Sedative-Hypnotic Drugs

Insomnia is characterized by the complaint of poor sleep,

with difficulty either in initiating sleep or maintaining sleep
throughout the night. It can occur exclusively in the course of
another physical disorder such as pain, mental disorder, e.g.
depression, or sleep disorder, e.g. sleep apnoea. In a large
proportion of patients it is a primary sleep disorder and causes
significant impairment in social, occupational or other
important areas of functioning.
One survey showed similar deficits in quality of life in insomniacs
as in patients with long-term disorders such as diabetes. About
60% of patients with insomnia have abnormal sleep.
 Normal sleep
Normal sleep consists of distinct stages,based on three
physiologic measures: the electroencephalogram, the
electromyogram, and the electronystagmogram.

Non-rapid eye movement(NREM) sleep: 70%-75%

Stage 1,2
Stage 3,4:slow wave sleep, SWS
Rapid eye movement(REM) sleep
Transmitters: waking state and sleep.
During the sleep dominates GABA.
Lüllmann, Color Atlas of Pharmacology – 2 ndndEd. (2000)
Lüllmann, Color Atlas of Pharmacology – 2 Ed. (2000)
 BASIC PHARMACOLOGY OF
SEDATIVE-HYPNOTICS

• An effective sedative (anxiolytic) agent should reduce

anxiety and exert a calming effect with little or no effect on
motor or mental functions.

• A hypnotic drug should produce drowsiness and

encourage the onset and maintenance of a state of sleep
that as far as possible resembles the natural sleep state.
 BASIC PHARMACOLOGY OF
SEDATIVE-HYPNOTICS

• Hypnotic effects involve more pronounced depression of

the central nervous system than sedation, and this can be
achieved with most sedative drugs simply by increasing
the dose.

• Graded dose-dependent depression of central nervous

system function is a characteristic of sedative-hypnotics.
 CHEMICAL CLASSIFICATION
1. Benzodiazepines: not to lead general anesthesia, raraly
death.

2. Barbiturates: the older sedative-hypnotics, general

depression of central nervous system. With such drugs,
an increase in dose above that needed for hypnosis may
lead to a state of general anesthesia. At still higher doses,
it may depress respiratory and vasomotor centers in the
medulla, leading to coma and death.

3. Other classes of drugs: chloral hydrate, buspirone, et al.

 Dose-response curves for two
hypothetical sedative-hypnotics
 Ⅰ.Benzodiazepines
• The first benzodiazepine, chlordiazepoxide, was
synthesised by accident in 1961.
 Ⅰ.Benzodiazepines
• Derivative of 1,4- benzodiazepines. About 20 are available
for clinical use. They are basically similar in their
pharmacological actions, though some degree of
selectivity has been reported. It is possible that selectivity
with respect to two types of benzodiazepine receptor may
account for these differences. From a clinical point of
view, difference in pharmacokinetic behaviour are more
important than difference in profile of activity.
 PHARMACOLOGICAL EFFECTS

1. Reduction of anxiety and aggression :

affects the hippocampus and nucleus
amygdalae

2. Sedation and induction of sleep:

(1) the latency of sleep onset is decreased;
(2) the duration of stage 2 NREM sleep is
increased;
(3) the duration of slow-wave sleep is
decreased.
PHARMACOLOGICAL EFFECTS

Reasons for their extensive clinical use:

(1) great margin of safety;
(2) little effect on REM sleep;
(3) little hepatic microsomal drug-
metabolizing enzymes;
(4) slight physiologic and psychologic
dependence and withdrawal syndrome;
(5) less adverse effects such as residual
drowsiness and incoordination movement.
3. Anticonvulsant and antiseizure
They are highly effective against chemically
induced convulsions caused by leptazol,
bicuculline and similar drugs but less so
against electrically induced convulsions.

The can enhance GABA-mediated synaptic

systems and inhibit excitatory transmission.
4. Muscle relaxation
relax contracted muscle in joint diease or
muscle pasm.

5. Other effects
lead to temporary amnesia
decrease the dosage of anesthetic;
depress respiratory and cardiovascular
fuction.
COMPARISON OF THE DURATIONS OF ACTION OF
THE BENZODIAZEPINES
Classifications
According to Duration of Action :

- Short acting: (3-5 hours).

Triazolam
- Intermediate: (6-24 hours).
Alprazolam
Lorazepam (ALEOT)
Estazolam
Oxazepam
Temazepam
Long acting: ( 24-72 hours)

Chlorazepate Chlordiazepoxide
Diazepam Flurazepam.
Quazepam Prazepam
Nitrazepam
According to uses
Sedative (Anxiolytics)
Alprazolam Chlordiazepoxide
Diazepam Prazepam

Hypnotics
Triazolam
Lorazepam Estazolam Temazepam
Flurazepam Nitrazepam Quazepam

Preanesthetics
Diazepam - Midazolam
Chemical structures of benzodiazepines
 MECHANISM OF ACTION
• Benzodiazepines act very selectively on
GABAA-receptors, which mediate the fast
inhibitory synaptic response produced by
activity in GABA-ergic neurons.

