フルラゼパム

DEA NFLIS-Drug Category -> Benzodiazepines

DEA Schedule IV Controlled Substance -> Depressants

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

Pharmaceuticals -> Nervous system -> Anxiolytics

OFF-WHITE TO YELLOW, CRYSTALLINE POWDER; SLIGHT ODOR TO ODORLESS; MODERATELY HYGROSCOPIC; MELTS WITH DECOMPOSITION AT ABOUT 212 °C; SOLUBILITY: 1 G IN 2 ML WATER; FREELY SOL IN ALCOHOL; SLIGHTLY SOL IN CHLOROFORM /FLURAZEPAM DIHYDROCHLORIDE/

1.00e-02 g/L

Breast Feeding; Lactation; Milk, Human; Benzodiazepines; Hypnotics and Sedatives

Pharmaceuticals

190-220

77-82 °C

WHITE RODS; PALE YELLOW CRYSTALS FROM METHANOL + ETHER; MP: 190-220 °C /FLURAZEPAM DIHYDROCHLORIDE/

79.5 °C

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 44 reports by companies from 3 notifications to the ECHA C&L Inventory.

DEA schedule IV controlled substance

Status: Active Update: 05-04-2022 https://echa.europa.eu/registration-dossier/-/registered-dossier/20551

General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension and CNS depression may be combated by judicious use of appropriate therapeutic agents. If excitation occurs in patients following Flurazepam overdosage, barbiturates should not be used. Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be useful in situations when an overdose with a benzodiazepine is known or suspected. (L1712)

PATIENTS RECEIVING ... /AMITRIPTYLINE & FLURAZEPAM/ CONCURRENTLY SHOULD BE WARNED ABOUT POSSIBLE ENHANCED CNS DEPRESSION. ... TRICYCLIC ANTIDEPRESSANTS ... ARE STRUCTURALLY & PHARMACOLOGICALLY RELATED TO AMITRIPTYLINE ... .

NEXT MORNING STUDIES OF THE EFFECTS OF ALCOHOL ON THE PERFORMANCE OF PSYCHOMOTOR SKILLS OF SUBJECTS WHO HAD ... FLURAZEPAM ... AS A HYPNOTIC THE NIGHT BEFORE SHOWED THAT A SIGNIFICANT & DETRIMENTAL "HANGOVER" INTERACTION TAKES PLACE.

... BENZODIAZEPINES SUCH AS ... FLURAZEPAM ... MIGHT BE EXPECTED TO INTERACT SIMILARLY WITH GALLAMINE TRIETHIODIDE & OTHER NONDEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS ... AS WELL AS DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS ... .

/DRUG INTERACTIONS/ ... ARE INFREQUENT ... EXCEPT FOR AN ADDITIVE EFFECT WITH OTHER CNS DEPRESSANTS ... HEAVY CIGARETTE SMOKING MAY DECREASE THE EFFECTIVENESS OF USUAL DOSES ... . /BENZODIAZEPINES/

For more Interactions (Complete) data for FLURAZEPAM (12 total), please visit the HSDB record page.

Flurazepam, as with other benzodiazepines, is rarely associated with serum ALT or alkaline phosphatase elevations, and clinically apparent liver injury is rare. Only a few case reports of acute liver injury from flurazepam have been published and mostly before 1980. The latency to onset of acute liver injury varied between 2 to 6 months and the pattern of liver enzyme elevations was cholestatic. The injury was usually mild-to-moderate in severity and self-limited in course. Fever and rash were not described nor autoantibody formation. Similar rare cases of self-limited, mild-to-moderate, cholestatic liver injury have been reported with other benzodiazepines including alprazolam, chlordiazepoxide, clonazepam, diazepam, lorazepam, and triazolam.

