[Metabolic changes from flunitrazepam (changes in lipid- and carbohydrate metabolism from flunitrazepam)].
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Adenosine Triphosphate↗
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Amnesic action of and skills related to driving after intravenous flunitrazepam.
Amnesic action, skills related to driving and the ability to discriminate the fusion of flickering light were measured double-blind in 29 healthy volunteers before and after three doses of intravenous flunitrazepam. Every subject experienced amnesia for the pinching of the abdomen after being injected with flunitrazepam. Even the smallest dose of flunitrazepam (0.01 mg/kg) caused the amnesia without affecting the level of consciousness. The late effects of flunitrazepam were the most harmful to coordination. With 0.01 mg/kg eye-hand coordination was slightly impaired for as long as 6 h after the injection, and after 0.02 and 0.03 mg/kg the impairment was still significant (P less than 0.05) at the last observation period 10 h after the injection. It was concluded that, because the amnesic action of flunitrazepam is more effective than that of clinically comparable doses of diazepam, further clinical experiments with flunitrazepam are warranted. Its longer and more harmful effects on psychomotor performance than those of equipotent doses of diazepam suggest that doses of 0.02 mg/kg or more of flunitrazepam should be avoided in outpatient anaesthesia or sedation.
Adult↗
Comparison of diazepam and flunitrazepam for sedation during local anaesthesia for bronchoscopy.
Diazepam and flunitrazepam were compared as amnesic and sedative adjuncts to local anaesthesia for diagnostic bronchoscopy in 92 patients. After local anaesthesia of the pharynx, larynx and trachea with lignocaine, atropine plus diazepam of flunitrazepam was injected i.v. The co-operation of the patients and the technical circumstances under which the bronchoscopy was performed were good in each group. None of the treatments significantly modified arterial pressure or heart rate. Two hours after the injection, flunitrazepam 0.01 mg kg-1 more frequently caused amnesia for pictures shown to the patients during the first 15 min after injection (failure to recall 42--75%, and for bronchoscopy 67%), than did diazepam 0.125 mg kg-1 (failure to recall 21--67%; bronchoscopy 38%). Double doses of the drugs caused amnesic actions similar to those of flunitrazepam 0.01 mg kg-1. When failure to recall was assessed on the following day, 29% and 5% of the patients remembered bronchoscopy after flunitrazepam 0.01 and 0.02 mg kg-1 respectively; after diazepam 0.125 and 0.25 mg kg-1 the corresponding percentages was 59% and 30% (P less than 0.05% v. fluintrazepam). The ability to stand and walk on a stright line was similar after the smaller doses of both drugs, but after the larger doses recovery was slower after flunitrazepam. Psychomotor performance was still distinctly impaired 2 h after the injection of the larger doses.
Adult↗
Flunitrazepam versus placebo premedication for minor surgery.
The clinical effects of oral flunitrazepam (2 mg on the night before operation followed by 2 mg on the morning of operation) and placebo as premedicants were tested in a double-blind study in 81 gynaecological patients. The separate or total concentrations of flunitrazepam and its demethylated metabolite in plasma (measured by gas chromatography) were correlated with the clinical effects of flunitrapam premedication, assessed both sugjectively and objectively. In most parameters tested (sleep on the night before operation, sedation, apprehension, headache, pulse rate), there was a positive, significant difference between the flunitrazepam group (n = 44) and the placebo group (n = 37). No significant difference was found between the two groups in emetic effect, excitement, systolic blood pressure increase, and vene-puncture, but the patients receiving flunitrazepam felt significantly more dizziness. The temperature of the left forefinger before, during and after the anaesthesia did not vary significantly between the two groups. There was no correlation between the plasma concentration of flunitrazepam and its demethylated metabolite (separate or total concentrations) and any of the parameters tested before induction of anaesthesia. Flunitrazepam is a new oral premedicant with prominent sedative and anxiolytic actions. When the drug is given as a sedative on the night before operation, followed by a second dose on the morning of operation, the beneficial effects last for at least 8 hours after the second dose.
Adult↗
Reduction of psychotomimetic side effects of Ketalar (ketamine) by Rohypnol (flunitrazepam). A randomized, double-blind trial.
