1.
Sedative, Hypnotic and
Anxiolytic Drugs
Prof. Amol B. Deore
Department of Pharmacology
MVP’s Institute of Pharmaceutical Sciences, Nashik

2.
Sedative, Hypnotic and Anxiolytic Drugs
Drugs that cause sedation and at the same time relieve anxiety
(anxiolytics) or can induce sleep.
They are used primarily to treat anxiety and insomnia.
In general, these drugs will induce sleep when given ill high doses at
night and will provide sedation and reduce anxiety then given in low
divided doses during the day.

3.
Sleep disorders
• Insomnia
• Hyposomnia
• Parasomnia
• Snoring
• Sleep apnea
• Narcolepsy

4.
SLEEP
Sleep is a naturally periodic state of mind
and body, characterized by altered
consciousness,
SLEEP CYCLE
REM stands for rapid eye movement. During
REM sleep, your eyes move quickly in
different directions. That doesn't happen
during NREM sleep. First comes NREM
sleep, followed by a shorter period of REM
sleep, and then the cycle starts over again.
Dreams typically happen during REM sleep.

5.
NREM Sleep Pattern

6.
Sedative
Sedative is a drug
that produces a
calming effect and
reduces excitement.
It may induce
drowsiness without
inducing sleep.

7.
Insomnia
Insomnia is a sleep disorder in
which you have trouble falling
and/or staying asleep.
Acute insomnia lasts from 1 night
to a few weeks. Insomnia is
chronic when it happens at least 3
nights a week for 3 months or
more.

8.
Hypnotic
Hypnotic is a drug that induces sleep resembling natural sleep.
Both sedation and hypnosis may be considered as different grades of
CNS depression.

9.
Anxiety
Anxiety is an unpleasant state of
tension, apprehension, or uneasiness
(a fear that arises from either a
known or an unknown source).
The physical symptoms of severe
anxiety are similar to those of fear
(such as tachycardia, sweating,
trembling, and palpitations) and
involve sympathetic activation.

10.
Anxiolytics
This are the medicines which are
used to relive the stress, tension,
anxiety generated by complex and
hectic modern daily life.
Because many antianxiety drugs
also cause some sedation, they
may be used clinically as both
anxiolytic and hypnotic (sleep
inducing) agents.

11.
Classification
Benzodiazepines (BDZ)
• Long acting benzodiazepines
• Ex. Diazepam, Flurazepam,
Clonazepam, Prazepam
• Intermediate acting
benzodiazepines
• Ex. Nitrazepam,
Lorazepam, Oxazepam,
Temazepam, Medazepam
• Short acting benzodiazepines
• Ex. Alprazolam, Triazolam,
Oxazolam, Estazolam,
Midazolam
Barbiturates
• Long acting Barbiturates
• Ex. Phenobarbital,
Mephobarbital,
Metharbital.
• Intermediate acting
Barbiturates
• Ex. Amobarbital,
Apobarbital, Butabarbital.
• Short acting Barbiturates
• Ex. Pentobarbital,
Secobarbital
• Ultra short acting
Barbiturates:
• Ex. Methohexital,
Thiomylol, Thiopental.
Newer Non-Benzodiazepine
Hypnotics
• Ex. Zolpidem, Zopiclone,
Eszopiclone, Zaleplon,
Buspirone, Doxepin.

12.
Benzodiazepines BDZ

13.
Mechanism of action of Benzodiazepines
GABA, the most potent inhibitory transmitter in the CNS controls the state of
neuronal excitability.
It acts by binding to the neuronal GABA receptor and opens the chloride
channels.

14.
The site of action of benzodiazepines in the CNS appears to
be limbic system, thalamus and reticular activating system
(which maintains consciousness, sleep, and alertness).
Benzodiazepines act by potentiating the action of
neurotransmitter GABA (gama amino butyric acid).

15.
BDZ bind selectively to subunits of the GABA receptors, a site distinct from that of
GABA or barbiturates binding site, and is designated as benzodiazepine binding site.
Thus, they increase the frequency of chloride channel opening and the chloride ion
concentration in the neuron.
This causes hyperpolarisation of the neuronal membrane, making it more difficult for
the excitatory neurotransmitters to depolarise the cell.
so neuronal transmission in brain and spinal cord decreases.

