Sedative and hypnotics

1. By:
Dr. Usman Younis

2. SEDATIVE
Drugs that calm the patient and reduce anxiety without inducing
normal sleep.

3. HYPNOTICS
Drugs that produce drowsiness and encourage the onset
of sleep

4. CLASSIFICATION OF DRUGS
 Barbiturates.
 Benzodiazepines ( BDZ ).
 Miscellaneous agents.
 Buspirone
 Chloral hydrate
 Zolpidem
 Zaleplon.
 zopiclon

5. BARBITURATES
 ARE
 CNS depressants
 which produce effects ranging from
 Sedation Reduction of anxiety Hypnosis
and Unconsciousness.
 Barbiturates were
in the past the mainstay of treatment.

6. BARBITURATES
Classification:
Long acting( 24-28 h): Phenobarbitone
Intermediate (8-24h): Amylobarbitone
Short-acting(3-8h):
• Pentobarbitone
• Secobarbitone
• Amobarbital
Ultrashort acting (25 minutes): Thiopentone, Methohexitone.
Bayere dicoverer
of barbiturates.

7. MECHANISM OF ACTION
 GABA the major inhibitory neurotransmitter in the
brain.
 It has specific receptors in chloride channels present
on the membrane of post synaptic neurons.
  regulates the entrance
of chloride into the
postsynaptic cells.

8. MECHANISM OF ACTION
 Binding of GABA to its receptor (GABA A receptor)
 Results in opening of the chloride channel and
  Increased conductance of cl¯ ions to inside the
post-synaptic neuron.  hyperpolarization of the
postsynaptic neuron and
  decreased synaptic neurotransmission.

9. MECHANISM OF ACTION
 Barbiturates increases the cl¯ ion channel opening
(at higher doses open cl¯ ion channels and block Na+
channels)
  Increased conductance of cl¯ ions to inside the
post-synaptic neuron.  hyperpolarization of the
postsynaptic neuron and
  decreased synaptic neurotransmission.

10. PHARMACOKINETICS
Lipid solubility and ionization influence the onset and
duration of action.
 The ultra-short acting
 Drug; Thiopentone is highly lipid soluble (high rate of entry
into CNS- quick onset of action).
b/c
Redistribute in the body from the brain to skeletal
muscles- adipose tissues.

11. PHARMACOKINETICS
 Long-acting agents (less lipid soluble) have slower onset and
longer duration of action.
 metabolized in the liver to inactive metabolites
 Excreted in the urine.
 Alkalinization of urine increases excretion (NaHCO3)
 Cross the placenta ( pregnancy).

12. PHARMACOLOGICALACTIONS
 At Low Doses :
Barbiturates produce sedation
At Higher Doses :
 Produce hypnosis Anaesthesia.
 Overdosage may cause respiratory
depression and death.

13. USES
 ANTICONVULSANT: Phenobarbitone. (tonic-cronic seizures
and eclampsia)
 INDUCTION OF ANESTHESIA: thiopentone and
methohexitone.
HYPNOTIC: pentobarbital (used as sleeping pills).
HYPERBILIRUBINEMIA : pentobarbital
To lower serum bilirubin :
a) Patients with chronic cholestasis
b) Neonatal jaundice (kernicterus)

14. ADVERSE EFFECTS
 Respiratory depression.
 Hangover: residual sedation after awakening.
 Tolerance.
 Physical dependence with prolonged use.
 Teratogenicity.
 Allergic reaction: urticaria and skin rash.
Toxicity : Respiratory depression, Cardiovascular collapse, coma
and death.

15. BENZODIZEPINES
 The most widely used anxiolytic drugs.
 They have largely replaced barbiturates in the
treatment of anxiety,
Since
 BZs are more effective and safer.
 BZs induce sleep when given in high doses at
night.
 provide sedation.
 reduce anxiety when given in low, divided
doses during the day.

16. BENZODIZEPINES
 Sedative (Anxiolytics) :
Alprazolam Chlordiazepoxide lorazepam
Diazepam lorazepam
 Hypnotics :
Triazolam Diazepam Alprazolam
Lorazepam Estazolam Temazepam
Flurazepam Nitrazepam Quazepam
 Preanesthetics :
Diazepam - Midazolam
Leo sternback

17. MECHANISM OF ACTION
 GABA the major inhibitory neurotransmitter in the
brain.
 It has specific receptors in chloride channels present
on the membrane of post synaptic neurons.
  regulates the entrance
of chloride into the
postsynaptic cells.

