BENZODIAZEPINES
HISTORICAL NOTES
Widely used as sedative-hypnotics and anxiolytics
Have supplanted the barbiturates
Were 1
st
real selective anxiolytics by mechanisms not through sedation
Were prototype real anxiolytics
Barbiturates: though 1
st
anxiolytics
Not truly anxiolytics
Cause sedation
latter masking anxiety
CHLORDIAZEPOXIDE
1st benzodiazepine synthesized in 1950s
1
st
to be introduced clinically in 1960s
Was more effective than barbiturates
Had better safety margin
Fatalities rare from overdose
DIAZEPAM
Marketed in 1963
Was 3-10 fold more potent than chordiazepoxide as anxiolytic
Several others
since marketed

…Cont.
Examples of long-acting BDZs
Chlordiazepoxide, diazepam, prazepam
and
clorazepate
Flurazepam and nitrazepam also have active
metabolites with long t1/2
CLINICAL IMPLICATION OF LONG DURATION OF
ACTION:
1.
Cumulative effects on multiple dosing may occur
2.
Excessive drowsiness may occur:
Hang-over effect next day
3.
Toxicity may occur, especially:
the elderly
hepato-compromized
slow metabolizers

…Cont
.
EXAMPLES OF SHORT-ACTING BDZs
Estazolam, oxazepam, lorazepam…etc:
Metabolized directly into inactive metabolites
(glucuronides)
Alprazolam, triazolam
Also short acting
THERAPEUTIC IMPLICATIONS OF SHORT ACTIVITY:
Short-acting BDZs favoured as hypnotics
But disadvantage:
May be associated with:
Daytime anxiety
Tenseness or panic or
Early morning insomnia next day
form of
withdrawal
symptoms (since they are short-acting )

…Cont.
ADVANTAGES OF LONG-ACTING BDZs
Less frequent dosing
Less variation in plasma concentration
Less severe withdrawal symptoms
DISADVANTAGES OF LONG-ACTING BDZs
Risk of drug accumulation
Risk of daytime psychomotor impairment
Risk of daytime sedation
