Sedatives & Hypnotic

By

Dr. N. C. Baruah

Physiology of sleep

• Sleep is a reversible process controlled by numbers of neuronal functions. In sleep the sensory and motor neurons are inactive and the cortical centres are less responsive to the external stimuli, whereas the cortical responses to the external stimuli are unresponsive in unconsciousness.

• The Reticular formation is a network of groups of nerve cells in the brain stem (mid brain, pons & medulla) that relays signals to the higher cortical centres of the brain for conscious response.

• The sleep-wake cycle is regulated by the reticular formation.

Physiology of sleep

• According to the Ascending Reticular Activating System (ARAS) hypothesis, the sleep-wake cycle and its regulation are maintained by endogenous circadian rhythm and homeostatic mechanisms of the body.

• Various neuronal pathways are involved in the functioning of the reticular formation which include the serotonergic (5-HT) neurons, cholinergic neurons, adrenergic neurons of the locus coeruleus (LC), dopaminergic neurons of the midbrain. The histaminergic neurons are also playing important roles in the sleep-wake cycles.

Physiology of sleep

• The histamine release is increased during wakefulness, which is under control of Glutaminergic-stimulatory and GABAergic-inhibitory pathways.

• The posterior hypothalamus is involved in arousal and anterior hypothalamus (the Suprachiasmatic nucleus, SCN) induces sleep.

• This SCN is also controlled by Glutaminergic-stimulatory and GABAergic-inhibitory pathways.

• The SCN receives visual signal from the retina via retinohypothalamic system and maintain circadian rhythm.

• The pineal gland receives GABAergic signal that decreases as the daylight decreases.

Physiology of sleep

• The SCN release less amount of Noradrenaline at the pineal gland because of inhibitory signal of GABA at daylight.

• At night or at darkness the GABA release is less so adrenaline release is more at the pineal gland.

• Then the pineal gland secretes more melatonin, which is responsible for induction of sleep.

• The amino acid tryptophan in the pineal gland is sequentially converted to serotonin, which is then converted to acetyl serotonin and then to melatonin.

Sedatives & Hypnotics

• The sedatives are the drugs which decrease

activity; moderate the excitements and produce

calming or drowsiness of the recipient without

inducing sleep.

• Many drugs have sedative effects.

• Sedatives are used in the management of

anxiety.

Hypnotics

• The Hypnotics induce and maintain sleep

resemble to normal sleep.

• The subject can be aroused easily.

• Hypnotics are used in the treatment of

insomnia.

Sedative–Hypnotics

• The sedatives differ from hypnotics in terms of

its dose and time of action.

• A hypnotic has quicker onset and shorter

duration of action with a steep rise in action.

• A sedative has slower onset, longer duration

and flat rise in action.

Classification of Sedative-Hypnotics

• The sedative-hypnotics are classified according to their chemical structures.

– Barbiturates

– Benzodiazepines

– Non-benzodiazepines

– Halogenated Sedative-Hypnotics

– Heterocyclic Sedative-hypnotics

– Miscellaneous compounds

Barbiturates

• The barbiturates are barbituric

acid (malonyl urea)derivatives.

• The barbituric acid does not

have a hypnotic property.

• The 5,5-di-alkyl or aryl substituted barbituric acid derivatives are potent hypnotics.

• The substitution of oxygen by sulphur at C-2 position produces thiobarbiturates with good lipid solubility.

• They are more potent and are used as general anesthetics.

Barbituric acid

1 2

3 4

5

Barbiturates

• Sodium salts of the Barbiturates are water soluble.

• These aqueous solutions are alkaline and are incompatible with acidic solution, which results in formation and precipitation of the free water-insoluble barbiturates.

• Barbiturates are central nervous system depressants.

• Barbiturates are sedative at low doses and hypnotics at higher doses.

• They can produce anaesthesia at more higher doses.

• Barbiturates have been used as sedative to relieve anxiety, as anticonvulsant in the epileptic seizures and as hypnotic to induce sleep.

• Barbiturates enhance chloride ion influx at GABA linked chloride channel.

Barbiturates are divided into four classes

• Barbiturates with long duration of action (more than 6 hours)- Mephobarbital, Phenobarbital (anticonvulsive).

• Barbiturates with intermediate duration of action (3-6 hours)-Amobarbital and Butobarbital

( sedative-hypnotics).

• Barbiturates with short duration of action (less than 3 hours)- Pentobarbital and Secobarbital

( sedative-hypnotics).

• Barbiturates with ultra short duration of action (~20 minutes) – Thiopental an Methohexital are used as intravenous anaesthesia.

Barbiturates

1

2

3

4

5

6

Barbiturates

Mephobarbital

Phenobarbital

Amobarbital

Butobarbital

Barbiturates

• .

Pentobarbital

Secobarbital

Benzodiazepines

• Benzodiazepines have been used most widely as Anxiolytic drugs.

• They are chemically seven member 1,4- benzodiazepines.

• Benzodiazepines have a higher therapeutic index, therefore safer than barbiturates.

• The hypnotic doses of benzodiazepines do not affect the respiratory and cardiovascular function.

