SEDATIVES AND HYPNOTICS

1. DRUGS ACTING IN CENTRAL NERVOUS SYSTEM, SEDATIVES AND HYPNOTICS
OBJECTIVES:
 Introduction- insomnia, sedatives and hypnotics definitions
 Sedatives and hypnotics Drugs classification.
 Ideal hypnotics properties.
 Barbituric acid derivatives- mechanism of action, classification of barbiturates SAR of barbiturates, barbiturates
drugs and their properties.
 Benzodiazepines, mechanism of action, SAR, drugs and their properties.
INTRODUCTION:
Insomnia is sleeplessness. Type of sleep disorder Individuals with insomnia find it difficult to fall asleep. People with
insomnia often don’t feel refreshed when they wake up from sleeping, either. This can lead to fatigue and other
symptoms.
Various medical disorders can cause insomnia. Various drugs causing insomnia are alcohol, antihypertensive,
antineoplastic, β-blockers, caffeine, oral contraceptives, theophylline etc.
SEDATION: IT IS A MILD DEPRESSION OF CNS without causing drowsiness, used in emotional stress,
hypertension, convulsions and preanaesthesia etc.
HYPNOSIS: it is a strong depression of CNS causing sleep and is used in insomnia. The drugs used as hypnotics can
be used as sedatives and anxiolytics (in low dose).
Sedatives and hypnotics are CNS depressants associated with reduction of anxiety and induction of sleep. Small
doses causes sedation and higher doses causes hypnosis.
Drug classification:

2. IDEAL HYPNOTICS PROPERTIES:
 It should decreases consciousness for sleeping without lingering effects.
 It should have no potential for decreasing or stopping respiration.
 It should not produce abuse, addiction, tolerance or dependence.
A). BARBITURIC ACID DERIVATIVES:
The barbiturates are the derivatives of 2, 4, 6-trioxohexa-hydropyrimidine that reversibly depresses the activity of
all the excited tissues and are synthesized by the condensation of malonic acid derivatives with urea derivatives. CNS
depressant barbiturates are mainly 5, 5- disubstituted barbiturates and 1, 5, 5-trisubstituted barbiturates.

3. Barbiturates are cyclic acyl derivatives of urea. These are acidic in nature due to Lactam – Lactam and keto-enol
tautomerism. (Lactam ketol, lactam enol, enolate)
Mechanism of action:
 Barbiturate promotes the binding of benzodiazepines to GABAA receptors.
 A barbiturate potentiates GABA-induced chloride currents causes bursts of channel opening. Only α and β (not γ)
subunits of GABA receptors are required for action.
 Cause increase in chloride conductance and activates the agonist.
Barbiturates subclasses:
 Long acting barbiturates (6-8 hours) Eg. Phenobarbitone, Metharbital methyl phenobarbitol
 Intermediate acting barbiturates (2-4 hours) Eg. Amobarital, butabarbital
 Short acting barbiturates (1-2 hours) Eg. Pentobarbital, Secobarbital
 Ultra short acing barbiturates (few seconds to few minutes) Eg. Thiopental.
SAR of barbiturates:
The main prototype drug in this category in Barbituric acid 2,4,6-trioxohexahydropyrimidine. It lacks CNS depressant
activity but substitution at various positions gives many compounds with sedative and hypnotic activity. Structural
modifications have been done at various at various positions of Barbituric acid.

4. Generally a substitution has been done at 1 st and 5 th position.
1. Both the H atoms at 5 th position replaced by alkyl group or aryl group so that drug can easily cross the blood brain
barrier (BBB). For example, phenobarbitone.
2. Branching of alkyl chain at 5 th position increases the lipid solubulity with shorter duration of action. Higher the branching
grater will be potency of the drug . for example, pentobarbitone is more potent than amylobarbitone. (
amylobarbitone)
3. Substitution made of –CH3 group at 1st
position increases the lipid solubility with shorter duration of action. For example,
phenylphenobarbitone.
4. Total number of alkyl groups at 5 th position must be between4 to 10 for maximum potency, beyond that CNS depressant

5. 5. Shortening of alkyl chain resist oxidation of the drug and it act as a long acting drug for example, baritone.
6. Substitution to both N1and N3 by alkyl groups eliminates sedatives action of a drug.
7. Substitution of polar groups like –OH, -NH2, -C=0 in to alkyl side chain at 5th
position. Reduces or abolishes hypnotic activity
of the drug.
8. Isosteric replacement of oxygen at 2nd
position by sulphur gives thiobarbiturates having increased
lipophilicity and shorter duration of action. Drug will have increased CNS depressant activity and known as ultra-short acting
barbiturates. For example, thiopentone.
9. Isometric replacement of oxygen at position 2, 4, 6 by more sulphur atoms abolishes the hypnotics’ activity of the
compound.
Various drugs belongs to the category are:
1. Barbital:
Properties: it is a white crystalline powder or colorless crystal. It is slightly soluble in water, soluble in boiling water. It
forms water soluble compounds with alkali hydroxides.
Mechanism of action: it inhibits central nervous system and causes its depression by stimulating the inhibitory
neurotransmitter system in rain called GABA (gamma amino butyric acid).
Synthesis:

6. Uses: it is generally used in the treatment of epileptic seizures.
It is also used as sedative and hypnotic in the treatment of insomnia.
2. Phenobarbital:
Properties: it is a white or colorless crystalline powder, very slightly soluble in water but soluble in solution of alkali
hydroxide, aqueous ammonia or carbonates solution.
Mechanism of action: it acts by stimulating GABA receptor and depression of CNS.
Uses: it is used both sedative and hypnotics.
Phenobarbitone has anticonvulsant effect so it is drug of choice in the treatment of grandmal and petitmal
epilepsy.
3. Amobarbital oramylobarbitone:
Properties: it is white crystalline powder, slightly soluble in water. It is soluble in aqueous solutions of basic hydroxides
and carbamate.

