Sedatives and hypnotics are central nervous system depressants that can calm anxiety or induce sleep. Barbiturates are a commonly used class that are classified based on duration of action from long to ultra-short acting. Their structure-activity relationship depends on factors like acidity, lipid-water solubility, and number/type of substituents. Barbiturates are metabolized in the liver through processes like oxidation, ring opening, and N-dealkylation to introduce more polar groups and facilitate excretion. Therapeutic uses include as sedatives, hypnotics, anticonvulsants, and for general anesthesia or psychiatric treatment.

1. 1
JSPM
Charak College of Pharmacy and Research, Wagholi
Sedatives and Hypnotics
Presented By:
Prof. S. S. Jangam
Department of Pharmaceutical Chemistry

2. SEDATIVES AND HYPNOTICS
Introduction:
Sedative:
A sedative drugs decreases activity and excitement of the patient and calms the anxiety by
producing mild depression of CNS without causing drowsiness or sleep.
Hypnotic:
A hypnotic drug produces drowsiness, compelling the patient to sleep by depressing the
CNS, particularly the reticular activity which characterizes the wakefulness.
Properties of Sedatives and Hypnotics:
•The presence of hydrophilic groups is necessary for their transport from gastrointestinal
tract to aqueous body Fluids while their penetration into CNS necessitates the drug to be
sufficiently lipophilic.
•They should possess such structural features which would normally resist their rapid
metabolism. In these agents, generally polar groups like, -CONHCONHCO (barbiturates), -
CONH2 (amides), -OH (alcohol), OCONH2 (carbamates) are attached to non polar moiety,
usually alkyl, aryl or halo alkyl groups.
2

3. Classifications:
1. Barbiturates:
Long acting Barbiturates: (6 hours or more) e. g. Barbital, Phenobarbital, Mephobarbital
Intermediate acting Barbiturates: (3-6 Hours) e. g. Amobarbital, Butabarbital, Probarbital
Short acting Barbiturates:(less than 3 hours)
e. g. Cyclobarbital, Heptabarbital, Pentobarbital, Secobarbital
Ultra-short acting Barbiturates: (I. V.) e. g. Hexobarbitone, Thiopentone
2. Benzodiazepines: e. g. Diazepam, Nitrazepam, Flurazepam, Lorazepam
3. Acyclic hypnotic containing nitrogen:
a. Urethanes: e. g. Urethanes
b. Ureides: e. g. Capuride, Bromvalurea, Carbromal
c. Carbamates: e. g. Meprobamate
d. Amides: e. g. Oxanamide, Valnoctamide
4. Cyclic hypnotic containing nitrogen:
a. Piperidinediones: e. g. Dihydroprylone, Methyprylone, Glutethimide
b. Quinazolinones: e. g. Methaqualone, Mecloqualone
3

4. 5. Alcohols: e. g. Chlorobutanol, Chloral Hydrate
6. Aldehydes: e. g. Paraldehyde
7. Acetylene derivatives: e. g. Carfimate
8. Miscellaneous agents:
a. Bromides: e. g. Potassium bromides
b. Acids and Esters: e. g. L-tryptophan, Etomidate
c. Antihistamine and Anticholinergics: e. g. Doxylamine, Diphenhydramine, Pyrilamine
d. Sulfones
e. Plant extracts: e. g. Rauwolfia serpentine
f. Endogenous peptide
4

5. BARBITURATES:
The first agent from this class that is Barbital (5,5-diethylbarbituric acid) was
introduced in 1903 by Fischer and Won Mebring followed by the introduction of
Phenobarbital in 1912. Since both these agents turn out to be powerful hypnotic
drugs, over 2500 barbiturates were synthesized and evaluated, of which very few
were proved of clinical utility. The parent compound in this series is Barbituric acid
or 2, 4, 6-trioxo hexahydropyrimidine which is devoid of CNS depressant activity
but the presence of alkyl or aryl group at position 5 confers sedative and hypnotic
activities.
H2C
N
H
NH
C
O
C
O
C
O
1
2
3
4
5
6
5

6. BARBITURATE CLASSIFICATION:
C
N
H
NR1
C
O
C
O
C
O
1
2
3
4
5
6R5
R'
5
(S)
Name
Substituents
R1 R5 R’
5
1. Long acting Barbiturates:
Barbital
Phenobarbital
Mephobarbital
H
C2H5
C2H5
H
C2H5
CH3
C2H5
6

7. Name
Substituents
R1 R5 R’
5
2. Intermediates acting Barbiturates:
Amobarbital
Butabarbital
Probarbital
H C2H5
CH2 CH2 CH
CH3
CH3
H
C2H5
H
C
CH3
CH2 CH3
H
C2H5
CH
CH3
CH3
C
N
H
NR1
C
O
C
O
C
O
1
2
3
4
5
6R5
R'
5
(S)
7

8. Name
Substituents
R1 R5 R’
5
3. Short acting Barbiturates:
Cyclobarbital
Heptabarbital
Pentobarbital
Secobarbital
C
N
H
NR1
C
O
C
O
C
O
1
2
3
4
5
6R5
R'
5
(S)
H
C2H5H
C2H5H
C2H5
H
C
CH3
CH2 CH2 CH3H CH2 CH CH2
H
C
CH3
CH2 CH2 CH3
8