16.
C E L L M E M B R A N E
Mechanism of Benzodiazepine
BDZ receptorGABA receptor
Chloride ion channel
GABA
Benzodiazepine
Hyperpolarization
Chloride ions
Chloride ions

17.
Pharmacological actions of Benzodiazepine

18.
• In smaller dose, BDZ cause sedation
and relief of anxiety.
• In higher dose, BDZ induce sleep
(hypnosis).
• They shorten the time spent in stage
4 of NREM and REM but increase
total sleep time.
• Sleep produced by them is more
refreshing and with less hangover
symptoms.
Sedative
hypnotic effect
• The BDZ exert a specific effect on
limbic system and therefore reduce
anxiety and thus produce a calming
effect without affecting sleep.
• Alprazolam has additional
antidepressant properties.
Antianxiety
effect

19.
• The long acting BDZ
Clonazepam produce
anticonvulsant effect by raising
the seizure threshold in the
limbic system by potentiating
GABA action
• lorazepam and diazepam
prevent the spread of seizure in
the brain.
Anticonvulsant
effect:
• The BDZ produce relaxation of
skeletal muscle by facilitating
GABA-nergic transmission in the
brainstem and spinal cord.
• Hence they used in acute spasm
of skeletal muscles caused by
trauma or inflammation and
muscular rigidity.
Skeletal muscle
relaxants:

20.
• Midazolam and diazepam are
used for preanesthetic
medications (given IM) and for
induction of general anesthesia
(given IV).
• This action is produce by
potentiation of GABA nergic
neurotransmission.
Anesthetic
action
• BZDs produce anterograde
amnesia, i.e. loss of memory for
the events happening after the
administration of BZDs.
• This property is an advantage
when BZDs are used in surgical
procedures as the patient does
not remember the unpleasant
events.
Amnesia

21.
Benzodiazepine indications

22.
Therapeutic uses of BDZ
Anxiety disorders
• Panic disorder, generalized anxiety disorder (GAD),
• Social anxiety disorder, performance anxiety,
• Posttraumatic stress disorder, obsessive–compulsive disorder,
• Extreme anxiety associated with phobias, such as fear of flying.
Sleep disorders
• Hypnotic agents,
• In the treatment of insomnia
Amnesia
• Premedication for anxiety-provoking and unpleasant procedures such as endoscopy,
dental procedures, and angioplasty

23.
Seizures
• types of seizures,
• status epilepticus,
• treatment of alcohol withdrawal and reduce the risk of
withdrawal-related seizures
Muscular disorders
• Skeletal muscle spasms,
• degenerative disorders, such as multiple sclerosis and cerebral
palsy.
Therapeutic uses of BDZ

24.
Adverse drug reaction of BDZ
Tolerance and dependence
• Both tolerance and dependence
liability are less with BZDs as
compared to barbiturates.
Central nervous system
• Confusion, disorientation, agitation,
slurred speech, headache, vertigo,
depression, vivid dreams,
hallucinations and tremors.
Gastrointestinal system
• Constipation, anorexia,
Urinary system
• Urinary incontinence, urinary
retention
Cardiovascular system
• Bradycardia, hypotension,
palpitation
Hematologic
• Agranulocytosis, neutropenia

25.
BARBITURATES

26.
Mechanism of action of barbiturates
Barbiturates depress the sensory and motor activity in the
cerebral cortex.
Barbiturates also act on the “reticular activating system” and
elevate firing threshold and depress the firing rate of neurons.
Barbiturates potentiate GABA action on chloride entry into the
neuron by prolonging the duration of the chloride channel
openings.

27.
Barbiturate bind selectively to subunits of the GABA receptors, a site distinct from
that of GABA or BDZ binding site, and is designated as Barbiturate binding site.
The sedative–hypnotic action of the barbiturates is due to their interaction with
GABAA receptors, which potentiate GABAergic transmission.
Barbiturates potentiate GABA action on chloride entry into the neuron by
prolonging the duration of the chloride channel openings.
This causes hyperpolarisation of the neuronal membrane, making it more difficult
for the excitatory neurotransmitters to depolarise the cell.
In this way, CNS depresses and patient sleeps

28.
C E L L M E M B R A N E
Mechanism of Barbiturates
BDZ receptor
GABA receptor
Chloride ion channel
GABA
Hyperpolarization of neuron
and decreased CNS activity. i.e.
CNS depression
Chloride ions
Chloride ions
Barbiturate receptor
Barbiturate

29.
Key Feature
Benzodiazepines,
increase the
frequency of
chloride channel
opening and the
chloride ion
concentration in
the neuron.
Barbiturates,
increase the
duration of
chloride channel
opening and the
chloride ion
concentration in
the neuron.

30.
Pharmacological actions of Barbiturates

31.
Sedation
• In low doses barbiturates show drowsiness and calmness and a sense well-being
(euphoria).
• This sedation is due to depression of reticular activating system (RAS) in the brain.
Hypnosis:
• They induce sleep in a dose 3 to 4 times higher than the sedative dose.
• A barbiturates show relief from insomnia by inducing stage 2 of the NREM sleep.
General anesthesia:
• Ultra short acting barbiturates (methohexital, thiopental) are administered IV for
induction of general anesthesia.
• They produce reversible loss of consciousness by blocking the impulse generation
and transmission from reticular activity system.

