HYPNOTICS AND SEDATIVES
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• SEDATIVES – reduce anxiety and exert a calming
effect
• HYPNOTICS – produces drowsiness and facilitates
the onset and maintenance of a state of sleep.
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Non Benzodiazepine hypnotics
• ZOLPIDEM
• ZALEPLON
• ZOPICLONE (ESZOPICLONE)
Miscellaneous
• MELATONIN
• RAMELTEON
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BARBITURATES CLASSIFIED ACCORDING TO THEIR
DURATIONS OF ACTION
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Barbiturates Bezodiazepines
• enhance the binding of GABA to • enhance the binding
GABAA receptors of GABA to GABAA
• Prolonging duration receptors
• Only α and β (not ϒ ) subunits • increasing the
are required for barbiturate frequency
action • Unlike barbiturates,
• Narrow therapeutic index benzodiazepines do
• in small doses, barbiturates not activate GABAA
increase reactions to painful receptors directly
stimuli.
• Hence, they cannot be relied on
to produce sedation or sleep in
the presence of even moderate
pain.
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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
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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.
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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.
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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.
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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.
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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.
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ADVERSE EFFECTS
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.
It may be due to automatism.
• Severe depression of respiration is coupled with central
cardiovascular depression, and results in a shock-like condition
with shallow, infrequent breathing.
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ADVERSE EFFECTS
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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.
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THE TREATMENT OF ACUTE BARBITURATE INTOXICATION
• If renal and cardiac functions are satisfactory, and the patient is
hydrated, forced diuresis and alkalinization of the urine will
hasten the excretion of phenobarbital.
• In the event of renal failure – hemodialysis
• circulatory collapse is a major threat. So hypovolemia must be
corrected & blood pressure can be supported with dopamine.
• Acute renal failure consequent to shock and hypoxia accounts for
perhaps one-sixth of the deaths.
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BENZODIAZEPINES
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COMPARISON OF THE DURATIONS OF ACTION OF
THE BENZODIAZEPINES
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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.
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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)
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• 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
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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.
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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.
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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.
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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.
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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.
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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.
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ZALEPLON ZOLPIDEM
• Its plasma t1/2 is ~1 • Its plasma t1/2 is ~2
hours hours
• approved for use • Cover most of a typical
immediately at 8-hour sleep period,
bedtime or when the and is presently
patient has difficulty approved for bedtime
falling asleep after use only.
bedtime.
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Eszopiclone
• Used for the long-term treatment of insomnia and for
sleep maintenance.
• t1/2 of ~6 hours.
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MELATONIN CONGENERS
RAMELTEON
• Synthetic tricyclic analog of MELATONIN.
• It was approved for the treatment of insomnia, specifically sleep onset
difficulties.
MECHANISM OF ACTION
• Melatonin levels in the suprachiastmatic nucleus rise and fall in a
circadian fashion
concentrations increasing in the evening as an individual prepares for
sleep, and then reaching a plateau and ultimately decreasing as the
night progresses.
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MELATONIN CONGENERS
Mechanism of Action
• Two GPCRs for melatonin, MT1 and MT2, are found in the
suprachiasmatic nucleus, each playing a different role in sleep.
• RAMELTEON binds to both MT1 and MT2 receptors with high
affinity.
• Binding of Melatonin to MT1 receptors promotes the onset of
sleep.
• Binding of Melatonin to MT2 receptors shifts the timing of the
circadian system.
• RAMELTEON is efficacious in combating both transient and
chronic insomnia
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Prescribing Guidelines for the Management of Insomnia
Hypnotics that act at GABAA receptors, including the benzodiazepine hypnotics
and the newer agents zolpidem, zopiclone, and zaleplon, are preferred to
barbiturates because they have a
• Greater therapeutic index
• Less toxic in overdose
• Have smaller effects on sleep architecture
• Less abuse potential.
Compounds with a shorter t1/2 are favored in patients with sleep-onset
insomnia but without significant daytime anxiety who need to function at
full effectiveness during the day.
• These compounds also appropriate for the elderly because of a decreased
risk of falls and respiratory depression.
• One should be aware that early-morning awakening, rebound daytime
anxiety, and amnestic episodes also may occur.
• These undesirable side effects are more common at higher doses of the
benzodiazepines.
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Prescribing Guidelines for the Management of Insomnia
• Benzodiazepines with longer t1/2
are favored for patients
– — who have significant daytime anxiety and
—– who may be able to tolerate next-day sedation.
• However can be associated with
-next-day cognitive impairment
-delayed daytime cognitive impairment (after 2-4 weeks of treatment) as a
result of drug accumulation with repeated administration.
• Older agents such as barbiturates, chloral hydrate, and meprobamate have high
abuse potential and are dangerous in overdose.
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CATEGORIES OF INSOMNIA
Transient insomnia Short-term insomnia Long-term insomnia
•Lasts <3 days •3 days to 3 weeks •lasted for >3 weeks
•—Caused by a brief •— Caused by a personal •—No specific stressor may
environmental or situational stressor such as illness, grief, be identifiable.
stressor. or job problems.
