Sedative-Hypnotic Drugs
and Anxiety Disorders.
Patrick T. Ronaldson, PhD
Department of
Medical Pharmacology
University of Arizona
Anxiety
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Term used to describe both symptoms and disorders
Occurs normally as signal of impending danger or threat
Very common, occurs in many disorders in addition to
the anxiety disorders
Differentiated from fear on basis of whether there is a
clear source of danger
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i.e. “fight or flight” response
Adaptive value :
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helps to plan and prepare for threat
moderate levels enhance learning and performance
Maladaptive when chronic / severe
Anxiety
Symptoms include :
 physiological symptoms of activated sympathetic
nervous system (increased heart rate, increased
respiration, sweating etc.)
 cognitive component (awareness of being
frightened)
 behavioral components (urge to escape)
Anxiety Disorders (DSM-IV)
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Panic disorder with or without agoraphobia
Agoraphobia without panic disorder
Specific phobias
Social phobia
Obsessive compulsive disorder
Posttraumatic stress disorder
Acute stress disorder
Generalized anxiety disorder
Anxiety disorder due to a general medical
condition
Substance-induced anxiety disorder
Anxiety disorder not otherwise specified
Anxiety Disorders: Prevalence
17%
13%
Lifetime Prevalence of Anxiety Disorders: 25%
7.8%
5%
3.5%
2.5%
Kessler RC, et al. Arch Gen Psychiatry 1994;51:8-19
Stein MB, et al. JAMA 1998;280:708-713
Kessler RC, et al. Arch Gen Psychiatry 1995;52:1048-1060
Spectrum of Depression
and Anxiety Disorders
Posttraumatic
stress disorder
Social
anxiety
disorder
Depression
Panic disorder
Obsessive-compulsive disorder
Generalized anxiety disorder
Neurobiology of Anxiety Disorders

CNS equilibrium is determined by a balance
between excitatory and inhibitory
neurotransmission
 Excitation
-> Glutamate is prototypical NT.
 Inhibition -> GABA is prototypical NT.

Inhibition via GABA is primarily mediated by the
ionotropic GABA-A receptor.
 GABA
binding to GABA-A results in an increase in
neuronal Cl- conductance and subsequent neuronal
hyperpolarization.
Neurobiology of Anxiety Disorders
Cl- - equilibrium potential is
approximately -80 mV
An increase in Cl- influx will
decrease the resting potential of a
neuron.
Therefore, the post-synaptic
neuron will require a greater
excitatory stimulus to fire an action
potential.
Neurobiology of Anxiety
Disorders
GABA Receptor
Benzodiazepines – major class of
anxiolytic drugs.
Act primarily via a selective
binding sites on the GABA-A
receptor.
- high-affinity site.
- low-affinity site.
POTENTIATE the effects of GABA
at the GABA-A receptor.
Drugs useful in the treatment
of anxiety disorders.
Generic name
Trade name
Half-life (hrs)
Dosage (mg/day)
Long-acting benzodiazepines
Diazepam
Chlordiazepoxide
Clorazepate
Estazolam
Prazepam
Quazepam
Halazepam
Clonazepam*
Flurazepam+
Valium
Librium
Tranxene
ProSom
Centrax
Doral
Paxipam
Klonopin
Dalmane
20-80
2-60
24-48
100
10-24
100
30-100
15-100
34
100
15-100
7.5-60
0.5-2.0
20-60
7.5-15
20-160
1.5-20
15-30
8
15
12
11
2
2
30-120
2-6
0.5-6
15-30
0.125-0.5
2-4
Short-acting benzodiazepines
Oxazepam
Lorazepam
Alprazolam
Temazepam+
Triazolam+
Midazolam#
Serax
Ativan
Xanax
Restoril
Halcion
Versed
Non-benzodiazepine sedative/hypnotics
Buspirone (BuSpar)
Zolpidem (Ambien)
Meprobamate (Miltown)
Chloral hydrate (Noctec)
Serotonin 1a agonist
binds to benzodiazepine receptor
* marketed as an anti-convulsant
+marketed as a hypnotic
#parenteral only
Statement from the British Committee
for the Review of Medicines.
“All benzodiazepines are efficacious in the shortterm treatment of anxiety and insomnia. There is no
evidence which can justify the particular use of any
particular benzodiazepine in either anxiety or
insomnia. The usual division of benzodiazepines
into rigid treatment categories of antianxiety agents
and hypnotics does not appear to be based on the
known pharmacological or clinical properties of this
group of compounds.”
Caveat – different benzodiazepines have additional actions (i.e., muscle
relaxants, anticonvulsants, anesthetics) and different half-lives.
Benzodiazepines - Properties
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Prototypical Benzodiazepine = Diazepam (Valium).
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Highly lipophilic – well-absorbed orally and easily crosses the
blood-brain and blood-placental barriers.
Hepatic metabolism – converted to hydrophilic metabolites for
renal elimination.
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Metabolite = desmethyldiazepam
Same metabolite for diazepam, chlordiazepam, prazepam, and
clorazepate.
Desmethyldiazepam itself is pharmacologically active as an
anxiolytic.
