Plasma Benzodiazepine Concentrations Research Articles

Comparison of plasma benzodiazepine concentrations following intranasal and intravenous administration of diazepam to dogs

To determine whether plasma concentrations of benzodiazepines (BDZ) in dogs following intranasal (IN) administration of diazepam are comparable to concentrations following IV administration. 6 (4 male, 2 female) healthy adult Greyhounds. Dogs were randomly assigned to 2 groups of 3 dogs in a crossover design. Diazepam (0.5 mg/kg of body weight) was administered intravenously to dogs in group 1 and intranasally to dogs in group 2. Blood was collected from the jugular vein of each dog into tubes containing lithium heparin before and 3, 6, 9, 12, 15, 20, 30, 60, 120, 240, and 480 minutes following diazepam administration. After a 4-day washout period, dogs in group 1 received diazepam intranasally, dogs in group 2 received diazepam intravenously, and blood was again collected. Plasma concentration of BDZ was determined by use of a fluorescence polarization immunoassay. Mean (+/- SD) peak plasma concentration of BDZ following IV administration (1,316 +/- 216 microg/L) was greater than that following IN administration (448 +/- 41 microg/L). Time to peak concentration was < or = 3 minutes following IV administration and 4.5 +/- 1.5 minutes following IN administration. Mean bioavailability of BDZ following IN administration was 80 +/- 9%. Diazepam is rapidly and efficiently absorbed following IN administration of the parenteral formulation. Plasma concentrations match or exceed the suggested therapeutic concentration (300 microg/L). Intranasal administration of diazepam may be useful for treatment of seizures in dogs by owners or when intravenous access is not readily available.

Chronic phenobarbital therapy reduces plasma benzodiazepine concentrations after intravenous and rectal administration of diazepam in the dog.

Disposition of diazepam (DZ) 2 mg/kg after single bolus intravenous (i.v.) and rectal (p.r.) administration before and after 30 day oral phenobarbital therapy was investigated in normal dogs. Adverse cardiovascular and neurologic effects for each drug, dosage and route of administration were evaluated. Plasma benzodiazepine concentrations were determined by fluorescence polarization immunoassay. This assay measured DZ and its active metabolites, oxazepam and nordiazepam to provide a total benzodiazepine concentration. Mean peak plasma concentrations after i.v. administration were 5963 and 5565 ng/mL, before and after phenobarbital treatment, respectively. After p.r. administration, mean peak concentrations were 629 ng/mL and 274 ng/mL and were reached within 30 min before and after phenobarbital treatment, respectively. The target concentration for potential seizure control (i.e. 150 ng/mL) was attained in five dogs in the post phenobarbital p.r. group with a median time to attainment of target concentration of 8 min. The administration of phenobarbital resulted in significantly lower areas under the plasma concentration vs. time curves (AUC) for both i.v. and p.r. administration. Similarly, there was a reduction in maximal plasma concentration, bioavailability (F), mean residence time, and time to target and peak concentrations in the postphenobarbital p.r. group, as compared to the prephenobarbital p.r. group. Adverse cardiovascular and neurologic effects were short-lived and were considered of minor clinical significance. Overall, chronic phenobarbital therapy in the dog reduces total benzodiazepine concentration after i.v. and p.r. administration presumably due to increased hepatic clearance of DZ and its metabolites oxazepam and nordiazepam. Despite this finding, administration of DZ rectally at 2 mg/kg may be a clinically useful alternative to i.v. administration to treat emergency seizures when i.v. therapy is not possible in dogs on chronic phenobarbital therapy.

A Clinical Scale to Assess Benzodiazepine Withdrawal

The objective, sensitive, and reliable quantitation of withdrawal symptoms is essential to assess physical dependence on drugs. Data collected from 23 patients abusing high doses of benzodiazepines (mean diazepam dose equivalents, 150 mg/day; range, 40-500) and from 40 long-term therapeutic users randomized to receive either placebo (N = 19) or diazepam (N = 21; mean diazepam dose equivalents, 15 mg/day; range, 5-40; mean duration of use, 72 months; range, 6-240) were analyzed. Information on the type and severity of symptoms was obtained from several assessment instruments. In the high-dose abuse group, plasma benzodiazepine concentrations were measured daily and the 3 consecutive days of greatest relative daily fall were considered the critical withdrawal period. Selection of the 22 items of the Clinical Institute Withdrawal Assessment-Benzodiazepines (CIWA-B) was based on statistically significant differences between baseline and critical withdrawal periods in high-dose subjects and between symptoms associated with placebo and diazepam in low-dose subjects, using contingency tables and logistic regression analysis. Of the 104 symptoms measured by the assessment instruments, 22 symptoms were found to distinguish withdrawal from prewithdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

A Methodological Comparison of Two Formulations of Temazepam in Pharmacokinetic and Pharmacodynamic Aspects

