Sedatives and hypnotics

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1. Sedatives and hypnotics
Abhijit Sukul

2. Sedative (Anxiolytic):
A sedative agent should reduce anxiety.
A sedative should exert a calming effect with
little or no effects on motor or mental
functions.
Depression of CNS should be the minimum
consistent with therapeutic efficacy.

3. Hypnotic:
A hypnotic drug should produce drowsiness.
Should encourage the maintenance of a
state of sleep that resembles the natural
sleep states.
CNS depression should be more
pronounced than sedation.

4. Hypnosis:
Hypnosis is a subconscious condition in which the objective
manifestations of the mind are more or less inactive, accompanied
by abnormal sensitibility.
Increasing dose Increasing dose
(Sedative) (Hypnotics)
CNS effect
CNS effect
Figure: Dose-response curves for two hypothetical sedative-hypnotics.

5. Classification:
Barbiturates:
Long acting: Phenobarbitone, Mephobarbitone.
Intermediate acting: Amytobarbitone.
Short acting: Hexobarbitone.
Ultra short acting: Thiopental-Na.
Benzodiapines: Diazepam, Lorazepam, Oxazepam.
Aldehyde derivatives: Paraldehyde.
Alcohol derivatives: Ethanol, Chloral hydrate.
Cabamets: Ethinmate.
Inorganic: KBr, NaBr.
Miscellaneous: Scopolamine, Antihistamine.
Newer agents: Zopiclone, Zolpidem.

6. Barbiturates:(Chemistry).
Barbiturates have been popular
hypnotics and sedatives of the
present century upto 1960s but are not
preferred now. However, they are
described first as they are the
prototype of CNS depressants.
Barbiturates are substituted derivatives
of barbituric acid (malonyl
urea).Barbituric acid as such is not a
hypnotic but compounds with alkyl or
aryl substitution on C-5 are.
Replacement of O with S at C-2 yields
thiobarbiturates,
Malonic
acid
↓
Barbituric
acid
↓
Barbiturates

7. Structures
which are more lipid
soluble and more potent.
Barbiturates have variable
lipid solubility; the more
soluble ones are more
potent and shorter
acting. They are insoluble
in water but their sodium
salts dissolve yielding
highly alkaline solution.
Basic structure of barbiturates

8. Classification:
According to chemical structure:
Oxybarbiturates: Oxygen present in position C2.
Thiobarbiturates: Sulfur present in position C2.
According to duration of action:
Long acting:
Duration of action: >6 hours.
Main use: As anticonvulsant
Examples: Phenobarbitone, Barbital.

9. Intermediate acting:
Duration of action: 3 – 5 hours.
Main use: As hypnotic.
Examples: Amobarbital, Butabarbital.
Short acting:
Duration of action: 2 hours.
Main use: As sedative.
Examples: Pentobarbital, Hexobarbital,
Secobarbital.
Ultra-short acting:
Acts within few seconds.
Duration of action: 30 minutes.
Main use: As intravenous anaesthetic.
Examples: Thiopental-Na.

10. According to therapeutic activity:
Anticonvulsant and sedative:
These are long acting barbiturates.
Duration of action: >6 hours.
Examples: Phenobarbitone, Barbital.
Sedative and hypnotics:
These are intermediate and short acting barbiturates.
Duration of action: 2 – 5 hours.
Examples: Amobarbital, Pentobarbital, Hexobarbital,
Secobarbital.
General anaesthesia:
These are ultra short acting barbiturates.
Acts within few seconds.
Duration of action: 30 minutes.
Examples: Thiopental-Na.

11. Modification of Barbiturates duration of
action:
Barbiturates
↓
High lipid soluble
↓
↑Absorption
↓
↑Metabolism
↓
↑Redistribution
↓
↓Duration of action
↓
↑Potency

12. SAR

13. Mechanism of action of barbiturates:
Barbiturates + GABA-receptor
↓
Activation of GABA receptor
↓
Opening of chloride channel
Increase the duration of GABA gated channels opening
↓
Hyperpolarization of cells
↓
Depression of CNS
Fig: Overview of the mechanism of action barbiturates

14. Pharmacological action of barbiturates:
1. CNS:
Low dose: Sedative action.
High dose: Hypnotic action.
More higher dose: Anesthesia and finally coma and death.
2. Respiratory depression:
Barbiturates suppress the hypoxic and chemoreceptor
response to CO2, and over dosage is followed by
respiratory depression and death.
3. Enzyme induction:
Barbiturates induce P-450 microsomal enzymes in the
liver. Therefore, chronic barbiturate administration
diminishes the action of many drugs that are
dependent on P-450 metabolism to reduce their
concentration.

15. 4. CVS:
Low dose: ↓ Blood pressure, but not marked.
High dose: Marked fall in B.P.
Toxic dose: Depression of vasomotor center.
↓
↓Cardiac contractility
↓
Reflex tachycardia
5. Smooth muscle:
Tone and motility of bowel is decreased slightly by
hypnotic doses.
6. Kidney:
Reduce urine flow by –
Reducing B.P.
Increasing ADH (anti-diuretic hormone)

16. Pharmacokinetics:
 Barbiturates are well absorbed from the GI
tract and distributed widely throughout the body.
 The rate of entry into CNS is dependent on
lipid solubility, highly lipid soluble thiopentone
take shorter time (4½ hrs) and less soluble
Pentobarbitone takes longer time (9 hrs).
 Plasma protein binding varies with the
compound, e.g. thiopentone 75%,
Pentobarbitone 35%.
 Barbiturates cross placenta and are
secreted in milk.

