A Brief presentation on benzodiazepines

2. Aliza ali khan
Roll no 42(M)
Exam roll no 2827
Final proff Pharm-D
Session 2015-2020
Faculty of Pharmacy Gomal University Dera Ismail Khan

3. Contents
1) Introduction
2) History
3) Classification
4) Chemistry of various
benzodiazepines
5) Structures
6) Synthesis
7) Mechanism of action
8) Therapeutic application
9) Adverse effects

4. Introduction
Definition
A class of drugs that act as tranquilizers and are
commonly used in the treatment of anxiety.
or
Benzodiazepines (BZD, BDZ, BZs), sometimes called
"benzos", are a class of psychoactive drugs whose core
chemical structure is the fusion of a benzene ring and
a diazepine ring.

5. The first such drug, chlordiazepoxide (Librium), was discovered
accidentally by Leo Sternbach in 1955, and made available in
1960 by Hoffmann–La Roche, which, since 1963, has also
marketed the benzodiazepine diazepam (Valium).In 1977
benzodiazepines were globally the most prescribed
medications. They are in the family of drugs commonly known
as minor tranquilizers

6. Classification
A) On the basis of
Use
B) On the basis of
Duration of action
On the basis of use
Sedative-Hypnotics
 Diazepam
 Alprazolam
 Nitrazepam
 Flurazepam
 Temazepam
 Triazolam
 Nordazepam
Antianxiety
 Diazepam
 Alprazolam
 Lorazepam
 Oxazepam
 Chlordiazepoxide
 Bromozepam
Anticonvulsants
 Diazepam
 Lorazepam
 Clonazepam
 Clobazam

7. On the bais of duration of action
Ultra short
acting
 Triazolam
 Midazolam
Short acting
 Oxazepam
 Alprazolam
Intermediate
acting
 Lorazepam
 Clonazepam
 Temazepam
 Bromozepam
Long Acting
 Chlordiazepoxi
de
 Diazepam
 Flurazepam
 Halazepam
 Prazepam
 Clorazepate
 Nordazepam

8. Chemistry of
various
benzodiazepines
Name of Drug Chemical formula Functional group
R1 R2 R3 R2
’ R7
Diazepam
C16H13ClN2O
CH3 O H H Cl
Bromazepam C14H10BrN3O H 0 H N Br
Lorazepam C16H13ClN2O H O OH Cl Cl
Oxazepam C15H11ClN2O2 H O OH H Cl
Alprazolam C15H11ClN2O3 CH3N=N N H H Cl
Clorazepate C16H11ClN203 H O COOH H Cl
Clonazepam C15H10ClN2O3 H O H cl NO2
Chlordiazepoxide C16H14ClN3O Double bond(=) HNCH3 H H Cl
Flurazepam C21H23ClFN3O CH2CH2N(C2H5)2 O H F Cl

9. Structures of
various
benzodiazepines

10. Structure of
various
benzodiazepines

11. Synthesis of benzodiazepines

12. Synthesis of diazepam

13. SAR(Structure-activity
relationship)

14. Ring A:
 The minimum requirement for 5-Phenyl 1,4
benzodiazepine 2one derivative to BZR
include an aromatic or hetero aromatic ring.
 An electronegative group substituted at 7
positon markedly increase activity and
binding affinity
 Substitution at 6,8 and 9 position decrease the
activity.
 On the other hand 1-4diazepenederivatives
having ring A replaced with heterocyclic ring
has weak activity as compared to phenyl
derivatives
Ring B
• A proton accepting group (Carbonyl oxygen) at
2-position of ring B is necessary to interact with
receptor histidine residue that act as a proton
donor and helps in ligand binding
• Electron donating group must be in same plane
with electronegative group on ring A, favoring a
coplanar spatial orientation of two moieties.
• Substitution of O with S effect selective binding
GABA BZR sub populations but anxiolytic
activity is maintained
• Derivative having 3-hydroxy moiety have
comparable potency to non-hydroxylated
analogue but are excreted faster
• Esterification of 3-hydroxy moiety is possible without
loss of activity possible without loss activity
• 1-position amide nitrogen and its substituent are not
required for in-vitro binding with BZR because many
N-alkyl side chains do not decrease BZR affinity.
• Neither 4, 5 double bond nor the nitrogen of 4-position
is required for activity
• If C=N is reduced BZR affinity is decreased but the
derivatives again oxidized in the body to C=N

15. • 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
benzodiazepines derivatives with high
affinity to BZR

16. Mechanism of
action
• Site of action: Hypothalamic, thalamic and
limbic system.
• BDZ works by increasing efficiency of a
natural brain chemical, GABA, to decrease
the excitability of neurons.
• GABA controls the excitability of neurons by
binding to the GABA(A) receptor. The
GABA(A) receptor located in the synapse of
neuron.
• All GABA(A) receptor contain an ion
channel that conduct chloride ions across
neuronal cell membrane and two binding
sites for the GABA,GABA(A) receptor
complexes also contain a single binding site
for BZDs.
• Binding of BZDs to this receptor complex
promotes binding of GABA, which in turn
increases the conduction of chloride across
the neuronal cell membrane.

17. Therapeutic uses

18. Side effects
Common side effects Long term side effects Withdrawal symptoms
CNS
 Depression
 Headache,
 Memory loss
 Impaired cognition
 Impaired motor skills
 Irritability,
 Short term
CNS
 Acute anxiety
 Agoraphobia
 Anhedonia
 Depression
 Inability to think cohesively
 Social phobias
CNS
 Depression
 An altered sense of reality
 Confusion and disorientation
 Hallucination
 Increased sensitivity to light,
and/or sound
 Nervousness
 Paranoia
 Seizures and convulsions
 Insomnia
 Irritability
GIT
 Diarrhea
 Dry mouth
 constipation
GIT
 Diarrhea
 Abdominal cramps
 Constipation
 Dry mouth
GIT
 Diarrhea
 Abdominal cramps
 Constipation
 Dry mouth
Muscles
Muscle weakness
Muscles
Muscle weakness
Muscles
Muscle weakness
Others
 Loss of appetite or increase of
appetite
 Low libido
 Erectile dysfunction
Others
 Loss of libido
Others
 Perfuse sweating
 Tachycardia
Skin
 Tingling
 Burning
 Or skin crawling sensations