce its central effects. 

Consistent with their depressant and sedative effects, benzodiazepines administered acutely typically decrease CFF threshold.119 120 Specifically, significant decreases have been reported for 1 mg alprazolam, 10 mg diazepam, and 15 mg quazepam 121 4 to 11 mg midazolam 122 7.5 to 50 mg oxazepam 123 1 and 2 mg lorazepam 124 and 0.5 mg triazolam and 1 mg flunitrazepam.120 As is evident, this effect on CFF threshold was observed at therapeutic doses of each drug, and when multiple doses were tested, the effect was dose-related. However, there are reports of acute, therapeutic doses of diazepam (5 mg)125 and lorazepam (1 and 2 mg)125,126 having no effect on CFF threshold. One study investigating numerous benzodiazepines120 reported next-day impairment after acute doses of triazolam (0.5 mg) and lormetazepam (1 to 2 mg). No studies were found that examined the effect of chronic benzodiazepine administration on CFF threshold. 

The in vivo interactions between midazolam and several macrolides were predicted using PBPK modeling of drug concentration and the time course of active enzyme concentration in the liver (123). Using a value for kE of 0.0005 min-1, the AUC of midazolam after oral administration was predicted to increase 2.9- or 3.0-fold following pretreatment with erythromycin (500 mg t.i.d. 

Phenotyping Midazolam test Midazolam is primarily metabolized to l -hydroxymidazolam by CYP3 A. It is rapidly and completely absorbed after oral administration (Gorski 1998). It is the practical probe drug to assess intestine and liver or liver CYP3A activities after oral (Thummel 1996) or intravenous administration respectively. 

Lamba JK, Lin YS, Schuety EG, Thummel KE (2002) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Del Rev 54 1271-1294 Lee JI, Chaves-Gnecco D, Amico JA et al. (2002) Application of simultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping. Clin Pharmacol Ther 72 718-728... 

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