ANTI ANXIETY DRUGS

Dr. FALADE Joshua [RN(nig) ,MBBS(nig), MSc(nig) , FMCPsych (nig),Cert in Tobacco

treatment( ontario), EMDAS in view(Italy), PGD in View(nig) MD in view(nig)]
Consultant Psychiatrist/ Addiction Physician/Senior Lecturer
 outline
Introduction
Drug classification
Pharmacodynamics of antianxiolytics
Benzodiazepines
Barbiturate
Azapirone
 INTRODUCTION

Anxiety
• Anxiety is an unpleasant emotional state, associated with
uneasiness (a fear that seems to arise from a unknown source),
discomfort and concern or fear about some defined or
undefined future threat.
• Some degree of anxiety is a part of normal life.

Treatment is needed when it is disproportionate to the
situation and excessive.

Some psychotics and depressed patients also exhibit
pathological anxiety.

The physical symptoms of severe anxiety are similar to
those of fear (such as tachycardia, sweating, trembling, and
palpitations) and involve sympathetic activation.
Physical symptoms of anxiety
 Classes of Anxiolytics

Anxiolytics are drugs that are used for controlling excessive
anxiety.

They differ from anti psychotics, and more closely resemble
sedative-hypnotics.

– No therapeutic effect to control thought disorder of schizophrenia

– Do not produce extrapyramidal side effects

– Have anticonvulsant property

– Produce physical dependence and carry abuse liability
 Classes of Anxiolytics

• Benzodiazepines: Diazepam, Chlordiazepoxide, Oxazepam,

Lorazepam, Alprazolam, Clonazepam, Flurazepam
• Azapirones: Buspirone, Gepirone, Ispapirone
• Sedative: Hydroxyzine
•Barbiturates: Amobarbital, Pentobarbital, Phenobarbital,
Thiopental
 Classes of Anxiolytics
• β blocker: Propranolol
• Antidepressants:
– Selective serotonin reuptake inhibitors (SSRIs):
Fluoxetine, Fluvoxamine, Paroxetine, Escitalopram,
Citalopram, Dapoxetine. (effective in obsessive compulsive
Disorder)
 Classes of Anxiolytics
– Serotonin and noradrenaline reuptake inhibitors (SNRIs):
Venlafaxine, Duloxetine.
• Benzodiazepine Antagonist: Flumazenil
Pharmacodynamics of Benzodiazepines, Barbiturates, &
Newer Hypnotics
Molecular Pharmacology of the GABAA Receptor

The benzodiazepines, the barbiturates, zolpidem, zaleplon,
eszopiclone and many other drugs bind to molecular
components of the GABAA receptor in neuronal membranes in
the CNS.

This receptor, which functions as a chloride ion channel, is
activated by the inhibitory neurotransmitter GABA.
Pharmacodynamics of Benzodiazepines, Barbiturates, &
Newer Hypnotics...

Multiple subunits of several of these classes have been
characterized, eg, six different α, four β, and three γ.

A major isoform of the GABAA receptor that is found in many
regions of the brain consists of two α1 subunits, two β2
subunits, and one γ2 subunit.

In this isoform, the two binding sites for GABA are located
between adjacent α1 and β2 subunits, and the binding pocket
for benzodiazepines (the BZ site of the GABAA receptor) is
between an α1 and the γ2 subunit.
Pharmacodynamics of Benzodiazepines, Barbiturates, &
Newer Hypnotics...

However, GABAA receptors in different areas of the CNS consist of
various combinations of the essential subunits, and the
benzodiazepines bind to many of these, including receptor isoforms
containing α2, α3, and α5 subunits.

Barbiturates also bind to multiple isoforms of the GABAA receptor but
at different sites from those with which benzodiazepines interact.

In contrast to benzodiazepines, zolpidem, zaleplon, and eszopiclone
bind more selectively because these drugs interact only with GABAA-
receptor isoforms that contain α1 subunits.
Pharmacodynamics of Benzodiazepines, Barbiturates, &
Newer Hypnotics...

The heterogeneity of GABAA receptors may constitute the
molecular basis for the varied pharmacologic actions of
benzodiazepines and related drugs.

In contrast to GABA itself, benzodiazepines and other
sedativehypnotics have a low affinity for GABAB receptors,
which are activated by the spasmolytic drug baclofen.
Pharmacodynamics of Benzodiazepines, Barbiturates, &
Newer Hypnotics...
Neuropharmacology

GABA (γ-aminobutyric acid) is a major inhibitory
neurotransmitter in the CNS .

