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Drugs

, Volume 20, Issue 5, pp 353–374 | Cite as

Flunitrazepam: A Review of its Pharmacological Properties and Therapeutic Use

  • M. A. K. Mattila
  • H. M. Larni
Review Article

Summary

Synopsis: Flunitrazepam1 is a benzodiazepine derivative whose hypnotic effect predominates over the sedative, anxiolytic, muscle-relaxing and anticonvulsant effects characteristic of benzodiazepines. Thus, it is used as a night-time hypnotic and in anaesthesiology; due to the pronounced hypnotic effect it is not appropriate as a daytime sedative. Asa hypnotic for insomnia its effect is usually characterised by a very fast onset of action and quiet sleep without interruptions. On the morning after a hypnotic dose some residual psychomotor impairment does occur, which is comparable to that with usual doses ofnitrazepam or flurazepam, but clinically apparent ‘hangover’ occurs infrequently.There is no pronounced cumulative effect with chronic use. In anaesthesiology it has proven to be useful as a hypnotic on the night before operation, as an oral, intramuscular or intravenous premedication, in induction and as a supplement to other anaesthetics. Its sedative and amnesic properties can also be beneficial in intensive care patients. Much of the usefulness of flunitrazepam in anaesthesia relates to its synergistic effect with other anaesthetics, to its effective amnesic action and its acceptable effects on circulation and respiration. Possible drawbacks include a somewhat unusual course of induction (when used for this purpose) and an often prolonged recovery. Although the safe dosage range is wide with flunitrazepam, its effective application both as a hypnotic for insomnia and in anaesthesiology is dependent upon use of the optimal dosage, and adequate knowledge of its pharmacokinetic properties.

Pharmacodynamic Studies: Flunitrazepam, like other benzodiazepines, has a selective effect on GABA (gamma-aminobutyric-acid)-mediated synaptic processes of the brain. Facilitation of the inhibitory effect of GABAergic synaptic transmission especially affects the limbic system. (The highly selective and saturable synaptic inhibition of GABA-mediated activities is accepted as the basis of the extraordinary safety range of benzodiazepines.) The different affinity of various benzodiazepines to specific benzodiazepine receptors correlates well with their pharmacological and therapeutic potencies. The relative weight-for-weight potency of flunitrazepam is high, on an average about 10 times as potent as diazepam; however, there is wide variation in this potency coefficient for different effects.

Flunitrazepam produces a dose- and time-dependent amnesic effect, which is more complete and somewhat longer than the amnesia after diazepam, but clearly less intense and shorter than that produced by lorazepam. This amnesic effect is an important characteristic of flunitrazepam’s use in different anaesthesia techniques, as it prevents patients from having unpleasant experiences during different stages of anaesthesia and operation.

The most typical feature of flunitrazepam on the cardiovascular system is peripheral vasodilatation. This is possibly due to its direct relaxing effect on the muscle fibres in the vascular wall. A decrease in cardiac output also occurs, which is more pronounced in patients with cardiovascular disease. This effect, together with a marked decrease in peripheral resistance, results in a significant reduction of systolic blood pressure. The primary phenomenon may be limited to this peripheral vasodilatation, with a secondary decrease in venous return. This emphasises the importance of normal blood volume and active fluid infusion when flunitrazepam is used intravenously.

Flunitrazepam has a depressive influence on respiration, even in small intravenous doses, and this effect is augmented by simultaneously administered analgesics or hypnotics. In occasional extreme cases there may be need for respiratory assistance. The effect on respiration results in a significant decrease in arterial oxygen tension; this may be corrected by increasing oxygen concentration in the inspired air.

Pharmacokinetic Studies: Knowledge of the pharmacokinetic behaviour of flunitrazepam is extremely important for optimum practical use of this drug, especially in anaesthesiology. Flunitrazepam is almost completely (80 to 90%) absorbed from the gastrointestinal tract, but the bioavailability of suppositories is only 50 %. After intramuscular injection the absorption corresponds with absorption via the oral route, thus differing profitably from diazepam which is erratically absorbed from intramuscular sites. Flunitrazepam is 80% bound to plasma proteins. Its pharmacokinetic behaviour can be illustrated with a 3-compartment model, which has important clinical implications. Rapid redistribution from the central (plasma) compartment to tissue compartments explains the discrepancy between the half-life of the drug and the duration of its clinical effects. Thus, the overall elimination half-life is about 20 hours, which is much longer than the duration of clinical effects. There is fairly good correlation between the clinical effects and the logarithm of the plasma concentration.

