Plasma Concentrations Of Diazepam Research Articles

EFFECT OF VOLUME OF WATER TAKEN WITH DIAZEPAM TABLETS ON ABSORPTION

Thirty-three patients received either 10 ml (group A) or 50 ml (group B) of water with diazepam tablets as premedication while in the supine position. Plasma diazepam concentrations were measured, a delay in the attainment of the peak plasma concentration being taken as an indication of delayed absorption and oesophageal hold-up. There was no difference between the two groups, although in an important minority (16.7% (group A) and 20% (group B], absorption was delayed to beyond 60 min. There was a wide scatter of plasma diazepam concentrations in both groups. Dysphagia during swallowing did not appear to delay absorption.

Development of tolerance to the anticonvulsant effect of diazepam in amygdala-kindled rats

The anticonvulsant long-term efficacy of diazepam was studied in amygdala-kindled rats. The drug was administered three times daily at doses of 5 mg/kg i.p. for 2 weeks in fully kindled animals. The severity of the kindled seizures was markedly reduced throughout the period of treatment, while tolerance developed to the effect of diazepam on seizure latency and duration and, less marked, on duration of amygdala afterdis-charges. Concomitant determination of plasma concentrations of diazepam and its major metabolite, desmethyldiazepam, showed that diazepam increased during the 2 weeks of treatment, suggesting that the observed tolerance was not metabolic but functional in nature. After cessation of treatment, there was no clear indication for withdrawal symptoms except a significant increase in kindled seizure duration after 2 days. The data demonstrate that amygdala-kindled rats are a useful model to study the long-term efficacy of anticonvulsant drugs.

Circadian stage-dependent changes in diazepam kinetics.

The effect of dosing time on diazepam kinetics was investigated in 28 healthy men. A 5-mg dose of diazepam was given orally or intravenously on two occasions, in the morning (9:30 A.M.) or in the evening (9:30 P.M.) under the postprandial condition or after a 9-hr fast. After oral doses under postprandial conditions, the mean peak total diazepam concentration in plasma was higher and the time to peak concentration was faster after morning dosing than after evening dosing, but neither mean elimination t1/2 nor AUC between morning and evening dosings differ. Intravenous diazepam did not eliminate the time-dependent changes in diazepam kinetics occurring soon after injection under postprandial conditions, although it diminished the difference. During the 9-hr fast, time-dependent changes in diazepam kinetics were marked, especially after intravenous injection. Diazepam free fraction was lower 0.5 hr after intravenous dosing in the morning, and there was a negative correlation (r = -0.678) between the diazepam free fraction and total diazepam plasma concentration. These results suggest that diurnal variations in rate of drug distribution because of alterations in protein binding as well as in absorption from the gastrointestinal tract contribute to time-dependent changes in diazepam kinetics.

Interactions between smectite, a mucus stabilizer, and acidic and basic drugs

The interaction of phenylbutazone and diazepam with smectite were studied in in-vivo and in-vitro. The kinetics of both drugs were investigated in healthy subjects after oral administration as monotherapy or in association with smectite. Smectite did not substantially alter the kinetics of phenylbutazone, whereas the peak plasma concentration of diazepam was reduced to 91%, and the time of peak concentration was prolonged by 153% of the control values. The in-vitro investigations were conducted at pH 5.5 and 8 and showed that there was no interaction between phenylbutazone and smectite, but that it adsorbed diazepam. The findings suggest that smectite delays the absorption of basic drugs and does not alter the absorption kinetics of acidic drugs.

Circadian stage-dependent changes in diazepam kinetics.

