Midazolam induction

Midazolam (Versed), a short-acting benzodiazepine CNS depressant, is used as a preanesthetic drug to relieve anxiety for induction of anesthesia for conscious sedation before minor procedures, such as endoscopic procedures and to supplement nitrous oxide and oxygen for short surgical procedures. When the drug is used for induction anesthesia, the patient gradually loses consciousness during a period of 1 to 2 minutes. 

Falk, J. L., Zhang, J., Chen, R., and Lau, C. E., A schedule induction probe technique for evaluating abuse potential Comparison of ethanol, nicotine and caffeine, and caffeine-midazolam interaction. Special Issue Behavioural pharmacology of alcohol. Behavioural Pharmacology 5(4-5), 513-520, 1994. 

Midazolam is a rapidly metabolized benzodiazepine (p. 228) that is used for induction of anesthesia. The longer-acting lorazepam is preferred as adjunct anesthetic in prolonged cardiac surgery with cardiopulmonary bypass its am-nesiogenic effect is pronounced. 

Midazolam (Versed), diazepam (Valium), and lo-razepam (Ativan) are benzodiazepine derivatives that are useful in anesthesia. Midazolam is the most popular of these agents for the induction of anesthesia. Its popularity is related to its aqueous solubility and to its short duration of action, which permits a prompt return of psychomotor competence. Unlike midazolam, lor-azepam and diazepam are not water soluble and must be formulated in propylene glycol the latter is irritating to the vasculature on parenteral administration. 

Nevertheless, the GABAergic properties of benzodiazepines remain their most important clinical application. Over the past 30 years, the most widely used benzodiazepine drug has been diazepam (1.6). It is an anxiolytic, sedative, and muscle relaxant the anxious, depressed person becomes more outgoing and relaxed. There have been many diazepam analogs. Oxazepam (4.177) and lorazepam (4.178) have similar effects. Temazepam (4.179), flunitrazepam (4.180), and flurazepam (4.181) are useful sedative-hypnotics. Clonazepam (4.182) is a clinically useful anticonvulsant. Brotizolam (4.183), a novel benzodiazepine analog, seems to be an effective sedative-hypnotic. Midazolam (4.184) is an imidazolo-benzodiazepine that is water soluble and thus easily injectable. It is a hypnotic sedative with marked amnestic (i.e., memory loss) properties and is used in dentistry, endoscopic procedures, and induction to anesthetics in the elderly and in... 

Dresser et al. administered St. John s wort (LI 160 300 mg t.i.d.) to 20 ethnically diverse individuals and observed a 44% increase in the systemic clearance of midazolam (Table 3) (98). In contrast, the oral clearance of midazolam was increased 1.7-fold (Table 3). The combined changes in midazolam disposition resulted in a significant reduction in the oral bioavailability of midazolam (Table 3). Gurley et al. examined the one-hour 1-hydroxymidazolam-to-midazolam serum ratio and concluded that St. John s wort administration for 28 days resulted in a significant increase in the ratio, which is indicative of CYP3A4 induction (100). 

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. 

Adrenocortical function has been assessed in a randomized trial after intravenous etomidate in 30 patients who required rapid-sequence induction and tracheal intubation (402). The controls received midazolam. Etomidate caused adrenocortical dysfunction, which resolved after 12 hours. 

Adjunctive use of potent opioids (eg, fentanyl and related compounds) contributes cardiovascular stability, enhanced sedation, and profound analgesia. Other intravenous agents such as the benzodiazepines (eg, midazolam, diazepam) have slower onset and recovery features and are rarely used for induction of anesthesia. However, preanesthetic administration of benzodiazepines can be used to provide a basal level of sedation and amnesia when used in conjunction with other anesthetic agents. 

Evaluation of the effect of hypnotic drugs on sleep induction and maintenance in patients with chronic primary insomnia is based on sleep laboratory studies and subjective data from clinical trials. The sleep induced by benzodiazepine hypnotics, including midazolam, triazolam, temazepam, flunitrazepam, quazepam, and flu-razepam, is characterized by shortened sleep-onset latency, decreased number of... 

Until recently, intestinal metabolism via CYP3A4-mediated metabolic pathways was thought to be insignificant because of the lower levels of expression compared with that seen in the liver and slower metabolic rates measured for intestinal microsomes (224). However, similar Km values have been reported for midazolam 1 -hydroxylation by microsomes obtained in the upper intestine and the liver (254,255). This correlation indicates that the upper intestine and hepatic CYP3 A4 are functionally equivalent. Such findings further establish the importance of the intestine in the elimination of orally administered substrates for CYP3 A4-mediated metabolic pathways. Additionally, coadministration of substrates/inhibitors that may alter the function of these proteins (induction, inhibition) could further be responsible for the variability in intestinal absorption (dmg interactions) seen for some dmgs. 