Benzodiazepines bind nonspecifically to bezodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

... FLURAZEPAM CAUSES AN IMPRESSIVE NUMBER OF SIDE EFFECTS. THE INCIDENCE APPEARS TO BE ABOUT 7%. EXCESSIVE DROWSINESS OCCURS IN ABOUT 2% OF CASES; IN ELDERLY OR DEBILITATED PATIENTS, THIS IS MORE COMMON, & THERE MAY ALSO BE VERTIGO, ATAXIA, & FALLING. RARE INSTANCES OF FAINTING, SLURRED SPEECH, LETHARGY, DISORIENTATION, & ALSO COMA CAN OCCUR EVEN IN YOUNGER PATIENTS ... ELEVATED SERUM LEVELS OF THE TRANSAMINASES, ALKALINE PHOSPHATASE, & BILIRUBIN HAVE BEEN REPORTED ON OCCASION ... . /FLURAZEPAM CHLORIDE/

OTHER REPORTED SIDE EFFECTS INCLUDE ... HEADACHE, HEARTBURN, UPSET STOMACH, NAUSEA, VOMITING, DIARRHEA, CONSTIPATION, GI PAIN, NERVOUSNESS, TALKATIVENESS, APPREHENSION, IRRITABILITY, WEAKNESS, PALPITATION, CHEST PAINS, BODY & JOINT PAIN, & GENITOURINARY COMPLAINTS. LESS FREQUENTLY SWEATING, FLUSHES, BLURRED VISION, DIFFICULTY IN FOCUSING, BURNING EYES, ... SHORTNESS OF BREATH, PRURITUS, SKIN RASH, ... BITTER TASTE, EXCESSIVE SALIVATION, ANOREXIA, ... DEPRESSION ... . /FLURAZEPAM DIHYDROCHLORIDE/

... FLURAZEPAM OCCASIONALLY INCREASE/S/ THE INCIDENCE OF NIGHTMARES, ESPECIALLY DURING THE FIRST WK OF USE. FLURAZEPAM OCCASIONALLY CAUSES GARRULOUSNESS, ANXIETY, IRRITABILITY, TACHYCARDIA, & SWEATING. EUPHORIA, RESTLESSNESS, HALLUCINATIONS, & HYPOMANIC BEHAVIOR HAVE BEEN REPORTED TO OCCUR DURING USE OF VARIOUS BENZODIAZEPINES.

... EQUALLY PARADOXICAL IS AN INCREASE IN ANXIETY ... BOTH PSYCHOSES & SUDDEN SUICIDAL IMPULSES HAVE OCCASIONALLY BEEN REPORTED IN PATIENTS RECEIVING HIGH DOSES ... IN GENERAL, THE CLINICAL TOXICITY ... IS LOW. /BENZODIAZEPINES/

For more Human Toxicity Excerpts (Complete) data for FLURAZEPAM (16 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

flurazepam

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

IN DOSES UP TO 80 MG/KG DURING VARIOUS PERIODS OF GESTATION IN THE RAT, NEITHER TERATOGENIC NOR POSTNATAL CHANGES WERE PRODUCED IN THE OFFSPRING. IN THE RABBIT, DOSES OF 20 MG/KG/DAY FROM DAY 6 THROUGH 18 PRODUCED NO OBSERVABLE ADVERSE FETAL EFFECTS.

N - Nervous system

QN - Nervous system

Flurazepam, a benzodiazepine derivative, is a hypnotic agent which does not appear to decrease dream time as measured by rapid eye movements (REM). Furthermore, it decreases sleep latency and number of awakenings for a consequent increase in total sleep time.

Flurazepam binds to an allosteric site on GABA-A receptors. Binding potentiates the action of GABA on GABA-A receptors by opening the chloride channel within the receptor, causing chloride influx and hyperpolarization.