• That is why, benzodiazepines replaced barbiturates as Anxiolytic in the treatment of anxiety.

Benzodiazepines

• They act in a different binding site of the GABA receptor linked chloride channel.

• Benzodiazepines have been used as hypnotics.

Flurazepam, Temazepam and Triazolam are

useful as long acting to short acting Anxiolytic.

• Psychological and physical dependence can

develop if high doses of benzodiazepines are

used for prolong periods.

• Flumazenil is a GABA antagonist that rapidly reverses the effects of benzodiazepines.

Benzodiazepines uses

• The most common Benzodiazepines used as

hypnotics are

• Chlordiazepoxide, Diazepam,

• Flurazepam, Quazepam,

• Oxazepam, Lorazepam,

• Temazepam.

• Triazolobenzodiazepines: Alprazolam,

Triazolam, Midazolam.

Benzodiazepines

Benzodiazepine

Diazepam

Flurazepam

Quazepam

Oxazepam

Lorazepam

Benzodiazepines

Temazepam

Alprazolam

Triazolam

Midazolam

Chlordiazepoxide

Zolpidem

Uses of Benzodiazepines

• Other uses of Benzodiazepines include:

• Anticonvulsant: Diazepam, Clonazepam and Lorazepam.

• Hypnotics: Flurazepam, Temazepam & Triazolam.

• Muscle relaxants: Diazepam.

Non-benzodiazepines

There are some Non-benzodiazepines which are used for short term and moderate acting hypnotics. They also exhibit high selectivity in binding to the GABA receptor.

The drugs of this group are Zolpidem, Eszolpiclone and Zaleplon

Zolpidem

Zaleplon

Melatonin agonist

• There are three melatonin receptors in the brain, the MT1, MT2 and MT3. activation of MT1 receptor induces sleep. Tryptophan is sequentially metabolised to melatonin.

• Tryptophan Serotonin N-acetyl serotonin Melatonin

Serotonin

Melatonin (hormone)

Ramelteon(drug)

Alcohol and their carbamate

• Alcohol and Carbamate derivatives: Ethchlorvynol, Meprobamate, Carisoprodol, Mephenesin and Chlorphenesin carbamate

• Ethchlorvynol is a mild sedative-hypnotic.

• It is chemically 1-chloro-3-ethyl-1-penten-4-yn-3-ol.

• This is a effective hypnotic but it has the addiction liability.

Ethchlorvynol

Alcohol and their carbamate

• Meprobamate is a skeletal muscle relaxant and

used and hypnotic-sedative and anti-anxiety agent.

• Carisoprodol is a derivative of Meprobamate and used as skeletal muscle relaxant

• Triclofos is a phosphate ester of ethanol.

• It is readily converted in the body to its active form trichloroethanol.

Meporobamate

Carisoprodol

Triclofos

Alcohol and their carbamate

.

Mephenesin

Chlorphenesin carbamate

Guaifenesin

Methocarbromol

Aldehyde and derivatives

• Chloral hydrate is rapidly absorbed from the stomach, but metabolized to active trichloroethanol, that gives longer duration of action.

Chloral

Chloral hydrate

Trichloroethanol

Aldehyde and derivatives: Paraldehyde

• Paraldehyde is potent hypnotic when applied orally or rectally.

• It is oxidised to acetic acid on storage.

• It has disagreeable taste and potent odour after administration, which is the reason of objection to the drug

Paraldehyde

Heterocyclic Sedative-hypnotics

• Amides and imides: Glutethimide (Doriden) is 2-ethyl-2-phenylglutarimide.

• It induces sleep in simple insomnia.

• The drug is presently not used because of addiction liability.

• Methyprylon (Noludar) is a piperidinedione derivative.

• Structurally it is related to barbiturates.

• It has been used to induce sleep in simple insomnia.

• Methaqualone is a quinazolinone derivative having sedative and hypnotic effects.

• It has been contraindicated in pregnancy.

• Long term use leads to psychological and physical dependence.

Heterocyclic Sedative-hypnotics .

Glutethimide

Methiprylon

Methaqualone

GABA receptor

+ + + + + + + + + +

+

- - - - - - - - - -

Cl-

Closed Cl- channel

GABA binding site, Empty

+ + + + + +

- - - - - - - -

No GABA at binding site , Chloride channel is closed

GABA receptor

+ + + + +

+ + + + +

+

- - - - - - - - - -

Cl-

Hyperpolarised membrane

GABA binding at receptor site,

+ + + + + +

- - - - - - - -

Binding of GABA at receptor opens Chloride channel

GABA

- - - - - - - - - - - - - - - -

Chloride channel

Cl- ions

+

Binding sites in the GABA receptor linked

Chloride channel

GABA

GABA

BDZ

Bar

References

• Foye’s Principles of Medicinal Chemistry, 7th

edition.

• Wilson & Gisvold’s Textbook of Organic

Medicinal and Pharmaceutical Chemistry, 12th

edition.

• Burger’s Medicinal Chemistry & Drug Discovery,

sixth edition, Vol-6.