What are sedatives and Hypnotics? Difference between them, various class of drugs employed as sedative and hypnotics, SAR, MOA and Uses

1. DRUGS ACTING ON
CENTRAL NERVOUS SYSTEM-
SEDATIVE AND HYPNOTICS
Prepared By:
Ms. Jyoti Rani
Assistant Professor
BUEST,SPES

2. In general sedative-hypnotics are drugs used to slow down mental and
physical functions of the body.These are also referred to as the CNS
depressants.
Sedatives are chemical agents tend to produce a calming effect, relax
muscles, and relieve feelings of tension, anxiety, and irritability.
INTRODUCTION
At higher doses, most of these sedative drugs will also produce
drowsiness and eventually produce sleep. Drugs that have such a sleep-
inducing effect are called hypnotic drugs or hypnotics.
There is, no sharp distinction between sedative and hypnotic and the same
drug may have both actions depending on the method of use and the dose
employed.

3. CLASSIFICATION
Sedative-Hypnotics
Barbiturates Benzodiazepines (BDZ) Newer Non-BDZ Hypnotics
LongActing
Barbital
Phenobarbital
ShortActing
Butabarbital
Pentobarbital
Ultra short Acting
Methobarbital
Chlordiazepoxide
Oxazepam
Lorazepam
Diazepam
Alprazolam
Zopiclone
Zolpidem
Zaleplone

4. BARBITURATES
Barbiturates are central nervous system (CNS) depressants (medicines that cause
drowsiness).
Barbiturates produce a wide spectrum of CNS depression, from mild sedation to coma,
and have been used as sedatives, hypnotics, anesthetics and anticonvulsants.
SAR. Barbiturates are substituted derivatives of barbituric acid
(malonyl urea).
(malonyl urea).
1. Barbituric acid as such is not a hypnotic but compounds with alkyl or aryl
substitution on C5 are.
2. Replacement of O with S at C2 yields thiobarbiturates which are more
lipid-soluble and more potent.
3. Barbiturates have variable lipid solubility, the more soluble ones are more potent and
shorter acting. They are insoluble in water but their sodium salts dissolve yielding
highly alkaline solution.

5. 4. Hypnotic activity. Side chains at position 5 (especially if one of them is branched)
is essential for activity.
5. Potency and duration of action. Length of side chain at position 5 influences
potency and duration of action.
Ex: Secobarbital and thiamylal are slightly more potent than pentobarbital and
thiopental, respectively.
6. More rapid onset and shorter duration of action. Sulfur instead of oxygen
atom at postion 2 has more rapid onset of action but shorter duration.
atom at postion 2 has more rapid onset of action but shorter duration.
Ex: thiamylal and thiopental have more rapid onset and shorter duration of action
than secobarbital and pentobarbital, respectively.
7. Increased incidence of excitatory side effects. Methylation at position 1
enhances excitatory side effects (Ex:methohexital)
8. Increased potency, rate of onset and short action. Generally an increase in the
lipophilicity of the compound results in more rapid onset of action accompanied with
an increase in potency.

6. MECHANISM OF ACTION OF BARBITURATES
 Most likely site of action of
barbiturates is gamma amino
butyric acid (GABA) receptor
complex.
 GABA is the principal inhibitory
neuro-transmitter in the
mammalian CNS. GABA receptor
mammalian CNS. GABA receptor
complex is made of 4 to 6
glycoprotein subunits assembled
to form a ligand-gated chloride ion
channel.
 The barbiturate receptor, located
either on α or β subunit also
facilitates GABA and is capable of
opening Cl¯ channel directly as
well.

