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Sedative-Hypnotic-Anxiolytics:
Benzodiazepines & others
Tracy A. Womble, Ph.D
Florida A&M University
College of Pharmacy and
Pharmaceutical Sciences
SEDATIVE-HYPNOTICS
History of Sedatives
• Alcohol, the oldest known sedative
– “When Noah left the Ark he planted a
vineyard, drank the wine, and was drunken,
and he was uncovered within his tent.”
Genesis 9:21
• 1900 Barbiturates: narrow TI
• 1960’s Chlordiazepoxide (Librium)
SEDATIVE-HYPNOTIC DRUGS
SEDATION
• Reduction of anxiety
• Calming effect
ANXIOLYTIC
• Drug that reduces anxiety
• Sedative
HYPNOSIS
• Induce sleep
– go to sleep fast, feel refreshed tomorrow !!!
What is Anxiety ?
• an unpleasant state of tension,
apprehension, or uneasiness; a
fear that seems to arise from a
sometimes unknown source.
Classification of Anxiety Disorders
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Generalized Anxiety Disorder (GAD)
Panic Disorder
Social Phobia
Simple Phobia
Obsessive Compulsive Disorder (OCD)
Classification of Anxiety Disorders
Generalized Anxiety Disorder (GAD)
exaggerated autonomic response, irritability,
difficulty in concentrating and swallowing, and
insomnia.
Panic Disorder - autonomic symptoms, hot
flashes, and fear of dying or going crazy.
Social Phobia - fear of eating, writing or
speaking in public.
Classification of Anxiety Disorders (Cont)
Simple Phobia - Phobias of heights, animals,
driving, or air travel.
Obsessive Compulsive Disorder (OCD) :
• Obsessions are persistent ideas
– e.g., recurrent thoughts of contamination.
• Compulsions are repetitive behaviors
– e.g., repetitive hand-washing.
• Significantly interfere with the patient’s social and
practical life.
Anxiolytics
• Benzodiazepines
• Buspirone
• SSRIs (Those FDA approved for
Anxiety)
• SNRIs (Those approved for Anxiety)
• Hydroxyzine
• Clomipramine
Sedative/Hypnotic/Anxiolytic
• Because many of the antianxiety drugs
also cause some sedation, the same
drugs often function clinically as both
anxiolytic and hypnotic (sleep-inducing)
agents.
• In addition, some have anticonvulsant
activity.
Dose Response Curve for
Sedative/Hypnotics
EFFECTIVE SEDATIVEHYPNOTIC DRUGS
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Lipid soluble
Absorbed well from the GIT
Good distribution to the brain
Metabolized before elimination from the
body
SEDATIVE-HYPNOTIC DRUGS
Benzodiazepines
Short
acting
Intermediate
acting
Long
acting
Barbiturates
Ultra short
acting
Short
acting
Long
acting
Miscellaneous agents
Buspirone
Chloral hydrate
Zaleplon
Zolpidem
Actions of Sedative Hypnotics
• Sedation / Anxiolytics
– Amnesia during surgical procedure
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Hypnosis (insomnia)
Adjunct to Anesthesia
Anticonvulsant effects (i.v.)
Muscle Relaxation
Respiration and Cardiovascular
Control of ethanol, sedative-hypnotic
withdrawal
Action Potential of a Neuron
SEDATIVE-HYPNOTIC DRUGS
BENZODIAZEPINES
• receptors
 Form part of GABAA receptor-chloride
ion channel macromolecular structure
 Binding facilitates the inhibitory
actions of GABA
 Increased GABA mediated chloride
ion conductance
Benzodiazepine Receptor
• Located on the GABAA receptor
– Divided into 3 main types (A,B and C)
• GABA A,B,C
– GABA A - ligand-gated Cl- ion channel
(ionotropic)
• GABA,B,C are metabotropic
• Hippocampus, striatum, spinal cord,
mediate anxiolysis
– Most common throughout CNS, mediate
sedation
Benzodiazepine Indications
• Sedation/Hypnotic
• Anxiety
• Anesthesia
• Alcohol withdrawal syndrome
• Anticonvulsant
• Muscular disorders
Benzodiazepine Receptor
• Ionotropic receptor – (GABAA) form ion
channels
– Metabotropic receptor – (GABAB ) BZP’s have very
low affinity for GABAB
• GABAA receptor- contains 5 subunits found in
many regions of brain, different regions of CNS
• contain different combinations
– (6) α, (3) β, (3) γ and (2) δ
Benzodiazepines (BZP)
Mechanism of Action
• BZP receptor linked to GABAA receptor complex
(bound to Cl- channels).
