SEDATIVE-HYPNOTIC DRUGS

PREPARED BY: RACEL A. TRANGIA, RPH

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 SEDATIVE-HYPNOTIC DRUGS
• BENZODIAZEPINES
- Clorazepate - Alprazolam
- Clonazepam -Estazolam
- Diazepam - Flurazepam
- Chlordiazepoxide - Oxazepam
- Temazepam - Nitrazepam
- Lorazepam - Quazepam
- Midazolam
- Triazolam
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• BARBITURATES
- Amobarbital
- Butabarbital
- Pentobarbital
- Secobarbital ( short to intermediate acting )
- Mephobarbital
- Phenobarbital ( long – acting )
- Thiopental ( ultra – short acting )

• BENZODIAZEPINE ANTAGONIST
- Flumazenil
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• NEWER HYPNOTICS
- Eszopiclone - Zaleplon

- Zolpidem

• MELATONIN RECEPTOR AGONIST

- Ramelteon
• 5-HT-RECEPTOR AGONIST
- Buspirone
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 DEFINITION OF TERMS
SEDATIVE = anxiolytic
= agent that reduce anxiety and exert a calming
effect.
HYPNOTIC = an agent that produce drowsiness and
encourage the onset and maintenance of a state of sleep.
= involve more pronounce depression of the CNS.

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• The benzodiazepines are widely used
sedative-hypnotics.

STRUCTURE ACTIVITY RELATIONSHIP:

• A substituent in the 7 position, such
as a halogen or a nitro group, is
required for sedative-hypnotic
activity.

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• The structures of
triazolam and
alprazolam include the
addition of a triazole
ring at the 1,2-position.
• Barbiturates
• Glutethimide and
meprobamate
 are equivalent to
barbiturates in their
pharmacologic effects
 They are rarely used.
• Ethanol and chloral hydrate

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• Zolpidem, Zaleplon, Eszopiclone
• Antipsychotics
• Antidepressants – currently used widely in
chronic anxiety d/o

• Hydroxyzine -- Antihistamines
-- exert marked effects on the
• Promethazine peripheral NS

• Diphenhydramine Antihistamines
Doxylamine OTC sleep aids
 SEDATIVE-HYPNOTICS
• PHARMACOKINETICS:
- most of the barbiturates and other sedative-hypnotics
as well as the newer hypnotics ( eszopiclone, zaleplon, zolpidem)
are absorbed rapidly into the blood following oral administration.
- lipid solubility plays a major role in determining the rate at which a
particular sedative-hypnotic enters the CNS. (this property is
responsible for the rapid onset of CNS effects of Triazolam,
Thiopental, newer hypnotics)

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 - All sedative-hypnotics cross the placental barrier during
pregnancy.

- If given during the predelivery period, they may contribute

to the depression of neonatal vital functions.

- Are also detectable in breast milk and may exert depressant

effects in the nursing infant.

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• BIOTRANSFORMATION:
- metabolic transformation to more water-soluble
metabolites is necessary for clearance of sedative-
hypnotics from the body through the microsomal
drug-metabolizing enzyme systems. Elimination
half-life of these drugs depends mainly on the rate
of their metabolic transformation.

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1. BENZODIAZEPINES

- Hepatic metabolism accounts for the clearance of all

benzodiazepines.
- Most undergo microsomal oxidation (phase I
reaction), including N-dealkylation, and aliphatic
hydroxylation catalyzed by CYP 450 especially CYP3A4.
Figure 4-4 14
 - The metabolites are subsequently conjugated (phase II reaction) to
form glucuronides that are excreted in the urine.

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 - Many phase I metabolites of
benzodiazepines are
pharmacologically active,
some with long half – lives.
(figure 22-5)
- Example,
desmethyldiazepam, which
has an elimination half-life of
more than 40 hours, is an
active metabolite of
chlordiazepoxide, diazepam,
prazepam, and clorazepate.
- Alprazolam and triazolam undergo
α-hydroxylation, and the
metabolites appear to exert short-
lived pharmacologic effects
because they are rapidly
conjugated to form inactive
glucuronides.

- The short elimination half-life of

triazolam (2–3 hours) favors its use
as a hypnotic rather than as a
sedative drug.

