Sedative-Hypnotic-Anxiolytics:

Benzodiazepines & others

Sedative-hypnotics
Sedative drug:
A drug which produces a calming effect and reduces anxiety,
excitement without inducing sleep or affecting the motor or
mental functions. Sedation is a minimum degree of CNS
depression.

Hypnotic drug:
A drug which produces drowsiness and facilitates onset and
maintenance of sleep which resembles the natural sleep
(patient can easily aroused). Hypnosis is a higher degree of
CNS depression than sedation.

Sedative-hypnotics produce dose-dependent CNS depression,

i.e. increasing the dose leads to a higher degree of CNS
depression.
 Anxiety
Anxiety is an unpleasant state of tension, apprehension, or
uneasiness--a fear that seems to arise from an unknown
source. Disorders involving anxiety are the most common
mental disturbances. The symptoms of severe anxiety are
similar to those of fear (such as, tachycardia, sweating,
trembling, palpitations) and involve sympathetic activation.
Episodes of mild anxiety are common life experiences and do
not warrant treatment. However, the symptoms of severe,
chronic, debilitating anxiety may be treated with antianxiety
drugs (sometimes called anxiolytic or minor tranquilizers).
 BENZODIAZEPINES

Benzodiazepines are the most widely used anxiolytic

drugs. They have largely replaced barbiturates and
meprobamate in the treatment of anxiety, since the
benzodiazepines are more effective and safer.
Approximately 20 benzodiazepine derivatives are
currently available (Alprazolam , Chlordiazepoxlde
,Clonazepam, Clorazepate ,Diazepam , Lorazepam,
Quazepam , oxazepam, Midazolam, Estazolam ,
Flurazepam, Temazepam ,Triazolam).
•
1-Benzodiazepines:

Classification of benzodiazepines:
short acting benzodiazepines:
Triazolam, Oxazepam and midazolam. They
have short t½ (2-4 hours) and metabolized to
active metabolites which have shorter t½ (1-1.5
hours).

Intermediate-acting benzodiazepines:
temazepam, lorazepam and alprazolam. They have
longer t½ (5-20 hours) and can be used once daily.
They have no active metabolites except
alprazolam.
Long-acting benzodiazepines:
Diazepam, clonazepam, flurazepam and
nitrazepam. They have long t½ (about 60
hours). They have active metabolites except
nitrazepam.
 Mode of action
The target for Benzodiazepines actions are the of γ-
aminobutyric acid (GABA). Binding of GABA to its receptor
on the cell membrane triggers an opening of a chloride
channel, which leads to an increase in chloride conductance.
The influx of chloride ions causes a small hyperpolarization
that moves the postsynaptic potential away from its firing
threshold and thus inhibits the formation of action potentials.
 Mode of action
• Benzodiazepines bind to specific, high affinity sites on the
cell membrane, which are separate from but adjacent to the
receptor for GABA. The benzodiazepine receptors are
found only in the central nervous system (CNS), and their
location parallels that of the GABA neurons. The binding of
benzodiazepines enhances the affinity of GABA receptors
for this neurotransmitter, resulting in a more frequent
opening of adjacent chloride channels. This in turn results in
enhanced hyperpolarization and further inhibition of
neuronal firing.
 Actions
The benzodiazepines have no antipsychotic activity, nor any
analgesic action and do not affect the autonomic nervous
system. All of the benzodiazepines exhibit the following
actions to a greater or lesser extent:
1. Reduction of anxiety: At low doses, the benzodiazepines
are anxiolytic. They are thought to reduce anxiety by
selectively inhibiting neuronal circuits in the limbic system
of the brain.
2. 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
•
 Actions
3.Anterograde amnesia: The temporary impairment of
memory with use of benzodiazepines is also mediated by
GABA receptors . this is also impair person’s ability to learn
and form new memories.
4.Anticonvulsant:by acting on the motor cortex.
5.Muscle relaxant: At high doses The benzodiazepines relax
the spasticity of skeletal muscle. Baclofen is an muscle
relaxant that is believed to effect GABA receptors at spinal
cord level.
 Therapeutic uses
The individual benzodiazepines show small differences in
their relative anxiolytic, anticonvulsant, and sedative
properties. However, the duration of action varies widely
among this group, and pharmacokinetic considerations are
often important in choice of drug.
 Therapeutic uses
1.Anxiety disorders: Any benzodiazepine can be used
as sedatives for excitement, aggression, violence.
Alprazolam has higher efficacy in anxiety associated
with panic (phobic) disorders
prazolamhahigr efficacy in anxiety associated with panic
(phobic) disorders.
 Therapeutic uses
2.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.
3.Amnesia: the short acting agent are often employed as
premedication for anxiety provoking and unplaseant procedure
such as bronchoscopic, endoscopic and some dental
procedure.
4. In anaesthesia  IV diazepam for minor surgical
procedures, and in preanaesthetic medication
(midazolam is preferred because it has more rapid
onset and can be used IV or IM).
 Therapeutic uses
5.Seizures: Clonazepam is useful in the chronic treatment of
epilepsy, whereas diazepam is the drug of choice in
terminating status epilepticus.
6.Sleep disorders: Not all of the benzodiazepines are useful as
hypnotic agents. The three most commonly prescribed
benzodiazepines for sleep disorders are long-acting
flurazepam , intermediate acting temazepam and short-acting
triazolam.
 Flurazepam:
• This long-acting benzodiazepine significantly reduces both
sleep-induction time and the number of awakenings, and
increases the duration of sleep. Flurazepam has a long-
acting effect and causes little rebound insomnia. With
continued use, the drug has been shown to maintain its
effectiveness for up to 4 weeks.
 Temazepam:
• This drug is useful in patients who experience frequent
wakening. However, the peak sedative effect occurs two to
three hours after an oral dose, and therefore it may be given
several hours before bedtime.
 Triazolam:
• This benzodiazepine has a relatively short duration of action
and is therefore used to induce sleep in patients with
recurring insomnia.
 Dependence
• Psychological and physical dependence on benzodiazepines
can develop if high doses of the drug are given over a
prolonged period. Abrupt discontinuation of the
benzodiazepines results in withdrawal symptoms, including
confusion, anxiety, agitation, restlessness, insomnia, and
tension. Because of the long half-lives of some of the
benzodiazepines, withdrawal symptoms may not occur until
a number of days after discontinuation of therapy..
 Adverse effects
Drowsiness and confusion: These effects are the two most
common side effects of the benzodiazepines. Cognitive
impairment can occur with use of benzodiazepines.
Precautions: Use benzodiazepines cautiously in treating
patients with liver disease. They potentiate alcohol and
other CNS depressants. Benzodiazepines are, however,
considerably less dangerous than other anxiolytic and
hypnotic drugs. As a result, a drug overdose is seldom
lethal, unless other central depressants, such as alcohol, are
taken concurrently.
 BENZODIAZEPINE ANTAGONIST
Adverse effects

