Anxiolytic sedatives
(Minor tranquilizers)
Anxiety is a sense of apprehensive expectation.
Anxiety may be helpful e.g. anxiety before students
examination but too much anxiety, however, can be
deleterious due to it interferes with normal functioning
Anxiolytics are used to control moderate or severe
anxiety in patients with anxiety disorders.
Classification
I) Benzodiazepines.
II) Nonbenzodiazepine agonists at BZR
III) GABAA partial allosteric modulators
IV) Serotonin receptor (5-HT1A) agonists
I) Benzodiazepines
Uses:
1. Drugs of choice for daytime anxiety and insomnia.
2. They are used as sleep inducers, selective AED
(triazolam) and muscle relaxants.
3. They cause transient analgesia (I.V. diazepam).
4. Combination of benzodiazepines with CNS
depressants can produce true surgical anesthesia.
Benzodiazepines are ideal anxiolytics due to:
 Devoid of the side effects of major tranquilizers
and barbiturate.
 High safety margin and few drug interactions
than the barbiturates (not affect drug
metabolism).
Side effects
Prolonged administration of large doses causes
physical dependence and tolerance which are
treated by gradual withdrawal.
Mechanism of Action
Anxiolytics produce their effects by enhancing the
GABAnergic transmission via an increase in chloride
conductance.
GABA is the major inhibitory neurotransmitter in CNS.
GABAA receptors are ligand-gated chloride channels.
Benzodiazepines bind to benzodiazepine receptor
(BZR). BZR is allosteric site and integral part of the
GABAA receptor-chloride channel complex.
The interaction of agonists, inverse agonists and
antagonists with the BZR can be represented by
the following three-state model:
BZR agonists (positive modulators): Binding of
benzodiazepine to BZR will increase the binding of
GABA to GABAA receptor which, in turn, modulates
the opening of chloride channels which may lead to
anxiolytic or anticonvulsant effect.
H3C
CH3
O
N
O
N
N
Cl
O
N
Ph
Diazepam
agonist
H3CO
N
F
O
H3CO
CH3
Flumazenil
antagonist
BZR
GABA
receptor
C2H5
CO2CH3
N
N
H
DMCM
inverse agonist
BZR inverse agonists (negative modulators) bind to
the GABAA receptors inducing action opposite to that
of GABA due to decrease in chloride conductance that
may increase the anxiety or produce convulsions.
BZR antagonists (neutral modulators) occupy the
GABAA receptors blocking access of agonists to the
BZR e.g. flumazenil.
Benzodiazepine antagonist
Flumazenil (Romazicon)
It is imidazobenzodiazepinone derivative. It has a high
affinity to bind BZR blocking the effects of
benzodiazepine e.g. sedation from benzodiazepines
overdose can be reversed by flumazenil.
It is ethyl 8-fluoro-5,6-dihydro5-methyl-6-oxo-4H-imidazo[1,5-a]
[1,4]benzodiazepine-3-carboxylate
O
N
O
N
F
N
CH
Structure activity relationships
O
The following structure features should be present in
benzodiazepines:
Ring A
An electronegative substituent at position 7 (Cl,NO2)
increases activity
Substituents at positions 6, 8 and 9 decrease the
activity.
Derivatives in which ring A (phenyl) is replaced by
heterocycle show less activity.
3
CH3
Ring B
The nitrogen at 1-position is essential for activity and Nsubstituent should be small whereas bulky groups
sterically reduce activity.
A proton-accepting group e.g.2-CO appears to be
necessary to interact with receptor histadine residue that
serves as a proton source.
Substitution of sulfur for oxygen at the 2-position (as in
quazepam) may affect selectivity for binding to receptors
but activity is maintained.
Alkyl substitution at 3-position reduces activity.
H
Compounds without 3-OH are nonpolar
O
1
9
N
, have long half-life and undergo hepatic
2
8
B
3
A
oxidation. Compounds with 3-OH are polar
N4
X 7
6
and excreted faster.
