Sedatives and hypnotics

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

HYPNOTICS
Drugs that produce drowsiness and encourage the onset
of sleep

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

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.

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.

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.

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.

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.

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.

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).

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

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)

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.

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.

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

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

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).

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.

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.

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) .

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

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)

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

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.

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

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

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

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

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.

Sedatives and hypnotics

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