EFFECTS OF FLURAZEPAM ON EEG DIFFER FROM THOSE OF BARBITURATES IN THAT FAST ACTIVITY SEEMS TO BE INCREASED ONLY IN FRONTAL LOBE & DOES NOT SPREAD TO OCCIPITAL LOBE. IN DOSES UP TO 30 MG IT NEITHER AFFECTS REM SLEEP NOR CAUSES A REBOUND AFTER WITHDRAWAL, BUT DOSES OF 60 MG SUPPRESS REM SLEEP WITHOUT REBOUND. FLURAZEPAM DECREASES SLEEP LATENCY, TIME IN STAGE 4, & WAKE TIME, & INCREASES TOTAL SLEEP TIME FOR AS LONG AS 22 NIGHTS OF USE. /FLURAZEPAM DIHYDROCHLORIDE/

MOST BENZODIAZEPINES DECREASE SLEEP LATENCY, ESPECIALLY WHEN FIRST USED, & DIMINISH THE NUMBER OF AWAKENINGS & TIME SPENT IN STAGE 0 (A STAGE OF WAKEFULNESS). THEY HAVE BEEN SHOWN TO INCREASE THE AWAKENING THRESHOLD. TIME IN STAGE 1 (DESCENDING DROWSINESS) IS USUALLY DECREASED BY FLURAZEPAM ... . TIME SPENT IN STAGE 2 (WHICH IS THE MAJOR FRACTION OF NON-RAPID EYE MOVEMENT (REM) SLEEP) IS INCREASED BY ALL BENZODIAZEPINES. BENZODIAZEPINES PROMINENTLY DECREASE THE TIME SPENT IN SLOW-WAVE SLEEP (SWS; STAGES 3 & 4); USUALLY BOTH STAGES 3 & 4 ARE SHORTENED ... . ALL BENZODIAZEPINES INCREASE REM LATENCY (TIME FROM ONSET OF SPINDLE SLEEP TO THE FIRST REM BURST), EXCEPT THAT FLURAZEPAM HAS BEEN REPORTED TO SHORTEN LATENCY IN SOME INSOMNIAC NEUROTIC OR PSYCHOTIC INDIVIDUALS. ... REM SLEEP MAY NOT BE SHORTENED WHEN LOWER DOSES OF FLURAZEPAM ... /WAS/ USED, EVEN THOUGH SUBSTANTIAL SHORTENING OF SLOW-WAVE SLEEP & PROLONGATION OF STAGE 2 SLEEP MAY OCCUR. ... DESPITE THE SHORTENING OF STAGE-4 & REM SLEEP, THE NET EFFECT OF ADMIN OF BENZODIAZEPINES IS AN INCREASE IN TOTAL SLEEP TIME.

WITH FLURAZEPAM ... THE REBOUND IN REM SLEEP APPEARS TO BE SLIGHT OR NEGLIGIBLE. DURING THE PERIOD OF SUCH REBOUND THE NUMBER OF DREAMS PER NIGHT IS ABOUT THE SAME AS BEFORE THE DRUG WAS TAKEN, BUT THEIR BIZARRE CHARACTER MAY INCREASE. THERE IS ALSO USUALLY A REBOUND IN SLOW-WAVE SLEEP WHICH MAY EXCEED THE REBOUND IN REM SLEEP. WITHDRAWAL OF FLURAZEPAM CAUSES ONLY A SLIGHT REBOUND. ... TOTAL WAKE TIME IS NOT CHANGED AFTER WITHDRAWAL OF FLURAZEPAM.

THE BENZODIAZEPINES SELECTIVELY ACT ON POLYSYNAPTIC & NOT MONOSYNAPTIC NEURONAL PATHWAYS THROUGHOUT THE CNS. THE ACTION IS MAINLY THAT OF PRESYNAPTIC INHIBITION, ALTHOUGH AT SOME SITES, SUCH AS IN CUNEATE NUCLEUS, THERE MAY BE POSTSYNAPTIC INHIBITION; WHETHER INHIBITION IS PRESYNAPTIC OR POSTSYNAPTIC, IT SIMULATES THAT OF GAMMA-AMINOBUTYRIC ACID. POLYSYNAPTIC RESPONSES MAY BE DIMINISHED OR AUGMENTED, ACCORDING TO WHETHER SYNAPTIC INHIBITION SUBSERVES AN INHIBITORY OR FACILITATORY FUNCTION IN THE INTEGRATED RESPONSE. /BENZODIAZEPINES/

For more Mechanism of Action (Complete) data for FLURAZEPAM (10 total), please visit the HSDB record page.

