Sedatives and Hypnotics and Antianxiety: Wilson and Gisvold's

Wilson and gisvolds
Textbook of organic medicinal and pharmaceutical chemistry
Sedatives and Hypnotics and Antianxiety

1/1/2011
Saeid kashefi
http://www.slideshare.net
2011
Introduction
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.
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.
Hypnotic-sedative are used in treatment of some of Insomnias (unsatisfactory or insufficient sleep)

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.
The combination of the terms sedative-hypnotic appropriately identifies the major pharmacological effects of
these drugs.
In reality, almost any drug that calms, soothes, and reduces anxiety is also capable of relieving insomnia.
Antianxiety drugs are used to treat excessive or inappropriate anxiety, such as post-traumatic stress,
generalised anxiety, panic attack, social phobia, and obsessive-compulsive disorders.
Unlike the narcotics, intoxicating doses of the sedative-hypnotics usually result in impaired judgement,
slurred speech, and loss of motor function.
Mechanism of action is by positive modulation of action of GABA at GABAA receptor.

They are primarily used for daytime sedation and the treatment of seizure disorders or mild anxiety.
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Classification:
According to chemical structures, sedative-hypnotics and antianxiety drugs are broadly classified as:
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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, anaesthetics, and anticonvulsants.
However, they can be addictive and abused.
Excessive doses can cause depression, slurred speech, slowed reflexes, and confusion.
Barbiturates were first introduced for medical use in the early 1900s.
More than 2,500 barbiturates have been synthesized, and in the height of their popularity about 50 were
marketed for human use.
Barbiturate Development
In 1864, von Baeyer synthesized the first barbiturate, barbituric acid.
Barbiturates are usually taken orally but are sometimes injected intravenously or intramuscularly (I.M.).
They are absorbed rapidly; 30-40% is bound to plasma protein, and the rest is distributed to muscle, fat,
and the liver (where they are ultimately inactivated).
Classification of Barbiturates
Barbiturates are classified in 4 types based on their duration of action;
1) Ultra-short acting
2) Short acting
3) Intermediate acting
4) Long acting
1) 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.
2) Short acting barbiturates: Action starts within 1/2 hour and lasts for about 4 hours.
Ex: Pentobarbitone, Quinalbarbitone, Secobarbitone, Cyclobarbitone
3)
Intermediate acting barbiturates: Action starts within 1/2 hour and lasts for about 6 hours.
Ex: Allobarbitone, Butobarbitone, Amylobarbitone
4) Long acting barbiturates: Action starts within 1/2 hour and lasts for 8 hours.
Ex: Barbitone, Phenobarbitone, and Methyl-Phenobarbitone.
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Chemistry of Barbiturates
Barbiturates are derivatives of barbituric acid (2,4,6-trioxyhexahydropyrimidine) which is devoid of hypnotic
and sedative activities.
Structure-Activity Relationships (SAR) of Barbiturates;
1) Hypnotic activity: Side chains at position 5 (especially if one of them is branched) is essential for activity.
2) 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.
3) More rapid onset and shorter duration of action: Sulphur instead of oxygen atom at position 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.
4) Increased incidence of excitatory side effects: Methylation at position 1 (Methohexital) enhances
excitatory side effects.
5) 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.
Introduction of polar groups (hydroxyl, keto, amino, or carboxyl) into C-5-alkyl side chain makes the
compound more hydrophilic in nature. Due to the polar nature, hydrophilic barbiturates do not dissolve in
microsomal membranes of liver and are excreted.
Branched, cyclic or unsaturated side chain at C-5 position generally reduce the duration of action due to an
increased ease of metabolic conversion to a more polar, inactive metabolite.
6) Stereoisomerism: Though their L-isomers are nearly twice as potent as their D-isomers, barbiturates are
marketed as racemic mixtures. Methohexital has two asymmetric carbon atoms, so exists as 4
stereoisomers (, -D, L-Methohexital).
Different activities among different stereoisomers (enantiomers or enantiomorphism) is consistent with site
of action at a chiral center of a receptor or enzyme.
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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 neurotransmitter in the mammalian CNS.
GABA receptor complex is made of 4 to 6 glycoprotein subunits assembled to form a ligand-gated chloride
ion channel
Barbiturates enhance and mimic the action of GABA at the GABA receptor complex.
Barbiturate binding to this receptor decreases the rate of GABA dissociation and increases the duration of
GABA-activated chloride channel opening. At slightly higher concentrations, barbiturates directly activate
chloride channel opening even in the absence of GABA, leading to barbiturate anesthesia.
Side-effects of Barbiturates
Side effects of barbiturates include hangover with drowsiness, dizziness, ataxia, respiratory depression,
hypersensitivity reactions, headache, particularly in elderly; paradoxical excitement and confusion
occasionally precede sleep.
Acidity:
Various type of barbiturates show acidic properties which is due to lactom-lactim and keto-Enol
tautomerism. All four hydrogens are involved.
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The salt formation readily takes place in Dioxi form
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Long acting
Barbiturates
1) Barbital
2) Phenobarbital
3) Mephobarbital
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Barbital S
Trade name: Barbitone, Veronal
Synthesis:
Uses:
1) Discontinued as sedative-Hypnotic but is interesting molecule, because of biological consequences of
its low lipid/water partition coefficient.
2) It is slowly eliminated mostly intact by the kidney.
Duration of action: 4-12 hr.
Onset of action: 0.5-1 hr.
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Phenobarbital S
Trade name: Luminal

