Hypnotics

HYPNOTICS AND SEDATIVES
Non Benzodiazepine hypnotics

• Cloral hydrate
• ZOLPIDEM
• ZALEPLON
• ZOPICLONE (ESZOPICLONE)
Miscellaneous
• MELATONIN
• RAMELTEON
BARBITURATES CLASSIFIED ACCORDING TO THEIR
DURATIONS OF ACTION
Barbiturates Bezodiazepines
• enhance the binding of GABA to
GABAA receptors • enhance the
• Prolonging duration binding of GABA to
• Only α and β (not ϒ ) subunits GABAA receptors
are required for barbiturate
action • increasing the
• Narrow therapeutic index frequency
• in small doses, barbiturates • Unlike
increase reactions to painful barbiturates,
stimuli.
• Hence, they cannot be relied on benzodiazepines
to produce sedation or sleep in do not activate
the presence of even moderate GABAA receptors
pain.
directly
BARBITURATES
Mechanism of Action- Bind to specific GABAA receptor subunits at
CNS neuronal synapses facilitating GABA-mediated chloride ion channel
opening, enhance membrane hyperpolarization.
Effects- Dose-dependent depressant effects on the CNS including

• Sedation
• Relief of anxiety
• Amnesia
• Hypnosis
• Anaesthesia
• Coma
• Respiratory depression steeper dose-response relationship than
benzodiazepines
BARBITURATES
ACTIONS
1. Depression of CNS: At low doses, the barbiturates
produce sedation (calming effect, reducing
excitement).
2. Respiratory depression: Barbiturates suppress the

hypoxic and chemoreceptor response to CO2, and
overdosage is followed by respiratory depression and
death.
3. Enzyme induction: Barbiturates induce P450
microsomal enzymes in the liver.
BARBITURATES
PHARMACOKINETICS
• All barbiturates redistribute in the body.
• Barbiturates are metabolized in the liver, and inactive metabolites

are excreted in the urine.
• They readily cross the placenta and can depress the fetus.
• Toxicity: Extensions of CNS depressant effects

dependence liability > benzodiazepines.
• Interactions: Additive CNS depression with ethanol and many

other drugs induction of hepatic drug-metabolizing enzymes.
THERAPEUTIC USES
ANESTHESIA (THIOPENTAL, METHOHEXITAL)
• Selection of a barbiturate is strongly influenced by the desired
duration of action.
• The ultrashort-acting barbiturates, such as thiopental, are used

intravenously to induce anesthesia.
ANXIETY
• Barbiturates have been used as mild sedatives to relieve anxiety,
nervous tension, and insomnia.
When used as hypnotics, they suppress REM sleep more than
other stages. However, most have been replaced by the
benzodiazepines.
THERAPEUTIC USES
ANTICONVULSANT: (PHENOBARBITAL, MEPHOBARBITAL)
• Phenobarbital is used in long-term management of tonic-clonic
seizures, status epilepticus, and eclampsia.
• Phenobarbital has been regarded as the drug of choice for

treatment of young children with recurrent febrile seizures.
• However, phenobarbital can depress cognitive performance in

children, and the drug should be used cautiously.
• Phenobarbital has specific anticonvulsant activity that is

distinguished from the nonspecific CNS depression.
ADVERSE EFFECTS
1. CNS: Barbiturates cause drowsiness, impaired concentration.
2. Drug hangover: Hypnotic doses of barbiturates produce a feeling of

tiredness well after the patient wakes.
3. Barbiturates induce the P450 system.
4. By inducing aminolevulinic acid (ALA) synthetase, barbiturates increase

porphyrin synthesis, and are contraindicated in patients with acute
intermittent porphyria.
5. Physical dependence: Abrupt withdrawal from barbiturates may cause tremors,
anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and
cardiac arrest.
6. Poisoning: Barbiturate poisoning has been a leading cause of death
resulting from drug overdoses for many decades.
ADVERSE EFFECTS
THE TREATMENT OF ACUTE BARBITURATE INTOXICATION
Treatment includes artificial respiration and purging the stomach of

its contents if the drug has been recently taken.
• No specific barbiturate antagonist is available.
• General supportive measures.
• Hemodialysis or hemoperfusion is necessary only rarely.
• Use of CNS stimulants is contraindicated because they increase

the mortality rate.
• Forced diuresis if renal function is ok, otherwise - dialysis
• Circulatory collapse prevented by adjusting hypovolemics and BP
by dopamine.
BENZODIAZEPINES
COMPARISON OF THE DURATIONS OF ACTION OF
THE BENZODIAZEPINES
Effects of benzodiazepine
• On increasing the dose sedation progresses to
hypnosis and then to stupor.
• But the drugs do not cause a true general anesthesia

because
-awareness usually persists
-immobility sufficient to allow surgery cannot be
achieved.
• However at "preanesthetic" doses, there is amnesia.

