Dr. S. Parasuraman M.Pharm., Ph.D.,
Senior Lecturer, Faculty of Pharmacy,
Bedong 08100, Malaysia.
• Anxiety It is an emotional state, unpleasant in
nature, 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
• Some psychotics and depressed patients also exhibit
• The physical symptoms of severe anxiety are similar to those
of fear (such as tachycardia, sweating, trembling, and
palpitations) and involve sympathetic activation.
• The anxiolytic-sedative drugs 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
Benzodiazepines (BZDs) Agonist at an
allosteric site prolong GABA action
open chloride channel
Benzodiazepines are the most widely used anxiolytic drugs.
They have largely replaced barbiturates in the treatment of
anxiety, because benzodiazepines are safer and more
• Benzodiazepines act preferentially on midbrain ascending
reticular formation and on limbic system. BZDs act by
enhancing presynaptic/postsynaptic inhibition through a
specific BZD receptor which is an integral part of the GABAA
receptor-Cl- channel complex (GABA receptor has five or
more span the postsynaptic membrane).
• Benzodiazepines modulate GABA effects by binding to a
specific, high-affinity site located at the interface of the α
subunit and the γ2 subunit [[Note: These binding site
sometimes called as benzodiazepine receptors i.e, BZ1, BZ2].
• 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
• 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.
• Sedative and hypnotic actions: All of the benzodiazepines
used to treat anxiety have some sedative properties, and
some can produce hypnosis (artificially produced sleep) at
higher doses. Their effects have been shown to be mediated
by the α1-GABAA receptors.
• 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.
• 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
• 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 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, and the extreme
anxiety sometimes encountered with specific phobias such
as fear of flying.
• 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.
• 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.
• 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.
• 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.
• 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.
• Administration of flumazenil may precipitate withdrawal in
dependent patients or cause seizures if a benzodiazepine is
used to control seizure activity.
Drugs Pharmacological properties
Chlordiazepoxide • First BZD to be used clinically.
• Oral absorption is slow.
• Produces a smooth long lasting effect
• Preferred in chronic anxiety states
• Its t1/2 is 5-15 hours but active metabolites are produced
which extend the duration of action.
• It has poor anticonvulsant action.
• Dose: 25-100 mg.
Diazepam • It is quickly absorbed
• t1/2 is 1 hour; elimination phase t1/2 is 20-30
• It is preferred in acute panic states and anxiety associated
with organic disease.
• Dose: 5-30 mg
Oxazepam • It is slowly absorbed
• t1/2 is 10 hours
• Directly conjugated with glucuronic acid and eliminated
• Used mainly in short lasting anxiety states
• Dose: 30-60 mg
Drugs Pharmacological properties
Lorazepam • Slow oral absorbed, less lipid soluble than
• t1/2 is 10-20 hours
• Directly conjugated with glucuronic acid and
• Quite sedative and capable of producing marked
• Dose: 1-6 mg
Alprazolam • High potency anxiolytic BZD which in addition has
some mood elevating action in mild depression.
• Also used as hypnotic
• Dose: 0.25- 1.0 mg
• It is the first azapirone, a new class of antianxiety drugs,
definitely different from BZDs.
– Does not produce significant sedation or cognitive/ functional
– Does not interact with BZD receptor or modify GABAergic
– Does not produce tolerance or physical dependence.
– Does not suppress BZD or barbiturate withdrawal syndrome.
• Buspirone is useful for the chronic treatment of Generalized
Anxiety Disorder (GAD) and has an efficacy comparable to
that of the benzodiazepines.
• 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.
• Buspirone has week dopamine D2 blocking action with no
antipsychotic or extrapyramidal effects.
• Mood elevation may be facilitated by central noradrenergic
– 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
– 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
Beta Blockers (adjuvant to BZDs)
• Many symptoms of anxiety (palpitation, rise in
BP, shaking, tremor, gastrointestinal hurrying, etc.) are due
to sympathetic over activity, and these symptoms reinforce
• Propranolol and other nonselective beta blockers help
• patients troubled by these symptoms, by cutting the vicious
cycle and provide symptomatic relief. They do not affect
psychological symptoms such as worry, tension and fear, but
are valuable in acutely stressful situations (examination
fear, unaccustomed public appearance, etc.).