benzodiazepines drugs with their uses

1. Benzodiazepine
s-DRM
By
Mrs. Dhanashri R Mali

2. Benzodiazepine
s-DRMBenzodiazepines
 The term benzodiazepine refers to the portion of
the structure composed of a benzene ring (A)
fused to a seven-membered diazepine ring (B).
 Approved for use ~ 50 years ago
– Chlodiazepoxide - 1960
– Diazepam - 1961

3. Benzodiazepine
s-DRM
MODE OF ACTION
Benzodiazepines binds to GABAA receptor
Facilitate GABA- GABAA receptor activity allosterically
 Frequency of the channel opening &  affinity of GABA for the receptor
 Chloride ion conductance
 Hyperpolarization of the neuronal cell membrane

4. Benzodiazepine
s-DRM
Pharmacological Effects
1. Reduction of anxiety and aggression
2. Sedation and induction of sleep:
(1) The latency of sleep onset is decreased;
(2) The duration of stage 2 NREM sleep is
increased;
(3) The duration of slow-wave sleep is
decreased.
3. Anticonvulsant and antiseizure
The can enhance GABA-mediated synaptic systems
and inhibit excitatory transmission.
4. Muscle relaxation
relax contracted muscle in joint disease or muscle
spasm.
5. Other effects
lead to temporary amnesia
decrease the dosage of anesthetic;

5. Benzodiazepine
s-DRMStructure Activity Relationship
 It is believed to participate in π-π
bonding with aromatic residue of
aromatic amino acids of the
receptor.
 1-4 diazepine derivative having
ring-A replaced with hetrocyclic
ring have weak activity and
affinity as compared to phenyl
derivatives
 Presence of an electron
withdrawing group in position 7 is
required for activity.
 More the electron-withdrawing
more will be the activity.
 Position 6,8 and 9 should not be
A B
C

6. Benzodiazepine
s-DRM
 A proton acceptingA proton accepting group
(carbonyl oxygen) at 2- position of ring B is
necessary to interact with receptor histidine
residue that act as proton donor and
help in ligand binding.
 Substitution 3-position methylene or imine
nitrogen is sterically unfavorable.
 Derivatives having 3-hydroxy moiety have
comparable potency to non-hydroxylated
analogue but are excreted faster.
 Saturation of the N4-C5 double bond or its
shifting to other positions decreases activity.
 The nitrogen atom at position 1, the N-
substituent should be small.

7. Benzodiazepine
s-DRM
 A phenyl ring in position 5 promotes
activity.
 Activity is increased when the phenyl is ortho or
diortho substituted with electron withdrawing
groups.
 Substitution in para position brings about
decrease in activity.
 This aromatic ring contribute favorable
hydrphobic or steric interactions to receptor
binding and its relationship to ring A
 Annelating the 1,2 bond of ring
B with an additional electron
rich ring such as triazole
(alprazolam) or imidazole
(midazolam) results in
pharmacologically active
benzodiazepine derivatives with

8. Benzodiazepine
s-DRM
Pharmacokinetic Aspects
 Well absorbed when given orally;
 Distribution volumes is big.
 Metabolic transformation in the
microsomal drug-metabolizing enzyme
systems of the liver, eventually excreted
as glucuronide conjugates in the urine.
 Rapid tissue redistribution  long acting
 long half lives and elimination half
lives (from 10 to > 100 hrs).
 · All BDZs cross the placenta 
detectable in breast milk  may exert
depressant effects on the CNS of the
lactating infant.

9. Benzodiazepine
s-DRM
Metabolism
 Hepatic metabolism.
 Almost all BDZs undergo microsomal oxidation
(N-dealkylation and aliphatic hydroxylation) and
conjugation (to glucoronides).
 Metabolites of some benzodiazepines are not
only active but also have long half-lives, thus
these drugs are long acting.
 Estazolam, oxazepam, and lorazepam, which
are directly metabolized to glucoronides have
the least residual (drowsiness) effects.
 Cytochrome inhibitors (erythromycin,
clarithromycin, ritonavir, itraconazole,
ketoconazole, nefazodone, and grapefruit juice)
can affect their metabolism.
 They have lower abuse potential and a much
greater margin of safety than the barbiturates.

