Sedativesandhypnotics Medicalchemistrybysaeidkashefi Manipaluniversity Mcops 150220123035 Conversion Gate01

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Wilson and gisvolds

Textbook of organic medicinal and pharmaceutical chemistry

Sedatives and Hypnotics and Antianxiety

1/1/2011

Saeid kashefi


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Sedatives and Hypnotics and Antianxiety http://www.slideshare.net 2011

SAEID KASHEFI Page 1

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.

Sedativesare chemical agents tend to produce a calming effect, relax muscles, and relieve feelings oftension, 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 Hypnot icdrugs or Hypnot ics.

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 ofthese drugs.

In reality, almost any drug that calms, soothes, and reduces anxiety is also capable of relieving insomnia.

Antianxietydrugs 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 GABAAreceptor.

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 acting4) 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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BarbitalS

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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PhenobarbitalS

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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AmobarbitalS

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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ButabarbitalS

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) Pentobarbitoneis 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

Duration of action:2-4 hr.



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Talbutal

Trade name:Lotusate

Uses:

1) As short acting barbiturate




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SecobarbitalS

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.

GlutethimideS

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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MethaqualoneS

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 sedative2) 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

alcohol ismon 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

Replacementof a H2atom 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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MeprobamateS

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 hydrateS

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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ParaldehydeS

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 notbe 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 aOH 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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ChlordiazepoxideS

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 630 hrs

Uses:

1) Used in the treatment of anxiety and tension


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DiazepamS

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 aprodrug

2) It is inactive itself, undergo rapid loss of water and then decarboxylation to Nordiazepam which has

longlife 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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LorazepamS

Synthesis:

Properties:1) It is white powder

2) Insoluble in water

3) 2-chloro substituted increases activity

4) Mean half-life is 12 hrs.

5) Metabolism is rapid because of 3-OH group

6) Lorazepam is related to oxazepam

7) Owing to its higher lipophilicity, Lorazepam

requires a lower dose than does oxazepam to

produce its anti-anxiety effects

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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AlprazolamS

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-axietyDrugs

Barbiturates

Barbiatal

Phenobarbital

Mephobar

bital

Amobarbital

Butabarbital

Pentobarbital

Secobarbital

Talobarbital

Non-barbiturates

Amides

and

imides

Glutethimide

Methaquallone

Methyprylon

Alcohols and

theircarbamatederivatives

Ethchloervynol

Meprobamate

Aldehydes

andtheir

derivatives

Chloralhydrate

Paraldehyde

Triclofossodium

Benzodiazepines

Clordiazepoxide

Diazepam

Oxazepam

Potassiumchlorazepate

Parazepam

Lorazepam

Halazepam

Flurazepam

Alprazolam


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Sedativesandhypnotics Medicalchemistrybysaeidkashefi Manipaluniversity Mcops 150220123035 Conversion Gate01