The effect of dosing time on diazepam kinetics was investigated in 28 healthy men. A 5-mg dose of diazepam was given orally or intravenously on two occasions, in the morning (9:30 A.M.) or in the evening (9:30 P.M.) under the postprandial condition or after a 9-hr fast. After oral doses under postprandial conditions, the mean peak total diazepam concentration in plasma was higher and the time to peak concentration was faster after morning dosing than after evening dosing, but neither mean elimination t1/2 nor AUC between morning and evening dosings differ. Intravenous diazepam did not eliminate the time-dependent changes in diazepam kinetics occurring soon after injection under postprandial conditions, although it diminished the difference. During the 9-hr fast, time-dependent changes in diazepam kinetics were marked, especially after intravenous injection. Diazepam free fraction was lower 0.5 hr after intravenous dosing in the morning, and there was a negative correlation (r = -0.678) between the diazepam free fraction and total diazepam plasma concentration. These results suggest that diurnal variations in rate of drug distribution because of alterations in protein binding as well as in absorption from the gastrointestinal tract contribute to time-dependent changes in diazepam kinetics.

Absolute bioavailability and effect of food and antacid on diazepam absorption from a slow-release preparation.

A series of healthy volunteers received a single 7.5-mg intravenous dose of diazepam on one occasion and a single 15-mg oral dose of slow-release diazepam (DZ-SR) on another occasion. Diazepam concentrations were measured by gas chromatography in multiple plasma samples drawn during seven days after each dose. Absorption of diazepam from DZ-SR was slow, with mean +/- S.E. peak concentrations attained at 3.8 +/- 0.5 hours after dosage. Absolute bioavailability of DZ-SR averaged 0.98 +/- 0.06. In two other studies, diazepam absorption from DZ-SR was evaluated when coadministered with a standard breakfast or with an antacid preparation (Maalox). Neither food nor antacid altered the rate of diazepam absorption and did not impair the completeness of absorption. Higher peak total plasma diazepam concentrations occurred in the postprandial as opposed to the fasting state, but this was an artifact of reduced protein binding (increased free fraction) due to fasting. Thus, diazepam absorption from DZ-SR is slow and essentially complete.

Time-of-day Effect of Intravenous Diazepam on Pharmacologic Actions in Man

Our group previously reported the time-of-day effect of oral administration on diazepam kinetics and its sedative action in healthy men. In these studies, it has been suggested that the absorption rate of diazempam from the gastrointestinal tract is faster in morning dosing than in evening dosing. The present study was performed to elucidate the mechanism of time-of-day effect on diazepam kinetics and dynamics, administering 5 mg diazepam (Cercine® injectable solution) intravenously under the same experimental conditions as the oral dose study described above. Eight healthy volunteers participated in the study. The subjects received a 5-mg dose of diazepam intravenously at 9: 30 a. m. and after a 2-wk interval, at 9: 30 p.m., in a randomly assigned cross-over study. Meals were standardized in order to fit the subjects' usual meal amount. Plasma diazempam concentrations were determined by gas chromatography (ECD). Changes in subjective feelings such as “mentally slow”, “feeble”, “clumsy”, and “lethargic” were more marked in the morning trial at 0.5 hr after injection. More marked sedative effects were demonstrated in the morning trial by using the digit symbol substitutiontest and the continuous number addition test. Mean (±SD) total diazepam concentrations in plasma in the morning trial vs in the evening trial were: 218 (±15) vs 192 (±12) ng/ml at 0.5 hr after drug administration (0.05<P<0.1); 164 (±39) vs 132 (±16) ng/ml at 1 hr after injection (P<0.05). The results suggest that there exists time-of-day effect of intravenous injection with diazepam injectable solution onsedative actions and kinetics, which may be clinically important in some situations. Inaddition, the time-dependent kinetics of diazepam after oral dosing cannot be explainedonly by the absorption rate from the gastrointestinal tract, since intravenousadministration of diazepam did not eliminate the difference in total plasma diazepamconcentrations between morning and evening dosing at 0.5 hr and 1 hr after injection.

Multiple-dose pharmacokinetics of diazepam following once-daily administration of a controlled-release capsule.

