Clinical Pharmacokinetics of Nitrazepam

1. In a randomized study of 22 patients in a maternity ward, the residual concentrations of two hypnotics, midazolam 15 mg p.o. and nitrazepam 5 mg p.o., in early breast milk and plasma were measured 7 h after intake on day 2 to day 6 postpartum. Milk pH, milk fat and binding to plasma proteins were also investigated. Sleep variables were scored on questionnaires. 2. No measurable (less than 10 nmol l‐1) concentrations of drug in milk were found in the group receiving 15 mg midazolam at night, either after the first night or after the fifth night. Additional investigations in two mothers demonstrated that midazolam and its hydroxymetabolite disappeared rapidly from milk with undetectable levels after 4 h. The mean (s.d.) milk to plasma ratio for midazolam was 0.15 (0.06) in six paired samples. It may be assumed that practically no midazolam is transferred via early milk to the baby if the baby is nursed more than 4 h after tablet intake. 3. Milk nitrazepam concentrations increased significantly from the first (30 nmol l‐1) to the fifth morning (48 nmol l‐1) in the group receiving 5 mg nitrazepam at night. The mean (s.d.) milk to plasma ratio of nitrazepam after 7 h was 0.27 (0.06) in 32 paired samples, and did not vary from day 1 to day 5. Plasma protein binding of nitrazepam in puerperal women was found to be lower than that in plasma of healthy controls. The average amount of nitrazepam received by the breast‐fed baby in the morning was calculated to increase from 1 to 1.5 micrograms 100 ml‐1 breast milk, from days 1 to 5. In the mothers nitrazepam was associated with better hypnotic effect, but a higher incidence of complaints than midazolam. 4. Milk pH, assuming anaerobic conditions, was found in 10 women to average 6.91 +/‐ 0.09 (s.d.) on days 2‐6 postpartum, which is less than previously reported. 5. It is concluded that both hypnotics may be used safely for a few days in the maternity ward. However, possible long‐term effects in the suckling infant of small doses of benzodiazepines ingested with breast milk remain to be investigated.

Section: Milk Transfersupporting

confidence: 90%

“…Nitrazepam, which has a mean elimination half-life of 29 h, accumulates in plasma and causes impaired psychomotor function on the day after administration (Kangas & Breimer, 1981). Thus, a shorter acting hypnotic may be preferable for use in the maternity ward.…”

Section: Introductionmentioning

confidence: 99%

Midazolam and nitrazepam in the maternity ward: milk concentrations and clinical effects.

Matheson

Lunde

Bredesen

1990

“…Its disposition in normal young subjects has been fairly well studied (Jochemsen et al, 1982a,b;Kangas etal., 1979a;Kangas & Breimer, 1981), but there is little information about elderly people and none at all about patients with liver disease. Castleden et al (1977), who measured nitrazepam plasma concentrations at 12, 36 and 60 h after administration and determined elimination halflives, suggested that nitrazepam kinetics is not influenced by age, whereas Kangas etal.…”

Section: Introductionmentioning

confidence: 99%

Effect of age and liver cirrhosis on the pharmacokinetics of nitrazepam.

Jochemsen¹,

Beusekom²,

Spoelstra³

et al. 1983

1 The effect of age and liver cirrhosis on the pharmacokinetics of i.v. administered nitrazepam was studied in nine healthy relatively young subjects (age 22-49 years), eight healthy elderly (age [67][68][69][70][71][72][73][74][75][76] years) and 12 patients with alcoholic liver cirrhosis (age 39-66 years).2 The elimination half-life of nitrazepam in the elderly subjects was longer than in the young ones but the difference did not reach statistical significance. Mean values (ranges) were 38 (26-64) h and 26 (19-31) h respectively. 3 The increase in elimination half-life was primarily due to an increase in volume of distribution, mean values (ranges) being 2.93 (1.96-5.33) 1/kg and 1.89 (1.44-2.23) 1/kg in the elderly and young groups respectively (P < 0.05).4 The protein unbound fraction of nitrazepam tended to be higher in the elderly subjects, although the difference between the two age groups was not significant: 13.9 (11.5-15.4) % and 13.0 (11.0-15.9) % in elderly and young respectively.5 Age had no effect on the clearance of total nitrazepam nor on the clearance of unbound nitrazepam (intrinsic clearance). Mean values (ranges) were 63 (50-87) ml/min and 489 (377-635) ml/min in the young and 64 (47-91) ml/min and 456 (348-652) ml/min in the elderly subjects respectively. 6 There were no significant differences in elimination half life, clearance and volume of distribution between patients with alcoholic liver cirrhosis and the total of healthy subjects of both age groups, mean values (ranges) being 31 (21-55) h, 59(26-85) ml/min and 2.17 (1.57-3.22) 1/kg respectively in patients and 31 (19-64) h, 63(47-91) ml/min and 2.38 (1.44-5.33) 1/kg in healthy subjects. 7 The protein unbound fraction of nitrazepam was substantially higher in the patient group: 18.9 (14.8-30.3) % as compared to 13.8 (11.0-15.9) % in the healthy subjects (P < 0.001). 8 Clearance calculated relative to unbound nitrazepam (intrinsic clearance) was significantly lower in the patient group: 320(163-482) ml/min as compared to healthy subjects, 472 (348-652) ml/min (P <0.001).9 The results of this study indicate that nitrazepam action following single dose administration may be more persistent in elderly than in young people; however, steady state levels of total and unbound nitrazepam during nightly intake of the drug will not be affected by age. On the other hand, steady state levels of unbound nitrazepam in patients with liver cirrhosis will generally be about 35% higher than in healthy subjects.