Effects on the (EEG) and Sleep Stages
• ↓ sleep latency
• ↓ number of awakenings
• ↓ time spent in stage 0, 1, 3, 4
• ↓ time spent in REM sleep (↑number of cycles of REM sleep)
• ↑ total sleep time (largely by increasing the time spent in
stage 2)
• Respiration-Hypnotic doses of benzodiazepines are without
effect on respiration in normal subjects
• CVS-In preanesthetic doses, all benzodiazepines decrease
blood pressure and increase heart rate
PHARMACOKINETICS
• A short elimination t1/2 is desirable for hypnotics,
although this carries the drawback of increased
abuse liability and severity of withdrawal after drug
discontinuation.
• Most of the BZDs are metabolized in the liver to

produce active products (thus long duration of
action).
• After metabolism these are conjugated and are

excreted via kidney.
ADVERSE EFFECTS
• Light-headedness
• Fatigue
• Increased reaction time
• Motor incoordination
• Impairment of mental and motor functions
• Confusion
• Antero-grade amnesia
• Cognition appears to be affected less than motor performance.
• All of these effects can greatly impair driving and other
psychomotor skills, especially if combined with ethanol.
FLUMAZENIL: A BENZODIAZEPINE RECEPTOR ANTAGONIST
• competitively antagonism
• Flumazenil antagonizes both the electrophysiological and behavioral

effects of agonist and inverse-agonist benzodiazepines and β -carbolines.
• Flumazenil is available only for intravenous administration.
• On intravenous administration, flumazenil is eliminated almost entirely

by hepatic metabolism to inactive products with a t1/2 of ~1 hour; the
duration of clinical effects usually is only 30-60 minutes.
FLUMAZENIL: A BENZODIAZEPINE RECEPTOR ANTAGONIST
PRIMARY INDICATIONS FOR THE USE OF FLUMAZENIL ARE:-
• Management of suspected benzodiazepine overdose.
• Reversal of sedative effects produced by benzodiazepines administered

during either general anesthesia.
The administration of a series of small injections is preferred to a single

bolus injection.
• A total of 1 mg flumazenil given over 1-3 minutes usually is sufficient to
abolish the effects of therapeutic doses of benzodiazepines.
• Patients with suspected benzodiazepine overdose should respond

adequately to a cumulative dose of 1-5 mg given over 2-10 minutes;
• A lack of response to 5 mg flumazenil strongly suggests that a

benzodiazepine is not the major cause of sedation.
Novel Benzodiazepine Receptor Agonists
• Z compounds
zolpidem , zaleplon , zopiclone and eszopiclone
• structurally unrelated to each other and to benzodiazepines
• therapeutic efficacy as hypnotics is due to agonist effects on the

benzodiazepine site of the GABAA receptor
• Compared to benzodiazepines, Z compounds are

-less effective as anticonvulsants or muscle relaxants
-which may be related to their relative selectivity for GABAA receptors
containing the α1 subunit.
Novel Benzodiazepine Receptor Agonists
• The clinical presentation of overdose with Z compounds is

similar to that of benzodiazepine overdose and can be
treated with the benzodiazepine antagonist flumazenil.
• Zaleplon and zolpidem are effective in relieving sleep-

onset insomnia. Both drugs have been approved by the
FDA for use for up to 7-10 days at a time.
• Zaleplon and zolpidem have sustained hypnotic efficacy

without occurrence of rebound insomnia on abrupt
discontinuation.

Hypnotics

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HYPNOTICS AND SEDATIVES

Non Benzodiazepine hypnotics

Effects- Dose-dependent depressant effects on the CNS including

2. Respiratory depression: Barbiturates suppress the

• Barbiturates are metabolized in the liver, and inactive metabolites

• Toxicity: Extensions of CNS depressant effects

• Interactions: Additive CNS depression with ethanol and many

• The ultrashort-acting barbiturates, such as thiopental, are used

• Phenobarbital has been regarded as the drug of choice for

• However, phenobarbital can depress cognitive performance in

• Phenobarbital has specific anticonvulsant activity that is

1. CNS: Barbiturates cause drowsiness, impaired concentration.

2. Drug hangover: Hypnotic doses of barbiturates produce a feeling of

3. Barbiturates induce the P450 system.

4. By inducing aminolevulinic acid (ALA) synthetase, barbiturates increase

Treatment includes artificial respiration and purging the stomach of

• No specific barbiturate antagonist is available.

• General supportive measures.

• Hemodialysis or hemoperfusion is necessary only rarely.

• Use of CNS stimulants is contraindicated because they increase

• But the drugs do not cause a true general anesthesia

• However at "preanesthetic" doses, there is amnesia.

• Most of the BZDs are metabolized in the liver to

• After metabolism these are conjugated and are

• Flumazenil antagonizes both the electrophysiological and behavioral

• Flumazenil is available only for intravenous administration.

• On intravenous administration, flumazenil is eliminated almost entirely

PRIMARY INDICATIONS FOR THE USE OF FLUMAZENIL ARE:-

• Management of suspected benzodiazepine overdose.

• Reversal of sedative effects produced by benzodiazepines administered

The administration of a series of small injections is preferred to a single

• Patients with suspected benzodiazepine overdose should respond

• A lack of response to 5 mg flumazenil strongly suggests that a

• structurally unrelated to each other and to benzodiazepines

• therapeutic efficacy as hypnotics is due to agonist effects on the

• Compared to benzodiazepines, Z compounds are

• The clinical presentation of overdose with Z compounds is

• Zaleplon and zolpidem are effective in relieving sleep-

• Zaleplon and zolpidem have sustained hypnotic efficacy

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