HYPNOTICS

AND
SEDATIVES

Dr. Nilesh Patel

M.Pharm, MBA, PhD
Assistant Professor
B. K. Mody Government Pharmacy
College, Rajkot
 Introduction

SEDATIVES – reduce anxiety and exert a

calming effect

HYPNOTICS - produces drowsiness and

facilitates the onset and maintenance of a state
of sleep.
 CATEGORIES OF INSOMNIA
Transient insomnia
•Lasts <3 days
•---Caused by a brief
environmental or situational
stressor.
•---Respond to attention to
sleep hygiene rules.
•--- Hypnotics should be
used at the lowest dose and
for only 2-3 nights.
Short-term insomnia Long-term insomnia
•3 days to 3 weeks •lasted for >3 weeks
•--- Caused by a personal •---No specific stressor may
stressor such as illness, grief, be identifiable.
or job problems.
•---A more complete medical
•---Sleep hygiene education evaluation is necessary in
is the first step. these patients, but most do
not need an all-night sleep
•---Hypnotics may be used study.
adjunctively for 7-10 nights.
•---- Hypnotics are best used
intermittently during this
time, with the patient
skipping a dose after 1-2
nights of good sleep.
 Introduction

Anxiolytics: Drugs used for the treatment of

symptoms of anxiety, including benzodiazepines.
Sedatives: Drugs causes calmness, relaxation,
reduction of anxiety. Sedatives may be referred to
as tranquilizers, depressants, anxiolytics,
soporifics, sleeping pills, downers, or sedative-
hypnotics, including barbiturates,
benzodiazepines, zolpidem.
Hypnotics: Drugs that induce sleep, used in the
treatment of severe insomnia, including
barbiturates, benzodiazepines, zolpidem.
• Benzodiazepines: wildly used, not to lead
general anesthesia, or death.
• 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,
leading to coma and death.
 BENZODIAZEPINES
• A phenyl fused with a 7-member
imine lactam
• Chlordiazepoxide (Librium) is the
first member of the
benzodiazepines synthesized.
 Effects of benzodiazepine

• On increasing the dose sedation progresses to

hypnosis and then to near-unconsciousness.

• But the drugs do not cause a true general

anesthesia because
• -awareness usually persists
• -immobility sufficient to allow surgery cannot
be achieved.
• However at "preanesthetic" doses, there is
amnesia.
COMPARISON OF THE DURATIONS OF
ACTION OF THE BENZODIAZEPINES
• The benzodiazepines are used for short-term
relief of severe, disabling anxiety or insomnia.
• Long-term use can be problematic due to the
development of tolerance and dependency.
• They act on the GABA receptor GABAA as agonist.
They began to be widely prescribed in the 1960s
and 1970s.
 PHARMACOKINETICS

• A short elimination t1/2 is desirable for hypnotics,

although this carries the drawback of increased
abuse liability and severity of withdrawal after
drug discontinuation.

• Most of the BZDs are metabolized in the liver to

produce active products (thus long duration of
action).

• After metabolism these are conjugated and are

excreted via kidney.
 ADVERSE EFFECTS

• Light-headedness
• Fatigue
• Increased reaction time & incoordination
• Impairment of mental and motor functions
• Confusion
• Antero-grade amnesia
• Cognition appears to be affected less than motor
performance.
• All of these effects can greatly impair driving and
other psychomotor skills, especially if combined
with ethanol.
The benzodiazepines are widely used
sedative-hypnotics. All of the
structures are 1,4-benzodiazepines,
and most contain a carboxamide
group in the 7-membered
heterocyclic ring structure. A
substituent in the 7 position, such as
a halogen or a nitro group, is
required for sedative- hypnotic
activity. The structures of triazolam
and alprazolam include the addition
of a triazole ring at the 1,2- position.
 Chemical Classification of BZP
Chlordiazepoxide, Diazepam, Flurazepam
• 2-Keto Benzos Clonazepam, Flunitrazepam
– Some administered as prodrug
– All have active metabolites, commonly desmethyldiazepam
– Long half-lives (most in excess of 60 hours)
• 3-hydroxy Benzos
– No active metabolites
Lorazepam, Oxazepam
– Not metabolized in the liver
– Intermediate half-lives (most ~ 8-20 hours)
• Triazolo Benzos
– Additional heterocyclic ring attached at the 1 and 2 positions
– Some active metabolites Alprazolam, Triazolam

– Short to intermediate half-lives (anywhere from 3-14 hours)

 2-Keto Benzos

*Chlordiazepoxide (Librium) *Diazepam (Valium)

• First isolated benzo • Most prolific and versatile
• Oxidized to benzo
desmethyldiazepam in the • Indicated for treatment of
liver anxiety, seizure, muslce
• Indicated for treatment of tension, insomnia, and alcohol
anxiety and insomnia withdrawal
 2-Keto Benzos

Flurazepam (Dalmane) Clonazepam (Klonopin)