17. Three stages need for terminate action.
Redistribution
Metabolism
Excretion
Redistribution: It is important in the lipid soluble
thiopentone and other ultra short acting
barbiturates. After their IV injection,
consciousness is regained in 15 – 20 min due to
redistribution. Effect of single dose of short acting
barbiturate may last just 6 – 10 hrs due to
redistribution, while elimination t½ is 15 – 50
hrs.

18. Metabolism: Drugs with intermediate lipid
solubility (short acting barbiturates) are
primarily metabolized in liver by oxidation,
dealkylation and conjugation. Their plasma
t½ ranges from 12 – 40 hrs.
Excretion: Barbiturates with low lipid solubility
(long acting agents) are significantly
excreted unchanged in urine. The t½ of
Phenobarbitone is 80 – 120 hrs.

19. Therapeutic use:
As sedative-hypnotics.
As anticonvulsant
As antiepileptic.
Pre-anesthetic medication.
General anesthesia.
Congenital non-haemolytic,
jaundice, kernicterus.

20. Adverse effect:
1. CNS related:
Drowsiness
Impaired concentration
Mental and physical sluggishness.
2. Drug hangover:
Tiredness
Lethargy
Weakness
Nausea
Dizziness
3. Idiosyncrasy:
In occasional patient barbiturates produce excitement.
This is more common in the elderly. Prescription of porphyria in
susceptible individuals.

21. 4. Tolerance:
Both cellular and pharmacokinetics tolerance develops
on repeated use.
5. Dependence:
Both physiological and psychological dependence occurs
on repeated use. Withdrawal symptoms are –
Excitement
Hallucinations
Delirium
Convulsions
6. Drug automation:
Drug accumulation in body and it is a toxic
effect.

22. Benzodiazepines:
Mechanism of action:
Benzodiazepines
↓
Binds with specific regulatory sit on the GABA receptor in the brain
↓
Opening of Cl- channels
↓
Influx of Cl-
↓
Enhancement of Cl- conductance
↓
Hyperpolarization of cells
↓
Action potential
↓
CNS Depression
(Postsynaptic inhibition)

23. Pharmacological action:
a. CNS:
Anxiolytic: At low doses, the benzodiazepines are anxiolytic.
Sedation and induction of sleep
Hypnotic: At higher doses (benzodiazepines) produce hypnosis
(artificially-produced sleep).
Muscle relaxation (skeletal): By increasing Pre-synaptic
inhibition in the spinal cord.
Anticonvulsant effects: Several of the benzodiazepines have
anticonvulsant activity and are used to treat epilepsy and other
seizure disorder.
Anterograde amnesia
b. Peripheral:
Neuromuscular blockade (high dose)
Coronary vasodilation (IV)

24. Therapeutic uses:
1. Anxiety disorders:
The benzodiazepines are useful in treating the anxiety that
accompanies some forms of depression and schizophrenia.
These drugs should not be used to alleviate the normal
stress of everyday life, but should be reserved for continued
severe anxiety, and then should only be used for short
periods of time because of addiction potential.
The long acting agents such as diazepam are often preferred in
those patients with anxiety that may require treatment for
prolonged period of time.
The antianxiety effects of the benzodiazepines are less subject to
tolerance than the sedative and hypnotic effects.
For panic disorders, alprazolam is effective for short and long-
term treatment, although it may cause withdrawal reactions
in about 30% of sufferers.

25. 2. Muscular disorders:
Diazepam is useful in the treatment of skeletal muscle
spasms and in treating spasticity from digestive
disorders.

3. Seizures:
Clonazepam is useful in the chronic treatment of epilepsy.
Chlirdiazepoxide, clorazepate, diazepam and
Oxazepam are useful in the treatment of alcohol
withdrawal.
4. Sleep disorders:
According to hypnotic action ..
Long acting: Flurazepam.
Intermediate acting: Temazepam.
Short acting: Triazolam.

26. Flurazepam:
Reduce sleep induction time.
Reduce the number of awakening
Increase the duration of sleep.
Cause little rebound insomnia.
Flurazepam and its active metabolites have a
half-life of approximately 85 hrs, which may
results in daytime sedation and accumulation
of the drug.
Side effects:
Daytime sleep
Accumulation of drug

27. Temazepam:
Reducing no. of wakening.
Use ful in insomnia.
The peak sedative effects occurs 2-3 hrs after an
oral dose, and therefore it may be given several
hours before bedtime.
Triazolam:
Relatively short duration of action.
Reduce induction period.
Use intermittently.
Side effects: Difficulty in going to sleep.
Tolerance frequently develops within a few days, and
withdrawal of the drug often results in rebound
insomnia.

28. Pharmacokinetics:
1. Absorption and distribution:
The benzodiazepines are lipophillic and are rapidly and
completely absorbed after oral administration and are
distribution throughout the body.
2 Duration of action:
Long acting: 1 – 3 days. Example: Diazepam, Flurazepam.
Intermediate acting: 40 – 30 hrs. Example: Lorazepam,
Temazepam.
Short acting: 3 – 8 hrs. Example: Oxazepam, Triazolam.
3. Fate / Metabolism:
Most benzodiazepines, including chlordiazepoxide and diazepam,
are metabolized by the hepatic microsomal metabolizing
system to compounds that are also active.
4. Excretion:
The benzodiazepines are excreted in urine as glucuronides or
oxidized metabolites.

29. Zolpidem:
Although the hypnotic zolpidem is not a
benzodiazepine, it acts on a subject of the
benzodiazepine receptor family. Zolpidem has no
anticonvulsant or muscle relaxing properties. It
shows no withdrawal effects, exhibits minimal
rebound insomnia and little or no tolerance occurs
with prolonged use.
Pharmacokinetics:
It is rapidly absorbed from the GIT.
Adverse effects:
Nightmares
Agitation
Headache
Dizziness

30. The End