The mean apparent half-life of flurazepam is 2.3 hours. The half life of elimination of N1-des-alkyl- flurazepam ranged from 47 to 100 hours

Half-life of flurazepam in plasma is 2 to 3 hr, but that of a major active metabolite (N-desalkylflurazepam) is 50 hr or more.

Elimination half-lives of metabolites: Desalkylflurazepam (47-100 hr) and N-1-Hydroxyethylflurazepam (2-4 hr) /From table/

MEAN HALF-LIFE (IN HOURS) ARE: 74 FOR YOUNG MALES & 160 FOR ELDERLY MALES; 90 FOR YOUNG FEMALES & 120 FOR ELDERLY FEMALES. /FLURAZEPAM HYDROCHLORIDE/

Flurazepam is rapidly metabolized and is excreted primarily in the urine. Both hydroxyethyl flurazepam (the major metabolite) and N-desalkyl flurazepam are active. The N-desalkyl metabolite is slowly excreted in the urine as the conjugated form

IT IS METABOLIZED IN LIVER. THE DIETHYLAMINE GROUP IS DESETHYLATED, THEN DEAMINATED, EVENTUALLY TO YIELD ALCOHOL, THE MAJOR METABOLITE IN MAN. ALCOHOL IS CONJUGATED TO FORM THE GLUCURONIDE. THE PHENYL RING IS ALSO HYDROXYLATED AT THE ORTHO POSITION, THEN CONJUGATED. THE HETEROCYCLIC RING IS ALSO HYDROXYLATED. /FLURAZEPAM DIHYDROCHLORIDE/

YIELDS 7-CHLORO-1-(2-ETHYLAMINOETHYL)-5-(2-FLUOROPHENYL)-1,3-DIHYDRO-2H- 1,4-BENZODIAZEPIN-2-ONE IN MAN & IN DOG & YIELDS 7-CHLORO-5-(2-FLUOROPHENYL)-1,3-DIHYDRO-2H-1,4-BENZODIAZEPIN-2-ONE IN MAN. /FROM TABLE/

YIELDS 7-CHLORO-1-(N-ETHYL-N-(2-HYDROXYETHYL)AMINOETHYL)-5-(2-FLUOROPHENYL)- 1,3-DIHYDRO-2H-1,4-BENZODIAZEPIN-2-ONE IN MAN & YIELDS 7-CHLORO-5-(2-FLUOROPHENYL)-1,3-DIHYDRO-3-HYDROXY-2H-1,4-BENZODIAZEPIN-2-ONE IN DOGS. /FROM TABLE/

AFTER CHRONIC ORAL DOSES OF FLURAZEPAM TO HUMAN SUBJECTS, UNCHANGED DRUG COULD NOT BE DETECTED IN BLOOD, & MAJOR CMPD PRESENT WAS N-DEALKYL-FLURAZEPAM. BIOLOGICAL HALF-LIFE OF THIS METABOLITE RANGED FROM 47-100 HR.

For more Metabolism/Metabolites (Complete) data for FLURAZEPAM (10 total), please visit the HSDB record page.

IHP475989U

FLURAZEPAM

Established Pharmacologic Class [EPC] - Benzodiazepine

Chemical Structure [CS] - Benzodiazepines

Flurazepam is a Benzodiazepine.

Drugs used to induce drowsiness or sleep or to reduce psychological excitement or anxiety.

Agents that alleviate ANXIETY, tension, and ANXIETY DISORDERS, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. ADRENERGIC BETA-ANTAGONISTS are commonly used in the symptomatic treatment of anxiety but are not included here.