• High potentcy (~ 20 times
• Longest half-life of any benzo stronger per miliigram than
(~ 40-250 hours) diazepam)
• Indicated primarily for • Causes moderate anterograde
treatment of insomnia, may amnesia
also serve as an anxiolytic
• Indicated for treatment of
anxiety, also a highly effective
anticonvulsant
 2-Keto Benzos
• The original date-rape drug,
and the origin of the term
“roofie”
• Pharmacologically very similar
to clonazepam, but possesses
much stronger amnesic
properties.
• One of only two drugs in the
U.S. for which a first
possession charge is a crime.
Flunitrazepam (Rohypnol) The other of the two is crack
cocaine.
 3-hydroxy Benzos

*Lorazepam (Ativan) *Oxazepam (Serax)

• Indicated for treatment of • Indicated for treatment of
anxiety, seizure, insomnia, anxiety, insomnia, and alcohol
panic disorder, and alcohol withdrawal.
withdrawal. • Common metabolite of many
• Unique among benzos in it’s 2-keto benzos following
use as an adjunctive anti- their oxidation to
emetic desmethyldiazepam
 Triazolo Benzos

*Alprazolam (Xanax) Triazolam (Halcion)

• First benzo approved by • Very rapid onset
FDA for treatment of panic • Very short half-life
disorder. • Possesses amnesic
• Also used as an adjunctive properties similar to
treatment for depression clonazepam
while adjusting to SSRIs. • Used almost exclusively as
a pre-op anesthetic
SAR of Benzodiazapines
Barbiturates Bezodiazepines
•enhance the binding of GABA to • enhance the
GABAA receptors
binding of GABA to
•Prolonging duration
GABAA receptors
•Only α and β (not ϒ ) subunits
are required for barbiturate • increasing the
action frequency
•Narrow therapeutic index • Unlike barbiturates,
•in small doses, barbiturates benzodiazepines do
increase reactions to painful
stimuli. not activate GABAA
•Hence, they cannot be relied on receptors directly
to produce sedation or sleep in
the presence of even moderate
pain.
 BARBITURATES
Mechanism of Action- Bind to specific GABAA receptor subunits at
CNS neuronal synapses facilitating GABA-mediated chloride ion channel
opening, enhance membrane hyperpolarization.

Effects- Dose-dependent depressant effects on the CNS including

• Sedation
• Relief of anxiety
• Amnesia
• Hypnosis
• Anaesthesia
• Coma
• Respiratory depression steeper dose-response relationship than
benzodiazepines
BARBITURATES
 BARBITURATES

ACTIONS
1. Depression of CNS: At low doses, the barbiturates
produce sedation (calming effect, reducing
excitement).

2. Respiratory depression: Barbiturates suppress the

hypoxic and chemoreceptor response to CO2, and
overdosage is followed by respiratory depression and
death.
3. Enzyme induction: Barbiturates induce P450
microsomal enzymes in the liver.
 BARBITURATES
PHARMACOKINETICS
• All barbiturates redistribute in the body.

• Barbiturates are metabolized in the liver, and inactive metabolites

are excreted in the urine.

• They readily cross the placenta and can depress the fetus.

• Toxicity: Extensions of CNS depressant effects

dependence liability > benzodiazepines.

• Interactions: Additive CNS depression with ethanol and many

other drugs induction of hepatic drug-metabolizing enzymes.
 THERAPEUTIC USES

ANESTHESIA (THIOPENTAL, METHOHEXITAL)

• Selection of a barbiturate is strongly influenced
by the desired duration of action.
• The ultrashort-acting barbiturates, such as
thiopental, are used intravenously to induce
anesthesia.
ANXIETY
• 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, most
have been replaced by the benzodiazepines.
 THERAPEUTIC USES
ANTICONVULSANT: (PHENOBARBITAL, MEPHOBARBITAL)
• 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.
• Phenobarbital has specific anticonvulsant activity that is
distinguished from the nonspecific CNS depression.
 ADVERSE EFFECTS

1. CNS: Barbiturates cause drowsiness, impaired concentration.

2. Drug hangover: Hypnotic doses of barbiturates produce a feeling of

tiredness well after the patient wakes.

3. Barbiturates induce the P450 system.

4. By inducing aminolevulinic acid (ALA) synthetase, barbiturates

increase porphyrin synthesis, and are contraindicated in patients with
acute intermittent porphyria.
 ADVERSE EFFECTS
5. Physical dependence: Abrupt withdrawal from barbiturates
may cause tremors, anxiety, weakness, restlessness, nausea
and vomiting, seizures, delirium, and cardiac arrest.
6. Poisoning: Barbiturate poisoning has been a leading
cause of death resulting from drug overdoses for many
decades.
It may be due to automatism.

• Severe depression of respiration is coupled with central

cardiovascular depression, and results in a shock-like condition
with shallow, infrequent breathing.
ADVERSE EFFECTS
THE TREATMENT OF ACUTE BARBITURATE INTOXICATION

Treatment includes artificial respiration and purging the

stomach of its contents if the drug has been recently taken.

• No specific barbiturate antagonist is available.

• General supportive measures.

• Hemodialysis or hemoperfusion is necessary only rarely.