10. Benzodiazepine
s-DRM
* Wilson and Gisvold’s Textbook of Organic Medicinal And Pharmaceutical Chemistry,446

11. Benzodiazepine
s-DRM

12. Benzodiazepine
s-DRM
Comparison of Benzodiazepines
Drug Peak Blood
Level (Hours)
Elimination
Half-Life1
(Hours)
Comments
Alprazolam 1-2 12-15 Rapid Oral
Absorption
Chlordiazepoxide 2-4 15-40 Active metabolites;
erratic bioavailability
from IM injection
Diazepam 1-2 20-80 Active metabolites;
erratic bioavailability
from IM injection
Lorazepam 1-6 10-20 No active metabolites
Temazepam 2-3 10-40 Slow oral absorption;
no active metabolites
Triazolam 1 2-3 Rapid onset; short
duration of action
Oxazepam 2-4 10-20 No active metabolites
1 Includes half-lives of major metabolites

13. Benzodiazepine
s-DRM
ADVERSE EFFECTS
 Light-headedness
 Fatigue
 Increased reaction time
 Motor incoordination
 Impairment of mental and motor functions
 Confusion
 Antero-grade amnesia
 Cognition appears to be affected less than
motor performance.
 All of these effects can greatly impair driving
and other psychomotor skills, especially if
combined with ethanol.

14. Benzodiazepine
s-DRM
Uses:
 Antianxiety drugs: Diazepam,
Chlordiazepoxide, Oxazepam,
Lorazepam, Alprazolam, Clonazepam,
Flurazepam
 Sedative and hypnotics
 Anticonvulsant: Nitrazepam,
Clonazepam
 Muscle relaxant properties
 General Anesthetics: Midazepam

15. Benzodiazepine
s-DRM
Benzodiazepin
es

16. Benzodiazepine
s-DRM
Chlordiazepoxid
e
7- chloro-2-(methylamino)-5-phenyl-3H-1,4-
benzodiazepine-4-oxide
Well absorbed after oral administration.
Peak plasma levels are reached in 2 to 4
hours.
The half-life is 6 to 30 hours.
Because of the long half-life of parent drug
and its active metabolites, this drug is long
acting and self-tapering.
Repeated administration of chlordiazepoxide
can result in accumulation of parent drug and
its active metabolites, and thus cause
excessive sedation.

17. Benzodiazepine
s-DRMDiazepam
 7-chloro-1,3-dihydro-1- methyl-5-phenyl-
2H-1,4-benzodiazepine-2-one
 prototypical and was the first member of
the benzodiazepine-2-one group to be
introduced.
 It is very lipophilic
 It is rapidly and completely absorbed
after oral administration.
 Max peak blood conc. occurs in 2 hours
 Elimination is slow, with a half-life : 46
hours.
 Log P: 3.86, Protein Binding: 99%

18. Benzodiazepine
s-DRM
Repeated administration of diazepam leads
to accumulation of an active nordazepam.
Diazepam clearance is decreased in the
elderly and in patients with hepatic
insufficiency, a dosage reduction may be
warranted.
Uses:
 Short-term management of anxiety:
 Insomnia associated with
 Sleepwalking; night terrors— Children
and adolescents (up to 18 years)
 Anesthetic premedication
 Adjunct in the management of seizures
 Muscle spasms