In a double-blind and cross-over study 12 healthy subjects took temazepam 20 mg in two different formulations (soft gelatine capsule or uncoated tablet) and matched placebo at one-week intervals. Plasma temazepam concentrations at 0.5, 1, 2, 3, 8, 12 and 24 hours after treatment were analyzed by gas chromatography. Psychomotor performance was measured objectively (digit symbol substitution, letter cancellation, Maddox wing test) and subjectively (visual analogue scales) before the drug intake and 1, 2 and 3 hours later and the plasma benzodiazepine concentrations were analyzed also by radioreceptor bioassay. The two different formulations were compared in pharmacokinetic and pharmacodynamic terms, and the gas chromatographic and radioreceptor assays were compared. The soft gelatine capsule produced higher peak plasma concentrations than the uncoated tablet. The computed AUCs and elimination half-lives proved to be similar after either formulation. A satisfactory correlation between the bioassayed benzodiazepine concentrations and chemically assayed temazepam was shown. In pharmacodynamic terms the results suggest a shorter and somewhat smaller subjective response for the capsule than for the tablet form.

Protracted Tinnitus after Discontinuation of Long-Term Therapeutic Use of Benzodiazepines

The presence of protracted tinnitus after discontinuation of long-term therapeutic doses of diazepam (less than or equal to 30 mg/day) is described in three patients. In one of these patients, the association of the tinnitus appearance with the drug discontinuation was documented in a double-blind, randomized, crossover single case study. Objective confirmation of drug use or of abstinence was performed by obtaining plasma benzodiazepine concentrations. The findings provide further documentation that sensory disturbances of short- and long-term duration are among the most distinctive clinical features of the benzodiazepine withdrawal syndrome.

Withdrawal reaction after long-term therapeutic use of benzodiazepines

We conducted a double-blind, placebo-controlled trail in which 40 patients who had undergone long-term therapy with benzodiazepines were switched to placebo or to diazepam in a dose approximately equivalent to their usual dose of the benzodiazepine; the dose of diazepam was then tapered during an eight-week period. Patients were assessed clinically and psychologically and had weekly sessions of behavioral therapy. The subjects who received placebo had more symptoms, assessed their symptoms as more severe, and stopped taking the study drug at a higher rate than those receiving the tapering doses of diazepam. The subjects in the placebo group also had symptoms shortly after being switched to placebo, whereas those in the diazepam group had symptoms much later. Some withdrawal symptoms were distinct from those of anxiety (e.g., tinnitus, involuntary movement, and perceptual changes). Withdrawal symptoms occurred earlier in patients who had received short-acting benzodiazepines than in those who had received long-acting benzodiazepines. Symptoms gradually disappeared over a four-week period in both the placebo and the diazepam groups. Serial determination of plasma benzodiazepine concentrations was a useful way to assess compliance, treatment outcome, and relapse during withdrawal. We conclude that a clinically important, mild, but distinct withdrawal syndrome occurs after discontinuation of long-term therapeutic use of benzodiazepines.

Actual versus reported benzodiazepine usage by medical outpatients.

Benzodiazepines are widely prescribed, and in 1979 almost 10% of the adult population was taking them. Prior studies of outpatient usage of benzodiazepines have relied on survey or prescription data, which may be confounded by noncompliance. To determine the actual use of benzodiazepines, plasma benzodiazepine concentrations were measured in 225 consecutive outpatients from a university cardiology outpatient service. Self reports indicated that the great majority of the patients (191) were taking at least one medicine, and 70 reported being on a psychotropic drug. Seventy-seven patients reported taking benzodiazepines, the majority being on bromazepam (20), diazepam (26) or oxazepam (19). In 25 of those 77 patients, the reported drug could not be detected in plasma. Conversely, in 10 of the 225 patients, benzodiazepines which were not reported were detected (diazepam or flurazepam). Of those taking benzodiazepines, many had a low concentration, suggesting intermittent rather than regular use. Thus, many patients for whom benzodiazepines are prescribed take them irregularly, and a small group uses them without reporting their prescription. These findings have implications for the clinical presentation of illness and for the possibility of drug interactions.

Behavioural pharmacology of benzodiazepines

1. Acute injections of benzodiazepines produce sedative effects in the rat that can be detected by decreases in spontaneous motor activity and exploration. The effects are found with low doses, are dose-related and correlate well with plasma concentrations. 2. With repeated daily doses there is tolerance to the sedative effects within 3–5 days even with benzodiazepines with short half-lives and no active metabolites. 3. In the rat there may be some pharmacokinetic tolerance accounting for some of the behavioural tolerance, but pharmacokinetic changes cannot explain the tolerance to low doses of chlordiazepoxide. 4. With chronically treated rats there is no relationship between plasma benzodiazepine concentrations and sedation. 5. There is rapid recovery from tolerance to the sedative effects and if the animals are tested undrugged there is no detectable effect 24 h after the last dose. 6. Anxiolytic effects emerge after a few days of benzodiazepine treatment, but after 10–20 days of treatment there is tolerance to these effects in the social interaction test and in the corticosterone-stress response.