Diazepam chronic administration

The relative contribution of the active metabolites of the benzodiazepines to the overall therapeutic effect of the parent compound will depend on the concentration of the metabolite formed, its agonist potency at central benzodiazepine receptors and its lipophilicity. For example, after the chronic administration of diazepam, desmethyldiazepam accumulates in the brain. As this metabolite has potency at the benzodiazepine receptors equal to diazepam, the metabolite probably plays an important part in the overall action of diazepam. In the case of clobazam, however, even though the active metabolite desmethylclobazam is present in higher concentrations than the parent compound after chronic administration, it has a lower potency than clobazam and therefore is of less importance than the parent compound with regard to the anxiolytic effect. 

Baclofen is at least as effective as diazepam in reducing spasticity and causes less sedation. In addition, baclofen does not reduce overall muscle strength as much as dantrolene. It is rapidly and completely absorbed after oral administration and has a plasma half-life of 3-4 hours. Dosage is started at 15 mg twice daily, increasing as tolerated to 100 mg daily. Adverse effects of this drug include drowsiness however, patients become tolerant to the sedative effect with chronic administration. Increased seizure activity has been reported in epileptic patients. Therefore, withdrawal from baclofen must be done very slowly. 

After chronic administration of diazepam, i.e. at steady state, plasma concentrations of desmethyidiazepam (the major metabolite in blood) are similar to those of diazepam. The hydroxylated metabolites of the benzodiazepines, together with benzodiazepines which have an hydroxyl group at the C3 position (e.g. lorazepam), are conjugated with glucuronic acid and it is these derivatives which account for the major fraction of the dose excreted in the urine. 

Toxic effects may occur with chronic administration, and patients taking diazepam need medical monitoring. In addition, dependence may develop with regular use of benzodiazepines, and withdrawal symptoms may occur with cessation. 

Severe withdrawal symptoms, including insomnia, irritability, agitation, withdrawal seizures, and delirium, have been described in both mice and humans chronically exposed to the anesthetics nitrous oxide, ether, and isoflurane (Arnold et al. 1993 Delteil et al. 1974 Deniker et al. 1972 Harper et al. 1980 Smith et al. 1979 Tobias 2000). These symptoms were controlled with the administration of y-aminobutyric acid (GABA)-ergic agents such as pentobarbital, midazolam, and diazepam (Arnold et al. 1993 Hughes et al. 1993). 

Branch RA, Morgan MH, James J, Read AE Intravenous administration of diazepam in patients with chronic liver disease. Gut 1976 17 975-983. 

Lorazepam is currently considered the BZ of choice. It takes longer to reach peak brain levels than diazepam but has a longer duration of action (12 to 24 hours). Patients chronically on BZs may require larger doses. The administration rate of diazepam and lorazepam should not exceed 5 and 2 mg/min, respectively, because the propylene glycol in the vehicle can cause dysrhythmia and hypotension. 

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 influence of the active metabolites becomes more significant with repeated administration of the parent drug, as might occur for the control of seizures (see Ch. 9), or chronic oral administration for continued sedation of a neonatal foal. Foals less than 21 days of age have a lower total body clearance of diazepam than older foals and adult horses and, therefore, a greater tendency to develop effects caused by drug accumulation (Norman et al 1997). 

Wagner, S.O., Sams, R.A. Podell, M. (1998) Chronic phenobarbital therapy reduces plasma benzodiazepine concentrations after intravenous and rectal administration of diazepam in the dog. Journal of Veterinary Pharmacology and Therapeutics, 21, 335-341. 

Heine PR, Weyer G, Breuel H-P, Miick W, Schmage N, Kuhlmann J, Lack of interaction between diazepam and nimodipine during chronic oral administration to healthy elderly subjects. Br J Clin Pharmacol (1994) 38, 39-43,... 

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