7. Classification of Barbiturates
Barbiturates are classified as ultra short, short, intermediate and long acting based on
their duration of action ;
(i) Ultra short acting barbiturates: The ultra short acting barbiturates produce
anesthesia within about one minute after intravenous administration. Those in current
medical use are Methohexital, Thiamylal and Thiopental.
(ii) Short acting barbiturates: Action starts within 1/2 hour and lasts for about 4 hours.
Ex: Pentobarbitone, quinalbarbitone, secobarbitone, cyclobarbitone
Ex: Pentobarbitone, quinalbarbitone, secobarbitone, cyclobarbitone
(iii) Intermediate acting barbiturates: Action starts within 1/2 hour and lasts for about
6 hours. Ex: Allobarbitone, butobarbitone, amylobarbitone
(iv) Long acting barbiturates: Action starts within 1/2 hour and lasts for 8 hours.
Ex: Barbitone, phenobarbitone and methylphenobarbitone. They are primarily used for
daytime sedation and the treatment of seizure disorders or mild anxiety.

8. (i) Short acting barbiturates:
Pentobarbitone
O
N
H
O
HN
O
5-ethyl-5-(pentan-2-yl)pyrimidine-
2,4,6(1H,3H,5H)-trione
5
4
3
2
1
6
Pentobarbitone
Pentobarbital (previously known as pentobarbitone is a short-
acting barbiturate but has been largely replaced by
the benzodiazepine family of drugs.
In high doses, pentobarbital causes death by respiratory arrest. It
is used for veterinary euthanasia and is used by some U.S. states
and the U.S. federal government for executions of convicted
criminals.
2,4,6(1H,3H,5H)-trione
The death of Marilyn Monroe in 1962 was
ruled as probable suicide due to an
overdose of pentobarbital.
Pentobarbital was widely abused and known on the streets
as "yellow jackets" due to the yellow capsule of the Nembutal
brand. Pentobarbital in oral (pill) form is no longer
commercially available.
Uses. typically used as a sedative, a pre-anesthetic, and
to control convulsions in emergencies.
It can also be used for short-term treatment of insomnia

9. Secobarbital (Quinal barbitone)
It is a short-acting barbiturate derivative drug that was patented
in 1934 in the United States.
It possesses anaesthetic, anticonvulsant, anxiolytic,
sedative, and hypnotic properties.
In the United Kingdom, it was known as quinalbarbitone.
It is the most frequently used drug in physician-assisted
suicide within the United States.
Secobarbital is considered to be an obsolete sedative-hypnotic
Secobarbital is considered to be an obsolete sedative-hypnotic
(sleeping pill), and as a result, it has largely been replaced by
the benzodiazepine family.
Secobarbital is indicated for:
• Treatment of epilepsy
• Temporary treatment of insomnia
• Use as a preoperative medication to produce anaesthesia
and anxiolysis in short surgical, diagnostic, or therapeutic
procedures which are minimally painful.
Seconal was widely abused,
known on the street as
"red devils" or "reds"

10. Butobarbitone
Butobarbital, also called butobarbitone is a hypnotic drug which
is a barbiturate derivative.
It is prescribed for severe insomnia.
(ii) Intermediate acting barbiturates:
Amobarbital
Amobarbital
Amobarbital (formerly known as amylobarbitone or sodium amytal
as the soluble sodium salt) is a drug that is
a barbiturate derivative. It is considered an intermediate acting
barbiturate.
It has sedative-hypnotic properties.
It was widely abused, known as
"Heavenly Blues"
on the streets, and was discontinued by Eli Lilly in the early 1980s.

11. (iv) Long acting barbiturates:
Barbitone*
It was the first commercially available barbiturate. It was used as a
sleeping aid (hypnotic) from 1903 until the mid-1950s.
Synthesis.
Barbital can be synthesized in a condensation reaction from urea and
diethyl-2,2-diethylmalonate:
Use. It is used as a hypnotic and sedative and may induce dependence.