A double-blind controlled trial based on 140 women undergoing abortus provocatus was employed to study whether the frequency of side effects after administration of the anaesthetic Ketalar (ketamine) could be reduced by a con-current dose of Rohypnol (flunitrazepam). The control group was given ketamine alone. The dosage of ketamine was 2 mg/kg body weight, supplemented if necessary by 1 mg/kg, in combination with either 2 mg flunitrazepam or placebo. No other anaesthetics were used. On several counts, the combination of ketamine and flunitrazepam was proved to reduce the adverse reactions seen with ketamine alone. Motor restlessness and confusion in the awakening state occurred with significantly less severity and frequency. Amnesia for dreams was significantly more frequent. Memory of dreams was often unpleasant after ketamine alone. The influence on pulse rate was significantly smaller and no significant changes in systolic blood pressure were seen, whereas a significant increase occurred with ketamine alone. Less pronounced fluctuations in diastolic blood pressure occurred with the combination ketamine-flunitrazepam. Respiratory rate increased significantly with both treatments, but respiratory minute volume was lower with the ketamine-flunitrazepam combination.
Abortion, Induced↗
[Flunitrazepam-pretreatment for prevention of adverse cardiovascular effects following ketamine].
In 18 patients with documented ischaemic heart disease the cardiovascular effects of ketamine (1.5 mg/kg iv) were studied under three different conditions: 1. in awake premedicated patients (n = 6); 2. after the previous administration of flunitrazepam (0.015 mg/kg iv, n = 6) and 3. under conditions of neuroleptanalgesia and muscle relaxation (n = 6). Flunitrazepam prevented or at least attenuated the increases in heart rate (30%), mean arterial pressure (37%), mean pulmonary artery pressure (165%), left ventricular filling pressure (230%), total peripheral resistance (50%), pulmonary vascular resistance (100%) and in the rate-pressure product (66%) which were associated with the use of ketamine as the sole anaesthetic agent. In addition, the flunitrazepam-pretreatment abolished the fall in cardiac index and stroke index which occured in patients given ketamine alone. Flunitrazepam therefore appears to be a promising drug to prevent adverse cardiovascular reactions, when ketamine should be chosen for induction of anaesthesia. Neuroleptanalgesia and muscle relaxation also proved effective in controlling the sympathomimetic actions of ketamine. The response of the mean pulmonary artery pressure and of the ventricular filling pressures to ketamine in this group was even more damped than in the patients pretreated with flunitrazepam alone.
Adult↗
Benzodiazepine receptors: labeling in intact animals with [3H] flunitrazepam.
[3H]Flumitrazepam appears to label specific benzodiazepine receptors in vitro after i.v. injection in mice. Benzodiazepine potencies in reducing [3H]flunitrazepam binding in vivo correspond to pharmacological potencies and parallel relative affinites for [3H]flunitrazepam binding sites in isolated brain membranes. However, 50% occupation of [3H]-flunitrazepam sites by benzodiazepines in vivo requires brain concentrations of the drugs about 1000 times higher than their Ki values for the binding sites in vitro. In pharmacologically active doses sodium pentobarbital, strychnine, picrotoxin and bicuculline fail to influence [3H] flunitrazepam binding in vivo.
Animals↗
Clinical studies of induction agents XLIII: Flunitrazepam.
Flunitrazepam (Ro 5-4200) has been studied as an induction agent in 220 volunteers or patients. It was assumed to be 10 times as potent as diazepam. The maximum soporific effect did not occur until 90-120 s after injection. There was great individual variation in response to flunitrazepam and some patients did not lose consciousness even after receiving 6 mg (approximately 0.1 mg/kg). Opiate premedication enhanced its action, but delayed recovery. There was a dose-related increase in minor respiratory upset with flunitrazepam in unpremedicated patients and a high frequency of arterial hypotension following large doses given to patients who had received opiate premedication. Venous sequelae were no more frequent than after comparable doses of diazepam. Flunitrazepam was not a very satisfactory drug for the induction of anaesthesia, and recovery was too prolonged for routine use.
Adolescent↗
Comparison of flunitrazepam and diazepam for oral premedication in older children.
A double-blind trial was conducted of two benzodiazepines, flunitrazepam and diazepam, given orally to 142 children (30 kg in weight or heavier) undergoing routine surgery. Flunitrazepam was associated with greater sedation before operation and less vomiting after operation than diazepam. Flunitrazepam caused a greater frequency of amnesia for the periods of induction and immediately after operation. Plasma concentrations were measured in 65 children and were found to be significantly greater in those children having amnesia for the induction period in both flunitrazepam and diazepam groups. In the diazepam group, plasma concentrations were significantly smaller in those who vomited than in those who did not vomit.
Anti-Anxiety Agents↗
A controlled long-term study of flunitrazepam, nitrazepam and placebo, with special regard to withdrawal effects.
