[Metabolic changes from flunitrazepam (changes in lipid- and carbohydrate metabolism from flunitrazepam)].
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Adenosine Triphosphate↗
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A comparison of the physical dependence inducing properties of flunitrazepam and diazepam.
Dogs dosed chronically (4-7 weeks) with oral flunitrazepam (7.6 mg/kg/day) or diazepam (24-36 mg/kg/day) administered in 4 equally divided doses had dose-related flumazenil precipitated benzodiazepine abstinence scale scores (BPAS) of comparable intensities despite the fact that plasma levels of flunitrazepam and its metabolites were much lower than nordiazepam levels in the diazepam-dependent dog. Both groups of dependent dogs had clonic and tonic-clonic seizures after oral and IV flumazenil. Precipitated abstinence signs persisted longer in the diazepam than in the flunitrazepam-dependent dogs. Differences in the pharmacokinetics of the drugs of dependence, their metabolites, and their interactions at receptor sites offer a partial explanation for the high level of dependence seen in the flunitrazepam dog. The finding that the estimated plasma free concentration of flunitrazepam and its metabolites is equal to or greater than that of diazepam and its metabolites together with the fact that flunitrazepam has a higher affinity for the benzodiazepine receptor than either diazepam, nordiazepam or oxazepam can explain why the intensity of the precipitated abstinence syndrome is comparable in flunitrazepam- and diazepam-dependent dogs. Although the flumazenil-induced precipitated abstinence syndromes observed in flunitrazepam- and diazepam-dependent dogs differed qualitatively they did not differ quantitatively. It is therefore concluded from these data that the doses of flunitrazepam and diazepam, chosen for producing comparable degrees of weight loss during dose escalation, did not differ in the degree of physical dependence that they produced in the dog.
Animals↗
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↗
Hypnotic action of flunitrazepam is reversed by proglumide in rats.
1. Caerulein, an analogue of cholecystokinin (CCK-8), like CCK-8, has been shown to produce hypnotic effects similar to those of benzodiazepine (flunitrazepam). 2. Proglumide antagonizes the action of CCK-8 and of its analogue. 3. The aim of the present study was to demonstrate whether proglumide would affect the potent hypnotic action of flunitrazepam in rats. 4. The association of proglumide with flunitrazepam suppress the increase of total sleep time and slow wave sleep seen after flunitrazepam alone. Proglumide alone has no effect on sleep stages. The authors report here for the first time that the hypnotic action of flunitrazepam is antagonized by proglumide in rat.
Animals↗
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↗
Hormone-stimulated steroidogenesis is coupled to mitochondrial benzodiazepine receptors. Tropic hormone action on steroid biosynthesis is inhibited by flunitrazepam.
The mitochondrial (peripheral-type) benzodiazepine receptor (MBR) is a drug binding site associated with outer mitochondrial membranes which is coupled to intramitochondrial cholesterol transport, the rate-determining step of steroid biosynthesis. To examine the relationship between MBR function and steroid synthesis regulated by polypeptide hormones, the Y-1 adrenocortical and MA-10 Leydig cell lines were used as model systems responsive to adrenocorticotropin and human choriogonadotropin, respectively. Flunitrazepam, a benzodiazepine which binds to MBR with high nanomolar affinity, inhibited the steroidogenic activity of these hormones, or the activation by 1 mM dibutyryl cAMP, in both cell lines by 30-60% with an IC50 of 500-1000 nM. Scatchard analysis in both cell lines revealed one class of specific binding sites for [3H] flunitrazepam verified as being MBR by displacement studies with a series of MBR ligands. The potencies of these ligands to compete against the antagonism of hormone-stimulated steroidogenesis by flunitrazepam correlated significantly with their abilities to compete against [3H]flunitrazepam binding to MBR (r = 0.99). An inhibition in pregnenolone formation was also observed in isolated mitochondrial preparations characterized as a reduction of cholesterol transport to inner mitochondrial membranes. These observations provide unequivocal evidence that the antagonistic action of flunitrazepam is mediated through its interaction with MBR demonstrating that these drug recognition sites are coupled to steroid biosynthesis activated by tropic hormones.
Animals↗
[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↗
Effects of zolpidem and flunitrazepam on nocturnal sleep of women subjectively complaining of insomnia.
Eighteen non-pregnant woman complaining about insomnia were polysomnographically investigated for 3 nights with weekly intervals. They received placebo, 2 mg flunitrazepam or 10 mg zolpidem according to a cross-over double blind design. The patients were selected by general practitioners on the basis of subjective complaints. Zolpidem is a recently introduced short-acting imidazopyridine hypnotic, binding to a subunit of the benzodiazepine 1 receptor. Flunitrazepam is a well-known hypnotic, binding to both the benzodiazepine 1 and 2 receptor subtypes. Objective recording did not substantiate the subjective complaint of insomnia. Sleep patterns during placebo differed only little from that expected from age matched healthy persons. Both flunitrazepam and zolpidem significantly shortened sleep onset (5 min of continuous sleep beginning with NREM 1 sleep). The sleep composition following flunitrazepam was characterized by an increase in NREM 2, a prolongation of the time of REM sleep, a reduction of REM sleep and an increase in NREM 3-4 sleep during the first 2 h of sleep. The sleep composition following zolpidem resembled more than seen in persons without sleep complaints. However, as compared to placebo, there was a decrease of the time spent awake during sleep and an increase in NREM 3-4 during the first 2 of sleep.
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↗
Expression of GABAA/benzodiazepine receptor alpha 1-subunit mRNA and [3H]flunitrazepam binding sites during postnatal development of the mouse cerebellum.