12. Phenobarbitone
O
N
H
O
HN
O
CH2
CH3
5-ethyl-5-phenylpyrimidine-
2,4,6(1H,3H,5H)-trione
Phenobarbitone
1
2
3
5
4
6
Phenobarbital, also known as phenobarbitone or phenobarb, or by the
trade name Luminal, is a medication of the barbiturate type. It is
recommended by the World Health Organization (WHO) for the treatment
of certain types of epilepsy in developing countries.
SIDE EFFECT Phenobarbital is a cytochrome P450 hepatic enzyme
inducer. The drugs that are metabolized by the CYP450 enzyme system
will have decreased effectiveness due to increases in their clearance
from the body thus reducing the amount of time they have to work.
2,4,6(1H,3H,5H)-trione
Methylphenobarbitone (Mephobarbital)
O
N
O N
H
O
CH2
CH3
H3C
5
4
3
2
1
6
Mephobarbital
5-ethyl-1-methyl-5-phenyl
pyrimidine-2,4,6(1H,3H,5H)-trione
Methylphenobarbital also known as mephobarbital and mephobarbitone
is a drug which is a barbiturate derivative .
It is the N-methylated analogue of phenobarbital and has similar
indications, therapeutic value, and tolerability.
Uses.
• It is used primarily as an anticonvulsant,
• but also as a sedative and anxiolytic.

13. BENZODIAZEPINES
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of psychoactive drugs
whose core chemical structure is the fusion of a benzene ring and a diazepine ring.
Chlordiazepoxide and diazepam were introduced around 1960 as antianxiety drugs.
In 1977 benzodiazepines were globally the most prescribed medications. They are in the family of drugs
commonly known as minor tranquilizers.

14. STRUCTURE–ACTIVITY RELATIONSHIPS OF BENZODIAZEPINES
1. All five agents contain the 5-phenyl- 1,4-
benzodiazepine-2-one backbone required for GABAA
activity.
2. All include an electronegative 7-position chloro
substitution as
required on ring A.
N
N
O
5-phenyl- 1,4-benzodiazepine
-2-one
1
2 4
3
5
6
7
3. Similarly, all contain a pendant 5-phenyl ring (ring C) that
is required for in vivo agonism and that can be
substituted with ortho-electronegative halogens to
increase lipophilicity, as is the
case with flurazepam, quazepam, and triazolam.
4. Interestingly, para-substitution on ring C leads to inactive
benzodiazepines, suggesting that steric restrictions are
important at this site.

15. SITE AND MECHANISM OF ACTION OF BDZs
 BZDs act by enhancing presynaptic/postsynaptic inhibition through a specific BZD
 receptor which is an integral part of the GABAA receptor–Cl¯ channel complex.
 The α/γ subunit interface carrys the BZD binding site. The modulatory BZD receptor
increases the frequency of Cl¯ channel opening induced by submaximal concentrations of
GABA.
GABA.
 The BZDs also enhance GABA binding to GABAA receptor. It is noteworthy that the BZDs
do not themselves increase Cl¯ conductance; have only GABA facilitatory but no GABA
mimetic action. This probably explains the lower ceiling CNS depressant effect of BZDs.

16. Diazepam*
N
O
N
Cl
7-Chloro-1,3-dihydro-1-methyl-
5-phenyl-3H-1,4-benzodiazepin-2-one
Diazepam
It is the oldest and all purpose BZD, used as anxiolytic, hypnotic,
muscle relaxant.
Use.Diazepam has a number of uses including:
• Treatment of anxiety, panic attacks, and states of agitation.
• Treatment of neurovegetative symptoms associated
with vertigo
• Treatment of the symptoms of alcohol, opiate,
and benzodiazepine withdrawal
• Short-term treatment of insomnia
• Treatment of muscle spasms
• Treatment of muscle spasms
Oxazepam
Oxazepam
OH
N
H
N
O
Cl
7-Chloro-3-hydroxy-5-phenyl-
1,3-dihydro-1,4-benzodiazepin-2-one
Oxazepam is a short-to-intermediate acting benzodiazepine with a
slow onset of action, so it is usually prescribed to individuals who
have trouble staying asleep, rather than falling asleep.It is a
metabolite of diazepam.
Use. It is commonly prescribed for anxiety disorders with
associated tension, irritability, and agitation