– BZP enhance GABAA effect.
– GABA: an inhibitory neurotransmitter
• Open Cl- channels in response to GABA activation,
hyperpolarization, decrease neuronal firing
• Effects: Sedative, Hypnotic, Anticonvulsant, MuscleRelaxant, Anxiolytic
Pharmacokinetics of Benzodiazepines
• Lipid-soluble: fast cross blood-brainbarrier: rapid onset of action.
– obese, elderly
• Biotransformation & Half-Life:
– Hepatic oxidation: long-t½, active
metabolites
– Glucuronidation: short-t½, no active metab.
Pharmacokinetics of Benzodiazepines
• Diazepam, Chlordiazepoxide, Clorazepate
and Flurazepam
– Converted initially to active metabolites with long
half-lives
 After several days of therapy accumulation
of active metabolites can lead to excessive
sedation
Pharmacokinetics of Benzodiazepines
BENZODIAZEPINES
• Diazepam, Chlordiazepoxide, Clorazepate*
desmethyldiazepam
active
oxazepam
metabolites
conjugation
* Prodrug
SEDATIVE-HYPNOTIC DRUGS
BENZODIAZEPINES
• Lorazepam and oxazepam
 Undergo extrahepatic conjugation
and do not form active metabolites
Biotransformation of BZPs
Benzodiazepine
Classification
Half Life (t½) (hrs.)
Therapeutic Use
Midazolam
(Versed)
Short Acting
2-6
Preanesthetic,
intraoperative
Triazolam
(Halicon)
Short Acting
2-3
Insomnia
Alprazolam
(Xanax)
Intermediate Acting
12-15
Anxiolytic, agoraphobia
Estazolam
(Prosom)
Intermediate Acting
10-24
Insomnia
Lorazepam
(Ativan)
Intermediate Acting
10-20
Anxiolytic, preanesthetic
Temazepam
(Restoril)
Intermediate Acting
10-40
Insomnia
Clonazepam
(Klonipin)
Long Acting
18-50
Anticonvulsant
Clorazepate
(Tranxene)
Long Acting
40-50
Anxiolytic,
anticonvulsant
Diazepam
(Valium)
Long Acting
20-80
Anxiolytic, status
epilepticus, muscle
relaxant, anesthetic
premed
Flurazepam
(Dalmane)
Long Acting
40-100
Insomnia
BZD: Adverse Effects
• BZD few SE
• Sedation, CNS Depression
– Worse if combined with EtOH
• Behavioral disinhibition
– Irritab, excitement, aggression
• Psychomotor & Cognitive Impairment
– coordination, attention (driving)
– poor visual-spatial ability (not aware of it)
– Ataxia, confusion
BZD: Adverse Effects
• Overdose: Rare fatalities if BZD
alone
• Hypnotic dose of BZP may worsen
snoring/OSA
• Severe CNS & Respiratory
Depression if combined
– alcohol, barbiturates, narcotics,TCA’s
Benzodiazepine Antagonist
• Flumazenil (Romazicon)
 Reverses the CNS effects of
benzodiazepines, Eszopiclone, Zaleplon and
Zolpidem
 Antagonist at the BZP receptor, no effect on
barbiturates.