Flumazenil is a GABA receptor antagonist that can rapidly

reverse the effects of benzodiazepines. The drug is available
by IV administration only. Onset is rapid but duration is short,
with a half-life of about one hour. Administration of
flumazenil may precipitate withdrawal in dependent patients
or may cause seizures if a benzodiazepine is used to control
seizure activity. Dizziness, nausea, vomiting, and agitation are
the most common side effects.
•
Advantages of benzodiazepines:
Wide safety margin (minor effect of respiratory and
vasomotor centers).

Lower liability for drug abuse (less addictive).

No effect on hepatic microsomal enzymes and so fewer

drug interactions than barbiturates.

No change in the normal sleep pattern (no depression of

REM sleep).

No hangover effect which means that sedation and

drowsiness persists in the next morning after taking
the hypnotic dose at night.

Flumazenil is a specific antagonist at benzodiazepine

receptor can be used in benzodiazepine overdose.
 OTHER ANXIOLYTIC AGENTS
Buspirone
Buspirone is useful in the treatment of generalized anxiety
disorders and has an efficacy comparable to the
benzodiazepines. The actions of buspirone appear to be
mediated by serotonin (5-HT1A) receptors. Further,
buspirone lacks anticonvulsant and muscle-relaxant
properties of the benzodiazepines and causes only minimal
sedation. Sedation and psychomotor and cognitive
dysfunction are minimal, and dependence is unlikely.
Buspirone has the disadvantage of a slow onset of action.
 OTHER ANXIOLYTIC AGENTS
Hydroxyzine
Hydroxyzine is an antihistamine with antiemetic activity. It
has a low tendency for habituation; thus it is useful for
patients with anxiety, who have a history of drug abuse. It is
also often used for sedation prior to dental procedures or
surgery.
Antidepressant
Many antidepressant have proven efficacy in managing the
long term symptoms of chronic anxiety disorder.
 2-Barbiturates:
Long-acting: Phenobarbital (phenobarbitone) has the
least lipid-solubility, slow GI absorption, slow onset
and long duration of action (6-8 hours).

Intermediate-acting: Amobarbital has moderate lipid-

solubility, moderate GI absorption, moderate onset and
moderate duration of action (4-6 hours).

Short-acting: Pentobarbital have high lipid-solubility,

rapid GI absorption, rapid onset and short duration of
action (2-4 hours).