“…However, since the piperazine N-oxide of loprazolam may have pharmacological activity approaching that of the parent drug (Miller, unpublished Our findings provide evidence that the absorption of loprazolam can be slow. Mean time to peak serum concentration was considerably greater than that usually quoted for benzodiazepines used as hypnotics (Breimer, 1979; 0E Curry & Whelpton, 1979;Greenblatt et al, 1981;Kangas & Breimer, 1981) and there was a marked lag time, on average 1-1.5 h after drug administration, before loprazolam was detectable in serum. Although onset of activity depends on concentration-effect relationships which are unknown for loprazolam, rate of absorption is usually the rate limiting factor in the transfer of drug molecules to their sites of action in the central nervous system, after oral dosing (Curry & Whelpton, 1979).…”

Section: Methodsmentioning

confidence: 71%

“…Furthermore, secondary peaks of unchanged loprazolam and RIA measured material occurred frequently. Similar observations have been made with loprazolam (Stevens et al, 1983) and other benzodiazepines (Breimer etal., 1977;Kangas & Breimer, 1981;Korttila & Kangas, 1977) and may relate to ingestion of food. Where secondary peaks represent the maximum serum concentrations of the drug, they may have an important influence on the assessment of absorption, but whether they denote pharmacologically active drug remains to be established.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics following single and repeated nightly administrations of loprazolam, a new benzodiazepine hypnotic.

McInnes¹,

Bunting²,

Ings³

et al. 1985

1 The pharmacokinetics of oral loprazolam and pharmacodynamic responses on the morning following nightly drug administration were examined after single and after seven consecutive 1 mg doses in six non-fasting healthy subjects. 2 The serum concentration-time profiles for unchanged loprazolam measured by a specific high pressure liquid chromatography/gas chromatography (h.p.l.c./g.c.) method and for benzodiazepine material measured by radioimmunoassay (RIA) were qualitatively similar although RIA levels were consistently higher. 3 Approximate elimination half-life of unchanged loprazolam after single doses was 8.0 h. For RIA measured material, approximate half-life was 11.7 h following acute administration and 12.8 h after seven consecutive doses. 4 Compared to results after single doses, maximum serum concentration and AUC were greater following 1 week's treatment. Using RIA results, the increases were 27.2% (95% CL 6.9 to 47.4%) and 35.1% (95% CL 15.8 to 54.3%) respectively and using h.p.l.c./g.c. data, 11% (95% CL -22.6% to 44.5%) and 41% (95% CL -50.9 to 133.0%).5 After repeated doses of loprazolam, there were no significant changes with respect to results after single doses in psychomotor function assessed objectively by critical flicker fusion threshold or choice reaction time, or in sleep quality or behaviour on awakening assessed subjectively by 10 cm analogue scales. 6 Mean time to maximum serum concentration was 4.95 h with considerable interindividual variability (range 1-12 h) and there was a lag time of 1-1.5 h before drug was detectable in blood. 7 Thus, although the elimination half-life of loprazolam suggests a short to intermediate duration of action, after night time administration following food, the present formulation exhibits slow and irregular absorption, and appreciable serum concentrations persist the next day. On repeated doses there is evidence of slight accumulation. It is postulated that this benzodiazepine has the pharmacokinetic characteristics of a hypnotic with anxiolytic properties the following day.