• The effect of benzodiazepines is to enhance

the response to GABA, by facilitating the
opening of GABA-activated chloride
channels (an increase in the frequency of
channel opening, but no change in the
conductance or mean open time).
 MECHANISM OF ACTION
• Benzodiazepines bind specifically to a
regulatory site on the receptor, distinct from
the GABA binding site, and enhanced
receptor affinity for GABA.

• The GABAA-receptors is a ligand-gated ion

channel consisting of a pentameric assembly
of subunits.
Mechanism of Action

Bzs binding to BZ receptors (BZ1 or BZ2) to

facilitate GABA-induced chloride channels hyperpolarization = GABA-mediated
inhibitory neurotransmission.
Bzs  facilitation of GABA action on GABA receptors 
chloride channels opening 

 chloride influx to the cell  cell membrane

hyperpolarization  inhibition of propagation of action
potential  inhibitory effect on different sites of the brain
especially motor cortex, and limbic system.
PHARMACOKINETIC ASPECTS
• Well absorbed when given orally;

• They bind strongly to plasma protein, and their high

lipid solubility cause many of them to accumulate
gradually in body fat. Distribution volumes is big.
• Metabolic transformation in the microsomal drug-
metabolizing enzyme systems of the liver, eventually
excreted as glucuronide conjugates in the urine.
• They vary greatly in duration of action,
and can be roughly divided into
– Short-acting compounds: triazolam,
oxazepam(15-30min, t1/2 2-3 h)
– Medium-acting compounds: estazolam,
nitrazepam (40min, t1/2 5-8 h)
– Long-acting compounds: diazepam,
flurazepam(50h)
PHARMACOKINETICS

1. most of them are well absorbed orally,

Rapid absorption
e.g. triazolam & Alprazolam
diazepam & chlorazepate
Slow absorption
e.g. lorazepam & oxazepam, temazepam
(LOT)
2. Chlorazepate is a prodrug converted by
acid hydrolysis in stomach to form
nordiazepam (desmethyldiazepam).

3. Can be given parenterally

Diazepam-Chlordiazepoxide (IV
only NOT IM)
Midazolam – Lorazepam (IV or
IM)
4. Bzs are lipid soluble and widely
distributed
5. Redistribution from CNS to skeletal
muscles, adipose tissue) (termination of
action).
6. Cross placental barrier during
pregnancy and are excreted in milk
(Fetal & neonatal depression).
7. Highly bound to plasma protein.

8. ALL Bzs are metabolized in the liver

Phase I: ( liver microsomal system)
Phase II: glucouronide conjugation
and excreted in the urine.
9. Many of Phase I metabolites are
active
active
 elimination half life of the parent
comp.  cumulative effect with multiple
doses

EXCEPT No active metabolites are

formed for (LEO) Lorazepam, Estazolam,
Oxazepam
Biotransformation of benzodiazepines
ADVERSE DRUG REACTION
• Acute toxicity: Benzodiazepines in
acute overdose are considerably less
dangerous than other sedative-hypnotic
drugs. Cause prolonged sleep,without
serious depression of respiration or
cardiovascular. The availability of an
effective antagonist, flumazenil.
ADVERSE DRUG REACTION
• Side-effects during therapeutic
use: drowsiness, confusion, amnesia,
impaired coordination. Main
disadvantages are interaction with
alcohol, long-lasting hangover and the
development of dependence.
• Tolerance and dependence:
induction of hepatic drug-metabolising
enzymes; a change at the receptor level;
 Ⅱ.BARBITURATES
Classification
(1)Ultra-short-acting barbiturates: act within
seconds, and their duration of action is
30min. Therapeutic use of Thiopental:
anesthesia
(2)Short-acting barbiturates: have a duration
of action of about 2h. The principal use of
Secobarbital : sleep-inducing hypnotics.
 Ⅱ.BARBITURATES
Classification

(3)Intermediate-acting barbiturates: have and effect

lasting 3-5h. The principal use of Amobarbital is as
hypnotics.
(4)Long-acting barbiturates: have a duration of action
greater than 6h. Such as Barbital and Phenobarbital.
Therapeutic uses: hypnotics and sedative, and
antiepileptic agents at low doses.
Classification :
 Long acting( 24-28 h): Phenobarbitone
 Intermediate (8-24h): Amylobarbitone
 Short-acting(3-8h):
• Pentobarbitone
• Secobarbitone
• Amobarbital
 Ultrashort acting (25 minutes):
thiopental
 BARBITURATES

Barbiturates depress the CNS at all

level in a dose-dependent fashion. Now
it mainly used in anaesthesia and
treatment of epilepsy; use as sedative-
hypnotic agents is no longer
recommended.
 BARBITURATES

Reasons:
(1) have a narrow therapeutic-to-toxic dosage
range.
(2) suppress REM sleep.
(3) Tolerance develops relatively quickly.
(4) have a high potential for physical
dependence and abuse.
(5) potent inducers of hepatic drug-
metabolising enzymea.
Chemical structures of barbiturates and
other sedative-hypnotics
 MECHANISM OF ACTION
(1) Barbiturates share with benzodiazepines
the ability to enhance the action of GABA,
but they bind a different site on the GABA-
receptor/chloride channel, and their action
seems to prolong the duration of the
opening of GABA-activated chloride
channels.
 MECHANISM OF ACTION
(2) At high doses, barbiturates can inhibit the
release of the Ca2+-dependent
neurotransmitter.
Mechanism of Action
1. Facilitation of GABA action on the
brain. increase the duration of the
GABA gated channel opening but in
large dose, they can directly activating
chloride channels. (not through BZD
receptors).
2. depress excitatory neurotransmitter
actions

3. Interfere with Na & K transport across

cell membranes (reticular activating
system inhibition).