7. Mechanism of action: it activates GABA receptor which increases the duration and conductance of chloride
channels and finally depresses the CNS.
Uses: it is used as sedative and hypnotic.
It has some anticonvulsant activity also, so use in the treatment of epilepsy.
4. Pentobarbital:
Properties: it is colorless or white crystalline powder which is slightly soluble in water, soluble in aqueous
solution of ammonia alkali hydroxides and carbamate.
Mechanism of action: it is ac t by stimulating GABA receptor by binding at distinct site.
Uses: it is used as sedative and hypnotic for short term preanaesthetic procedure It is used in emergency to
control convulsions.

8. BENZODIAZEPINES
Benzodiazepines have sedative, hypnotic, anti-anxiety, anticonvulsant and muscle relaxant properties. They are most widely used
anxiolytic drug used oo treat anxiety, insomnia and a range of other conditions. Benzodiazepines have largely replaced barbiturates in
the treatment of anxiety, because they
are safer and more effective. At low dose are useful as sedative and at high doses produce a hypnotic
effect. Basic structure of benzodiazepines is
Benzodiazepines are lipophilic, rapidly and completely absorbed after oral administration and distributes throughout the
body. These are excreted in the urine as glucuronides or oxidized metabolites.
Mechanism of action of benzodiazepines: benzodiazepines work by increasing the effect of the neurotransmitters HABA
which is responsible for reducing the activity of neurons that causes stress and anxiety.
SAR OF BENZODIAZEPINES:
The basic ring structure of benzodiazepines is as follows:
Several substitutions have been made to the basic skeleton of benzodiazepines to get various compounds.
1. In the ring A an electron withdrawing group like -Cl, -Br, -NO2, or CN at 7th position Increasing the activity. For
example Flurazepam.
2. Small groups like –CH3, or C2H5 attached to the nitrogen atom at 1 st position in the ring B has optimal activity.
For example Flurazepam.

9. 3. Replacement of carbonyl function with two hydrogen’s at 2nd positions gives Medazepam which is
less effective.
4. Introducing of carbonyl functional group at the 3rd position increases the duration of action and also favor,
formation of water soluble salts.
5. Saturation of 4,5 double bond reduces potency.
6. A phenyl substituent at 5th position increases activity. If this phenyl group has electronegative substituent like –
CL and –F at the ortho and diorhto positions activity is improved.
Various drugs belong to the category:
1. Chlordiazepoxide:

10. Properties: it is white or yellowish crystalline powder. It is practically insoluble in water. It should be stored be
stored in tightly closed container protected from light. Mechanism of action: it increases activity GABA ( γ-
amino butyric acid) in the brain. Uses: it is used in the treatment of anxiety and insomnia.
It is also used in the treatment of withdrawal symptoms from alcohol Eg.
Muscle spasms.
It is used in combination with clidinium bromide to treat symptoms of irritable bowel syndrome.
2. Diazepam:
Properties: it is a white or yellowish white crystalline powder. It is sparingly soluble in water. It should be stored
in well closed container protected from light.
Mechanism of action: it produces effects by interacting with GABA receptors which are the main inhibitors in
action. Diazepam increases the action of GABA and cauases depression of the CNS reduces anxiety.
Synthesis:

11. Uses: it is used in the treatment of anxiety and insomnia.
It is also used to treat symptoms of alcohol withdrawal
It is used as a premedication for the induction of sedation.
It is used to treat muscle spam, seizures and restless legs syndrome.
3. Oxazepam:
Properties: it is a white crystalline powder, practically insoluble in water. It should be kept in a well closed,
light resistant container. It is a metabolite of diazepam and itself gets converted into glucuronide on metabolism.
Mechanism of action: its mechanism of action is just similar to that of diazepam.
Uses: it is used in the treatment of insomnia.
It is commonly given for anxiety disorder associated with agitation and tension

12. 4. Alprazolam:
Properties: it is a white crystalline insoluble in water. It is closed in well closed container and protected from light. It
is well absorbed and metabolized by liver. Mechanism of action: it produces effects by interacting with GABA
receptors which are the main inhibitors in action. Diazepam increases the action of GABA and causes depression of
the CNS reduces anxiety.
Uses: it is used in the treatment of anxiety. It is used as sedative, hypnotic, and skeletal muscle relaxant, anti-
convulsion and antidepressant.
5. Zolpidem:
Properties: it is white or almost crystalline powder which is hygroscopic in nature and slightly soluble in water. It is stored
in airtight container and protected from light.
Mechanism of action: Zolpidem have high affinity towards α1 subunits of GABAA receptors and increase its activity.
Uses: it is used as hypnotic and sedative in treatment of insomnia.

15. qq