Synthesis:
Properties
1) White glistering small crystals
2) pKa 7.1
3) Insoluble in water and soluble in alcohol
4) 65% of drug as metabolized largely to inactive p-hydroxy phenyl derivatives
Uses:
1) Long acting sedative-Hypnotic
2) Used as Anti-convulsant especially in generalized tonic-clonic and partial seizures.
3) Useful in nervous and related tension state.
30-120= Sedative
50-100= Anti-convulsant
100-320=Hypnotic

Onset of action: 0.5-1 hr.
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Mephobarbital
Methylphenobarbitone
Trade name: Prominal
Properties:
1) Mephobarbital is white crystalline,
2) Water insoluble powder
3) It is soluble in aqueous solutions of alkali hydroxides and carbonates
Uses:
1) Principle use is Anti-convulsant
2) It is metabolically N-Dealkylated to Phenobarbitone which is considered responsible for almost all
activity, long acting barbiturate.
Onset of action: 0.25 hr.
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Intermediate acting
Barbiturates
1) Amobarbital
2) Butabarbital
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Amobarbital S
Amobarbitone
Trade name: Amytal
Synthesis:
Properties:
1) It occurs as white crystalline powder.
2) It is slightly soluble in water but freely soluble in alkali hydroxide and carbonate solutions.
Uses:
1) An intermediate acting barbiturate
2) Used as Anti-convulsant
3) Used in surgery (pre-operative)

Onset of action: 0.25-0.5 hr.
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Butabarbital S
Butobarbitone
Trade name: Butisol
Synthesis:
Properties:
1) It is white crystalline powder
2) Slightly soluble in water

Uses:
1) An intermediate acting barbiturate
2) Used principally as Sedative-Hypnotic
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Short acting
Barbiturates
1) Pentobarbital
2) Secobarbital
3) Talbutal
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Pentobarbital
Pentobarbitone
Trade name: Nembutal
Properties:
1) Pentobarbitone is available as Pentobarbitone sodium salt.
2) Pentobarbitone and its sodium salt are available as white, crystalline powder.
3) Pentobarbitone is slightly soluble in water, whereas its sodium salt is freely soluble in water.
Uses:
1) As short acting barbiturate in producing sedation and as Anti-convulsant

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Talbutal
Trade name: Lotusate
Uses:
1) As short acting barbiturate
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Secobarbital S
Quinalbarbitone
Trade name: Seconal
Synthesis:
Properties:
1) Its sodium salt
2) Quinalbarbitone sodium is a white powder.
3) It is freely soluble in water.
Uses:
1) Its short acting barbiturate
2) It is widely used as sedative and hypnotic
3) It is used in epilepsy
4) Used as local anesthetic
5) In toxic reactions of strychnine
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MISCALLANEOUS
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Amides and imides:

A group of acyclic amides and imides, some bearing a close structural relationship to the barbiturates, have
proved to be effective as sedative-Hypnotic drugs.
Numerous heterocyclic derivatives with low toxicity for hypnotic and sedative properties were synthesized.
Glutethimide S
Synthesis:
Properties:
1) Glutethimide is Colorless or white color
3) Soluble in alcohol
4) It should be stored in light protected containers.
Uses:
1) Glutethimide is used as hypnotic in all types of insomnia. It induces sleep without
2) Clinical use now limited due to addition and chronic use leads to toxic psychosis and convulsions
Duration of action: 4-8 hr
Onset of action: 30 min
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Methaqualone S
Synthesis:
Properties:
1) It is a Quinazolione derivative
2) Methaqualone is white crystalline,
4) It should be stored in a light protected container.
Uses:
1) Methaqualone is used as a hypnotic and as daytime sedative
2) Administered along with anti-histamine agent like Diphenhydramine
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Methyprylon
Properties:
1) Methyprylon is a white crystalline powder having characteristic odor.
2) It is sparingly soluble in water but freely soluble in alcohol, chloroform, and ether.
3) It should be stored in well-closed containers.
Uses:
1) It is useful for induction of sleep within 15 to 30 minutes in patients with simple insomnia
2) Closely resemble secobarbital in its onset and duration of action.
3) Habituation, tolerance, physical dependence and addiction can occurs
Duration of action: intermediate
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Alcohols and their carbonated derivatives

Ethanol has a long history of use as sedative and hypnotic
Because of the many problems associated with the use of alcohol, such as the development of chronic
alcoholism on continued use, other depressant drugs have been favored for sedative-hypnotic use.
Widely used in self-medication as a sedative-hypnotic
Seldom preferred medically due to many hazards
Hypnotic activity of the normal alcohols increases as the molecular weight and the lipid-solubility
increases, reaching a maximum depressant effect at 8 carbons.
branching of alkyl chains increases depressant activity, and the order of potency in an isomeric series of
alcohols is
3 > 2 > 1
Replacement of a H2 atom by halogen has an effect equivalent to increasing the alkyl chain and for the
lower molecular weight alcohols, result in increased potency.
Most of alcohols and Carbamates have suppressed as sedative and hypnotics. Some dysfunctional
compounds (Diol Carbamates) have present action on the cord in addition to brain and are retained for
their skeletal muscular relaxant properties.
Ethchlorvynol
Properties:
1) Ethchlorvynol is a colourless to yellow color liquid with characteristic odor.
2) It is light sensitive drug hence should be protected from light.
Uses:
1) Is most useful in the induction of sleep for patients with simple insomnia
2) It is use as daytime sedative
Duration of action: 5hr.
Onset of action: fairly rapid hr.
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Meprobamate S
Synthesis:
Properties:
1) Meprobamate is an odourless, white color crystalline aggregate with bitter taste.
2) It is insoluble in water but soluble in alcohol and slightly soluble in ether.
Uses:
1) Meprobamate is used to induce sleep in anxiety and tensive patients.
2) It also possesses anticonvulsant and muscle relaxant properties.
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Aldehydes and their derivatives