The hypnotic effect of flunitrazepam (Ro 5-4200), nitrazepam and a placebo was studied in 117 outpatients using hypnotics for at least 3 months prior to the study. They obtained various neurotropic drugs and this and other treatments were unchanged throughout the trial period of 13 weeks. This consisted of 3 weeks on the previously used hypnotic, 3 weeks on a test drug (during the first of these a doubling of the dose was permitted if the initial dose of 1 mg flunitrazepam, 5 mg nitrazepam or one tablet of placebo was not satisfactory) and 4 weeks' observation after a request to stop medication with the test drug. The effects were evaluated every week by self-ratings. Also noted were: the frequency of dose increase after 1 week of the test period, number of drop-outs in the test period, and failure in the attempt to stop taking the test drug. A "psychological concentration test" was done, as was a follow-up interview. The self-ratings had a good reliability and showed that more patients experienced shorter sleep induction, longer sleep time, better sleep quality and a subjective feeling of having had a better rest with flunitrazepam than with either nitrazepam or placebo. There were no differences between the nitrazepam and the placebo groups. Tiredness was the most common side effect and appeared in the same frequency in all groups. The number of patients who increased the dose after 1 week's medication, as well as the number of drop-outs, was significantly higher in the nitrazepam and placebo groups than in the flunitrazepam group. There was no difference in the ability to discontinue the medication between the test groups or between groups having previously used different hypnotics. The "psychological concentration test" did not reveal any differences between groups. It was concluded that withdrawal of a hypnotic in chronic users was not facilitated by the use of a placebo. This was interpreted as due to a strong psychological dependence upon the hypnotics and their lack of pharmacological effects during long-term treatment.
Adult↗
[Flunitrazepam, trazodone and sulpiride in the treatment of recovery reactions after ketamine anesthesia].
The authors studied the effects of flunitrazepam, trazodone and sulpiride on recovery reactions following ketamine anaesthesia, in male patients aged between 15 and 25 years, following minor orthopaedic surgery. Only flunitrazepam and trazodone proved to be effective, whilst sulpiride was quite useless in the prevention of recovery reactions. The authors nevertheless feel that trazodone is preferable to flunitrazepam since it reduces all recovery reactions and, in particular, because it reduces the agitation induced by ketamine, rendering the pseudo-hallucinations pleasant, and because it is free of the hypnotic component of flunitrazepam, often inconstant and sometimes responsible for the patient swallowing his tongue.
Adolescent↗
The effect of diazepam, flunitrazepam and droperidol with an analgesic on blood pressure and heart rate in man.
The effects of i.v. diazepam (0.3 mg/kg), droperidol (5 mg) and a new benzodiazepine, 5-(a-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one (flunitrazepam, Ro 5-4200) (0.03 mg/kg) on blood pressure and heart rate was studied in 62 healthy volunteer students. Observations were made after each drug alone, after diazepam and flunitrazepam each combined with pethidine (1 mg/kg), and after droperidol combined with fentanyl (0.2 mg). The doses of the benzodiazepines were halved in those subjects given pethidine but the dose of droperidol was the same with and without fentanyl. The blood pressure was measured by auscultation and the heart rate by counting the radial pulse. The systolic and diastolic blood pressure was regularly decreased by not more than 20 and 11 mmHg, respectively. Changes in the heart rate were slight. Flunitrazepam did not have greater effects than diazepam or droperidol through the combination of flunitrazepam and pethidine seemed to induce a greater fall in systolic blood pressure than did the combination of diazepam and pethidine. None of the changes observed was clinically significant.
Adult↗
[Analytical data of flunitrazepam (rohypnol), a new benzodiazepine-derivative, in special consideration of its metabolites (author's transl)].
The article describes analytical data (TLC, GLC, IR, UV and MS) of flunitrazepam, 7-amino-flunitrazepam, desmethylflunitrazepam, 3-hydroxyflunitrazepam, 7-amino-desmethyl-flunitrazepam and many other benzodiazepine-derivatives, especially aminobenzophenones. Also extraction from biological specimen is reported.
Anti-Anxiety Agents↗
The actions of flunitrazepam (Rohypnol) on heart and respiratory rates and skin potential fluctuations during the sleep cycle in normal volunteers and neurotic patients with insomnia.