Previous studies have shown that the alpha subunit of the GABAA receptor contains the flunitrazepam binding site. In the present study, in situ hybridization and receptor autoradiography were used to examine the temporal and spatial relationships between alpha 1 subunit mRNA and [3H]flunitrazepam binding sites in the developing mouse cerebellum. A [35S]cRNA probe was used to study the expression of GABAA/benzodiazepine receptor alpha 1 subunit mRNA by in situ hybridization. At postnatal day (P) 1, a diffuse band of labeling was observed in the molecular/Purkinje cell layer; subsequently, this band became progressively more concentrated and restricted to the interface between the granular and molecular layers. By P5-P7, high intensity labeling was clearly associated with Purkinje cells. Clusters of grains became visible over basket and stellate cells in the molecular layer between P11 and P13; the internal granule cell layer and the deep cerebellar nuclei showed an increasingly strong hybridization signal during postnatal development. The external germinal layer was devoid of labeling throughout its existence. The developmental distribution of [3H]flunitrazepam binding sites was studied by receptor autoradiography. Cerebellar labeling was detectable at birth, with the highest levels present over the deep cerebellar nuclei, and relatively low levels equally distributed over the molecular and Purkinje cell layers. Cerebellar cortical grain density increased gradually during postnatal weeks 1 and 2, with the molecular, Purkinje and granule cell layers remaining essentially equally labeled. Between P11 and P15, the labeling over the molecular layer increased dramatically, reaching the high adult levels by P20. As with the in situ hybridization studies, there was a complete absence of [3H]flunitrazepam binding sites in the external germinal layer throughout development. These results indicate that, in the Purkinje cell, the production of mRNA and the synthesis of the alpha 1 subunit occur prior to the formation of afferent inhibitory synapses, suggesting that GABAA/benzodiazepine receptor expression precedes, and is independent of GABAergic synaptic input.
Aging↗
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↗
Inter- and intraindividual variability in the concentration-effect (sedation) relationship of flunitrazepam.
1. The relationship between plasma flunitrazepam concentrations and the degree of sedation was evaluated in 20 healthy subjects receiving two single oral doses of 1 mg flunitrazepam on two different occasions (1 week apart). The degree of sedation was rated blindly during the two treatment sessions in parallel with blood sampling (48 h). 2. A strong correlation between the concentrations of flunitrazepam in plasma and the degree of sedation was found according to the sigmoid Emax model. The plasma drug concentration producing 50% of maximal effect (EC50) was found to be 7.0 and 6.5 ng ml-1 on the two occasions, respectively. The variability in EC50 between subjects was larger (C.V. 39%) than the variability within subjects (C.V. 27%). 3. The steepness of the concentration-response curve as reflected in the slope factor(s) showed a virtual 'all or none' response to flunitrazepam with s values ranging from 3 to 30 with a mean of about 14. 4. The results in young healthy subjects suggest that the present dosage recommendations for temporary insomnia (1-2 mg) may be inappropriate; the dose can probably be reduced to 0.5 mg in some patients to achieve moderate sedation.
Dose-Response Relationship, Drug↗
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↗
[Premedication in retrobulbar anesthesia. A blood gas analysis comparison of sublingual flunitrazepam and intravenous midazolam].
Benzodiazepines for sedation may decrease the PaO2, the arterial O2 saturation (SaO2), and the CO2 response more in the elderly than in the young. The purpose of this study was to assess changes in blood gases due to i.v. midazolam or sublingual flunitrazepam given as premedication in elderly patients for unilateral cataract surgery. METHODS. Fifty patients over 65 years of age with treated arterial hypertension and other co-existing diseases (ASA III-IV) were randomly assigned to have: (1) i.v. midazolam titrated until they became drowsy (17 patients; 2.85 +/- 0.84 mg [mean +/- SD]); (2) sublingual flunitrazepam (16 patients; 0.005 mg/kg); or (3) no sedation (17 patients; controls). On entering the operating theatre, the radial artery was cannulated and the first blood gas analysis was obtained. The premedication was then given. At 5, 10, 20, and 30 min after premedication, before and 10 min after retrobulbar block, before operation, 5 and 15 min after the beginning of the operation, 10 and 20 min after administration of 500 mg acetazolamide i.v. during the operation, and 10 and 20 min after the operation additional arterial blood samples were analysed (a total of 15 measuring points). Pulse oximetry, invasive blood pressure, and ECG were continuously monitored. All patients received oxygen 3 l/min during the operation by nasal cannula. Differences between the three groups were analysed by Student's t-test or U-test and a P value < 0.05 was considered significant. RESULTS. The patient demography, including duration of anaesthesia and operation, was similar in the three groups (Table 1). No significant differences were seen in heart rate, mean arterial pressure, PaO2, pulse-oximetric oxygen saturation (SpO2), base excess, or serum bicarbonate levels. The PaCO2 increased in patients after midazolam (P < 0.01) and flunitrazepam (P < 0.05) until the beginning of the operation compared with the control group (Fig. 3); 20 min after the operation there was still a significant difference between the midazolam group and the controls. SaO2 was significantly (P < 0.05) lower in the midazolam group 10 and 20 min after administration of premedication compared with the control group, but was within physiological limits (Fig. 5). Despite titration, 2 patients had severe respiratory insufficiency 3 min after midazolam: the SpO2 decreased below 85% and the paO2 below 55 mmHg. The paCO2 was higher (P < 0.05) in the midazolam group 10 min after acetazolamide compared with the controls. CONCLUSIONS. The results of the study show the potential hazards of i.v. midazolam in the elderly. If sedation is required for cataract surgery under local anaesthesia, we recommend sublingual flunitrazepam or the use of benzodiazepines with lower hypnogenic effects in the elderly. A thorough preoperative discussion of anaesthesia and the operation might be an adequate substitute for any premedication in high-risk patients; the best blood gas analysis results were obtained in the control group.
Administration, Sublingual↗
[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↗