4. are less selective in action than BZD.

 Pharmacokinetics
• High lipid solubility allows rapid transport across
the blood-brain barrier and results in a short onset.
• Removal from the brain occurs via redistribution to
the other tissues results in short duration of action.
• Barbiturates and their metabolites the excretion via
the renal route. Alkalinization of the urine expedites
the excretion of barbiturates. Treatment of acute
overdosage: Sodium bicarbonate.
Pharmacokinetics
1. All barbiturates are weak acids
2. are lipid soluble
4. absorbed orally.
3. distribute throughout the body
5. Thiobarbiturates are very lipid soluble
(high rate of entry into CNS- very brief onset
of action).
6. Redistribute in the body from the brain to
skeletal muscles- adipose tissues.

7. metabolized in the liver to inactive

metabolites
8. Excreted in the urine.
Alkalinization increases excretion (NaHCO3)

9. Cross the placenta ( # pregnancy).

 Therapeutic uses

• Sedative-hypnotic agents
• Be used in the emergency treatment of
convulsions as in status epilepticus.
• Anesthetic (or be given before
anesthetic)
• Combination with antipyretic-analgesic
• Treatment of hyperbilirubinemia and
kernicterus in the neonate.
 Adverse effects
• After effect: hangover---dizzy, drowsiness,
amnesia, impaired judgment, disorientation.

• Tolerance: decreased responsiveness to a

drug following repeated exposure because of
down-regulation of receptors and induction of
hepatic drug-metabolising enzymes.
 Adverse effects
• Dependence: including psychologic and
physiologic dependence. Withdrawal
symptoms: excitation, insomnia, tremor,
anxiety, hallucinations and sometimes
convulsions.
• Depressant effect on respiration: can cross the
placental barrier during pregnancy and secrete
to breast milk.
• Others: Skin eruptions and porphyria
Treatment of acute overdosage
• An overdose can result in coma, diminished
reflexes, severe respiratory depression,
hypotension leading to cardiovascular collapse,
and renal failure.
• Treatment (A.B.C):
(1) supporting respiration and circulation.
(2) alkalinizing the urine and promoting diuresis.
(3) Hemodialysis or peritoneal dialysis.
 Ⅲ.Nonbarbiturate sedative-
hypnotics
Chloral hydrate
(1) relatively safe hypnotic, inducing sleep
in a half hour and lasting about 6h.
(2) used mainly in children and the elder,
and the patients when failed to other drug.
Chemical structures of newer hypnotics
 Zolpidem (Ambien)

 imidazopyridine derivative.
 acts on benzodiazepine receptors (BZ
1) &
facilitate GABA mediated neuronal
inhibition.
 Its action is antagonized by flumazenil.
 rapidly absorbed from GIT and
metabolized to inactive metabolites via
liver CYT P450.
 Short duration of action ( 2- 4 h).
 Only hypnotic effect
 Its efficacy is similar to
benzodiazepines.
 Minor effect on sleep pattern, but high
doses suppress REM.
 Respiratory depression occur at high
doses in combination with other CNS
depressant as ethanol.
 has no muscle relaxant effect.
 has no anticonvulsant effect.
 Minimal psychomotor dysfunction
 Minimal tolerance & dependence.
 Minimal rebound insomnia.
Uses
a hypnotic drug for short term treatment
of insomnia

Dose should be reduced in hepatic or

old patients.
Adverse Effects
GIT upset
Drowsiness
Dizziness

Drug interactions
Rifampicin (decreases half life)
Cimetidine (increases half life)
 Zaleplon

 Binds to BZs receptors and facilitate

GABA
actions.
 Zaleplon

 Rapid absorption
 rapid onset of action
 Short duration of action (1 hr)
 Metabolized by liver microsomal
enzymes
 metabolism is inhibited by cimetidine.
 Only hypnotic effect
 decreases sleep latency
 Little effect on sleep pattern
 Potentiates action of other CNS
depressants (alcohol).
 Dose reduction as before.
 Used as hypnotic drug
 Advantages
Less impairment of pyschomotor
performance than BZs or zolpidem.
 Clinical uses of sedative-hypnotics

For relief of anxiety

For insomnia
For sedation and amnesia before and during medical and
surgical procedures
For treatment of epilepsy and seizure states
As a component of balanced anesthesia (intravenous
administration)
For control of ethanol or other sedative-hypnotic
withdrawal states
For muscle relaxation in specific neuromuscular disorders
As diagnostic aids or for treatment in psychiatry