Ultrashort-acting: Thiopental has very high lipid-

solubility, very rapid onset (within 30 seconds) and
very short duration of action (20-30 minutes).
 BARBITURATES
• Mode of action
The sedative hypnotic effect of barbiturates is due to their
interaction with GABAA receptors, which enhances
GABAergic transmission
 BARBITURATES

Actions
Depression of CNS: At low doses, the barbiturates produce
sedation .At higher doses, the drugs cause hypnosis,
followed by anesthesia and finally coma and death.
 BARBITURATES

Actions
Respiratory depression: Barbiturates suppress the hypoxic
and chemoreceptor response to CO2, and overdosage is
followed by respiratory depression and death.
Enzyme induction: Barbiturates induce P-450 microsomal
enzymes in the liver. Therefore, chronic barbiturate
administration diminishes the action of many drugs that are
dependent on P-450 metabolism to reduce their
concentration.
 BARBITURATES

Therapeutic uses
Anesthesia: Selection of a barbiturate is strongly influenced
by the desired duration of action. The ultra-short-acting
barbiturates, such as thiopental, are used intravenously to
induce anesthesia.
Anticonvulsant: Phenobarbital is used in long-term
management of tonic-clonic seizures, status epilepticus, and
eclampsia. Phenobarbital has been regarded as the drug of
choice for treatment of young children with recurrent febrile
seizures. However, phenobarbital can depress cognitive
performance in children, and the drug should be used
cautiously.
Disadvantages of barbiturates:

Narrow safety margin (overdoses lead to marked

depression of respiratory and vasomotor centers).

High liability for drug abuse (more addictive) with

marked withdrawal symptoms.

Powerful microsomal enzyme inducers leading to

many drug interactions.
They alter normal sleeping pattern (depression of
REM sleep and increase duration of NREM
sleep). After discontinuation, there is rebound
increase in REM sleep and nightmares.

Hangover effect occurs.

No specific antagonist in available. •

 BARBITURATES

Adverse effects
CNS: Barbiturates cause drowsiness, impaired
concentration, and mental and physical sluggishness.
Drug hangover: Hypnotic doses of barbiturates produce a
feeling of tiredness well after the patient awakes. This drug
hangover leads to impaired ability to function normally for
many hours after waking. Occasionally, nausea and
dizziness occur.
 BARBITURATES
Addiction: 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.
•
 Orexin Receptor Antagonists: Sleep-Enabling Drugs

Orexin A and B are peptides found in specific

hypothalamic neurons that are involved in the control
of wakefulness and that are silent during sleep. Orexin
levels increase in the day and decrease at night. Loss
of orexin neurons is associated with narcolepsy, a
disorder characterized by day time sleepiness and
cataplexy. This has prompted the development of a
new class of hypnotic drugs, orexin antagonists, which
include the drugs almorexant and suvorexant.
 Other hypnotic agents
Zolpidem : Although the hypnotic zolpidem is not a
benzodiazepine, it acts on a subset of the benzodiazepine
receptor family. Zolpidem has no anticonvulsant or muscle
relaxing properties. It shows no withdrawal effects, exhibits
minimal rebound insomnia and little or no tolerance occurs
with prolonged use. Zolpidem is rapidly absorbed from the
gastrointestinal tract, and has a rapid onset of action and
short elimination half-life (about 3 hours).
 Other hypnotic agents
Zaleplon: it is very similar to zolpidem
Eszopiclone: it is an oral nonbenzodiazeoine hypnotic and
also used for treating insomnia
Ramelteon and tasimelteon: are selective agonist at the MT1
and MT2 subtypes of melatonin receptor. Ramelteon is
indicated for the treatment of insomniain which falling
asleep is the primary compliant. The potential for abuse of
remelteon is is believed to be minimal and no evidence of
dependence or withdrawal effect has been observed.
Therefore the drug can be administered for long period.
common adverse effect of ramelteon include dizzeness and
fatigue
 Other hypnotic agents
Chloral hydrate: Chloral hydrate is a trichlorinated
derivative of acetaldehyde that is converted to
trichloroethanol in the body. The drug is an effective
sedative and hypnotic that induces sleep in about 30 minutes
and lasts about 6 hours. Chloral hydrate is irritating to the
gastrointestinal tract and causes epigastric distress. It also
produces an unusual, unpleasant taste sensation.
Antihistamines: Antihistamines with sedating properties,
such as diphenhydramine and doxylamine, are effective in
treating mild types of insomnia. However, these drugs are
usually ineffective for all but the milder form of situational
insomnia. Further, they have numerous undesirable side
effects that make them less useful than the benzodiazepines.