18. MECHANISM OF ACTION
 BZs bind to specific, high affinity BZ receptors
present in CNS.
 These receptors are separate but adjacent to the
receptor for GABA.
 The binding of BZ enhances the affinity of the
GABA receptors for GABA neurotransmitter.
 Resulting in a more frequent opening of adjacent
chloride channels.
 The increased influx of Cl- into the neuron results
in enhanced.
 Hyperpolarization and inhibition of neuronal
firing

19. PHARMACOKINETICS
 BZs are lipophilic.
 Rapidly and completely absorbed after oral administration.
 Redistribution from CNS to skeletal muscles, adipose tissue.
 Cross placental barrier during pregnancy.
 Metabolized by the liver.
 Highly bound to plasma protein.
 Excreted in urine and milk (Fetal & neonatal depression).

20. Therapeutic uses
ANXIETY DISORDERS : alprazolam, lorazepam,
lorazepam, diazepam and chlordiazepoxide.
Alprazolam has anxiolytic-antidepressant effect.
Diazepam is preferred in acute panic-anxiety.
Chlordiazepoxide is preferred in chronic anxiety states.

21. Therapeutic uses
INSOMNIA : in ability to sleep.
Triazolam, lorazepam is effective in treating individuals
who have difficulty in going sleep.
Flurazepam, temazepam & nitrazepam is useful for
insomnia caused by inability to stay asleep.

22. Therapeutic uses
To control withdrawal symptoms of alcohols
diazepam- chlordiazepoxide.
Anticonvulsants:
 Diazepam – Lorazepam: Status epilepticus
 Clonazepam-Clorazepate: in chronic treatment of epilepsy.
Muscle relaxation: in spastic states (Diazepam) .

23. Therapeutic uses
In Anesthesia :
Preanesthetic medication diazepam
Induction of balanced anesthesia (Midazolam)

25. ADVERSE EFFECTS
 Ataxia (motor incoordination), cognitive impairment.
 Hangover, drowsiness, confusion (especially in long acting
drugs)
 Tolerance
 Physical and Psychological dependence (in high doses)
 Withdrawal symptoms (Abrupt discontinuation of BZs)
 Insomnia, anorexia, anxiety, agitation, tremors
and convulsion.(Abrupt discontinuation of BZs)

26. DOSE RESPONSE CURVE OF DRUGS
Drug-A = Barbiturates , Drug-B = Benzodiazepines.

27. MISCELLANEOUS
AGENTS

28. ZOLPIDEM
 A hypnotic.
Rapid onset and a short duration of action
(about 4 hours)
Its efficacy is similar to benzodiazepines.
 Minor effect on sleep pattern, but high doses
suppress REM.

29. MECHANISM OF ACTION
Zolpidem binds selectively to a subset of the
BZs receptor family
and facilitates GABA-mediated neuronal
inhibition.

30. Advantages
. Rapid onset
. No withdrawal effects.
. Minimal insomnia.
. Little or no tolerance with prolonged use.
. Minimal muscle relaxing effect.
. Respiratory depression occurs only if large
doses of zolpidem are ingested.
. Antagonized by flumazenil

31. THERAPEUTIC USES AND
ADVERSE EFFECTS
 a hypnotic drug for short term treatment of insomnia
 Dose should be reduced in hepatic or old patients.
Adverse Effects
GIT upset
Drowsiness
Dizziness

32. BUSPIRONE
 Buspirone is a non-sedating.
 Alternative to BZs
but
 It may take up to four weeks
to act. (Useful in chronic anxiety states)

33. Advantages
 No hypnotic, anticonvulsant, or
muscle relaxant properties.
 It has minimal abuse liability.
 Buspirone causes less psychomotor
impairment than BZs and does not affect
driving skills.
 The drug does not potentiate the CNS
depressant effects of other sedative-hypnotics,
ethanol or tricyclic antidepressants.