The study was designed to determine the steady-state pharmacokinetic profile of diazepam and desmethyldiazepam following a 15-mg controlled-release capsule dosed once daily at either 7 a.m. or 11 p.m. compared with the respective profiles of the conventional 5-mg tablet dosed three times a day at 7 a.m., 12 p.m., and 5 p.m. Plasma concentrations of diazepam and desmethyldiazepam were assayed by an electron-capture gas-liquid chromatographic method. Plasma concentrations indicated that there were no differences between the pharmacokinetic profiles following the 7 a.m. or 11 p.m. dosings of the controlled-release capsule. Steady-state concentrations of diazepam were attained between days 7 and 9 during the controlled-release dosing, and the accumulation profiles are similar to those observed for the conventional tablet given three times a day. Nearly identical areas under the diazepam plasma concentration-time curves (AUC) on day 1 and at steady state for both regimens indicate equal extents of absorption from the two formulations. In addition, the steady-state AUCs for desmethyldiazepam were independent of formulation. The data indicate that a single daily dose of the 15-mg controlled-release capsule results in accumulation and steady-state profiles comparable to those observed following a regimen of the 5-mg conventional tablet three times a day.(ABSTRACT TRUNCATED AT 250 WORDS)

Repeated diazepam dosing in cirrhotic patients

Five medically stable male patients with cirrhosis and four healthy age- and sex-matched controls received single 5-mg oral doses of diazepam (DZ) daily for 22 consecutive days. Plasma concentrations of DZ and its major metabolite desmethyldiazepam (DMDZ) were measured daily during the period of dosing and in the 7-day washout period that followed. Clinical self-ratings of sedation, fatigue, mood state, and sleep patterns were obtained daily during the period of dosage with the use of visual analogue scales. Steady-state plasma DZ concentrations were higher (165 and 98 ng/ml), and DMDZ concentrations tended to be higher (399 and 206 ng/ml), in cirrhotics than in controls. Increases in self-rated daytime sedation also were greater in cirrhotics than in controls and correlated strongly with total DZ and DMDZ plasma concentration during the first 2 wk of diazepam dosing. Thus, reduced clearance of DZ in cirrhotics leads to increased cumulation during long-term dosing. This in turn is associated with increased clinical sedation. Sedative effects are partly offset as treatment proceeds because of adaptation or tolerance. Based on kinetic findings, diazepam can be given safely to cirrhotic patients provided daily dosage is reduced by approximately 50%. Clinical Pharmacology and Therapeutics (1983) 33, 471–476; doi:10.1038/clpt.1983.64

Prolonged accumulation of diazepam in obesity.

Six obese (mean weight 92 kg) and five normal (60 kg) subjects received 2 mg diazepam nightly for 30 nights. Determination of diazepam and desmethyldiazepam plasma concentrations during the dosing period and for a withdrawal period indicated that accumulation half-life for both diazepam (7.8 days in obese vs. 3.1 days in normal subjects, P less than 0.05) and desmethyldiazepam (30.3 vs. 7.2 days, P less than 0.05) was markedly prolonged in obese subjects. However, mean steady-state plasma concentrations of diazepam (68 vs. 67 ng/ml) and desmethyldiazepam (156 vs. 91 ng/ml) did not significantly differ between groups. To determine the basis for this delay in accumulation in obese subjects, single-dose pharmacokinetics of diazepam and desmethyldiazepam were determined. Diazepam elimination half-life was greatly prolonged in the obese subjects (82 vs. 32 hours, P less than 0.005), with no change in total metabolic clearance (32 vs. 26 ml/min). Instead, a large increase in volume of distribution (228 vs. 70 liters, P less than 0.01) was the reason for prolongation of the elimination half-life. Similarly for desmethyldiazepam, elimination half-life was prolonged in obese subjects (130 vs. 56 hours, P less than 0.01), without a change in total metabolic clearance (13.7 vs. 19.2 ml/min), due to increased volume of distribution (151 vs. 73 liters, P less than 0.01). During chronic dosing with diazepam, obese patients may experience a much slower onset of maximal drug effect compared to normal-weight patients because of the greatly delayed accumulation of diazepam and desmethyldiazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Bromazepam and Diazepam in Generalized Anxiety