5
1`
6`
5`
C
2`
3`
4`
Saturation of 4, 5 double bond is not
important for activity because in vivo activity
results from oxidation back to C=N.
Annelating the 1,2 bond of ring B with
electron-rich (proton-accepting) ring such as
s-triazolo (triazolam) or imidazolo(midazolam)
results in active derivatives with high affinity to
the BZR.
Ring C
A phenyl at 5-position promotes activity
due to its hydrophobic interactions with
receptor. If phenyl group is ortho (2’) or
diortho (2’, 6’) substituted with electronattracting groups, activity is increased.
Classification and Metabolism of benzodiazepines
They can be divided into:
A) Diazepam type.
B) 3-Hydroxy and 3-carboxy benzodiazepines.
C) Benzodiazepines containing F or Cl in the side chain
NHCH
or in ring.
N
D) 1,2-Annelated benzodiazepines.
.HCl
3
Cl
N
O
A) Diazepam type.
Chlordiazepoxide (Librium)
7-Chloro-2-methylamino-5-phenyl-3H-1,4benzodiazepine-4-oxide. HCl
It is well absorbed from GIT and its half-life is 6-30
hours (long-acting).
It undergoes N-demethylation and hydrolysis of
amidine to give active metabolite demoxepam.
The N-oxide of demoxepam is reduced to another
active metabolite, nordazepam (N-desmethyl
diazepam) which is also the active metabolite for
diazepam.
It is hydroxylated at C3 to the active metabolite
oxazepam which is rapidly glucuronated and excreted
in the urine.
Uses: anxiolytic, sedative, anticonvulsant and skeletal
muscle relaxant.
Librax = Librium + clidinium brmide (anticholinergic
agent) for GIT disorders such as peptic ulcer
and irritable colon.
H
H
O
N
O
N
Diazepam
Halazepam
OH
N
Cl
N
Cl
Clorazepate
Nordazepam
(active)
H
Oxazepam
(active)
H
O
N
O
N
O
Chlordiazepoxide
Cl
N
Cl
O
HO
N
O
OH
HOOC
Demoxepam
(active)
OH
Oxazepam glucuronid
CH3
Diazepam (Valium)
7-Chloro-1,3-dihydro-1-methyl-5-phenyl2H-1,4-benzodiazepin-2-one
O
N
Cl
N
It is very nonpolar and rapidly absorbed with a half-life
of about 20-50 hours (long-acting). The metabolism
is by N-demethylation to the active nordazepam
that undergoes metabolism to active metabolite
oxazepam
Assay: Non-aqueous titration with 0.1M perchloric
acid.
Uses: It is widely used as anti-anxiety, hypnotic,
sedative, anticonvulsant and premedication in
anesthesiology.
B) 3-Hydroxy and 3-carboxy benzodiazepines
Oxazepam (Serax)
Oxazepam is prototype for the 3-hydroxy compounds. It is active
metabolite of diazepam which much more polar than diazepam
and so, marketed separately as short-acting anxiolytic agent.
Lorazepam (Ativan)
It is the ´2-chloro analog of oxazepam and has a short half-life (26 hours).
H
O
N
H
O
OH
N
Cl
N
OH
Cl
N
Cl
Lorazepam (Ativan)
7-Chloro-1,3-dihydro-3-hydroxy-5phenyl-2H-1,4-benzodiazepin-2-one
7-chloro-5-(2-chlorophenyl)1,3-dihydro-3-hydroxy-2H-1,4benzodiazepin-2-one.
Clorazepate dipotassium (Tranxene)
H
O
N
7-Chloro-2,3-dihydro-2-oxo-5phenyl-1H-1,4-benzodiazepine-3carboxylic acid dipotassium salt
monohydrate.
-
COO K
Cl
N
+
. KOH
It is polar, inactive prodrug. It is quickly converted in the GI tract
to a nonpolar nordazepam via 3-decarboxylation.
Nordazepam has a long half-life and then undergoes hepatic
conversion to oxazepam.