• Use of CNS stimulants is contraindicated because they

increase the mortality rate.
THE TREATMENT OF ACUTE BARBITURATE INTOXICATION

• If renal and cardiac functions are satisfactory, and the patient is

hydrated, forced diuresis and alkalinization of the urine will
hasten the excretion of phenobarbital.

• In the event of renal failure - hemodialysis

• circulatory collapse is a major threat. So hypovolemia must be

corrected & blood pressure can be supported with dopamine.

• Acute renal failure consequent to shock and hypoxia accounts for

perhaps one-sixth of the deaths.
 SAR of Barbiturates
• A good hypnotic barbituric acid derivative must have the
following properties:
1. The acidity value within certain limits to give proper
ratio of ionized (dissociated) and unionized forms, which
is important to cross blood brain barrier (BBB). It takes
approximately 40%–60% dissociation to enable a
barbiturate to cross BBB and exert effects on CNS.
Determination of the pKa can thus be predictive of the CNS
activity.
2. Lipid water solubility (partition coefficient) should be in
certain limits.
• On the basis of acidity values, barbiturates are divided
into two classes
• They are inactive since they are not acidic. These
classes of agents depend on metabolism to produce
1,5,5´ trisubstituted barbituric acids, which are acidic.
Attachment of alkyl substituent to both N1 and N3
renders the drug nonacidic, making them inactive.
 SAR of Barbiturates

• The keto and enol tautomeric forms of barbituric

acid with the sites of substitution in the
hypnotically active barbiturates identified as 1, 2,
and 5.
• Substitution at carbon 5
• * Hypnotic activity is introduced
• Branched chain--> greater hypnotic activity than straight
chain
• Phenol group (like phenobarbital)--> Greater
anticonvulsant activity
• Presence of hydrophilic groups such as –OH, -SH, -NH2, -
COOH, -SO2 decreases lipophilicity so decreases activity
Carbon 2
• No substitution (oxygen) - oxybarbiturates (ex.
pentobarbital and secobarbital)
• Substitution with sulfur - thiobarbiturates (ex.
thiopental and thiamylal)
• Sulfuration at carbon 2 increases lipid solubility
• Greater hypnotic potency More rapid onset, but
shorter duration of action e.g. thiopental has
faster onset and shorter duration than
pentobarbital
• Nitrogen 1
* Addition of a methyl group to nitrogen (e.g.
methohexital)
– Short duration of action
 General Synthesis for Barbiturates

• Substituted malonic acid esters undergo

condensation with urea or thiourea
• in the presence of a base to give the desired
barbiturates
• X : O, barbituric acid derivatives
• X : S, thiobarbituric acid derivatives
 Glutethmide

• Glutethimide is a hypnotic sedative that was introduced by Ciba in

1954 as a safe alternative to barbiturates to treat insomnia. Before
long, however, it had become clear that glutethimide was just as
likely to cause addiction and caused
similar withdrawal symptoms. Doriden was the brand-name
version.
• Glutethimide (3-ethyl-3-phenylgutarimide) is synthesized by
addition of 2-phenylbutanenitrile to the methylacrylate , and the
subsequent alkaline hydrolysis of the nitrile group in the obtained
compound into an amide group, and the subsequent acidic
cyclization of the product into the desired glutethimide.
 Ethchlorvynol
• Ethchlorvynol was a GABA-ergic sedative and hypnotic medication
developed by Pfizer in the 1950s. In the United States it was sold
by Abbott Laboratories under the trade name Placidyl.
• Ethchlorvynol is a member of the class of sedative-
hypnotic carbinols, which includes methylparafynol and tert-amyl
alcohol. It is not a benzodiazepine, carbamate, or barbituric acid
derivative, and its molecular structure is considerably simpler. The
systematic name of ethchlorvynol is usually given as ethyl 2-
chlorovinyl ethynyl carbinol or 1-chloro-3-ethylpent-1-en-4-yn-3-ol.
Its empirical formula is C7H9ClO.
 Triclofos sodium
• Triclofos is a sedative drug used rarely for treating insomnia, usually
as a second-line treatment after other drugs have failed.
• Triclofos may cause dependence and should not be withdrawn
suddenly. This drug should only be used for the short term relief of
severe insomnia and should not be mixed with alcohol or other
depressant drugs.
• Triclofos is a prodrug which is metabolised in the liver into the
active drug trichloroethanol. This delayed action means that the
half-life of triclofos is fairly long
• Trichloroethanol may cause liver damage and triclofos should not
be used for extended periods.
 Paraldehyde
• Paraldehyde is the cyclic trimer of acetaldehyde molecules.
• Formally, it is a derivative of 1,3,5-trioxane, with a methyl
groups substituted for a hydrogen atoms in each carbon. The
corresponding tetramer is metaldehyde.
• It was commonly used to induce sleep in sufferers from delirium
tremens but has been replaced by other drugs in this regard. It is
one of the safest hypnotics and was regularly given at bedtime
in psychiatric hospitals and geriatric wards up to the 1970s.