Anxiolytic drugs

Tranquilizers or anxiolytics
are used for treatment of
neurotic conditions with
expressed anxiety, fear,
excitement etc.
Anxiety, which arises as an
answer to not certain
situation, is a protective
reaction and mobilizes the
resources of organism for
overcoming antisocial
behavior and for preparation
to future . When anxiety is
too much expressed
compared to the reason, or
there is no reason for anxiety,
it is diagnosed as a
Pathological anxiety can
deteriorate patient
normal activity leading
to somatic disease. In
persons with
pathological anxiety the
activity of GABA-ergic
inhibiting system of
prefrontal cortex is
decreased, also the
quantity of
benzodiazepine
receptors is reduced.
Tranquilizers remove
disbalance between
the mechanisms of
psychical adaptation,
as a result agitation,
alarm, anxiety, fear,
aggression are
removed. In addition,
tranquilizers promote
stability to stress,
improve adaptation in
extreme situations.
 Classification of anxiolytic drugs
1. Agonists of benzodiazepine receptors or
benzodiazepines
Diazepam Fenazepam
 2. Serotonine receptor agonists

Buspirone
 4. Drugs with the different
3. Barbiturates action mechanism (Zolpidem,
Meprobamate)
 Benzodiazepines
 BDZ are selective agonists of
BDZ receptors. BDZ receptors
are associated with GABAА
receptors.
 GABA-А receptors are hetero-
oligomer glycoproteins (200-
400 kDA), contain 3
substructures (α, β, γ), each of
them can be in 3 isoforms. Also
other substructures were
found- δ, ε, ρ. In various
regions of CNS receptors can
have different structure and
different interaction with
pointed substructures of
GABA.
 GABA by interaction with the
modulating receptor area, results
in opening of chlorine channels,
strengthening of chlorine ions
inflow into the cell, in a result of
which hyperpolarization is
developed. Hyperpolarization
inhibits neurotransmission and
neuronal cell activity. BDZ
binding toBDZ part of GABA-А
receptor complex, by allosteric
mechanism open chlorine
channels.
 BDZ increase GABA affinity
toward their receptors. BDZ
increase frequency of opening
chlorine channels in a presence of
GABA. BDZ increase force of
 BDZ have the following effects.

 Anxiolytic
 Sedative
 Myorelaxant
 Anticonvulsant
 Amnestic (amnesia-loss of
memory)
 Anxiolytic effect
 Anxiolytic effect is stipulated
by the action of frontal
cortex, limbic system GABA
receptors. These CNS parts
are responsible for regulation
of emotion al behavior.

Sedative action
 Sedative action is stipulated by decrease of attention, decrease of
thought and motor reactions, somnolence, weakness. It is conditioned
by strengthening of GABA mediated inhibiting action in the regions of
thalamus and reticular formation, BDZ, by decreasing emotional
tension, lead to hypnotic effect, shorten time of latent period of the
sleep, increase general duration and depth of sleep.
Usually, majority of hypnotic drugs shorten the stage of
rapid sleep, but for BDZ this action is comparatively less.
BDZ diminish the proportion of slow sleep; the secretion
of growth hormone is not disturbed although. Long-
term usage of BDZ as hypnotic agents is undesirable as
tolerance and dependence can develop to them.
Some BDZ have activating effect, leading to increase in
mood, improving memory. These anxiolytics, which
have activating component and less sedative, hypnotic,
anticonvulsant and myorelaxant effects are called “daily
tranquilizers”. These are Mezapam and Tofizopam.
 Muscle relaxant action
 Muscle relaxant action is
stipulated by the central action.
Benzodiazepines diminish tone,
contraction force of skeletal
muscles and volume of active
movements. This action is
conditioned by potentiating of
GABA mediated inhibition in the
spinal cord and removal of the
activating influencing of reticular
formationon the spinal cord. The
myorelaxant effect isn`t
accompanied by the changes in
coordination.
 Antiseizure action
 Antiseizure action is
conditioned by potentiation
of GABA mediated inhibition
in hippocampus, spinal cord,
cerebellum. Clonazepam has
selective anticonvulsant
effect, is used in epilepsy.
 Anterograde amnesia
 BDZ cause anterograde
amnesia – impossibility to
remember actions during the
administration of
preparation.
 By duration of action we differ
Long acting BDZ (T1/2 = 24-48 hours and more)