Electrophysiologic studies have shown that
benzodiazepines potentiate GABAergic inhibition at all
levels of the neuraxis, including the spinal cord,
hypothalamus, hippocampus, substantia nigra, cerebellar
cortex, and cerebral cortex.
Pharmacodynamics of Benzodiazepines, Barbiturates, &
Newer Hypnotics...

Benzodiazepines appear to increase the efficiency of
GABAergic synaptic inhibition.

The benzodiazepines do not substitute for GABA but
appear to enhance GABA’s effects allosterically without
directly activating GABAA receptors or opening the
associated chloride channels.
Pharmacodynamics of Benzodiazepines, Barbiturates, &
Newer Hypnotics...

The enhancement in chloride ion conductance induced by
the interaction of benzodiazepines with GABA takes the
form of an increase in the frequency of channel-opening
events.

Barbiturates also facilitate the actions of GABA at multiple
sites in the CNS, but—in contrast to benzodiazepines—they
appear to increase the duration of the GABA-gated chloride
channel openings.
Pharmacodynamics of Benzodiazepines, Barbiturates, &
Newer Hypnotics...

At high concentrations, the barbiturates may also be GABA-
mimetic, directly activating chloride channels.

These effects involve a binding site or sites distinct from the
benzodiazepine binding sites.

Barbiturates are less selective in their actions than
benzodiazepines.

This is because they also depress the actions of the excitatory
neurotransmitter glutamic acid via binding to the AMPA receptor.
Pharmacodynamics of Benzodiazepines, Barbiturates, &
Newer Hypnotics...

Barbiturates also exert nonsynaptic membrane effects in
parallel with their effects on GABA and glutamate
neurotransmission.

This multiplicity of sites of action of barbiturates may be
the basis for their ability to induce full surgical anesthesia
and for their more pronounced central depressant effects
(which result in their low margin of safety) compared with
benzodiazepines and the newer hypnotics
 Benzodiazepines

Benzodiazepines are the most widely used anxiolytic drugs.

They have largely replaced barbiturates in the treatment of
anxiety, because benzodiazepines are safer and more
effective.
Benzodiazepines...
Benzodiazepines...
Benzodiazepines...
 Benzodiazepines...
 Chemical structure of Diazepam
 Benzodiazepines...
• Benzodiazepines act preferentially on midbrain ascending
reticular formation and on limbic system.

They act by enhancing presynaptic/postsynaptic inhibition
through a specific BZD receptor which is an integral part of the
GABAA receptor-Cl- channel complex.
Benzodiazepines...
 Benzodiazepines...

Benzodiazepines modulate GABA effects by binding to a
specific, high-affinity site located at the interface of the α
subunit and the γ2 subunit.

These binding sites are sometimes called benzodiazepine
receptors i.e, BZ1, BZ2.
 Benzodiazepines...

Binding of GABA to its receptor triggers an opening of a
chloride channel, which leads to an increase in chloride
conductance.

Benzodiazepines increase the frequency of channel
openings produced by GABA (influx of chloride ion cause
hyperpolarization).
 Benzodiazepines...
Pharmacological action:
• Reduction of anxiety: At low doses, the benzodiazepines
are anxiolytic.

They are thought to reduce anxiety by selectively enhancing
GABAergic transmission in neurons having the α2 subunit in
their GABAA receptors, thereby inhibiting neuronal circuits in
the limbic system of the brain.
 Benzodiazepines...

Sedative and hypnotic actions: All of the benzodiazepines
used to treat anxiety have some sedative properties.

Some can produce hypnosis (artificially produced sleep) at
higher doses.

Their effects have been shown to be mediated by the α1-
GABAA receptors.
Benzodiazepines...
 Benzodiazepines...

Anterograde amnesia: The temporary impairment of memory
with use of the benzodiazepines is also mediated by the α1-
GABAA receptors.

This also impairs a person’s ability to learn and form new
memories.
 Benzodiazepines...

Anticonvulsant: Several of the benzodiazepines have
anticonvulsant activity and some are used to treat epilepsy
(status epilepticus) and other seizure disorders.

This effect is partially, although not completely, mediated
by α1-GABAA receptors.
 Benzodiazepines...

Muscle relaxant: At high doses, the benzodiazepines relax
the spasticity of skeletal muscle, probably by increasing
presynaptic inhibition in the spinal cord, where the α2-
GABAA receptors are largely located.

