Chlordiazepoxide drug administration

A series of three experiments explored the relative effects of -amphetamine (10 mg), methylphenidate (10 mg), chlordiazepoxide hydrochloride (10 mg), and placebo on memory and mood (54). After drug administration, subjects were tested on the Paced Sequential Memory Task (PSMT) and the Nowlis Mood Adjective Check List over a 4-hr test period. The results indicated that -amphetamine significantly reduced subjective ratings of fatigue and increased subjective ratings of vigor compared to the other drags. In addition, performance on the PSMT was enhanced by d-amphetamine compared to placebo and methylphenidate. Methylphenidate was not found to enhance either mood or performance in this experiment. 

Figure 19.1 The elevated plus-maze. (Top) The apparatus is arranged with two open arms, two closed arms and a central zone, raised above the ground. Animals are placed in the central zone (usually facing an open arm) and their movements scored for number of entries to the open and closed arms and the percentage time spent in the open arms. (Bottom) Chronic administration (5 days) of the anti-anxiety drug, chlordiazepoxide, increases the percentage time spent on the open arms to approximately 50% of the total. (Figure kindly provided by S. E. File)...

The short-term effects are mainly those of sedation but following longer-term use accumulation may occur, particularly in the case of drugs like diazepam and chlordiazepoxide that have long half-lives due to their active metabolites. After long-term administration (weeks to months) tolerance develops. While most patients rapidly become tolerant to the sedative side effects of these drugs, some patients, particularly the elderly, experience excessive sedation, poor memory and concentration, motor incoordination and muscle weakness. In extreme cases in the elderly, an acute confusional... 

Figures (5) and (6) show respectively the predicted profiles for propranolol and chlordiazepoxide. It is immediately apparent that propranolol is a drug candidate which could be considered for delivery using this route of administration. The delivery of chlordiazepoxide is, however, unlikely to succeed. The primary reason for this is the large value of kg such that drug transfer out of the stratum corneum is slow. Thus drugs which are very lipophilic in nature can partition well into the stratum corneum but transfer out of this region impedes the arrival of the drug at the cutaneous vasculature. The only method of circumventing this...

Pharmacokinetics. Benzodiazepines are effective after administration by mouth but enter the circulation at very different rates that are reflected in the speed of onset of action, e.g. alprazolam is rapid, oxazepam is slow (Table 19.8). The liver metabolises them, usually to inactive metabolites but some compoimds produce active metabolites, some with long t) which greatly extends drug action, e.g. chlordiazepoxide, clorazepate and diazepam all form desmethyldiazepam (t/ 80 h). 

Parenteral administration via the intramuscular route should be avoided with diazepam and chlordiazepoxide secondary to variability in the rate and extent of drug absorption. Intramuscular lorazepam provides rapid, reliable, and complete absorption however, the preparation requires refrigeration. 

Figure 1-3. Serum concentration-time curve after administration of chlordiazepoxide as an intravenous bolus. The experimental data are plotted on a semilogarithmic scale as filled circles. This drug follows first-order kinetics and appears to occupy two compartments. The initial curvilinear portion of the data represents the distribution phase, with drug equilibrating between the blood compartment and the tissue compartment. The linear portion of the curve represents drug elimination. The elimination half-life (f gj) can be extracted graphically as shown by measuring the time between any two plasma concentration points that differ by twofold. (See Chapter 3 for additional details.) (Modified and reproduced, with permission, from Greenblatt DJ, Koch-Weser J. Drug therapy Clinical pharmacokinetics. N Engl J Med 1975 293 702.)...

Diazepam is rapidly and completely absorbed after oral administration. Maximum peak blood concentration occurs in 2 hours, and elimination is slow, with a half-life of approximately 20 to 50 hours. As with chlordiazepoxide, the major metabolic product of diazepam is N-desmethyIdiazepam, which is pharmacologically active and undergoes even slower metabolism than its parent compound. Repeated administration of diazepam or chlordiazepoxide leads to accumulation of N-desmethyIdiazepam, which can be detected in the blood for more than 1 week after discontinuation of the drug. Hydroxylation of N-desmethyIdiazepam at the 3-position gives the active metabolite oxazepam (Fig. 22.18). 

The FDA (USP DI Volume III) defines the term as Drug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), are of the same dosage form, route of administration and are identical in strength or concentration (e.g., chlordiazepoxide hydrochloride,... 

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