Diazepam, Chlordiazepoxide, Flurazepam

 Middle acting BDZ (T1/2 = 6-24 hours)
Oxazepam, Lorazepam, Alprazolam
 Short acting BDZ (T 1/2< 6 hours)

Midazolam, Triazolam
 Pharmacokinetics of BDZ
At enteral rout of administration absorbtion is very good.
Their maximal plasma concentration reaches after 1 hour.
They have high affinity to plasma proteins and due to
lipophylicy can be accumulated in adipose tissues.
All BDZ are metabolized and excreted by urine as a
glucoronide conjugates or oxidates. They differ by their
duration of action.
Some representatives are transformed into active metabolites,
N-dezmethyldiazepam (Nordiazepam). Its` T1/2 is 60 hours
and has ability to accumulate in body leading to “abstinent
syndrome”. Short-acting BDZ are conjugated with glucuronic
acid and is excreted from body.
Because BDZ have big role in BDZ biotrasformation, in elder
patients, children, or patients with liver diseases they can have
longer duration of action.
 Uses of BDZ
Anxiolytics for treatment of
chronic, heavy anxiety Hypnotic drugs
conditions
Antiepileptic drugs: Myorelaxants during physical
diazepam, clonazepam trauma, neurodegenerative
diseases accompanied by
muscle cramps
General anesthetic drugs in
a combination with main
anaesthetic drugs for
premedication
Sedative drugs during procedures,
which are accompanied with
short, nondesirable and acute
pains (endoscopy etc.)
In diseases accompanied
with affective disorders
such as angina pectoris,
myocardial infarction,
hypertension, peptic ulcer,
bronchial asthma etc.
 Side effects of BDZ
A-type side effects
 somnolence,
 inhibition of thought and
motions,
 violation of coordination,
 loss of memory,
 muscle weakness
 BDZ potentiate the action of
CNS inhibitors (alcohol,
sedative and hypnotic drugs).
 Most of BDZ have teratogenic
effect and contraindicated in
pregnancy.
 Tolerance and dependence.
 Almost all BDZ lead to tolerance.
 BDZ don`t induce euphoria, but
long-term usage leads to
dependence.
 If patient interrupt drug
administration suddenly, it leads
to expressed
 anxiety,
 tremor,
 dizziness,
 nervousness,
 loss of appetite, sometimes`
convulsions.
• Short-term BDZ frequently lead to
abstinent syndrome.
 Toxicity during overdosage

 BDZ comparing to the other

sedative-hypnotic drugs are less
dangerous, but these drugs are
frequently used to commit
suicide. During overdosage long-
term sleep without disturbances
of respiratory and cardio-vascular
systems can be noticed. In a
combination with CNS
inhibitors, especially with
alcohol, heavy, life-threating
inhibition of respiratory center
can be noticed.
 Endogenous BDZ substances

 From brain tissue is extracted

endogenous substance
Diazepam-binding-inhibitor
(DBI), which binding to BDZ
site of GABA receptors, leads
to opposite action of BDZ.
This substance has
anxiogenic ancconvulsant
effects.
 Action mechanism
Barbiturates
 Strengthen GABA mediated
inhibiting effect by allosteric or
partially by direct inhibitory
effect.Barbiturates bind with
barbiturate part of GABA
receptor complex,resulting in
opening of chlorine channels by
allosteric mechanism. They
particularly lengthen duration of
opening of chlorine channels and
quantity of influx Cl ions. In high
doses barbiturates possess ability
independently to open chlorine
channels, thus having intrinsic
sympathomimetic activity toward
 diminish the
processes of
excitation because
neutralize an action
of stimulating
amino acid,
particularly
glutamate, because
they block also
AMPA receptors,
resulting in
weakening of
depolarization and
neuronal excitation.
 In higher dosage
block Na + channels
and inhibit
neurotransmission.
 Effects of barbiturates
 On the CNS barbiturates have
dose-dependent action: sedation
hypnotic effect anethesia coma
 They have anticonvulsant action
 Muscle relaxant action is more
expressed at high doses, causing
anaesthesia and it is related to
strengthening of GABA-ergic
inhibition in area of spinal cord,
reticular formation
 Respiratory system: Inhibition of respiratory center (high doses)
 CVS: Decline of arterial pressure due to (-) inotropiceffect (because of
depressionof cardio-vascularcenter and ganglion blockingaction).
Reflex tachycardia is possible
 Urogenital system: oliguria, due to increase of ADH secretion.
 Liver: Under the influence of barbiturates the microsomal enzymes
of liver are exposed to induction (are activated), and as a result the
metabolism of many preparations, taken simultaneously with
barbiturates, and also barbiturates is accelerated.