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• Benzodiazepines for which the parent drug or active metabolites
have long half – lives are more likely to cause cumulative effects (ex.
excessive drowsiness) with multiple doses.
• Cumulative and residual effects such as excessive drowsiness appear
to be less of a problem with drugs as estazolam, oxazepam, and
lorazepam, which have relatively short half-lives and are metabolized
directly to inactive glucuronides.
• The metabolism of several commonly used BZ including diazepam,
midazolam, and triazolam is affected by inhibitors and inducers of
hepatic P450 isozymes

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check table 22-1 Pharmacokinetic properties of some
benzodiazepines and newer hypnotics in humans.

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2. BARBITURATES
- With the exception of phenobarbital, only insignificant quantities
of the barbiturates are excreted unchanged.

- The major metabolic pathways involve oxidation by hepatic

enzymes to form alcohols, acids, and ketones which appear in the
urine as glucuronide conjugates.

- Elimination half-lives of secobarbital and pentobarbital range from

18 to 48 hours in different individuals.

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 - The elimination half-life of phenobarbital in humans is 4-5
days.

- Multiple dosing with these agents can lead to cumulative

effects.

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Marilyn Monroe died
of barbiturate
overdose in 1962
Benzodiazepines
Rohypnol (flunitrazepam)
Mexican Valium, roofies, roaches

•Not licensed for medical use in US and Canada,

but used in Europe and South America
•Widely smuggled into U.S.
•Used as a club drug. Used at raves
•Known as a date rape drug
3. NEWER HYPNOTICS
Zolpidem
- an imidazopyridine
- is rapidly metabolized to inactive metabolites via oxidation and
hydroxylation by hepatic cytochromes P450 including the
CYP3A4 isozyme.
• Zaleplon
- is a pyrazolopyrimidine
- is metabolized to inactive metabolites mainly by hepatic aldehyde
oxidase and partly by the cytochrome P450 isoform CYP3A4.
- Dosage should be reduced in patients with hepatic impairment and
in the elderly.
- Cimetidine, which inhibits both aldehyde dehydrogenase and
CYP3A4, markedly increases the peak plasma level of zaleplon

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• Eszopiclone
- is a cyclopyrrolone.
- is an (S) enantiomer of zopiclone, a hypnotic drug.
- metabolized by hepatic cytochromes P450 (especially CYP3A4) to
form the inactive N-oxide derivative and weakly active
desmethyleszopiclone.
- The elimination half-life of eszopiclone is prolonged in the elderly and
in the presence of inhibitors of CYP3A4 (eg, ketoconazole). Inducers of
CYP3A4 (eg, rifampin) increase the hepatic metabolism of eszopiclone.
- Excreted in the urine
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 Ramelteon/Tasimelteon
• Is an agonist at MT1 and MT2 subtype of melatonin receptors located in the
suprachiasmatic nuclei of the brain.
• Melatonin: hormone secreted by the pineal gland that helps to maintain the
circadian rhythm underlying the normal sleep- wake cycle
• A novel hypnotic drug prescribed specifically for patients who have difficulty in
falling asleep.
• It reduces the latency of persistent sleep with no effects on sleep architecture
and no rebound insomnia or significant withdrawal symptoms.
• rapidly absorbed after oral administration and undergoes extensive first-pass
metabolism, forming an active metabolite with longer half-life (2–5 hours)
than the parent drug.

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- CYP1A2 is mainly responsible for the metabolism of ramelteon, but the
CYP2C9 isoform is also involved.
- The drug should not be used in combination with inhibitors of CYP1A2
(eg, ciprofloxacin, fluvoxamine, tacrine, zileuton) or CYP2C9 (eg,
fluconazole) and should be used with caution in patients with liver
dysfunction.
- CYP inducer rifampin reduces the plasma levels of both ramelteon and
its active metabolite.
- Adverse effects include dizziness, somnolence, fatigue, and endocrine
changes (decreases in testosterone and increases in prolactin)

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• Concurrent use with the antidepressant fluvoxamine
increases the peak plasma concentration of ramelteon over
50-fold!
• Tasimelteon is similar and is approved for non-24 hour
sleep-wake disorder.
• These drugs have no direct effects on GABAergic
neurotransmission in the central nervous system.