9. Name
Substituents
R1 R5 R’
5
4. Ultra-short acting Barbiturates:
Hexobarbitone
Thiopentone
C
N
H
NR1
C
O
C
O
C
O
1
2
3
4
5
6R5
R'
5
(S)
CH3
CH3
H C2H5
H
C
CH3
CH2 CH2 CH3
9

10. Structure-Activity Relationship:
In 1951, Sandberg postulated that a good hypnotic Barbituric acid derivative must
have:
•The acidity value within certain limits to give proper ratio of ionized (dissociated)
and unionized (undissociated) forms which is important to cross blood brain
barrier.
•Lipid water solubility (partition coefficient) between certain limits.
(A) Acidity:
On the basis of acidity values, barbiturates are divided into two classes:
Hypnotic class:
•5,5-disubstituted Barbituric acids
•5,5-disubstituted thiobarbituric acids
•1,5,5-trisubstituted Barbituric acids
10

11. Inactive class:
•1-substituted Barbituric acids
•5-substituted Barbituric acids
•1,3-disubstituted Barbituric acids
•1,5-disubstituted Barbituric acids
•1, 3, 5, 5-tetrasubstituted Barbituric acids
(B) Lipid-Water solubility:
Once the acidity value criterion is satisfied, the lipid water solubility or partition
coefficient is calculated to find out whether the compound is active or not. The
following structural skeleton is essential for hypnotic activity.
11

12. C
N
H
NR1
C
O
C
O
C
O
1
2
3
4
5
6R5
R'
5
(S)
Sum
Value
Duration of action
1. 7-9 Rapid onset and shortest duration
2. 5-7 Intermediate duration of action
3. 4 Slowest onset and longest duration (Two ethyl groups or ethyl and phenyl)
(1) The sum of the carbon atoms of both substituents at carbon 5 should be
between 6 and 10 in order to attain optimal hypnotic activity. The sum is also
index of duration of action.
(2) Within the same series, the branched chain isomer has greater lipid solubility
and hypnotic activity but has shorter duration of action.
12

13. The greater the branching, more potent will be the drug e. g. Pentobarbital is more
potent than Amobarbital.
C
N
H
NH
C
O
C
O
C
O
1
2
3
4
5
6CH
H2CH3C
H2CH2CH3C
H3C
Pentobarbital
5-ethyl-5-(pentan-2-yl)pyrimidine-2,4,6(1H,3H,5H)-trione
C
N
H
NH
C
O
C
O
C
O
1
2
3
4
5
6CH2
H2CH3C
H2CCHH3C
Amobarbital
CH3
5-ethyl-5-isopentylpyrimidine-2,4,6(1H,3H,5H)-trione
13

14. (3) However, the stereoisomer posses approximately same potencies.
(4) Within the same series the unsaturation (i. e. allyl, alkenyl, cycloalkenyl
analogues) may result into greater potency than the saturated analogues with the
same number of carbon atoms.
(5) Alicyclic or aromatic substituted analogues are more potent than analogues with
aliphatic substituents with the same number of carbon atoms.
(6) Introduction of halogen atom into the 5-alkyl substituent increases the potency.
(7) Introduction of the polar substituent (OH, NH2, COOH, CO, RNH, SO3H) into
aromatic group at C-5 results in decreased lipid solubility and potency.
(8) Alkylation at 1 or 3 position may results in compounds having shorter onset and
duration of action since N-methyl group reduces acidity value.
(9) Replacement of oxygen by sulfur at 2-carbons shortens the onset and duration of
action due to increased lipid solubility.
(10) Introduction of more sulfur atoms (C-4 and C-6) decreases the hypnotic activity.
14

15. Metabolism:
A few barbiturates (which already possess enough polar groups) with low lipid water
partition coefficient are largely excreted unchanged in the urine.
While barbiturates with non polar structure (lipophilic character) are metabolized
resulting into the introduction of more polar groups in the structure which may be
excreted in the urine in free form or as conjugates of glucuronic acid.
Liver remains as the principal site of metabolism. The metabolic changes that may
occur with the non polar barbiturates include-
(1) Oxidation of radical present at C5 to yield hydroxyl, keto or carboxy derivatives.
(2) Opening of the barbiturate ring by hydrolytic cleavage.
(3) N-dealkylation (N-demethylation) in N-substituted barbiturates.
(4) De-sulfurisation of 2-thiobarbiturates is a common metabolic process e. g.
thiopental when metabolized, results into pentobarbital molecule.
15

16. C
N
H
NH
C
O
C
S
C
O
1
2
3
4
5
6CH
H2CH3C
H2C
H2
CH3C
CH3
5-ethyl-dihydro-5-(pentan-2-yl)-2-thioxopyrimidine-4,6(1H,5H)-dione
Thiopental
C
N
H
NH
C
O
C
O
C
O
1
2
3
4
5
6CH
H2CH3C
H2C
H2
CH3C
CH3
5-ethyl-5-(pentan-2-yl)pyrimidine-2,4,6(1H,3H,5H)-trione
Pentobarbital
All these metabolic changes result in an increase in polar characteristic of the
barbiturate molecule.
16

17. Therapeutic Uses:
1. Non analgesic sedative and hypnotic drugs
2. Anticonvulsant agents
3. General anaesthetics
4. In psychiatric treatments, as diagnostic and therapeutic aids.
17

18. 18