The

Sedative/Hypnotics
Durmishkhan Akhsabadze,MD
Overview

Benzodiazepenes Barbiturates Atypical

Short-acting Ultra-short-acting • Zopiclone (ImovaneR)

• Triazolam •Thiopental • Eszopiclone

• Lorazepam (AtivanR) Short-acting • Zaleplon (StarnocR)

•Diazepam (ValiumR) • Secobarbi • Zolpidem (AmbienR)

tal
Intermediate-acting • Chloral Hydrate
Long-acting
•Alprazolam • Buspirone (BuSparR)
• Phenobar
Long-acting bital • Ramelteon, tasimelteon

• Flurazepa • Suvorexant
m
Metabolism

Benzodiazepines

Often converted to active metabolites in

liver
• Diazepam, flurazepam

• May accumulate over several days

Some are conjugated outside the liver

• Lorazepam, oxazepam

• Do not form active metabolites

Metabolism

Barbiturates

Extensively metabolized in the liver (secobarbital, etc)

• Phenobarbital can be excreted in urine unchanged.

Unclassified Drugs
• Rapid metabolism by liver enzymes; short duration of
action
• Used as sleep aides
Dose-response

Coma
(Barbiturates)

Medullary depression

Central Anesthesia (Benzodiazepines)

nervous
system effects Hypnosis

Sedation, Possible selective

disinhibition, anticonvulsant and muscle-
anxiolysis relaxing activity
Increasing sedative-hypnotic
dose
Dose-response

Sedation, anxiolysis
• At low doses of both sets of drugs

• Benzodiazepines used more frequently for

anxiolysis
• Newer, unclassified agents have a flatter curve
Dose-response

Antiseizure activity
• Present with low doses of barbiturates (phenobarbital)

• Present at high doses of benzodiazepines (lorazepam,

midazolam)
Dose-response

Hypnosis
• Benzodiazepines can induce sleep

• REM is often reduced (fewer dreams)

• Rebound effect: Hyper-REM sleep

• Fewer side effects with new agents

• E.g.: Zopiclone

• For insomnia
• Rapid effect
• Minimal daytime cognitive impairment
Dose-response

Anesthesia

Amnesia, suppressed reflexes

Anterograde amnesia common with

benzodiazepines
• See

Anesthesia with most barbiturates

• Thiopental

Short-term sedation with benzodiazepines

• Intravenous lorazepam (Ativan)

• Intravenous diazepam (Valium)

Dose-response

Medullary suppression,
coma
• Respiratory arrest

• Hypotension

• Cardiovascular collapse

• Death
Benzodiazepines
GABAA receptor-chloride ion channel macromolecular complex.
GABA Cl-
GABA
α β Benzodiazepine
β α s
Extracellular γ
Flumazenil

Zolpidem

Barbiturates

Intracellular Ion
channel
Benzodiazepines

GAB Cl- GABA

Present in many regions of the brain
A α β Benzodiazepine
• Cerebral cortex (confusion, amnesia) Extracellula β γ α
s Flumazenil
r
• Thalamus (disinhibition, sedation, Zolpidem
motor inhibition)
Barbiturate
• Limbic structures (anxiolysis, sedation) Intracellular s Ion
channel
Benzodiazepines

Causes increased flow through

chloride channel GAB Cl- GABA
A α β
• Increases the frequency of opening by Benzodiazepine
Extracellula β γ α
the channel r
s Flumazenil

• By helping GABA to inhibit the γ subunit Zolpidem

Barbiturate
• Binds between the α and γ units
Intracellular s Ion
• Acts through many types of channel
receptors
Benzodiazepines
Anxiety states use of benzodiazepines
• Alprazolam (Xanax)

• Clonazepam, lorazepam, diazepam

• antidepressants) Muscle

spasticity
•Diazepam

Ethanol

withdrawal
• Use of long-
acting
benzodiazepine
s recommended
Benzodiazepines

GAB Cl- GABA

Flumazenil (AnexateR) is an antagonist A α β Benzodiazepine
to benzodiazepines Extracellula β γ α
s Flumazenil
r
• Used as a reversal agent in Zolpidem
overdoses
Barbiturate
• Binds at a similar site to the Intracellular s Ion
channel
the most common side effect of diazepam is sedation.diazepam may also impair coordination and
balance,decrease memory and concentration,and produce confusion.as a class,all benzodiazepines
should be excluded from use in conjucation with alcohol,barbiturates,neuroleptics,or 1st generation
anhistamines.
Barbiturates