Substances that do not act as agonists or antagonists but do affect the GAMMA-AMINOBUTYRIC ACID receptor-ionophore complex. GABA-A receptors (RECEPTORS, GABA-A) appear to have at least three allosteric sites at which modulators act: a site at which BENZODIAZEPINES act by increasing the opening frequency of GAMMA-AMINOBUTYRIC ACID-activated chloride channels; a site at which BARBITURATES act to prolong the duration of channel opening; and a site at which some steroids may act. GENERAL ANESTHETICS probably act at least partly by potentiating GABAergic responses, but they are not included here.

Flurazepam hydrochloride is rapidly (30 minutes) absorbed from the gastrointestinal tract

Flurazepam is rapidly metabolized and is excreted primarily in the urine. Less than 1% of the dose is excreted in the urine as N1-desalkyl-flurazepam.

HYPNOTIC, FLURAZEPAM HYDROCHLORIDE, HAS BEEN SHOWN TO BE RAPIDLY & COMPLETELY ABSORBED IN DOG & MAN. ELIMINATION IS ALSO RAPID & DUE SOLELY TO BIOTRANSFORMATION. /FLURAZEPAM HYDROCHLORIDE/

ORAL ... ((14)CARBON) FLURAZEPAM ... IN DOG & MAN ... ELIMINATED MAINLY IN 3 DAYS. DOG EXCRETED 36 & 49% OF (14)CARBON IN URINE & FECES (PROBABLY VIA BILE) FOLLOWING ORAL DOSE & 27 & 54% FOLLOWING IV DOSE. AFTER ORAL DOSE, HUMANS EXCRETED ... IN FECES (9%) & ... IN URINE (81%). PLASMA (14)CARBON ... PEAKED IN 1 HR FOLLOWING ORAL DOSE IN BOTH SPECIES.

ALL BENZODIAZEPINES BIND TO HUMAN PLASMA ALBUMIN. THE EXTENT OF BINDING VARIES FROM PROBABLY ONLY A FEW PERCENT WITH FLURAZEPAM TO NEARLY 99% WITH DIAZEPAM.

THE BIOAVAILABILITY OF FLURAZEPAM VARIES BETWEEN 30 & 60%. AFTER A SINGLE ORAL DOSE OF 30 MG, THE PLASMA CONCN RISES TO A PEAK OF 1 TO 2 NG/ML AT 1 HR & FALLS RAPIDLY WITH HALF-LIFE OF ABOUT 3 HR... AFTER A 30 MG DOSE OF FLURAZEPAM, THE PEAK CONCN (AT 1 TO 3 HR) OF THE DESALKYL METABOLITE IS 0.5 TO 1.8 NG/ML & THAT OF THE DESAMINO COMPOUNDS IS 6 TO 8 NG/ML. THE ELIMINATION HALF-LIFE OF THE DESAMINO COMPOUND IS 10 TO 20 HR & THAT OF THE DESALKYL METABOLITE IS 1 DAY OR LONGER. THEREFORE, WITH DAILY ADMIN, THESE METABOLITES ACCUMULATE TO RATHER HIGH CONCN OVER A PERIOD OF SEVERAL DAYS TO A FEW WK. SINCE PHARMACOLOGICAL ACTIVITY IS ATTRIBUTABLE TO THESE METABOLITES, A FEW DAYS OF DAILY ADMIN ARE REQUIRED FOR THE ONSET OF THE FULL EFFECT OF FLURAZEPAM, & RESIDUAL EFFECTS ("HANGOVER") ARE COMMON. LESS THAN 0.2% OF FLURAZEPAM IS EXCRETED UNCHANGED; 30 TO 55% OF THE DRUG IS CONVERTED TO THE DESAMINO METABOLITE.

MEDICATION

Use (kg; approx.) in Germany (2009): >100

For short-term and intermittent use in patients with recurring insomnia and poor sleeping habits