In a double-blind, placebo-controlled study, 48 anxious outpatients with a primary diagnosis of generalized anxiety disorder were randomly assigned to 4 weeks of treatment with bromazepam (18 mg/day), diazepam (15 mg/day), or placebo, after a 1-week washout period. From week 1 onward both active drugs were superior to placebo in relieving anxiety symptoms. Bromazepam was found to be significantly more effective than diazepam with respect to the somatic anxiety factor and the total score for the Hamilton Anxiety Rating Scale and the fear/anxiety factor of the Patient's Self-Rating Symptom Scale. Plasma concentrations of diazepam plus active metabolites were correlated significantly (r = 0.60, p less than 0.05) with the percentage reduction in self-rating anxiety scores. Bromazepam plasma concentration measurements showed greater variability than those of diazepam and were not found to be correlated significantly with clinical response. It is suggested that the use of strict diagnostic criteria (1978 draft of the third edition of Diagnostic and Statistical Manual of Mental Disorders), adequate sample sizes, and a 4-week study period gave increased sensitivity for the detection of significant differences between the two benzodiazepines.

Repeated diazepam dosing in cirrhotic patients: cumulation and sedation.

Five medically stable male patients with cirrhosis and four healthy age- and sex-matched controls received single 5-mg oral doses of diazepam (DZ) daily for 22 consecutive days. Plasma concentrations of DZ and its major metabolite desmethyldiazepam (DMDZ) were measured daily during the period of dosing and in the 7-day washout period that followed. Clinical self-ratings of sedation, fatigue, mood state, and sleep patterns were obtained daily during the period of dosage with the use of visual analogue scales. Steady-state plasma DZ concentrations were higher (165 and 98 ng/ml), and DMDZ concentrations tended to be higher (399 and 206 ng/ml), in cirrhotics than in controls. Increases in self-rated daytime sedation also were greater in cirrhotics than in controls and correlated strongly with total DZ and DMDZ plasma concentration during the first 2 wk of diazepam dosing. Thus, reduced clearance of DZ in cirrhotics leads to increased cumulation during long-term dosing. This in turn is associated with increased clinical sedation. Sedative effects are partly offset as treatment proceeds because of adaptation or tolerance. Based on kinetic findings, diazepam can be given safely to cirrhotic patients provided daily dosage is reduced by approximately 50%.

Psychomotor Effects of Diazepam in Anxious Patients and Healthy Volunteers

Psychomotor effects of diazepam, 5 and 10 mg, were compared to placebo in 30 highly anxious, nonpsychotic outpatients and age and sex-matched healthy volunteers. Diazepam did not reduce anxiety according to psychiatrists' ratings, but 10 mg of diazepam three times a day reduced the scores of the self-rated visual analogue scale for anxiety compared to placebo. Diazepam, 5 mg, was devoid of adverse psychomotor effects, but diazepam, 10 mg, impaired tracking and divided attention task performance in patients and volunteers alike. Plasma, erythrocyte, and saliva diazepam and N-desmethyldiazepam concentrations did not correlate with the impairment of psychomotor skills over time.

RO 15–1788 ANTAGONIZES THE EFFECTS OF DIAZEPAM IN MAN WITHOUT AFFECTING ITS BIOAVAILABILITY

In a double-blind, placebo-controlled three-way cross over study, the efficacy of Ro 15-1788 200 mg, a new benzodiazepine antagonist, in blocking the amnesic, cognitive, psychomotor and subjective effects of diazepam 20 mg, was investigated in a group of six healthy male volunteers. The amnesic effects of diazepam were markedly attenuated by the combined administration of Ro 15-1788. The psychomotor and subjective effects of diazepam by mouth were most pronounced 2.5 h after administration. Concurrent oral administration of Ro 15-1788 completely prevented these effects at 2.5 h. Plasma diazepam concentrations observed after administration of the combination of diazepam and the antagonist did not differ from those observed following diazepam alone.