• Receptors present in the brain GAB Cl- GABA

A α β
• Reticular activating system Benzodiazepine
Extracellula β γ α
s Flumazenil
• Barbiturates may also r
antagonize glutamic acid Zolpidem
Barbiturate
• Barbiturates are not antagonized
Intracellular s Ion
by flumazenil
channel
• Pharmacokinetics of barbiturates:
–– Liver metabolized, sometimes to active compounds
–– General inducers of cytochrome P450s
–– Contraindication in porphyrias
• Tolerance to and dependence on sedative-hypnotics:
–– Chronic use leads to tolerance
–– Cross-tolerance occurs between BZs, barbiturates, and ethanol
–– Psychologic and physical dependence occur
–– But abuse liability of BZs is < ethanol or barbiturates
–– Withdrawal signs of BZs:
oo Rebound insomnia
oo Anxiety
oo Seizures when BZs were used as antiepileptic or in high doses
–– Withdrawal signs of barbiturates and ethanol: anxiety, agitation,
life-threatening seizures (delirium tremens with alcohol)
–– Management of withdrawal: supportive and long-acting BZs
• Drug interactions: GABAA drugs are:
–– Additive with other CNS depressants (possible life-threatening
respiratory depression), such as anesthetics, antihistamines, opiates,
β-blockers, etc.
–– Barbiturates induce metabolism of most lipid-soluble drugs, such as
oral contraceptives, carbamazepine, phenytoin, warfarin, etc.
Barbiturates

Causes increased flow through

chloride channel GAB Cl- GABA
A α β
• By helping GABA to inhibit the γ subunit Benzodiazepine
Extracellula β γ α
s Flumazenil
• Increases the duration of chloride r
Zolpidem
flow through the open channel
Barbiturate
• Binds on the α and β units
Intracellular s Ion
• Acts through many types of channel
receptors
Barbiturates
Induction of anesthesia
• Thiopental

• Diazepam and midazolam have also been used for

induction

Seizure control
• Phenobarbital
Atypical
Drugs

Drugs that act

• benzodiazepine receptor

• the melatonin receptor

• the serotonin receptor

• the orexin receptor

Atypical Drugs Acting Through the Benzodiazepine
Receptor
Zolpidem causes increased flow
through chloride channel. Cl-
α β
• By helping GABA to inhibit the
Extracellular β γ α
γ subunit

• Binds between the α and γ units Zolpidem

• Acts through only one type of

receptor Intracellular
• Receptors containing the
α1 subunit

• More specific action:

insomnia
zolpidem has a rapid onset of action(15 min after administartion) and is metabolized by
liver p450 microsomal oxidases.its elimination half-life is normally about 3 hours,but may
prolonged in patients with liver disease.

zolpidem has the following important properties:

1.less potential for tolerance and addiction.the incidence ow withdrawal
symptoms(and,therefore,physical dependence)is much lower than with benzo drugs.
2.no anticonvulsant properties in regular doses.
3.no muscle relaxing effects and not used for anesthesia.
Atypical Drugs Acting Through the Benzodiazepine
Receptor

Cl-
Benzo-
α β
Flumazenil (Anexate®)is an antagonist α diazepines
Extracellular β γ
to these drugs. Flumazenil

• Used as a reversal agent in

overdoses

• Binds at a similar site to Intracellular

the benzodiazepines
Atypical Drugs Acting Through the Melatonin
Receptor
Ramelteon (Rozerem®) Tasimelteon (Heltioz®)

• Melatonin agonist in suprachiasmatic nuclei • Melatonin agonist in suprachiasmatic

nuclei
• Used in insomnia Initially for N24HSWD (non-24-hour
• sleep- wake disorder) in blind people

• Low risk for abuse; less addictive than

other medications

• Metabolized to an active metabolite by

CYP 1A2 and 2C9
• Will interact with fluvoxamine and
the azole antifungals
Atypical Drugs Acting Through the Orexin
Receptor
Suvorexant(Belsomra)

• Orexin receptor antagonist

• Hypnotic properties

• Safety profile:

• Safety in addictive risk persons

unknown

• Safety in pregnancy unknown

• Safety in breastfeeding unknown

• Interact with all CYP 3A4 drugs

Atypical Drugs Acting Through the Serotonin
Receptor
Buspirone(BuSpar®)

• Selective anxiolytic • Side effects: CYP 3A4

interactions, tachycardia, miosis,
• Minimal sedative effects and motor GI distress
effects, or rebound
• Safe in pregnancy
• Acts on 5-HT1A (serotonin) receptors

• Slow (10 days) onset

• Generalized anxiety
disorders (not in panic
disorders)

 (see psychiatry lectures for

more information)
Atypical Drugs
Summary
Sleep disorders/insomnia Anxiety in people who rely on their
motor skills
• Used to use flurazepam and
triazolam, but not so much now. • Buspirone (Buspar®) has little
psychomotor side effect.
• Zolpidem, zaleplon, zopiclone and
eszopiclone have fewer side • Low risk of addiction
effects.

• Alpha-specific atypical agents acting

through the BZP receptor are very
effective agents in sleep/insomnia.