Metabolism of flunitrazepam is nearly complete. There are several metabolites, but the most important are the 7-amino, the 1-desmethyl, and the 3-hydroxy derivatives. Some of the metabolites are active and may have an important influence on clinical effects. Excretion is via the urine, and thus renal insufficiency results in accumulation of the metabolites. In patients with normal renal function there is no progressive accumulation of metabolites with a daily dose of 2mg flunitrazepam. Metabolism and elimination are age-dependent, and the dose must be reduced in elderly patients.

Therapeutic Trials: Flunitrazepam has been studied in 2 areas of use — as a night hypnotic and in different applications in anaesthesiology.

The hypnotic effects of flunitrazepam have been studied in both ‘normal’ people and in insomniacs. In a dose of 2mg flunitrazepam is an effective and fast sleep-inducing drug with a sufficient duration of action to maintain quiet sleep until morning. In double-blind trials it was significantly better than a placebo, barbiturates or nitrazepam. Flunitrazepam causes a significant latency in the appearance of the first REM (rapid eye movement) period, and decreases the number of REM periods during the night, but not the duration of individual REM periods. There is a marked shift of REM periods to the last two-thirds of the night. These effects on sleep patterns are probably less ’unphysiological’ than the effects of barbiturates. The data concerning residual effects of flunitrazepam in the morning are somewhat divergent. Some authors claim that there is no morning-after hangover, but others have demonstrated impaired psychomotor skills the next morning. There may be residual anxiolysis on the following day, which can be desirable or undesirable depending on the patient’s daily activity and requirements.

Flunitrazepam 2mg appears to be suitable for use as a premedication on the night before anaesthesia. On operation day the effect can be increased by another 2mg given orally or intramuscularly. The patient will be sleepy and anxiety minimised until anaesthesia. Anaesthesia induction may be performed with intravenous flunitrazepam. The dose is dependent on age and physical status and the use of other anaesthetics, but 0.02 to 0.03mg/kg is most frequently used. In some resistant patients anaesthesia cannot be induced with flunitrazepam. Typically, such patients are addicted to sedatives, especially benzodiazepines, or alcohol. In such cases the effect of flunitrazepam may be potentiated with agents such as fentanyl and nitrous oxide or thiopentone. Indeed, flunitrazepam shows typical synergism with nitrous oxide, analgesics and ketamine. Synergism with muscle relaxants is less obvious. The course of anaesthesia with flunitrazepam is usually quiet and even. Depending on the dose of flunitrazepam, and use of other anaesthetics, the recovery may be either relatively fast or prolonged. Typically, during recovery the patient will fall asleep when he is free from pain or is undisturbed. The amnesic properties of flunitrazepam have been widely applied in supplementation of other general or local anaesthesias using incremental doses of flunitrazepam. Properly titrated doses improve different stages and different types of anaesthesia. Postoperative nausea and vomiting are reduced by flunitrazepam. In intensive care, its amnesic and hypnotic effects and synergism with analgesics can be applied to improve the patient’s tolerance of unpleasant therapeutic procedures.

Side Effects: The only common side effect of flunitrazepam when used as a hypnotic is a possible residual effect on the morning following the night of drug intake. The use of flunitrazepam in anaesthesia results in prolongation of recovery, this effect being highly dose-dependent. However, when patients are kept under proper postoperative observation the long standing anxiolytic, sedative and synergistic effect with analgesics may be advantageous. In some cases disturbing cough or hiccup may occur at induction. During injection of flunitrazepam the patient often experiences pain along the injection vein. However, significantly fewer long term venous sequelae occur than with intravenous diazepam (with propyleneglycol as solvent). No allergic reactions have been reported with flunitrazepam.

Dosage and Administration: Flunitrazepam is relatively contraindicated in patients with myasthenia gravis. Its use during early pregnancy and in Caesarean section, as a part of general anaesthesia, is unsettled. Doses of 0.02mg/kg or more should be avoided in outpatients, because of possible long lasting disturbances in coordination.

The usual dose of flunitrazepam as a sleep-inducing agent is 2mg orally. In older patients 1 mg may be more suitable. As a premedication 2mg orally on the night before operation, and then 2mg orally or 1.5 to 2 mg intramuscularly for adult patients 2 to 3 hours prior to anaesthesia is recommended. The usual induction dose is 0.02 to 0.03mg/kg. As a supplement 0.005 to 0.01 mg/kg is usually sufficient. These doses should be reduced in patients with cardiovascular disease and in older patients.

Keywords

Diazepam Thiopentone Flunitrazepam Induction Agent Nitrazepam 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© ADIS Press Australasia Pty Ltd 1980

Authors and Affiliations

  • M. A. K. Mattila
    • 1
  • H. M. Larni
    • 1
  1. 1.Department of AnaesthesiologyKuopio University Central HospitalKuopio 21Finland

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