Baclofen is a muscle relaxant that is believed to affect
GABA receptors at the level of the spinal cord.
 Benzodiazepines...
Therapeutic uses:
• Benzodiazepines show small differences in their relative anxiolytic,
anticonvulsant, and sedative properties.
• Anxiety disorders: Benzodiazepines are effective for the treatment of
the anxiety symptoms secondary to panic disorder, generalized anxiety
disorder (GAD), social anxiety disorder, performance anxiety,
posttraumatic stress disorder, obsessive-compulsive disorder.

Also effective for the treatment of the extreme anxiety sometimes
encountered with specific phobias such as fear of flying.

Therapeutic uses...:

Muscular disorders: Diazepam is useful in the treatment of

skeletal muscle spasms, such as occur in muscle strain, and
in treating spasticity from degenerative disorders, such as
multiple sclerosis and cerebral palsy.
Therapeutic uses..:
• Amnesia: The shorter-acting agents are often employed as
premedication for anxiety-provoking and unpleasant
procedures such as endoscopic, bronchoscopic, and certain
dental procedures as well as angioplasty.
Therapeutic uses:


Seizures: Clonazepam is occasionally used in the treatment of
certain types of epilepsy, whereas diazepam and lorazepam
are the drugs of choice in terminating grand mal epileptic
seizures and status epilepticus.

Sleep disorders: Not all benzodiazepines are useful as
hypnotic agents, although all have sedative or calming effects.

They tend to decrease the latency to sleep onset and increase
Stage II of non-rapid eye movement (REM) sleep.
Adverse effects:
• Drowsiness, sedation, light-headedness, psychomotor and cognitive
impairment, vertigo, confusional state (especially in the elderly),
increased appetite and weight gain, alterations in sexual function.
• Rashes are uncommon.
• Some women fail to ovulate while on regular use of BZDs.
• The major constraint in their long-term use for anxiety disorders is
their potential to produce dependence.
 Barbiturates

The barbiturates were formerly the mainstay of treatment
to sedate patients or to induce and maintain sleep.

Today, they have been largely replaced by the
benzodiazepines, primarily because barbiturates induce
tolerance and physical dependence and are associated with
very severe withdrawal symptoms.
Barbiturates...
 Barbiturates...

All barbiturates are controlled substances.

Certain barbiturates, such as the very short-acting
thiopental, have been used to induce anesthesia but are
infrequently used today due to the advent of newer agents
with fewer adverse effects.
 Barbiturates...
Mechanism of action

The sedative–hypnotic action of the barbiturates is due to
their interaction with GABAA receptors, which enhances
GABAergic transmission.

The binding site of barbiturates on the GABA receptor is
distinct from that of the benzodiazepines.
Barbiturates...
 Barbiturates...

Barbiturates potentiate GABA action on chloride entry into the
neuron by prolonging the duration of the chloride channel
openings.

In addition, barbiturates can block excitatory glutamate receptors.

Anesthetic concentrations of pentobarbital also block high-
frequency sodium channels.

All of these molecular actions lead to decreased neuronal activity.
 Barbiturates...
Actions

Barbiturates are classified according to their duration of
action.

For example, ultra–short-acting thiopental acts within
seconds and has a duration of action of about 30 minutes.

In contrast, long-acting phenobarbital has a duration of
action greater than a day.
 Barbiturates...
Actions

Pentobarbital, secobarbital, amobarbital, and butalbital
are short-acting barbiturates.
 Barbiturates...
Actions

1. Depression of CNS: At low doses, the barbiturates produce
sedation (have a calming effect and reduce excitement).

At higher doses, the drugs cause hypnosis, followed by
anesthesia (loss of feeling or sensation), and, finally, coma and
death.

Thus, any degree of depression of the CNS is possible,
depending on the dose.
 Barbiturates...

Barbiturates do not raise the pain threshold and have no
analgesic properties.

They may even exacerbate pain. Chronic use leads to
tolerance.
2. Respiratory depression: Barbiturates suppress the hypoxic
and chemoreceptor response to CO2, and overdosage is
followed by respiratory depression and death.
 Barbiturates...

Therapeutic uses
1. Anesthesia: The ultra–short-acting barbiturates, such as
thiopental, have been used intravenously to induce
anesthesia but have largely been replaced by other agents.
2. Anticonvulsant: Phenobarbital has specific anticonvulsant
activity that is distinguished from the nonspecific CNS
depression.
 Barbiturates...

It is used in long-term management of tonic–clonic
seizures.

However, phenobarbital can depress cognitive
development in children and decrease cognitive
performance in adults, and it should be used only if other
therapies have failed.