• The newer melatonin specific agents

are rapidly increasing in popularity.
benzodiazepines,antihistamines,and sedating antidepressants should
be avoided in treatment of insomnia in the elderly due to their adverse
effects.ramelteon,a melatonin agonist,is safe and effective in reducin
time to sleep onset in the elderly.
 Alcohol
All alcohols cause CNS depression, in part through GABA mimetic
activity.All alcohols cause metabolic acidosis.
Note
Drugs that cause disulfiram-like
effects:
• Metronidazole
• Griseofulvin

Clinical Correlate
Alcohol and Pregnancy
Fetal alcohol syndrome is
characterized by growth
restriction,
midfacial hypoplasia,
microcephaly,
and marked CNS dysfunction,
including the frequent
occurrence of
mental retardation.
Question 1: Who Wants to GABA Cuppa
Coffee?

Which statement about benzodiazepines is true?

A. Benzodiazepines act through the excitation of GABA on the

GABAA receptor-chloride ion channel macromolecular complex.

B. Benzodiazepines bind to a region between the α and β portions of

the GABAA receptor-chloride ion channel macromolecular complex.

C. Benzodiazepines bind to a region on the α portion of the GABAA

receptor-chloride ion channel macromolecular complex.

D. Benzodiazepines bind to a region between the α and γ portions of

the GABAA receptor-chloride ion channel macromolecular complex.
Question 1: Who Wants to GABA Cuppa
Coffee?

Which statement about benzodiazepines is true?

A. Benzodiazepines act through the excitation of GABA on the

GABAA receptor-chloride ion channel macromolecular complex.

B. Benzodiazepines bind to a region between the α and β portions of

the GABAA receptor-chloride ion channel macromolecular complex.

C. Benzodiazepines bind to a region on the α portion of the GABAA

receptor-chloride ion channel macromolecular complex.
D. Benzodiazepines bind to a region between the α and γ portions of
the GABAA receptor-chloride ion channel macromolecular complex.
Question 2: Comparing Ben and
Barb

Pick the correct statement.

A. Both barbiturates and benzodiazepines can be reversed by flumazenil.

B. Both barbiturates and benzodiazepines act by binding to a specific

α subunit of the GABAA receptor-chloride ion channel
macromolecular complex.

C. Both barbiturates and benzodiazepines enhance the inhibitory actions

of GABA on the GABAA receptor-chloride ion channel macromolecular
complex.

D. Both benzodiazepines and barbiturates have strong anti-seizure activity

at low doses.
Question 2: Comparing Ben and
Barb

Pick the correct statement.

A. Both barbiturates and benzodiazepines can be reversed by

flumazenil.

B. Both barbiturates and benzodiazepines act by binding to a specific

α subunit of the GABAA receptor-chloride ion channel
macromolecular complex.
C. Both barbiturates and benzodiazepines enhance the inhibitory actions
of GABA on the GABAA receptor-chloride ion channel macromolecular
complex.
D. Both benzodiazepines and barbiturates have strong anti seizure activity
at low doses.
Case: 45-year-old Man with Anxiety, and Inability to Cope with
Stress

A 45-year old emergency room physician is complaining of anxiety,

difficulty sleeping, and an inability to cope with the stresses of his work.
Buspirone is prescribed. Which of the following statements is true about
this medication?

A. The patient may not notice improvement for up to 10 days.

B. Buspirone has a high addictive potential and should not be given to

a person with ready access to medications.

C. Buspirone acts through antagonizing orexin receptors in the brain.

D. Buspirone may cause sedation and motor coordination issues. It

should not be used.
Case: 45-year-old Man with Anxiety, and Inability to Cope with
Stress

A 45-year old emergency room physician is complaining of anxiety,

difficulty sleeping, and an inability to cope with the stresses of his work.
Buspirone is prescribed. Which of the following statements is true about
this medication?

A. The patient may not notice improvement for up to 10

days.
B. Buspirone has a high addictive potential and should not be given to
a person with ready access to medications.

C. Buspirone acts through antagonizing orexin receptors in the brain.

D. Buspirone may cause sedation and motor coordination issues. It

should not be used.
Case: 21-year-old Woman with Rapid Heart Rate, Sweating, and
Anxiety
A 21-year old grocery store clerk complains of occasional rapid heart rate,
sweating, anxiety, and nausea. Episodes are brought about when her
supervisor is present. She does not complain of any symptoms when she
is on holidays or in social circumstances not related to work. The best
medication to use in this situation is:

A. Propranolol

B. Eszopiclone

C. Zopiclone

D. Tasimelteon

E. Alprazolam
Case: 21-year-old Woman with Rapid Heart Rate, Sweating, and
Anxiety
A 21-year old grocery store clerk complains of occasional rapid heart rate,
sweating, anxiety, and nausea. Episodes are brought about when her
supervisor is present. She does not complain of any symptoms when she
is on holidays or in social circumstances not related to work. The best
medication to use in this situation is:

A. Propranolol

B. Eszopiclone

C. Zopiclone

D. Tasimelteon

E. Alprazolam