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 Buspirone
• Has selective anxiolytic effects.
• It relieves anxiety without causing marked sedative, hypnotic, or euphoric
effects.
• It has no anticonvulsant or muscle relaxant properties.
• Buspirone does not interact directly with GABAergic systems.
• It may exert its anxiolytic effects by acting as a partial agonist at brain 5-
HT1A receptors, but it also has affinity for brain dopamine D2 receptors.
• Buspirone treated patients show no rebound anxiety or withdrawal signs on
abrupt discontinuance.
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• the anxiolytic effects may take 3-4 weeks to become established, making
the drug unsuitable for management of acute anxiety states.
• It is used in generalized anxiety states but is less effective in panic disorders.
• Rapidly absorbed orally but undergoes extensive first-pass metabolism via
hydroxylation and dealkylation reactions to form several active metabolites.
• The major metabolite is 1-(2-pyrimidyl)-piperazine (1-PP), which has α2-
adrenoceptor-blocking actions.
• Elimination half-life is 2 – 4H.
• Inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice,
nefazodone) can markedly increase its plasma levels.

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• Buspirone causes less psychomotor impairment and does not affect
driving skills.
• The drug does not potentiate effects of conventional sedative-
hypnotic drugs, ethanol, or tricyclic antidepressants.
• Blood pressure may be significantly elevated in patients receiving
MAO inhibitors.
• Buspirone is an FDA category B drug in terms of its use in pregnancy.
• The frequency of adverse effects is low, with the most common
effects being headaches, dizziness, nervousness, nausea and light-
headedness

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• EXCRETION:
- the water soluble metabolites of sedative-hypnotics, mostly formed
via the conjugation of phase I metabolites, are excreted mainly via the
kidney.

- Phenobarbital is excreted unchanged in the urine to a certain

extent (20-30% in humans), and its elimination rate can be increased
by alkalinization of the urine.
( This is partly due to increased ionization at alkaline pH since
phenobarbital is a weak acid).

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 Factors affecting Biodisposition
• Can be influenced by several factors, particularly: a.
alterations in hepatic function resulting from disease or
drug-induced increases or decreases in microsomal enzyme
activities, b. in very old patients and in patients with severe
liver disease. c. Activity of hepatic microsomal drug-
metabolizing enzymes.

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• Mechanism of Action of Benzodiazepines
- The mechanism of action for Benzodiazepines is to depress the
central nervous system (CNS).
- Benzodiazepines cause CNS depression by increasing the action of
the neurotransmitter gamma-aminobutyric acid (GABA).
(When GABA action is increased, the Cl channels remain open and the
firing action potentials decrease).

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 Mechanism of action of
Benzodiazepines
• The targets for benzodiazepine actions are the γ-
aminobutyric acid (GABAA) receptors (GABA is the
major inhibitory neurotransmitter in the CNS)
• The GABAA receptors are composed of a
combination of five α, β, γ subunits that span the
postsynaptic membrane
 Mechanism of action of
Benzodiazepines
• Binding of GABA to its receptor triggers an
opening of the central ion channel,
allowing chloride through the pore.
• The influx of chloride ions causes
hyperpolarization of the neuron and
decreases neurotransmission by inhibiting
the formation of action potentials
 Mechanism of action of
Benzodiazepines
• BZDs modulate GABA effects by binding to
a specific high- affinity site (distinct from
the GABAA binding site) located at the
interface of the α subunit and the γ on the
GABAA – these binding sites are
sometimes labeled “Benzodiazepine
receptors”
 Mechanism of action of
Benzodiazepines
• BZD increases the frequency of channel
openings produced by GABA
(Note: Binding of a BZD to its receptor site
increases the affinity of GABA for the
GABA- binding site)
 Mechanism of action of
Barbiturates:
 Binds indiscriminately to GABA
channels to enhance Cl- transport and
increase conductance at Cl- channels.
• The sedative–hypnotic action of the
barbiturates is due to their interaction
with GABAA receptors, which enhances
GABAergic transmission.
• The binding site of barbiturates on the
GABA receptor is distinct from that of
the benzodiazepines (α, β)

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 Mechanism of action of
Barbiturates:
• Barbiturate potentiate GABA action
on chloride entry into the neuron by
prolonging the duration of the
chloride channel openings.
• In addition, barbiturates can block
excitatory glutamate receptors.