Similarly, phenobarbital may be used for the treatment of
refractory status epilepticus.
 Barbiturates...
3. Sedative/hypnotic: Barbiturates have been used as mild
sedatives to relieve anxiety, nervous tension, and insomnia.

When used as hypnotics, they suppress REM sleep more
than other stages.

However, the use of barbiturates for insomnia is no longer
generally accepted, given their adverse effects and
potential for tolerance.
 Barbiturates...

Butalbital is commonly used in combination products (with
acetaminophen and caffeine or aspirin and caffeine) as a
sedative to assist in the management of tension-type or
migraine headaches.
 Barbiturates...
Pharmacokinetics

Barbiturates are well absorbed after oral administration
and distribute throughout the body.

All barbiturates redistribute from the brain to the
splanchnic areas, to skeletal muscle, and, finally, to adipose
tissue.
 Barbiturates...

This movement is important in causing the short duration
of action of thiopental and similar short-acting derivatives.

Barbiturates readily cross the placenta and can depress the
fetus. These agents are metabolized in the liver, and
inactive metabolites are excreted in urine.
 Barbiturates...
Adverse effects

Barbiturates cause drowsiness, impaired concentration,
and mental and physical sluggishness.

The CNS depressant effects of barbiturates synergize with
those of ethanol.
Barbiturates...
 Barbiturates...
Adverse effects…

Hypnotic doses of barbiturates produce a drug “hangover”
that may lead to impaired ability to function normally for
many hours after waking.

Occasionally, nausea and dizziness occur.

Barbiturates induce cytochrome P450 (CYP450) microsomal
enzymes in the liver.
 Barbiturates...
Adverse effects...

Therefore, chronic barbiturate administration diminishes
the action of many

drugs that are metabolized by the CYP450 system.

Barbiturates are contraindicated in patients with acute
intermittent porphyria.
 Barbiturates...
Adverse effects...

Abrupt withdrawal from barbiturates may cause tremors,
anxiety, weakness, restlessness, nausea and vomiting,
seizures, delirium, and cardiac arrest.

Withdrawal is much more severe than that associated with
opiates and can result in death.

Death may also result from overdose.
 Barbiturates...
Adverse effects...

Severe depression of respiration is coupled with central
cardiovascular depression and results in a shock-like
condition with shallow, infrequent breathing.

Treatment includes supportive care and gastric
decontamination for recent ingestions.
 Benzodiazepine antagonist
• Flumazenil is a GABA-receptor antagonist that can rapidly
reverse the effects of benzodiazepines.
• The drug is available for intravenous (IV) administration only.

Onset is rapid, but duration is short, with a half life of about 1
hour.

Frequent administration may be necessary to maintain reversal
of a long-acting benzodiazepine.
 Benzodiazepine antagonist...

Administration of flumazenil may precipitate withdrawal in
dependent patients or cause seizures if a benzodiazepine is
used to control seizure activity.
 Azapirone
Buspirone
• It is the first azapirone, a new class of antianxiety drugs, definitely
different from BZDs.

Does not produce significant sedation or cognitive/ functional
impairment.

Does not interact with BZD receptor or modify GABAergic transmission.

Does not produce tolerance or physical dependence.

Does not suppress BZD or barbiturate withdrawal syndrome.
 Azapirone...
 Chemical structure(Buspirone)
 Azapirone...

Buspirone is useful for the chronic treatment of
Generalized Anxiety Disorder (GAD).

It has an efficacy comparable to that of the
benzodiazepines.
 Azapirone...
Buspirone- MOA
• The mechanism of anxiolytic action is not clearly known, but may
be dependent on its selective partial agonistic action on 5-HT1A
receptors.

By stimulating presynaptic 5-HT1A autoreceptors, it reduces the
activity of dorsal raphe serotonergic neurones.

Antagonism at certain postsynaptic 3-HT1A receptors has also
been demonstrated.
 Azapirone...

Buspirone has week dopamine D2 blocking action with no
antipsychotic or extrapyramidal effects.

Mood elevation may be facilitated by central noradrenergic
action.
 Azapirone...
Pharmacokinetics:
– Rapidly absorbed
– Undergoes first pass metabolism
– Metabolite is active and excreted through both urine and faeces.
– t1/2 is 2-3.5 hr; Buspirone has the disadvantage of a slow onset of
action.
 Azapirone...
Side effects: Side effects are minor:

dizziness, nausea, headache, light-headedness and rarely
excitement.

May increase the BP in patients with MAO inhibitors.

Dose: 5-15 mg
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