17. Chlorazepate
N
O
H
N
Cl O
OH
Clorazepate
7-Chloro-2,3-dihydro-2-oxo-5-phenyl-1H-
1,4-benzodiazepine-3-carboxylic acid
Clorazepate is an unusually long-lasting benzodiazepine and
serves as a majoritive prodrug for the equally long-lasting
desmethyldiazepam, which is rapidly produced as an active
metabolite. Desmethyldiazepam is responsible for most of the
therapeutic effects of clorazepate, a small amount of
desmethyldiazepam is further metabolised into oxazepam.
Use. Clorazepate is used in the treatment of anxiety
disorders and insomnia. It may also be prescribed as
an anticonvulsant or muscle relaxant.
Lorazepam
1,4-benzodiazepine-3-carboxylic
Lorazepam
Lorazepam
Cl
N
H
N
Cl
O
OH
7-Chloro-5-(2-chlorophenyl)-3-hydroxy-
1,3-dihydro-1,4-benzodiazepin-2-one
It is used to treat anxiety disorders, trouble sleeping, severe
agitation, active seizures including
 status epilepticus,
 alcohol withdrawal, and
 chemotherapy-induced nausea and vomiting.

18. Alprazolam
Cl
N
N
N
N
Alprazolam
8-Chloro-1-methyl-6-phenyl-4H-
[1,2,4]triazolo[4,3-a] [1,4]benzodiazepine
It is a short-acting tranquilizer of the triazolobenzodiazepine
(TBZD) class, which are benzodiazepines (BZDs) fused with
a triazole ring.
Use. Alprazolam is mostly used in short term management
of anxiety disorders, panic disorders, and nausea due
to chemotherapy.
Newer Non-BDZ Hypnotics
Zolpidem
Zolpidem is a nonbenzodiazepine Z drug which acts as
a sedative and hypnotic.
Zolpidem is a GABAA receptor agonist of the
imidazopyridine class.
MOA. It works by increasing GABA effects in the central
nervous system by binding to GABAA receptors at the
same location as benzodiazepines.
Use. It is a medication primarily used for the short-term
treatment of sleeping problems.

19. MISCELLANEOUSSEDATIVE-HYPNOTICS
Piperidine derivatives (Amides & imides): Glutethimide.
Alcohol & their carbamate derivatives: Meprobomate, Ethchlorvynol.
Aldehyde & their derivatives: Triclofos sodium, Paraldehyde.
Numerous heterocyclic derivatives such as piperidines, alcohol & their
carbamates derivatives and aldehydes with low toxicity for hypnotic and
sedative properties were synthesized.

20. Glutethimide
PIPERIDINE DERIVATIVES (AMIDES & IMIDES)
It is fast acting sedative (30 minutes) with a long
duration (6 hrs.). Effectiveness lasts for longer a
period (5–7 days).
Uses. It is used as hypnotic in all types of insomnia.
Uses. It is used as hypnotic in all types of insomnia.
It induces sleep without depressing respiration.

21. ALCOHOL & THEIR CARBAMATE DERIVATIVES
Meprobamate is a carbamate derivative used as an anxio-
-lytic drug. It was the best-selling minor tranquilizer for a
time, but has largely been replaced by the benzodiazepines
due to their wider therapeutic index and lower incidence
of serious side effects.
Uses. It is used to induce sleep in anxiety and tensive
patients. It also possesses anticonvulsant and muscle
Meprobamate
O
NH2
O
O
H2N
O
2-methyl-2-propylpropane-1,3-diyl
dicarbamate
Ethchlorvynol
It was a GABA-ergic sedative and hypnotic medication
developed by Pfizer in the 1950s.
Uses. It is a short term hypnotic used to treat insomnia. It has
rapid onset, short duration of action and effective for 1–2
weeks.
patients. It also possesses anticonvulsant and muscle
relaxant properties.
dicarbamate

22. ALDEHYDE & THEIR DERIVATIVES
Paraldehyde
is the cyclic trimer of acetaldehyde molecules. It is a central
nervous system depressant and was soon found to be an
effective anticonvulsant, hypnotic and sedative. It was
included in some cough medicines as an expectorant .
Uses. Paraldehyde is one of the oldest hypnotic. It is used as
a hypnotic and sedative.
Triclofos Sodium
Triclofos is a sedative drug used rarely for treating
insomnia. Triclofos is a prodrug which is metabolised
in the liver into the active drug trichloroethanol. The
half-life of triclofos is fairly long and it may cause
drowsiness the next day.
a hypnotic and sedative.

23. Thank you