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 ORGAN LEVEL EFFECTS
• SEDATION = BZ, barbiturates, and most older sedative-
hypnotic drugs exert calming effects with concomitant
reduction of anxiety at relatively low doses.
= the anxiolytic actions of sedative-hypnotics are
accompanied by some depressant effects on psychomotor
and cognitive functions.
= the BZ also exert dose-dependent anterograde
amnesic effects.
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• HYPNOSIS = all of the sedative-hypnotics induce sleep if high
enough doses are given.
= the effects on the stages of sleep depend on several
factors, including: the specific drug, the dose, and the
frequency of its administration.
** the 4 general effects of BZ and older sedative-hypnotics
on patterns of normal sleep.
(check the book)

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• ANESTHESIA = high doses of certain sedative-hypnotics
depress the CNS to the point known as stage III of general
anesthesia.
* among the Barbiturates, THIOPENTAL & METHOHEXITAL
are very lipid-soluble, penetrating brain tissue rapidly
following IV administration.
* Among BZ, DIAZEPAM, LORAZEPAM, MIDAZOLAM are
used intravenously in anesthesia often in combination with
other agents.

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• ANTICONVULSANT EFFECTS = are capable of inhibiting the
development and spread of epileptiform electrical activity in
the CNS.
= several BZ including – CLONAZEPAM, NITRAZEPAM,
LORAZEPAM, DIAZEPAM are selective clinically useful in the
management of seizures.
= of the barbiturates – PHENOBARBITAL, METHARBITAL are
effective in the treatment of generalized tonic-clonic
seizures.

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• MUSCLE RELAXATION = some like the carbamates
( Meprobamate) exert inhibitory effects on polysynaptic
reflexes and internuncial transmission and at high doses
may also depress transmission at the skeletal
neuromuscular junction

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• EFFECTS ON RESPIRATION & CARDIOVASCULAR
FUNCTION
= at hypnotic doses in healthy patients, the effects are comparable
to changes during natural sleep.
= however, even at therapeutic doses, sedative-hypnotics can
produce significant respiratory depression in patient with
pulmonary disease.
= depression of the medullary respiratory center is the usual cause
of death due to overdose.

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= at doses of causing hypnosis, no significant effects on the
CVS observed among healthy patients.

= in hypovolemic states, heart failure, and other CV

diseases, normal doses of sedative-hypnotics may cause
cardiovascular depression.

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= at toxic doses, myocardial contractility and
vascular tone may both be depressed by central and
peripheral effects leading to circulatory collapse.

= Respiratory and cardiovascular effects are more

marked when sedative-hypnotics are given
intravenously.

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• TOLERANCE
= decreased responsiveness to a drug following repeated exposure
= common feature of sedative-hypnotic use.

• It may result in the need for an increase in the dose required to

maintain symptomatic improvement or to promote sleep.
• Partial cross-tolerance occurs between the sedative-hypnotics and
also with ethanol.

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• PHYSIOLOGIC DEPENDENCE
= an altered physiologic state that requires continuous
drug administration to prevent an abstinence or withdrawal
syndrome.

= characterized by increased anxiety, insomnia, CNS

excitability that may progress to convulsions.

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• Psychological and physical dependence on BZDs can develop if high doses
of the drugs are given for prolonged period
• ALL benzodiazepines are controlled substances
• Abrupt Discontinuation of the BZDs results in withdrawal symptoms,
including confusion, anxiety, agitation, restlessness, insomnia, tension
and (rarely) seizures
▪ Most sedative-hypnotics – including BZ are capable of
causing physiologic dependence when used on a long-
term basis.
• The abrupt cessation of Zolpidem, Zaleplon,
Eszopiclone may also result in withdrawal symptoms,
though of less intensity than with BZ.