C) The inclusion of halogen, (C1 or F)
on the aromatic ring or basic side chain seems to
increase the activity and emphasize the anticonvulsant
and hypnotic activity of this class of drugs.
Flurazepam HCl (Dalmane)
7-chloro-1-[2-(diethylamino)ethyl]
-5-(2-fluorophenyl)-1, 3-dihydro-2H1, 4-benzodiazpin-2-one
dihydrochloride.
Et
N
CF3
Et
CH3
. 2HClO
O
N
N
O
N
N
Cl
O2N
N
Cl
N
F
F
Flurazepam
Flunitrazepam
It is water soluble agent and its major
metabolite is N1-dealkyl flurazepam, which
has a very long half-life and persists for
several days.
Flunitrazepam (Rohypenol)
5-(2-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro
-2H-1,4-benzodiazepin-2-one
D) 1,2-Annelated benzodiazepines.
Fused triazolobenzodiazepines
Examples: alprazolam; Xanax
triazolam; Halcion
8-chloro-6-(o-substitutedphenyl)-1methyl-4H-s-triazolo[4,3-a][1,4]
benzodiazepine
H 3C
N
N
N
Cl
N
X
X = H : Alprazolam
X = Cl:Triazolam
They are metabolized by hydroxylation of the methyl group on
the triazolo ring to the methyl alcohol or by 3-hydroxylation of
the benzodiazepine ring. The resulting OH compound is active
but is quickly conjugated and excreted and so, the duration of
action is short.
It is used as a sedative-hypnotic drug and not impair
daytime function.
II) Nonbenzodiazepine agonists at BZR
Imidazopyridines derivatives
They are nonbenzodiazepine compounds
having affinity for BZR and show in vivo activity.
R2
N
O
N
Zolpidem R1 = R2 = R3 = CH3
Alpidem R1 = R2 = Cl, R3 = (CH2)CH3
N
R1
R3
R3
Zolpidem (Ambien)
N,N-Dimethyl-2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide
hemitartrate
It is a hypnotic and a relatively selective positive modulator
at the benzodiazepine binding site. It is a relatively fast in
action and produce no active metabolites.
Alpidem
It was withdrawn from the market following reports of
hepatic dysfunction.
III) GABAA partial allosteric modulators
N
CONH2
N
It offers some advantages over full agonists:
Partial agonists seem to have lesser side
N
F
effects such as sedation and also
Br
less abuse potential.
Imidazenil
It is an imidazobenzodiazepine carboxamide that is more potent
than diazepam.
When it is given with diazepam, it blocks the sedative effects of
diazepam.
IV) Serotonin receptor (5-HT1A) agonists
O
N
. HCl
Buspiron, (Buspar):
N
N
N
O
N
It acts as anxiolytic without causing
sedation.
It acts as a partial agonist of serotonin at 5-HT1A receptor
suppressing serotoninergic activity. It also has
antidopaminergic activity,
Physiochemical properties
Most benzodiazepines have relatively high lipid ⁄ water
partition coefficients and are completely absorbed
from GIT.
The 3-OH polar compounds tend to be slowly
absorbed than nonpolar ones.
The benzodiazepines tend to be highly bound to
plasma proteins; the more nonpolar the drug, the
greater the binding. They are also very effectively
distributed to the brain.
Compounds without 3-OH group have long half-lives
and undergo conversion to the 3-hydroxyl compounds
by hepatic oxidation.
Compounds with 3-OH (oxazepam, lorazepam) are
short-acting because they are rapidly conjugated and
urinary excreted. So, they can be used in elderly or
hepatic patients.
Chronic administration of long-acting
benzodiazepines(chlordiazepoxide,diazepam,
chlorazepate,flurazepam) leads to toxic effects
e.g. excessive sedation. This is due to
accumulation of active metabolite nordazepam
in blood for more than one week after
discontinuation of the drug.
The major factors considered when selecting an
agent include the rate of absorption and
presence or absence of active metabolites.