32.
Anticonvulsant action:
• The Long acting Barbiturates (phenobarbital, mephobarbital) showing
anticonvulsant action by blocking the excess neuronal firing.
• They are indicated in the therapy of grand mal epilepsy and cortical focal seizure.
Respiratory depression:
• Barbiturates in large doses show respiratory depression by depressing respiratory
center in medulla oblongata.
Enzyme induction:
• Barbiturate especially phenobarbital can increase functioning of hepatic
microsomal enzyme activity. This process is called enzyme induction.
• This results in increase in the metabolism and hence decreased effectiveness of
many drugs.

33.
Therapeutic use of Barbiturates

34.
Adverse Drug Reaction
• Due to residual depression of the CNS may
be accompanied by headache, nausea,
vomiting, vertigo and diarrhea, distortions
of mood, impaired judgement etc.
Hangover:
• Barbiturates, if administered to a woman
during labour, may depress the fetal
respiration.
Depression
of fetal
respiration:

35.
• When a barbiturate is employed as a hypnotic, because
of confusion and amnesia, a patient may repeatedly take
the barbiturate at night and poison himself.
Drug
automatism:
• Repeated administration of barbiturates causes
tolerance to their sedative and hypnotic actions.Tolerance:
• Repeated ingestion of barbiturates causes drug
dependence.
Drug
dependence:
• Urticaria, angioneurotic edema, agranulocytosis and
thrombocytopenic purpura.
Allergic
reactions:

36.
Acute Barbiturate Poisoning
Causes
• Used as sleeping pills for suicidal attempt.
• Drug automatism (memory loss)
Symptoms
• CNS depression, particularly the respiratory
depression, and a peripheral circulatory collapse.
• The frequent and often fatal complications are
atelectasis, pulmonary edema and pneumonia.
• wheezing, hypotension, hypopyrexia, salivation,
coma, and death may occur.

37.
Management of Barbiturate Poisoning
Hospitalization
Gastric lavage
Adequate
tissue
oxygenation
Forced
diuresis
Intravenous
fluids
Alkalinisation
of the urine
Prophylactic
antibiotics

38.
Gastric lavage
If the patient is conscious and less than
four hours have elapsed since ingestion,
vomiting may be induced with syrup of
ipecac or concentrated salt solution.
In comatose patients, endotracheal
intubation should precede gastric
intubation to prevent aspiration.

39.
Adequate tissue oxygenation
If the respiration is not much affected,
oxygen can be given by a nasal catheter.
Endotracheal intubation is performed when
spontaneous respiration is inadequate and
also to remove secretions.
If assisted ventilation is required for more
than 24 hours, tracheostomy is usually
performed.

40.
Forced diuresis
Mannitol, an osmotic diuretic, is given IV,
initially in the dose of 100-120 ml of 25%
solution.
Subsequently, a sustained infusion of 5%
mannitol alternately in normal saline and a
litre of 5% dextrose is administered.
Alternatively, furosemide is used in the
dose of 20 mg along with 500 ml of 1.2%
sodium bicarbonate and one litre of 5%
dextrose IV.

41.
Intravenous fluids
Fluids must be given in sufficient
quantity as an adjuvant to forced
diuresis, in order to prevent dehydration
and for maintaining the blood volume.
Normal saline with dextrose is employed
for this purpose.
If hypotension does not respond to
replacement by fluids, vasopressor
agents like dopamine may be used.

42.
Alkalinisation of the urine
• Sodium bicarbonate 50ml of a 7.5% solution may be added to every
litre of fluid intended for IV administration.
• The urinary pH should be maintained between 7.5 and 8.5.
• This increases the excretion of long acting barbiturates, such as
phenobarbitone

43.
Prophylactic antibiotics
These should not be used on routinely but may be necessary
in those requiring tracheostomy or catheterisation.

44.
Hemodialysis
All are more effective in removing long acting
barbiturates than short acting ones.
In general, peritoneal dialysis is more suitable
than forced diuresis in patients who have
severe cardiac and renal impairment.
Hemodialysis is about forty times more
effective than forced diuresis in promoting
barbiturate elimination.

45.
Newer Non-Benzodiazepine Hypnotics

46.
Zolpidem
The hypnotic zolpidem is not structurally related to
benzodiazepines, but it selectively binds to the benzodiazepine
receptor subtype
Zolpidem has no anticonvulsant or muscle-relaxing properties.
It shows few withdrawal effects, exhibits minimal rebound
insomnia, and little tolerance occurs with prolonged use.

47.
Zaleplon
Zaleplon is an oral nonbenzodiazepine
hypnotic similar to zolpidem

48.
Prof. Amol Deore