Anxiolytics and Hypnotics :
Anxiety
• It is an unpleasant state of tension, apprehension or
uneasiness-a fear that seems to arise from an unknown
source.
• The symptoms of severe anxiety are similar to those of fear
such as:
• Tachycardia
• Sweating
• Trembling
• Palpitation.
• Symptoms of severe and chronic anxiety , may be treated
with anti-anxiety drugs sometimes called anxiolytics.
Classification of Hypnotics, Anxiolytics
•Benzodiazepines:
 Alprazolam
 Clonazepam
 Lorazepam
 Diazepam
 Flurazepam
Benzodiazepine antagonists
Flumazenil
Other Anxiolitic drugs:
Buspirone
Antidepressants
Barbiturates
Amobarbital
Phenobarbital
Pentobarbital
Thiopental
Non-barbiturate
 Anti-histamines
 Doxepin
General Definitions
•Sedative: Calm down, treat agitation
•Hypnotic: Induce sleep
–go to sleep fast, feel refreshed tomorrow !!!
•Anxiolytic: Reduce anxiety
– physical, emotional, cognitive
Benzodiazepines (BZD):
• Benzodiazepines are the most widely used
anxiolytic drugs. They have largely replaced
barbiturates in the treatment of anxiety,
because benzodiazepines are safer and more
effective.
Mechanism of Action
• The targets for benzodiazepine actions are the γaminobutyric acid (GABAA ) receptors. [Note: GABA is the
major inhibitory neurotransmitter in the central nervous
system (CNS).] These receptors are primarily composed of
α, β, and γ subunit .Benzodiazepines modulate GABA
effects by binding to a specific, high-affinity site located at
the interface of the α subunit and the γ2 subunit.
• The benzodiazepine receptor locations in the CNS parallel
those of the GABA neurons. Binding of GABA to its
receptor triggers an opening of a chloride channel, which
leads to an increase in chloride conductance.
Benzodiazepines increase the frequency of channel openings
produced by GABA. The influx of chloride ions causes a
small hyperpolarization that moves the postsynaptic
potential away from its firing threshold and, thus, inhibits
the formation of action potentials.
Therapeutic Effects
Sedative,
 Hypnotic,
Anticonvulsant,
Muscle-Relaxant.
Anxiety disorder.
Adverse Effects
• Sedation,
• CNS Depression
• Behavioral Disturbance
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Irritability, excitement, aggression
coordination, attention (driving)
poor visual-spatial ability
Ataxia, confusion
Drowziness
• Overdose: Rare fatalities if BZD alone
• Severe CNS & Respiratory Depression if combined
with:
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alcohol
barbiturates
narcotics
tricyclic antidepressants
BENZODIAZEPINE ANTAGONIST
• Flumazenil is a GABA-receptor antagonist
that can rapidly reverse the effects of
benzodiazepines. The drug is available for
intravenous (IV) administration only. Onset
is rapid, but duration is short, with a half
life of about 1 hour. Frequent
administration may be necessary to
maintain reversal of a long-acting
benzodiazepine.
Administration
of
flumazenil may precipitate withdrawal .
• Dizziness, nausea, vomiting, and agitation
are the most common side effects.
OTHER ANXIOLYTIC AGENTS
• 1) Antidepressants
• Selective serotonin reuptake inhibitors may be used
alone, or prescribed in combination with a low dose of a
benzodiazepine during the first weeks of treatment. After
four to six weeks, when the antidepressant begins to
produce an anxiolytic effect, the benzodiazepine dose
can be tapered. SSRIs have a lower potential for physical
dependence than the benzodiazepines, and have become
first-line treatment for GAD. While only certain SSRIs
have been approved by the FDA for the treatment of
GAD, the efficacy of these drugs for GAD is most likely
a class effect. Thus, the choice among these
antidepressants can be based upon side effects and cost.
Long-term use of antidepressants and benzodiazepines
for anxiety disorders is often required to maintain
ongoing benefit and prevent relapse.
• 2) Buspirone
• Buspirone is useful for the chronic treatment of
GAD and has an efficacy comparable to that of
the benzodiazepines. This agent is not effective
for short-term or “as-needed” treatment of
acute anxiety states. The actions of buspirone
appear to be mediated by serotonin (5-HT1A)
receptors, although other receptors could be
involved, because buspirone displays some
affinity for DA2 dopamine receptors and 5-HT2A
serotonin receptors. Thus, its mode of action
differs from that of the benzodiazepines.
• The frequency of adverse effects is low, with the
most common effects being headaches,
dizziness, nervousness, and light-headedness.
Barbiturates
•All derivatives of Barbituric acid
•Depressants of the central nervous system (CNS) that impair or
reduce the activity of the brain by acting as a Gamma Amino
Butyric Acid (GABA) potentiators
•Categorized as hypnotics and also called “downers”
•Produce alcohol like symptoms such as impaired motor control
(ataxia), dizziness, and slower breathing and heart rate
Barbiturates
•
•
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Amobarbital
Pentobarbital
Secobarbital
Phenobarbitol
Thiopental
Mechanism of Action
Barbiturates potentiate the effect of GABA at the GABA-A
receptor. The GABA-A receptor is a ligand gated ion
channel membrane receptor that allows for the flow of Cl
through the membrane in neurons. GABA is the principle
neurotransmitter for this receptor which upon binding causes
the channel to open and creates a negative change in the
transmembrane potential. This makes it an Inhibitory
neurotransmitter
GABA binding site
Barbiturate binding site
Mechanism of Action
Facilitation of GABA action on the brain.
increase the duration of the GABA gated
channel opening but in large dose, they can
directly activating chloride channels.
Pharmacological Actions:
• Depression of CNS
At low doses produce sedation
At high doses drugs causes hypnosis, followed
by anesthesia and finally coma and death.
• Respiratory depression
• Enzyme induction: induce P450 microsomal
enzyme in liver.
Adverse effects
•Drowsiness
•Impaired concentration
•Mental and physical sluggishness
•Hypnotic doses produces feeling of tiredness after
wake.
•Impaired ability to function normally
•Nausea
•Dizziness
Non- barbiturate sedatives
ANTIHISTAMINES
antihistamine with sedating properties such as
diphenhydramine and doxylamine are effective
in treating mild type of insomnia.
They have numerous undesirable side effects
make them less useful.
Zolpidem:
• This hypnotic drug is not structurally related
to benzodiazepine but it selectively bind to
the benzodiazepine receptor .
• It is rapidly absorbed from the GIT & its onset
of action is rapid & short elimination half life.
• Adverse effects: nightmares, agitation,
headache, GI upset, dizziness