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 CLINICAL USES OF SEDATIVE-HYPNOTICS: (table 22-2)
• For relief of anxiety • As a component of balanced
anesthesia (IV
• Insomnia administration)
• Sedation and amnesia before and
during medical and surgical • For control of ethanol or other
procedures sedative-hypnotic withdrawal
states
• Treatment of epilepsy and seizure
states • For muscle relaxation in specific
neuromuscular disorders
• As diagnostic aids or for treatment
in psychiatry
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 Duration of action of Benzodiazepines
Long acting (1-3 days)
- Clorazepate - Chlordiazepoxide - Diazepam - Flurazepam
Quazepam
Intermediate acting (10- 20 hours)
- Alprazolam - Estazolam - Lorazepam - Temazepam
Short- acting (3- 8 Hours)
- Oxazepam - Triazolam
Therapeutic Uses of BZDs
 1. Anxiety Disorders
- BZDs are effective for the treatment of the anxiety symptoms secondary to:
Panic d/o
Generalized Anxiety D/o
Social anxiety d/o
Performance anxiety
Post traumatic stress d/o
Obsessive- compulsive d/o
Extreme anxiety associated with phobias
Depression and schizophrenia
 1. Anxiety disorders

- BZDs should be reserved for severe anxiety only

- Because of their addiction potential, they should only be used for short periods of
time
- Longer- acting agents: Clonazepam, Lorazepam, Diazepam preferred in patients
with anxiety that may require prolonged treatment
- For Panic d/o: Alprazolam is effective for short and long term treatment, although
it may cause withdrawal reactions in about 30% of patients
 2. Sleep Disorders

• A few of the BZDs are useful as hypnotic agents

• In the treatment of insomnia, it is important to balance the sedative effect
needed at bedtime with the residual sedation (“hangover”) upon awakening
• Commonly prescribed benzodiazepines for sleep disorders include
intermediate- acting temazepam, and short acting triazolam.
• Long- acting flurazepam is rarely used, due to its extended half- life which
may result in excessive daytime sedation and accumulation of the drug,
especially in the elderly
 3. Amnesia
• The shorter- acting agents are often employed as premedication for
anxiety- provoking and unpleasant procedures, such as endoscopy,
dental procedures, and angioplasty
• Cause a form of conscious sedation, allowing the person to be
receptive to instructions during these procedures
• Midazolam- BZD used to facilitate amnesia while causing sedation
prior to anesthesia
 4. Seizures
• Clonazepam is occasionally used as an adjunctive therapy for
certain types of seizures
• Lorazepam and diazepam- DOC in terminating status
epilepticus
• Chlordiazepoxide, Clorazepate, Diazepam, Lorazepam and
Oxazepam- useful in acute alcohol withdrawal and reduce the
risk of withdrawal- related seizures
 5. Muscular disorders
• Diazepam- useful in treating skeletal muscle spasms (occurs in muscle
strain) and in treating spasticity from degenerative disorders, such as
multiple sclerosis and cerebral palsy
Therapeutic Uses of Barbiturates
 Duration of action of Barbiturates
Long- acting (1-2 days)
Phenobarbital

Short- acting (3-8 hours)

Pentobarbital , Secobarbital, Amobarbital

Ultra short- acting (20 mins)

Thiopental
 Barbiturates
• Formerly the mainstay of treatment to sedate patients or to induce or
maintain sleep
• Today, they have been largely replaced by BZDs
• ALL barbiturates are controlled substances
• Thiopental, have been used to induce anesthesia but are infrequently
used today due to the advent of newer agents with fewer adverse effects
 1. Anesthesia
The ultra short- acting Barbiturates such as thiopental have been used IV to
induce anesthesia but have been largely replaced by other agents
 2. Anticonvulsant
• Phenobarbital has specific anticonvulsant activity
• Long term management of tonic- clonic seizures
 3. Sedative/ hypnotic
• Barbiturates have been used as mild sedatives to relieve anxiety, nervous
tension, and insomnia
• The use of Barbiturates for insomnia is no longer generally accepted,
given their adverse effects and potential for tolerance
• Butalbital- commonly used in combination products (w/ acetaminophen,
and caffeine or aspirin and caffeine) as a sedative to assist in the
management of tension- type or migraine headache
 CLINICAL TOXICOLOGY:
Adverse effects of Barbiturates:
• Cause drowsiness
• Impaired concentration
• Mental and physical sluggishness
• CNS depressant effects of Barbiturates synergize with those of ethanol
• Hypnotic doses of barbiturates produce a drug “hangover” that may lead to impaired
ability to function normally for many hours after waking
• Nausea and dizziness (Occasionally occurs)
• Barbiturates induce cytochrome P450 (CYP450) microsomal enzymes in the liver
(chronic barbiturate administration diminishes the action of many drugs metabolized
by the CYP450 system