 Management of BZP overdose
 t½ 0.7-1.3 hr – sedation commonly recurs,
requires repeated admin.
Barbiturates
• Not used for anxiety or insomnia
– Used for induction of anesthesia
• Potentially Fatal Respiratory Depression
– narrow TI
• Induce P450 system: interactions
Barbiturates
• Gen Anesthesia (induction) - thiopental
• Sedative - Amobarbital, pentobarbital
• Anticonvulsant – Phenobarbital
• Abrupt withdrawal after physical dependence
may result in death
• Increase porphyrin synthesis, contraindicated
in pts. w/ acute intermittent porphyria
Action of Barbiturates
• CNS–
– Low dose, sedation. High dose, hypnosis, anesthesia,
finally coma and death. CNS depression dependent on
dose. No analgesic properties.
• Respiratory Depression
– Suppress hypoxic and chemoreceptor response to CO2
• Enzyme Induction
– induce P450 microsomal enzymes.
Barbiturate Poisoning
• Lethal dose >10x hypnotic dose
• Tx of acute barbiturate poisoning is
supportive
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Hemodialysis or hemoperfusion
Purging of stomach
Diuresis/alkalinization of urine
Airway ventilation
Gastric lavage if < 24hr since ingestion
• Admin. Activated charcoal to shorten t½
• CNS stimulants contraindicated, increases
mortality
Non-Benzodiazepine Sedative Hypnotics
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Zolpidem (Ambien)
Zaleplon (Sonata)
Eszopiclone (Lunesta
Buspirone (Buspar)
Chloral Hydrate
(Aquachloral)
• Propofol (Diprivan)
Benzodiazepine-Receptor Agonists
• Zolpidem (Ambien), Zaleplon (Sonata),
Eszopiclone (Lunesta)
• Structurally similar to BZPs
• Sedation and hypnosis
• Effects reversed by Flumazenil
Zolpidem (Ambien)
• Ambien, Ambien CR, Zolpimist
• Acts at subset of BZP receptors
• no anticonvulsant or muscle relaxation
properties
• no withdrawal effect, Minimal rebound
insomnia, t½ 2-3 hrs,
• Little to no tolerance with prolonged use
• Adverse effects - nightmares, agitation, h/a,
GI upset, dizziness and daytime drowsiness
Zaleplon (Sonata)
• Similar to Zolpidem hypnotic action
• Less residual s/e on psychomotor and
cognitive than zolpidem and BZPs
• Causes fewer cognitive side effects
• t½ < 1 hr.
Eszopiclone (Lunesta)
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Used in tx of insomnia
Effective up to 6 months
Rapidly absorbed (1 hour)
metabolized by oxidation /demethylation
t½ ~ 6 hrs
Adverse effects – anxiety, dry mouth, chest
pain, h/a, migraine, peripheral edema,
somnolence, unpleasant taste
Buspirone (Buspar)
• mediated by serotonin ((5-HT1A)
• minimal sedation, no physical dependence or
tolerance, no withdrawal
• Not a BZP, not hypnotic, no CNS depression w/
alcohol
• no anticonvulsant or muscle relaxant, minimal
sedation
Buspirone (Buspar)
• tx of GAD, onset of action – 1 wk
• Effects not reversed by Flumazenil
• hypothermia, inc. prolactin, GH release
• < motor function interference (important in
elderly)
• < nicotine cravings in tobacco users
Chloral Hydrate
• Prodrug - active. metab. inc.
anticoagulant effect
– (displace form protein binding site)
• Sedative / hypnotic
–onset ~ 30 min. DOA 6 - 10 hrs.
• Irritating to GI tract
– Produces unusual, unpleasant taste
sensation, synergizes w/ alcohol
Propofol (Diprivan)
• i.v. sedative/hypnotic
• induction/maintenance of anesthesis
• smooth onset ~ 40s, facilitates CNS
depression
• no postaneshetic n/v