The actions of flunitrazepam (Rohypnol) were assessed on the sleep cycle, heart and respiratory rates and skin potential fluctuations of normal volunteers and neurotic patients with insomnia by means of all night recordings. The most conspicuous effect of flunitrazepam (2 mg p.o.) in the healthy subject's sleep cycle was an increase of the latency for the appearance of the first REM period. In the insomniacs the compounds was effective in inducing and maintaining sleep. Flunitrazepam diminished heart rates during the REM phases and significantly decreased the variability indices, this effect being more prominent in the normal subjects. Skin potential fluctuations during stages 2 and REM sleep were also decreased although tolerance developed rapidly in this connection.
Adult↗
Quantitative gas chromatographic analysis of flunitrazepam in human serum with electron-capture detection.
A rapid method for the determination of flunitrazepam and desmethylfflunitrazepam in human serum in the range 10-300 ng/ml is described. Both drugs are isolated from biological material by means of a single extraction, part of the organic phase is evaporated to dryness and the residue is dissolved in a small volume of benzene. Without further purification, the substance is determined gas chromatographically with an electron-capture detector configuration of 63Ni-type. The method permits the quantitative determination of at least 25-300 ng/ml with an overall recovery of flunitrazepam of 99.7 +/- 4.9% and of desmethylflunitrazepam of 98.6 +/- 7.8% from serum. All calculations were carried out by a data system that was programmed for this purpose. The limit of detection for flunitrazepam is of the order of 1 ng/ml in serum. The method is sufficiently sensitive and specific for therapy control purposes. The time needed for an analysis is less than 1 h.
Anti-Anxiety Agents↗
Comparison of I.M. pethidine, diazepam and flunitrazepam as premedicants in children undergoing otolaryngological surgery.
Pethidine 1 mg kg-1, diazepam 0.25 mg kg-1 and flunitrazepam 0.02 mg kg-1 i.m. wer compared as premedicants in a double-blind study in 145 children undergoing otolaryngological surgery. Both flunitrazepam and pethidine had an anxiolytic effect in the children of less than 5 yr whereas diazepam had little effect. All of the drugs were anxiolytic in the children aged 5 yr and older. Sleep following thiopentone was restless more often in the younger than in the older children. Cardiovascular responses to thiopentone and to tracheal intubation were most obvious following benzodiazepines in children of less than 5 yr. After anaesthesia 10--33% of the older children could not recall pictures shown to them before anaesthesia. Forty-five (+/-SD 13) min after injection, the concentration of diazepam in serum was similar in both age groups; after 90 min it decreased in the younger and increased in the older children. All concentrations of flunitrazepam were significantly greater in the older compared with the younger children.
Adolescent↗
Comparison of diazepam and flunitrazepam as adjuncts to general anaesthesia in preventing arousal following surgical stimuli.
A comparison has been made between the effects of the administration of flunitrazepam 1 mg i.v. and diazepam 10 mg i.v. in 90 female patients undergoing abdominal surgery. The drugs were given immediately before the skin incision as a booster to the induction agent thiopentone. The response to the incision, the quality of anaesthesia and the need for supplementary medication during maintenance were monitored. A standard post-anaesthesia interview was performed to evaluate the amnesic action and patient acceptability. The skin incision caused only slight increase in arterial pressure and heart rate in both groups. Only six patients of the diazepam group reacted to the incision with defensive movements. The overall quality of anaesthesia was better (P less than 0.05) and the need for supplementary doses of pethidine lower (P less than 0.01) in the flunitrazepam group. Recovery was equally good and the duration of sleep after operation was the same in both groups. The frequency of nausea after operation was low. The post-anaesthesia interview revealed that flunitrazepam possesses a more specific anterograde amnesic action than diazepam. Acceptability of the anaesthesia to the patient was equally good in both groups.
Abdomen↗
Relative amnesic actions of diazepam, flunitrazepam and lorazepam in man.
1. Ten postcards were shown to groups of ten to twenty patients over 60, 90 or 270 min after intravenous injection of saline, diazepam (10 and 20 mg), flunitrazepam (1 and 2 mg) and lorazepam (4 mg). 2. Incidence of amnesia was estimated by the patients' ability to recall or recognize these cards and to recall various other incidents in the para-anaesthetic period. 3. The use of a dummy confirmed the reliability of the method of testing for amnesia in man. 4. Flunitrazepam produced a dose-related incidence of amnesia slightly longer than with the equivalent (1 x 10) dose of diazepam. 5. The onset of amnesia was slower with lorazepam (4 mg) but appeared to last for up to four hours. 6. This amnesic action of lorazepam was paralleled by a useful sensitive effect but there was no similar correlation for diazepam and flunitrazepam. 7. With three drugs of different duration of action it should be possible to produce amnesia for any required clinical situation.
Amnesia↗