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 CLINICAL TOXICOLOGY:
Adverse effects of Barbiturates:
• Contraindicated in patients with acute intermittent porphyria
• Abrupt withdrawal from barbiturates may cause tremors, anxiety,
weakness, restlessness, nausea and vomiting, seizures, delirium, and
cardiac arrest (can result in death)
• Death may result from overdose
• Severe depression of respiration is coupled with central cardiovascular
depression and results in a shock-like condition with shallow, infrequent
breathing (treatment includes supportive care and gastric
decontamination for recent ingestions)
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 CLINICAL TOXICOLOGY:
Adverse effects of Benzodiazepines
• Drowsiness and confusion (most common side effects)
• Ataxia (occurs at high doses)
• Cognitive impairment (decreased long- term recall and retention of new knowledge)
• Triazolam- shows a rapid development of tolerance, early morning insomnia, and
daytime anxiety, as well as amnesia and confusion
• Should be used cautiously in patients with liver disease
• Alcohol and other CNS depressants enhance the Sedative- hypnotic effects BZDs
• BZDs are considerably less dangerous than the older anxiolytic and hypnotic drugs (as
a result, a drug overdose is seldom lethal unless other central depressants, such as
alcohol, are taken concurrently
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 CLINICAL TOXICOLOGY:
Adverse effects of Benzodiazepines
• anterograde amnesia
• light-headedness
• Paradoxic excitement in children
• Menstrual irregularities

• BDZs during labor can have effects on newborn

 Floppy baby syndrome

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 Benzodiazepines vs. Barbiturates
Criteria BZ Barb.
Relative Safety High Low
Maximal CNS depression Low High
Respiratory Depression Low High
Suicide Potential Low High
Abuse Potential Low High
Antagonist Available? Yes No
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Orexin receptor antagonists: Sleep-enabling drugs

• Almorexant
• Suvorexant

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 Benzodiazepine antagonist: FLUMAZENIL
- Act as a competitive BZ antagonist
MoA: GABA receptor antagonist that can rapidly reverse the effects of
Benzodiazepines
- The drug is available for IV administration only
- When given intravenously, flumazenil acts rapidly but has a short half-
life (0.7–1.3 hours) due to rapid hepatic clearance.
• It blocks many of the actions of BZ, Zolpidem, Zaleplon, and
Eszopiclone but does not antagonize the CNS effects of other sedative-
hypnotics, ethanol, opioids, or general anesthetics.
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• Flumazenil is approved for use in reversing the CNS depressant effects
of BZ overdose and to hasten recovery following use of these drugs in
anesthetic and diagnostic procedures.

• Frequent administration may be necessary to maintain reversal of a

long- acting BZ

• Adverse effects:
agitation, confusion, dizziness, nausea and vomiting

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• Administration of flumazenil may precipitate withdrawal
in dependent patients or cause seizures if a
benzodiazepine is used to control seizure activity

• In patients who have ingested benzodiazepines with

tricyclic antidepressants, seizures and cardiac
arrhythmias may follow flumazenil administration.

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 CLINICAL TOXICOLOGY OF SEDATIVE-HYPNOTICS
• FDA assignment of individual benzodiazepines to either
category D or X in terms of pregnancy risk:
• Most barbiturates are FDA pregnancy category D.
• Eszopiclone, ramelteon, zaleplon, and zolpidem are
category C
• Buspirone is a category B drug

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 Drug Interactions:
• most common drug interactions involving sedative-hypnotics are
interactions with other CNS depressant drugs, leading to additive
effects.
• These interactions have some therapeutic usefulness when these
drugs are used as adjuvants in anesthesia practice.
• such interactions can lead to serious consequences, including
enhanced depression with concomitant use of many other drugs.

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• Additive effects can be predicted with concomitant use of
alcoholic beverages, opioid analgesics, anticonvulsants,
and phenothiazines.

• Less obvious but just as important is enhanced CNS

depression with a variety of antihistamines,
antihypertensive agents, and TCA antidepressants.

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