Few aldehydes and their derivatives are valuable hypnotic drugs. Chloral hydrate acts as hypnotics.
It acts principally through it is metabolite trichloro ethanol. Paraldehyde is a cyclic trimmer derivative of
acetaldehyde.
Chloral hydrate S
Synthesis:
Properties:
1) Chloral hydrate is white crystalline powder, Colorless, slightly bitter taste, and characteristic odor
2) It is Very soluble in water and in alcohol
Uses:
1) Chloral hydrate is a sleep-inducing drug used in the early 1900s but seldom used today.
2) It is a short acting agent useful gastric patients
3) Chloral hydrate is used as hypnotic to treat insomnia and to allay anxiety as sedative.
4) The sleep is light, and the patient is readily aroused
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Paraldehyde S
Synthesis:
Properties:
1) Paraldehyde is available as Colorless or pale yellow color liquid.
2) It has strong characteristic odor and is soluble in water.
3) Paraldehyde should be stored in airtight, light protected containers
4) The drug is more potent and toxic than ethanol but less so than chloral hydrate
5) The chief objection to the use of paraldehyde is disagreeable taste, which is difficult to mask
.
Uses:
1) Used exclusively in the management of hospitalized patients undergoing alcohol withdrawal
2) CNS depressant activity resembles at of alcohol and chloral hydrate
Duration of action: 8 hr
Onset of action: 15 min
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Triclofos sodium
Properties:
1) Triclofos sodium is hygroscopic, white color,
2) Water soluble powder
Uses:
1) Used as hypnotic and sedative
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Benzodiazepine derivatives:
Azepine and its tautomers:
Azepine usually denotes 1H, which itself is very unstable and rapidly rearranges to its tautomer 3H
azepine, which is most stable of all Azepines. 2H and 4H are also theoretically possible.
Benzodiazepine derivatives have become increasingly important as antianxiety, anticonvulsant,
antipsychotic, and sedative-hypnotic drugs.
The initial synthesis of the 1,4-benzodiazepines
Diazepines are unsaturated seven membrane ring containing two nitrogen atoms (1,2;1,3;1,4 diazepines
or derivatives of them)
Benzodiazepine and benzodiazepine like drugs bind to a benzodiazepine recognition site, one of
allosteric sites that modulate the effect of GABA binding to GABAA receptor
The benzodiazepine recognition site is an in the extracellular N terminus of the 1,2,3,5 subunits
The field of Chlordiazepoxide by stem bach.
SAR of benzodiazepines for antianxiety acting has been studied, the general structure is:
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1) An electronegative substitution at position 7 is required for activity and more electronegative it is, the hyper
activity.
2) Position 6, 8, 9 should not be substituted
3) Phenyl at position 5 promotes activity.
If this phenyl group is ortho position (2) or Diortho (2, 6) substituted with electron attracting substituents,
activity is increased,
If this phenyl group is Para, substitution decreases activity greatly.
4) Saturation of 4-5 double bond or a shift of it to 3-4 position decreases activity.
5) Alkyl substitution at position 3 decreases activity, substitution with a OH group does not
6) Presence or absence of 3-hydroxyl group is important pharmacokinetically
7) The 2-carbonyl function is optimal for activity, as is the nitrogen atom at position 1
8) The N-substituent should be small; such drugs bind to plasma proteins, the more non-polar the better
binding and greater distribution to brain.
They have few interactions. Low drug abuse, greater margin of safety.
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Chlordiazepoxide S
Trade mane: Librium

Synthesis:
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Properties:
1) Is a colorless crystalline substance
2) Light soluble in water but insoluble in aqueous solution
3) Absorbed well from GIT and excreted slowly
4) Demoxepam is metabolite, which converts to Nordiazepam, which in turn converts to oxazepam,
and this undergoes conjugation to excrete the glucuronides.
5) It is belong to category of sedative
6) Half-life 6 30 hrs
Uses:
1) Used in the treatment of anxiety and tension
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Diazepam S
Trade name: Valium

