Sedatives and Hypnotics
Sedatives and hypnotics are CNS depressants associated with the
reduction of anxiety (anxiolytic) and induction of sleep. A large number of
compounds related to different chemical groups are currently used as sedative
and hypnotics.

CNS depression ranges from mild sedation to sleep, depending on route
of administration and dose (small doses  sedation, ↑ doses 
hypnosis and ↑↑ doses  surgical anaesthesia).
 Sedation:
It is mild depression without causing drowsiness, used in emotional
strain, excitation, hypertension, convulsions, preanesthesia and
potentiation of analgesic drugs.
 Hypnosis:
It is strong depression causing sleep, used in insomnia.

The drugs used as hypnotics are often used as sedatives and anxiolytics
(by low dose) but not all anxiolytics cause sedation and hypnosis.

Ideal Hypnotic Properties:
1- It should decrease the consciousness for sleeping without lingering
effects (sleep induction and maintenance).
2- It should have no potential for  or stopping (arresting)
respiration.
3- It should produce no abuse, addiction, tolerance or dependence
(as in barbiturate tolerance).
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
Sleep Factors:
These are factors which control sleep, and any imbalance in them make
disturbances and difficulty to sleep.
1- Catecholamines ( sleep).
2- Serotonin (↑ sleep).
3- Histamine ( sleep).
4- Acetylcholine (↑ sleep).
5- Growth hormone (↑ sleep).
6- Melatonin (↑ sleep).

Classification of Hypnotics:
A. Barbiturates (barbituric acid derivatives).
B. Non-barbiturates.
A- Barbituric Acid Derivatives

Barbiturates were among the most frequently used sedative and hypnotic
drugs. Also, they are used as anticonvulsants. These days their use are
minimized (as sedative/hypnotic) due to their tolerance, dependence and
toxicity (respiratory depression) and interaction with other drugs.

Mechanism of Action:
Barbiturates enhance GABA binding ↑ chloride influx  inhibitory
action (sedation, hypnosis and anticonvulsant actions).

pKa and Structure of Barbiturates:
In 1951, Sandberg postulated that to possess a good hypnotic activity, a
barbiturate must be a weak acid and must have a lipid/H2O partition
2
coefficient between certain limits to provide good lipid solubility. The CNS
depressant barbiturates are mainly the 5,5-disubstituted barbiturates,
and 1,5,5-trisubstituted barbiturates.

Ideal Hypnotic Activity:
1- The barbiturate should be weak acid.
2- ↑ Partition coefficient because ↑ pKa  acidity  polarity↑
lipophilicity ↑ crossing BBB.
 The acidity of barbiturates in aqueous solution depends on the
number of substituents attached to barbituric acid at 1, 3 and 5,
positions.

General Method of Preparation of Barbiturates:
The common method of synthesis of 5,5-disubstituted barbiturates
involves the condensation of disubstituted diethyl malonate and urea or
thiourea in absolute ethanol, in the presence of sodium ethoxide. The
substituted diethyl malonate required for this reaction is usually
prepared by treatment of diethyl malonate with calculated amount of
sodium ethoxide in absolute ethanol to give the monosodium derivative
which is readily converted to the monoalkyl derivative via interaction
with the appropriate alkyl halide. This process is repeated to introduce
the second alkyl group.
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
Structure-Activity Relationships (SAR):
1- Both hydrogens at position 5 of barbituric acid must be substituted
for maximal activity. This is likely due to susceptibility to rapid
metabolic attack at this position.
2- Increasing the length of an alkyl group at position 5 increases the
potency (up to 5-6 carbons), beyond that CNS depressant action
decreases and convulsion action may result.
3- Branching and/or unsaturation in the alkyl group at position 5 ↑ CNS
depressant activity with shorter duration (↑ lipid solubility).
4- A phenyl group at position 5 ⇒ anticonvulsant activity as it ↑ CNS
depressant activity and prolong the duration of action.
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5- Halogenation to the alkyl substituents at position 5 ↑ potency.
6- Substitution on one imide by alkyl group ⇒↑ lipid solubility ⇒ rapid
onset and short duration of action ⇒↑ anticonvulsant / ↑ anesthetic
activities.
7- Substitution to both N1 and N3 by alkyl groups ⇒ No acidity ⇒ inactive
agents.
8- Introduction of a polar functional group, e.g., OH, C=O, amino in the
alkyl group at position 5 destroys the CNS depressant activity.
9- Isosteric replacement of oxygen at position 2 by sulphur
(2-thiobarbiturates) ⇒↑ CNS depressant activity and shortens the
duration of action due to  polarity ⇒↑ lipophilicity ⇒ ultrashort acting
barbiturates.
Barbiturates are classified according to their duration of action into four
classes:
1. Long acting barbiturates (> 6 hours)
2. Intermediate acting barbiturates (3-6 hours)
3. Short acting barbiturates (duration 1-3 hours)
4. Ultrashort acting barbiturates (10-30 minutes)
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1-
Long Acting Barbiturates
Phenobarbital (Luminal)
5-Ethyl-5-phenylbarbituric acid
Phenobarbital is a long acting hypnotic with anticonvulsant activity. It is
administered orally or parenterally as the water soluble sodium salt.
2-
3-
Intermediate Acting Barbiturates