Diazepam Kinetics in Patients with Severe Burns

Because of the increased tolerance of burn patients to sedatives and anesthetic drugs, the effects of severe thermal injury on the pharmacokinetics of diazepam following a single 5− to 10-mg intravenous dose were evaluated in eight patients with burns covering an average of 65% of body surface at a mean of 17 days after injury. Pharmacokinetic parameters were determined from multiple plasma diazepam concentrations measured for 7 days after administration of the diazepam. Eight healthy control subjects, matched with patients for age and sex, were studied identically. The elimination half-life of diazepam was greater, although not significantly so, in burn patients than in control patients (72 and 36 h, respectively). Volume of distribution was also increased in burn patients (2.88 v 1.53 L/kg, P < 0.1), but clearance was comparable in the two groups (0.64 v 0.53 ml/min/kg). However, these results were confounded by a significantly greater free fraction of diazepam in the plasma of burn patients than in control patients (3.43% v 1.24%, P < 0.01). After correction for differences in binding, the volume of distribution of unbound diazepam was comparable between groups (94 v 131 L/kg; not significant), but clearance of free diazepam was significantly reduced in burn patients (24 v 46 ml/min/kg, P < 0.05). If the present data can also be applied to other drugs, then the increased tolerance of patients with burns to sedative and anesthetic drugs cannot be explained on a pharmacokinetic basis but may instead be related to qualitative changes in receptors or in responses of target organs in the central nervous system of burn patients. The reduced clearance of diazepam may be attributable to burn injury and/or concomitant administration of other drugs. Repeated administration of diazepam following burns may result in extraordinary accumulation of drug in the body.

Effect of ranitidine on the steady state pharmacokinetics of diazepam

In 6 healthy volunteers the steady state pharmacokinetics of diazepam (5 mg p.o. once daily) was investigated in a randomized cross-over study with and without concomitant doses of ranitidine (150 mg bid). Following the last dose of diazepam on Day 10 of each part of the study, the plasma concentrations of diazepam were monitored for one dosing interval plus the subsequent 2 days. In addition, urinary excretion of 6-β-hydroxycortisol and 17-hydroxycorticosteroids were measured, their ratio being taken as an indicator of hepatic enzyme activity. Coadministration of ranitidine significantly reduced (p<0.03) the trough and steady state concentrations (mean ± SD) of diazepam (114±36 Vs 104±30 ng/ml and 170±55 Vs 125±36 ng/ml, respectively). Plasma protein binding of diazepam (98.5±0.3%) was not affected by ranitidine. The half-life of elimination of diazepam (42.5±13.5 h) did not change significantly but its apparent oral clearance (assuming complete absorption) was significantly increased (p<0.005) by ranitidine, from 22.6±9.2 to 30.0±9.1 ml/min. Urinary excretion of 6β-OH-cortisol (p=0.029) and 17-OH-corticosteroids (p=0.041) were significantly elevated by ranitidine, but their ratio did not change. In addition, in 4 additional subjects the disposition of diazepam following a single intravenous dose of 0.1 mg/kg was not significantly altered by ranitidine. Thus, the lowered steady state concentration of diazepam is most likely due to diminished absorption caused by the concurrent administration of ranitidine. However, it may be more important clinically that, unlike cimetidine, ranitidine did not impair the hepatic elimination of diazepam.