•—A more complete medical
•—Respond to attention to •—Sleep hygiene education evaluation is necessary in
sleep hygiene rules. is the first step. these patients, but most do
not need an all-night sleep
•— Hypnotics should be •—Hypnotics may be used study.
used at the lowest dose and adjunctively for 7-10 nights.
for only 2-3 nights.
•—- Hypnotics are best used
intermittently during this
time, with the patient
skipping a dose after 1-2
nights of good sleep.
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LONG-TERM INSOMNIA
Nonpharmacological treatments are important for all patients with long-
term insomnia.These include
• Reduced caffeine intake
• Avoidance of alcohol
• Adequate exercise
• Relaxation training
• Behavioral-modification approaches, such as sleep-restriction and
stimulus-control therapies.
• Nonpharmacological treatments for insomnia have been found to be
particularly effective in reducing sleep-onset latency and time awake
after sleep onset.
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Management of Patients after Long-Term Treatment with
Hypnotic Agents
• If a benzodiazepine has been used regularly for >2 weeks, it
should be tapered rather than discontinued abruptly.
• In some patients on hypnotics with a short t1/2, it is easier to
switch first to a hypnotic with a long t1/2 and then to taper.
• The onset of withdrawal symptoms from medications with a
long t1/2 may be delayed.
• Consequently, the patient should be warned about the
symptoms associated with withdrawal effects.
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Atypical Anxiolytics
• Buspiron
• Ipsapirone
• Gepirone
• Buspirone relieves anxiety
-without causing marked sedative, hypnotic, or
euphoric effects.
– no anticonvulsant or muscle relaxant properties.
• Buspirone does not interact directly with GABAergic
systems.
• Anxiolytic effects of buspirone is by acting as a partial
agonist at brain 5-HT1A receptors.
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• the anxiolytic effects of buspirone may take more than
a week
• unsuitable for management of acute anxiety states
• no rebound anxiety or withdrawal signs on abrupt
discontinuance
• The drug is not effective in blocking the acute
withdrawal syndrome resulting from abrupt cessation
of use of benzodiazepines or other sedative-hypnotics
• Buspirone has minimal abuse liability
• The drug is used in generalized anxiety states
• but is less effective in panic disorders
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MCQs
Q1. Sleep promoting effect of ramelteon is
mediated by receptor:
• A. GABAA receptor
• B. Opiate receptors
• C. GABAB receptor
• D. Melatonin receptors MT1 and MT2
• Ans- D
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Q2. Which one of the following effects is NOT
seen with barbiturates?
• A. Analgesic
• B. Anticonvulsant
• C. Induction and maintenance of anaesthesia
• D. Sedation
• Ans- A
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Q3. An ideal hypnotic drug should NOT have:
• A. rapid onset of action
• B. sustained effect throughout the night
• C. without any residual effect in the following
morning
• D. increase in sleep latency
• Ans- D
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Q4. True statement about effect of
bezodiazepines on sleep is:
• A. Time spent in stage 2 is decreased
• B. Time spent in stages 1, 3 and 4 is increased
• C. Shortening of REM sleep
• D. Increase sleep latency
• Ans- C
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Q5. Beta carboline at benzodiazepine receptor
act as:
• A. Agonist
• B. Inverse agonist
• C. Antagonist
• D. Partial agonist
• Ans- B
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Q6. Benzodiazepine antagonist is:
• A. Naloxone
• B. Zolpidem
• C. Nalorphine
• D. Flumazenil
• Ans- D
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Q7. Benzodiazepines act by:
• A. Activating GABAA receptors directly
• B. Modulating the effects of GABA on
GABAA receptors
• C. Antagonistic effect on GABAA receptors
• D. GABA mimetic effect
• Ans- B
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Q8. Administration of barbiturate is
contraindicated in:
• A. Kernicterus
• B. Anxiety
• C. Epilepsy
• D. Acute Intermittant porphyria
• Ans-D
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Q9. Which is NOT true about Flumazenil?
• A. Acts on GABAA receptor
• B. Specific antagonist of benzodiazepine
• C. Given intravenously
• D. May be used in barbiturate poisoning
• Ans- D
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Q10. True statement about zolpidem:
• A. Relieve sleep onset insomnia
• B. Cause profound rebound insomnia
• C. Cause profound REM suppression
• D. Has strong anticonvulsant effect
• Ans- A
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Bibliography
• Essentials of Medical Pharmacology -7th edition by KD Tripathi
• Goodman & Gilman’s the Pharmacological Basis of Therapeutics 12th
edition by Laurence Brunton (Editor)
• Lippincott’s Illustrated Reviews: Pharmacology – 6th edition by Richard A.
Harvey
• Basic and Clinical pharmacology 11th edition by Bertram G Katzung
• Rang & Dale’s Pharmacology -7th edition
by Humphrey P. Rang
• Clinical Pharmacology 11th edition By Bennett and Brown, Churchill
Livingstone
• Principles of Pharmacology 2nd edition by HL Sharma and KK Sharma
• Review of Pharmacology by Gobind Sparsh
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THANKS
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