Figure 2 Simulation of the effect of enzyme induction on oral midazolam AUC. Hepatic extraction in the absence of an inducer was set at 0.44. The initial intestinal extraction was varied from 0.0 to 0.9. The inducer was assumed to cause an equivalent change in hepatic and intestinal intrinsic clearance. Mucosal and hepatic plasma flows were assumed to be 240 and 780 mL/min. Simulations were obtained from Eq. (6), assuming an initial intestinal extraction ratio of 0.00, 0.07, 0.27, 0.43, 0.60, and 0.88.

Other CYP3A4 inducers have also been reported to exert a pronounced effect on oral midazolam AUC (78), presumably through induction of intestinal and hepatic CYP3A4. For example, administration of phenytoin and carba-mazepine led to a 94% reduction in midazolam AUC compared with an untreated control population. Induction of CYP3A by St. John s wort, a widely used herbal supplement for the treatment of mild to moderate depression, has also attracted considerable interest. The major bioactive ingredient of St. John s wort, hyperforin, is a very potent in vitro activator of hPXR (79,80). Several groups have investigated induction of midazolam clearance by St. John s wort (81-83). As in the case of rifampin, clearance of oral midazolam... 

General anesthetics are rarely given alone. In addition to the analgesic agents just mentioned, benzodiazepines (midazolam, Versed diazepam, Valium ) are commonly used as adjuncts for the relief of anxiety, amnesia, and sedation prior to induction of anesthesia. Neuromuscular blockers (e.g., succinylcholine or pancuronium) can also be administered during the induction of anesthesia to relax skeletal muscles. 

The most used and validated probe drugs for C YP3 A phenotyping are midazolam and 14C-erythromycin (Watkins 1994). Alfentanyl, alprazolam, dapsone, dextromethorphan, lidocaine. nifedipine, omeprazole, quinine, verapamil have also been used but less frequently, and CYP3A specificity for some of them has been questioned. The endogenous 6(->-hydroxycortisol test (measurement of 6 3-hydroxycortisol cortisol ratio in urine) is only useful for detecting CYP3A induction, and may be influenced by renal CYP3 A activity. 

Droperidol 5-7.5 mg given during induction of anesthesia was associated with impaired well-being scores 6 hours postoperatively in a randomized double-blind comparison of similar doses of droperidol (n = 78) and midazolam (n = 72) for preventing postoperative nausea and vomiting (2). 

Sevoflurane often causes postoperative delirium and agitation in children, and this may be severe. The effect of intravenous clonidine 2 pg/kg on the incidence and severity of postoperative agitation has been assessed in a double-blind, randomized, placebo-controlled trial in 40 boys who had anesthetic induction with sevoflurane after oral midazolam premedication (32). There was agitation in 16 of those who received placebo and two of those who received clonidine the agitation was severe in six of those given placebo and none of those given clonidine. 

The pharmacology and adverse effects of midazolam in infants and children have been reviewed (4). The optimal dose of intramuscular midazolam for preoperative sedation has been studied in a double-blind prospective study of 600 patients who were age-stratified (51). The patients received intramuscular atropine 0.6 mg and one of five doses of midazolam 15 minutes before induction of anesthesia. For the age groups 20-39, 40-59, and 60-79 years, the optimal sedative and amnesic effects of midazolam were 0.10, 0.08, and 0.04 mg/kg respectively. The frequency with which the undesirable adverse effects of reduced blood pressure, oxygen desaturation, oversedation, loss of eyelash reflex, and tongue root depression occurred increased with age, and optimal doses for a low incidence of adverse effects were 0.08, 0.06, and 0.04 mg/ kg in the same age groups respectively. 

In a study of the effects of itraconazole 200 mg/day and rifampicin 600 mg/day on the pharmacokinetics and pharmacodynamics of oral midazolam 7.5-15 mg during and 4 days after the end of the treatment, switching from inhibition to induction of metabolism caused an up to 400-fold change in the AUC of oral midazolam (54). 

CANNABIS ANXIOLYTICS AND HYPNOTICS-BZDs-alprazolam, diazepam, midazolam, triazolam Unpredictable changes in plasma concentration. Risk of toxicity or therapeutic failure, particularly of drugs with a narrow therapeutic index Induction or inhibition of CYP3A4-mediated metabolism by cannabis. It is not yet known whether the effects are dependent on the degree of cannabis consumption Be aware. Watch for signs of toxicity, especially when cannabis use abruptly changes... 

Interactions. Enzyme induction of CYP 3A, e.g. by rifampicin, reduces the plasma concentration of itraconazole. Additionally, its affinity for several P450 isoforms, notably CYP 3A4, causes it to inhibit the oxidation of a number of drugs, including phenytoin, warfarin, cyclosporine, tacrolimus, midazolam, triazolam, cisapride and terfenidine (see above), increasing their intensity and/or duration of effect. 

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