19. Benzodiazepine
s-DRM
Name of
drug
Structure IUPAC Name Onset
of
action
Peak
Blood
Level
(Hrs)
Eliminati
on Half-
Life (Hrs)
Active
metaboli
te
Uses
Long Acting
Chlordiazep
oxide
7-chloro-2-
(methylamino) -5-
phenyl-3H-1,4-
benzodiazepine
4-oxide
15-
30
min
2-
4(po)
5-30 3-100
Sedative and
Hypnotics
Diazepam 7-chloro-1,3-
dihydro-1-
methyl-5-phenyl-
2H-1,4-
benzodiazepine-2-
one
Withi
n 15
min
1(po) 20-50 3-100
Sedative and
Hypnotics
skeletal muscle
relaxant,
anticonvulsant
and antianxiety
agent.
Flurazepam 7-chloro-1-[2-
(diethylamino)ethy
l]-5-(2-
fluorophenyl) -1,
3-dihydro-2H-1, 4-
benzodiazepine-2-
one
dihydrochloride
Withi
n 15
min
0.5-2 inactive 47-100
Sedative and
Hypnotics
Quazepam 7-chloro-5-(2-
fluorophenyl)-1-
(2,2,2-
trifluoroethyl)-3H-
1,4-
15-
30
min 1-2 39 --
Sedative and
Hypnotics

20. Benzodiazepine
s-DRM
Prazepam 7-chloro-1-
(cyclopropylmethy
l)- 1,3-dihydro -5 -
phenyl-2H-1,4-
benzodiazepine-2-
one
Withi
n 15
min 1(po) 20-50 3-100
Sedative and
Hypnotics
Halazepam 7-chloro-1,3-
dihydro-5-
phenyl-1(2,2,2-
trifluoroethyl)-2H-
1,4-
benzodiazepine-2-
one
30-
60
min 1-3 6-20 47-100
Anxiolytics,
anticonvulsant,
sedative,
muscle relaxing
effects
Intermediate acting
Nitrazepam 7-Nitro-5-phenyl-
1,4-
benzodiazepin-2-
one
Withi
n 15
min 1(po)
6-20 sedatives and
hypnotics,
and
myoclonic
seizures.
Clorazepate
Dipotassium
7-chloro-2,3-
dihydro-2-oxo-5-
phenyl-1H-1,4-
benzodiazepine-
3-carboxylic acid
dipotassium salt
monohydrate
15-
30
1 Inactiv
e
40-50 Anxiolytics,
Sedative and
Hypnotics
Oxazepam 7-chloro-1,3-
dihydro-3-
hydroxy-5-phenyl-
30-
60 2-3 4-8 -
Sedative and
Hypnotics

21. Benzodiazepine
s-DRM
Lorazepam 7-chloro-5-(2-
chlorophenyl)-
3-dihydro-3-
hydroxy-2H-1,4-
benzodiazepine-2-
one
15-
30
min
1-1.5
(po)
2-6 -
Sedative and
Hypnotics
Temazepam. 7-chloro-1,3-
dihydro-3-hydroxy-
1-methyl-5-phenyl
-2H-1,4-
benzodiazepine-2-
one
30-
60
min
0.75-
1.5
10-20
Anxiolytics,
Sedative and
Hypnotics
TRIAZOLOBENZODIAZEPINES
Alprazolam 8-chloro-1-methyl-
6-
phenyl-4H-s-
triazolo[4,3-
a][1,4]benzodiazep
ine
15-
30
min
0.7-
1.6
6-20 --
Anxiolytics,
Sedative and
Hypnotics
Triazolam 8-chloro-6-(o-
chlorophenyl)-
1-methyl-4H-s-
triazolo[4,3-a][1,4]
benzodiazepine
15-
30
min
0.75-
2
1.6-5.5
amnesic,
anxiolytic,
sedative,
anticonvulsant,
and muscle
relaxant
Midazolam. 8-chloro-6-(2-
fluorophenyl)-1-
methyl-4H-
imidazo[1,5-
a][1,4]benzodiazep
Mos
t Ra
pid
0.5-1
(IV
1-4 -
General
anesthetics,
Anticonvulsant

22. Benzodiazepine
s-DRM