Apobarbital

Butalbutal

Talbutal

Butabarbital
Short Acting Barbiturates
Cyclobarbital (Phandorn)
5-Ethyl-5-(1-cyclohexenyl)barbituric acid
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Cyclobarbital is a short acting hypnotic, with 1-cyclohexenyl group at
position 5. The normal synthetic route for barbiturates is not applicable for such
derivative, it s prepared as follows:
4-
Ultrashort Acting Basrbiturates

Thiopental

Methohexital
They are (discussed before) the most lipophlic derivatives (general
anesthetics).
Metabolism of Barbiturates
1-
Oxidation of substituents at carbon 5 by CYP2C19.
2-
Aromatic hydroxylation if present.
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3-
Oxidative desulfuration if there is C=S ⇒ C=O (more hydrophilic),
e.g. thiopental  pentobarbital.
4-
N-dealkylation (mephobarbital  Phenobarbital).
B- Non-barbiturate Sedatives and Hypnotics
Many organic compounds of various chemical structures are capable of
producing sedation and hypnosis. The major groups of this class are:
1-
1-
Acyclic Ureides.
2-
Amides and Imides.
3-
Alcohols.
4-
Aldehydes.
Acyclic Ureides (Acyl Ureas)
Ureides are the monoacyl derivatives of urea. These derivatives are
structurally-related to barbiturates particularly those containing bromine atom
at the -carbon of the acyl group.
Carbromal
Adalin, Bromadal, Nictal: 2-Bromo-2-ethylbutyroylurea
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Preparation: (Synthesis)
2-
Amides and Imides (Piperidinediones)
Glutethimide (Doriden)
3-Ethyl-3-phenyl-piperidine-2,6-dione
It is structurally related to barbiturates and it is an effective sedative /
hypnotic.
Synthesis:
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Methyprylon
Noludar, 3,3-diethyl-5-methyl-2,4-piperidinedione
These two drugs (piperidinediones) are safer than barbiturates especially
in respiratory depression but they cause tolerance and dependence.
3-
Alcohols
Ethanol has long been known for its sedative effect, the administration of
ethanol produce immediate feeling of stimulation followed by depression. Some
other alcohols produce weak to moderate sedative and hypnotic activity.
Structure-Activity Relationships of Alcohols as CNS Depressants:
1.
The hypnotic activity of normal alcohol increases as the molecular
weight and lipid solubility increase up to 8 carbons.
2.
Branching of the alkyl chain increase the activity.
3.
Replacement of hydrogen by a halogen in the alkyl chain greatly
increase the activity.
Amylene Hydrate (t-Pentanol)
2-Methyl-2-butanol
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Amylene hydrate is used as mild hypnotic and mainly used as a solvent
for tribromoethanol in rectal anesthesia. It is prepared via hydration of Amylene
(trimethylethylene).
Chlorobutanol
Chloretone, Chlorbutol: 1,1,1-Trichloro-2-methyl-2-propanol.
2-Trichloromethyl-2-propanol.
Chlorobutanol is used as mild sedative, it is prepared from acetone and
chloroform in the presence of solid potassium hydroxide.
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4-
Aldehydes and Their Derivative
Chloral Hydrate
Notec, Trichloroacetaldehyde monohydrate
The CNS depressant activity of chloral hydrate is assumed to be due to its
in vivo metabolism to trichloroethanol. It is prepared by prolonged chlorination
of ethanol, the final product is crystalline additive compound (Chloral
alcoholate), which is collected, distilled with H2SO4 to yield which is mixed with
equimolar amount of water to yield chloral hydrate.
Paraldehyde
Paracetaldehyde, 2,4,6-trimethyl-s-trioxane
Paraldehyde is a viscous liquid characterized by strong pungent odour
and taste.
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