Desmethyldiazepam is converted to oxazepam in the
liver.
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Short-acting metabolite.
Directly glucuronidated (as is lorazepam and flurazepam) and
excreted by the kidney.
Benzodiazepines - Properties
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Pharmacological Effects:
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Reduction of anxiety.
Induction of sleep.
Anesthesia – some benzodiazepines.
Respiratory depression not as great as observed with
barbiturates.
Adverse Effects – primarily observed at plasma
concentrations exceeding anxiolytic range.
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Expected side effects: sedation, ataxia, dependence.
Impaired cognition and motor function.
Confusion.
Amnesia.
Fatal overdose is uncommon, except when taken with alcohol.
Benzodiazepines - Properties
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Benzodiazepines may induce tolerance in some
individuals.
 Discontinuation
of benzodiazepine therapy in tolerant
patients MUST be gradual.
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Avoid hyperexcitability and possible seizures (more common
with short-acting benzodiazepines).
 Block
sedative side-effects of benzodiazepines with
flumazenil (benzodiazepine receptor antagonist).
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Precipitate withdrawal symptoms in patients dependent on
benzodiazepines (i.e., anxiety, insomnia, convulsions).
Benzodiazepines - Indications
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Anxiety and Insomnia
Sedation
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Mania
 Drug-induced hyperexcitability – PCP intoxication.
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Spasticity
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Cerebral Palsy
Tetanus toxin toxicity.
Anesthesia
Alcohol withdrawal syndrome.
Seizures.
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Clonazepam in myoclonic disorders.
Diazepam, midazolam, and lorazepam in status epilepticus.
 Only effective early during status epilepticus.
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Evidence for seizure-induced translation change in GABA-A subunit
expression.
Benzodiazepines –
Mechanism of Action
GABA Receptor
GABA-A receptors – highly
variable (i.e., consist of different
complements of alpha, beta, and
gamma subunits).
= different sensitivities to
benzodiazepines.
= a2 subunit is critical in
sedative effects.
Benzodiazepines do NOT activate
the receptor directly.
= increase frequency of
chloride-channel opening
produced by GABA.
Autoradiography of
GABA-A Receptors.
a2 subunit
Data shows that a2
subunit is localized to
limbic system
= Sedation.
a3 subunit
Further evidence – sitedirected mutagenesis
against a2 subunit
eliminates sedative effects
of benzodiazepines.
Pharmacological Effects of Benzodiazepines
are Concentration-Dependent.
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Nanomolar Concentrations
sedation – via a2 subunit.
 Action effectively blocked by flumazenil.
 Anxiolytic
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Micromolar Concentrations
– diazepam, midazolam, lorazepam.
 Activity due to binding of benzodiazepines to lowaffinity site on GABA-A receptor.
 Anesthesia
Practical Points regarding
Benzodiazepines.
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Lowest effective dose for the shortest possible time.
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Discontinuance withdrawal is most common with shortacting benzodiazepines.
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Minimizes dependence and withdrawal.
Cessation of long-acting drugs produces a tapering effect due to
long elimination half-life.
Patients on short-acting benzodiazepines need weeks to months
to be weaned.
Generally, benzodiazepines are safe drugs with few
medical complications and do not interact adversely with
other medications.
Newer sedative/hypnotic drugs.
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Different mechanisms of action as compared to
benzodiazepines.
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Do not act on GABA-A receptors.
May interact only with specific GABA-A receptor subunits.
Designed to produce anxiolytic effects without
undesirable side effects associated with
benzodiazepines.
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Daytime sedation and drowsiness.
CNS depression in combination with alcohol.
Potential for dependence.
Buspirone (BuSpar®)
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Partial agonist at the serotonin 1a receptor.
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Relieves anxiety without producing sedation, impairment of motor
skills, or memory loss.
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Does not induce withdrawal symptoms upon discontinuation.
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Does not act immediately.
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Can take up to 1 week to become effective.
Used for chronic anxiety states.
Pharmacokinetics:
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Rapidly absorbed orally.
Rapid first-pass effect.
Elimination half-life = 2-4 hrs.
Metabolism is primarily hepatic.
Serotonin Pathways in the CNS
Serotonin and Anxiety
Serotonin
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supported by efficacy of SSRIs
major nuclei:
CRN
limbic/ prefrontal cortex structures
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Mediates fear/ anticipatory anxiety
RRN
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prefrontal cortex, basal ganglia, thalamus,
limbic cortex, substantia nigra, periaqueductal
grey
Modulates cognitive/ behavioural components
strong feedback relationship with limbic cortex.
Zolpidem (Ambien®)
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Produces sedative properties by binding selectively to a1-subunit.
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Same site that also binds benzodiazepines.
 Evidence – pharmacological effects blocked by flumazenil.
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Structurally unrelated to benzodiazepines.
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Used clinically for treatment of insomnia.
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Minimal muscle relaxing and anticonvulsant effects.
Less potential for dependence and withdrawal.
Pharmacokinetics:
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Elimination half-life = 1.5-3.5 hrs.
Largely metabolized in the liver.