Anxiolytic and Hypnotic Drugs

PHRM 306
Sedative-Hypnotic-Anxiolytic Drugs
• A sedative drug decreases activity, moderates
excitement, and calms the recipient.
• A hypnotic drug produces drowsiness and
facilitates the onset and maintenance of a
state of sleep that resembles natural sleep,
and from which the patient can be easily
aroused.
• An anxiolytic drug reduces anxiety.
 Overview
• Anxiety is an unpleasant state of tension,
apprehension, or uneasiness-a fear that seems
to arise from a sometimes unknown source.
• Disorders involving anxiety are the most
common mental disturbances.
 Overview
• The physical symptoms of severe anxiety are
similar to those of fear (such as tachycardia,
sweating, trembling, and palpitations) and
involve sympathetic activation.
• Episodes of mild anxiety are common life
experiences and do not warrant treatment.
 Overview
• However, the symptoms of severe, chronic,
debilitating anxiety may be treated with
antianxiety drugs (sometimes called anxiolytic
or minor tranquilizers) and/or some form of
behavioral or psychotherapy.
 Overview
• 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.
 Benzodiazepines
• Benzodiazepines are the most widely used
anxiolytic drugs.
• They have largely replaced barbiturates and
meprobamate in the treatment of anxiety,
because the benzodiazepines are safer and
more effective.
• Lethal dose of Benzodiazepines is over 1000
times greater than the therapeutic dose.
 Types
• Five types of Benzodiazepines
• 2-keto compounds: chlordiazepoxide,
clorazepate, diazepam, flurazepam,
halazepam, prazepam, and others.
• 3-hydroxy compounds: lorazepam,
lormetazepam, oxazepam, temazepam
 Types
• 7-nitro compounds: clonazepam,
flunitrazepam, nimetazepam, nitrazepam
• Triazolo compounds: adinazolam, alprazolam,
estazolam, triazolam
• Imidazo compounds: climazolam, loprazolam,
midazolam
 Benzodiazepines M/A
• Binding of GABA to its receptor (GABAA)
triggers an opening of a chloride channel,
which leads to an increase in chloride
conductance.
• Binding of a benzodiazepine to its receptor
site will increase the affinity of GABA for the
GABA-binding site (and vice versa) without
actually changing the total number of sites.
 Benzodiazepines M/A
• Activation of the GABAA receptor increases
chloride conductance through the ion
channel, hyperpolarizing and thereby reducing
the excitability of the postsynaptic neuron.
Figure
Schematic diagram of benzodiazepine-GABA-chloride ion channel complex.
 Actions
• All benzodiazepines exhibit the following
actions to a greater or lesser extent:
• Reduction of anxiety: At low doses, the
benzodiazepines are anxiolytic.
• Sedative and hypnotic actions: All of the
benzodiazepines used to treat anxiety have
some sedative properties, and some can
produce hypnosis (artificially produced sleep)
at higher doses.
 Actions
• Anterograde amnesia: The temporary
impairment of memory with use of the
benzodiazepines is also mediated by the GABA
receptors. This also impairs a person's ability
to learn and form new memories.
 Actions
• Anticonvulsant: Several of the
benzodiazepines have anticonvulsant activity.
• Muscle relaxant: At high doses, the
benzodiazepines relax the skeletal muscle
 Dependence
• Psychological and physical dependence on
benzodiazepines can develop if high doses of
the drugs are given over a prolonged period.
• Abrupt discontinuation of the
benzodiazepines results in withdrawal
symptoms, including confusion, anxiety,
agitation, restlessness, insomnia, tension, and
rarely, seizures.
 Dependence
• Long half-lives of benzodiazepines
(flurazepam) : withdrawal symptoms may
occur slowly.
• Benzodiazepines with a short elimination
half-life (triazolam): induce more abrupt and
severe withdrawal reactions than those seen
with drugs that are slowly eliminated.
 Adverse effects
• Drowsiness and confusion:
• These effects are the two most common side
effects of the benzodiazepines.
• Ataxia occurs at high doses and precludes
activities that require fine motor coordination,
such as driving an automobile.
 Adverse effects
• Precautions:
• Benzodiazepines should be used cautiously in
treating patients with liver disease.
• They should be avoided in patients with acute
narrow-angle glaucoma.
• Alcohol and other CNS depressants enhance
the sedative-hypnotic effects of the
benzodiazepines.
 Barbiturates
• The barbiturates were formerly the mainstay
of treatment to sedate the patient or to
induce and maintain sleep.
• Today, they have been largely replaced by the
benzodiazepines, primarily because
barbiturates induce tolerance,
drug-metabolizing enzymes, physical
dependence, and are associated with very
severe withdrawal symptoms.
 Barbiturates
• Foremost is their ability to cause coma in toxic
doses.
• Certain barbiturates, such as the very
short-acting thiopental, are still used to induce
anesthesia.
 Mechanism of action
• Barbiturates both enhance and mimic the
action of GABA.
• By binding to their receptor, barbiturates
decrease the rate of dissociation of GABA
from its receptor and increase the duration of
GABA-activated chloride ion channel
openings.
 Mechanism of action
• At slightly higher but still clinically relevant
concentrations, barbiturates directly activate
chloride channels, even in the absence of
GABA.
• Barbiturate enhancement of the action of
GABA may be responsible for its
sedative-hypnotic effects, whereas the
GABA-mimetic effect at slightly higher
concentrations may be responsible for
“barbiturate anesthesia.”
 Actions
• Anesthesia: Thiopental (IV), which acts within
seconds and has a duration of action of about
30 minutes
• Seizures: Phenobarbital, which has a duration
of action greater than a day
• Sedative and hypnotic (but not antianxiety)
agents: Pentobarbital, secobarbital and
amobarbital are short-acting barbiturates