Flurazepam
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Mechanism of action
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.
Pharmacodynamics
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.
Pharmacokinetics
Half-life
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/
Absorption
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.
Metabolism
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.
Protein binding
83%
External links
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