Synthesis:
Properties:
1) It is white or Colorless crystalline,
3) It should be stored in a well-closed container, protected from light.
Uses:
1) It is used for the control of anxiety and tension state, the relief of muscle spasm, and for the
management of acute agitation during withdrawal from alcohol
2) It has significant anticonvulsant properties
3) Diazepam is metabolized in the liver, one of the metabolites being the 3-hydroxy derivative,
oxazepam, which is also active as sedative and muscle relaxant.
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Oxazepam
Trade name: Serax
Properties:
1) It has a lower incidence of side-effect and reduced toxicity, perhaps due to the ease of conjugation
of the 3-OH group
2) It is one of metabolites of diazepam
3) More polar in nature
4) Duration of action is short
Uses:
1) As anti-anxiety agent
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Clorazepate dipotassium
Properties:
1) This is considered as a prodrug
2) It is inactive itself, undergo rapid loss of water and then decarboxylation to Nordiazepam which has
long life and undergo hepatic conversion to form oxazepam
Uses:
1) As an anti-anxiety agent
2) Its biological activity is due to its rapid invivo decarboxylation and formation of Nordiazepam
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Prazepam
Properties:
1) Prazepam occurs as Colorless, crystalline powder.
2) It is practically insoluble in water but soluble in alcohol and chloroform.
3) The major metabolite is Nordiazepam and hence has long half-life (half-life 63 hrs.)
Uses:
1) It is sedative and antianxiety drug
2) It is used for short-term relief from anxiety
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Lorazepam S
Synthesis:
Properties:
1) It is white powder
6) Lorazepam is related to oxazepam
2) Insoluble in water
7) Owing to its higher lipophilicity, Lorazepam
3) 2-chloro substituted increases activity
requires a lower dose than does oxazepam to
4) Mean half-life is 12 hrs.
produce its anti-anxiety effects
5) Metabolism is rapid because of 3-OH group
Uses:
1) It is used for insomnia due to anxiety
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Halazepam
Properties:
1) It is white crystalline powder
2) Active metabolite is Nordiazepam and oxazepam
Uses:
1) As anxiolytic; half-life is 14 hours
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Flurazepam hydrochloride
Properties:
1) Flurazepam is white or yellow crystalline powder and is odourless
2) Flurazepam occurs as hydrochloride salt
3) Freely soluble in Water and alcohol
Uses:
1) Flurazepam is a hypnotic or minor tranquilizer
2) Exclusively for insomnia
3) Metabolite is N-dealkyl flurazepam.
4) Long half-life, hence has long lasting effect may be up to 1 month.
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Alprazolam S
Synthesis:
Properties:
1) It is a Triazolo analogue of 1,4-benzodiazepine
2) It is short acting benzodiazepine as protein binding is low and oxidative metabolism of methyl group is
rapid
Used:
1) It is highly potent as anxiolytic an a milligram basis.
Mechanism of action
Alprazolam is a short acting benzodiazepine receptor agonist acting at various sites in the CNS.
It has been used for short-term relief of anxiety and mental depression.
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Sedative-Hypnotics and Anti-axiety

Drugs
Barbitura
tes
Non-barbiturates
Barbiatal
Amobar
bital
Pentobarb
ital
Phenoba
rbital
Butabarb
ital
Secobar
bital
Mephobar
bital
Benzodiazepines
Clordiazepoxide
Diazepam
Talobarbi
tal
Oxazepam
Potassium
chlorazepate
Parazepam
Amides
and
imides
Alcohols and
their
carbamate
derivatives
Glutethimide
Ethchloervyno
l
Methaquallon
e
Meprobamat
e
Methyprylon
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Aldehydes
and
their
derivatives
Lorazepam
Chloral
hydrate
Halazepam
Paraldehyde
Flurazepam
Triclofos
sodium
Alprazolam
Page 39
SAEID KASHEFI
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Wilson and gisvolds

Textbook of organic medicinal and pharmaceutical chemistry

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Hypnotic-sedative are used in treatment of some of Insomnias (unsatisfactory or insufficient sleep)

Mechanism of action is by positive modulation of action of GABA at GABAA receptor.

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Structure-Activity Relationships (SAR) of Barbiturates;

Sedatives and Hypnotics and Antianxiety

Mechanism of Action of Barbiturates

Sedatives and Hypnotics and Antianxiety

The salt formation readily takes place in Dioxi form

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Trade name: Barbitone, Veronal

Sedatives and Hypnotics and Antianxiety

Trade name: Luminal

Duration of action: 4-12 hr.

Sedatives and Hypnotics and Antianxiety

Trade name: Prominal

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Duration of action: 2-8 hr.

Sedatives and Hypnotics and Antianxiety

2) Slightly soluble in water

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Duration of action: 2-4 hr.

Sedatives and Hypnotics and Antianxiety

Trade name: Lotusate

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Amides and imides:

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Duration of action: intermediate

Sedatives and Hypnotics and Antianxiety

Alcohols and their carbonated derivatives

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Aldehydes and their derivatives

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Trade mane: Librium

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Trade name: Valium

Sedatives and Hypnotics and Antianxiety

Trade name: Serax

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

Sedatives and Hypnotics and Antianxiety

6) Lorazepam is related to oxazepam

7) Owing to its higher lipophilicity, Lorazepam

3) 2-chloro substituted increases activity

requires a lower dose than does oxazepam to