Absolute Bioavailability of Oral and Intramuscular Diazepam

Twenty-two healthy volunteers aged 20-78 years received single 5-mg doses of diazepam by intravenous injection, by mouth in the fasting state, and by a deltoid intramuscular injection. The kinetic profile of diazepam by each route was determined from multiple plasma diazepam concentrations measured 7-14 days after each dose. After intravenous injection, diazepam volume of distribution (Vd) was larger in women than in men, but increased with age regardless of sex. Elimination half-life was longer in elderly than in young men (101 v 32 h, P less than 0.025), partly due to the increased Vd as well as to a significant reduction in total metabolic clearance (0.24 v 0.46 ml/min/kg, P less than 0.05). However, the prolonged half-life in elderly as opposed to young women (99 v 44 h; P less than .01) was due mainly to increased Vd because clearance was not significantly changed (0.29 v 0.35 ml/min/kg). In all subjects, oral diazepam was rapidly absorbed; peak plasma levels were reached an average of 0.9 h after dosage. Absolute bioavailability averaged 94%, indicating essentially complete absorption. Neither age nor sex significantly influenced oral absorption. In all male subjects, and in 8 of 12 women, absorption of diazepam after deltoid intramuscular injection was rapid and essentially complete. However, in three young and one elderly women, absorption was slower and apparently incomplete. Age as such did not significantly influence absorption of intramuscular diazepam.

KINETICS OF HIGH-DOSE I.V. DIAZEPAM

The pharmacokinetics of high-dose i.v. diazepam were studied in two patients in an intensive care unit. The first patient received up to 240 mg of diazepam daily for 21 days while the second received 60 mg daily for 30 days. Plasma concentrations of diazepam and its major metabolite, desmethyldiazepam, were very large but, despite severe underlying disease and simultaneous administration of several other drugs, the half-lives of diazepam and desmethyldiazepam washout were consistent with those found in healthy persons. Washout half-lives in the first patient were, if anything, shorter than expected, possibly caused by simultaneous administration of phenobarbitone. Thus the kinetics of diazepam are apparently not altered by administration of large doses.

Impairment of diazepam metabolism by low-dose estrogen-containing oral-contraceptive steroids.

The longterm use of low-dose estrogen containing oral contraceptives (OCs) and its impairment of diazepam clearance is reported. 8 healthy women, ranging in age from 52 to 72 years, participated in the study. All of the women had been taking low-dose estrogen containing OCs for more than 3 months. 1 of the subjects was a cigarette smoker. 8 healthy controls (all nonsmokers) who were not using OCs also participated. They ranged in age from 27-31 years. Diazepam (10 mg) was given by intravenous infusion over 15-30 seconds. Venous blood samples were drawn into heparinized tubes before the infusion, at the end of the infusion, at 5, 15, 30, and 45 minutes, at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours, and daily for 7 days after the infusion. Plasma concentrations of diazepam after intravenous infusion were analyzed by weighted iterative nonlinear least-squares regression techniques. The volume of distribution of diazepam was not significantly different between the groups, but the apparent elimination half-life of diazepam was significantly longer and the total metabolic clearance significantly less in the OC users than in the control group. The differences were not confounded by variations in protein binding. The mean diazepam free fraction was identical in the 2 groups. The clinical result of the decrease in diazepam clearance reported here would be increased steady-state plasma diazepam concentration after longterm use at a given daily dose, with the potential for increasing the clinical effects of diazepam in this population.

Long-term use of diazepam

Plasma concentrations of diazepam and its major active metabolite nordiazepam were measured in 108 neurosurgical patients taking diazepam in doses of 5 to 40 mg/day for periods from one month to 16 years. Diazepam was used for relief of pain or muscle spasm, or anxiety and sleeplessness associated with these two symptoms, and was considered to be beneficial by 83% of the patients, although use of other drugs confounded this evaluation. Concentrations of total diazepam-nordiazepam ranged from 0 to 2,584 ng/mL, with nordiazepam being the predominant metabolite. Low concentrations (less than 250 ng/mL) were found in 35 of the 108 patients, with 19 having concentrations lower than 100 ng/mL. High concentrations (greater than 900 ng/mL) were found in 20 patients and did not occur more frequently than in other studies of long-term diazepam ingestion. Even with long-term use, diazepam seemed to retain its efficacy and did not lead to any clear-cut abuse.