Drugs have low therapeutic index. Barbiturates are used as general

anesthetic and antiepileptic drugs. Their usage as anxiolytic and
hypnotic drugs is not recommended, because they disturb the rapid
stage of sleep.
 Pentobarbitale (Nembutal) Phenobarbitale
 has sedative, hypnotic effect,  has strong antiepileptic and
has 6-12 hours duration of minimal sedative effect, is
action and is used as general mainly used as antiepileptic
anesthetic. In some countries drug
is used to maintain drug
coma during brain ischemia,
Thiopental is widely used as
as well as for efthanasia and
i/v injections for general
for death-sentence.
anesthesia.
Antiepileptic action is less
expressed.
 Side effects
 Barbiturates are activators of
liver metabolic enzymes,
particularly are strong
stimulators of cytochrome
P450 system, that`s why can
precipitate different
undesirable effects during
combined drug usage.
 The side effects are also
tolerance and physical
dependence.
 GABA - ergic substances
 There are also endogenous
benzodiazepine substances –
agonists of benzodiazepine
receptors, and also not
benzodiazepine molecules, having
affinityand internal
activitytowardsbenzodiazepine
receptors. These endozepines also
increase GABA mediated
permeability of chlorine channels.
 From the brain tissue also was taken
Diazepam-binding inhibitor (DBI),
which binds to GABA receptors BDZ
site leading to opposite effect. This
substance has anxiogenic and
convulsant effect.
 It is supposed that endozepins and
DBI substances have role in the
different anxiogenic effects
 Inverse agonists of benzodiazepine
receptors
 Inverse agonists of
benzodiazepine receptors
(substances that have affinity to
BDZ receptors, contacting with
them, cause an opposite
benzodiazepine effect) are β-
carbolines. Binding with BDZ
receptors, they lead to
anxiogenic effect – cause an
alarm, anxiety, cramps. Such
phenomenon is possible to
explain by the special structure
of benzodiazepine receptor area.
 It is assumed that it can exist in two
conformations A and В. Conformation A
results in activating of GABA mediated
current of chlorine ions, hyperpolarization
and inhibition, conformation B–vice versa,
unable to activate the action of GABA. In
normal conditions equilibrium between
these two conformations is present. BDZ
bind to conformation A, move an equilibrium
toward this conformation and facilitate the
action of GABA. Inverse agonists bind to
conformation B and render an opposite
effect.
 The competitive antagonist Flumazenil
binds with both conformations, sodoes not
disturb conformationequilibrium, but blocks
the effects of both substances -BDZ and
inverse agonists. During intoxication by BDZ,
antagonists of BDZ receptors- Flumazenil is
used, which displaces BDZ and recover
normal activity of receptors.
 Buspirone
 Buspirone and the same drugs
(Ipraspirone, Gepirone) are
partial agonists of 5-НТ1А
serotonine receptors. Are used in
different anxious states, but are
not effective in panic states. Is
considered to be daily-
tranquilizer.
 Activating presynaptic5-НТ1А
receptors diminishes release of
serotonine and other mediators,
resultingin anxiolytic effect.
 Inhibits adrenergic locus
coeruleus and weakens
“wakening reaction”. The
anxiolytic effect of Buspirone is
developed slowly.
 Side effects
Buspirone possesses less and
mild side effects, than BDZ.
They are expressed by
 dizziness,
 nausea,
 headache,
 anxiety.
 Buspirone doesn`t have
sedative effect and
disturbances in coordination.
 Other drugs
Hydroxizine hydrochloride (atarax)
 is diphenylmethane derivative.
Has expressed sedative and
moderate anxiolytic activity,
which is due to blockade of H1
receptors in subcortical
structure. Hydroxizine has also
cholinolytic, spasmolytic,
antihistamine and
antipsychotic effects. Is
administered for the treatment
of anxiety, psychomotor
excitation, premedication, as
sedative and antiprurital drug.
 β-adrenoblockers
 Some drugs of this group
(propranolol) is used for the
treatment of anxiety and
some forms of panic states,
which are accompanied with
sweating, muscle tremor and
tachycardia.