DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

benzodiazepines and β adrenergic antagonists are effective acutely; the
use of β adrenergic antagonists is generally limited to treatment of situational
anxiety. Chronic treatment with SSRIs, SNRIs, and buspirone
is required to produce and sustain anxiolytic effects. When an immediate
anxiolytic effects is desired, benzodiazepines are typically
selected.
Benzodiazepines, such as alprazolam, chlordiazepoxide,
clonazepam, clorazepate, diazepam, lorazepam, and oxazepam, are
effective in the treatment of generalized anxiety disorder, panic disorder,
and situational anxiety. In addition to their anxiolytic effects,
benzodiazepines produce sedative, hypnotic, anesthetic, anticonvulsant,
and muscle relaxant effects. The benzodiazepines also impair
cognitive performance and memory, adversely affect motor control,
and potentiate the effects of other sedatives including alcohol. The
anxiolytic effects of this class of drugs are mediated by allosteric
interactions with the pentameric benzodiazepine- GABA A
receptor
complex, in particular those GABA A
receptors comprised of α2, α3,
and α5 subunits (Chapters 14 and 17). The primary effect of the anxiolytic
benzodiazepines is to enhance the inhibitory effects of the
neurotransmitter GABA.
One area of concern regarding the use of benzodiazepines in
the treatment of anxiety is the potential for habituation, dependence,
and abuse. Patients with certain personality disorders or a history of
drug or alcohol abuse are particularly susceptible. However, the risk
of dependence must be balanced with the need for treatment, since
benzodiazepines are effective in both short- and long- term treatment
of patients with sustained or recurring bouts of anxiety. Further, premature
discontinuation of benzodiazepines, in the absence of other
pharmacological treatment, results in a high rate of relapse.
Withdrawal of benzodiazepines after chronic treatment, particularly
those with short durations of action, can include increased anxiety
and seizures. For this reason, it is important that discontinuation be
carried out in a gradual manner.
Benzodiazepines cause many adverse effects, including sedation,
mild memory impairments, decreased alertness, and slowed
reaction time (which may lead to accidents). Memory problems can
include visual- spatial deficits, but will manifest clinically in a variety
of ways, including difficulty in word- finding. Occasionally, paradoxical
reactions can occur with benzodiazepines such as increases
in anxiety, sometimes reaching panic attack proportions. Other
pathological reactions can include irritability, aggression, or behavioral
disinhibition. Amnesic reactions (i.e., loss of memory for particular
periods) can also occur. Benzodiazepines should not be used
in pregnant women; there have been rare reports of craniofacial
defects. In addition, benzodiazepines taken prior to delivery may
result in sedated, under- responsive newborns and prolonged withdrawal
reactions. In the elderly, benzodiazepines increase the risk
for falls and must be used cautiously. These drugs are safer than classical
sedative- hypnotics in overdosage and typically are fatal only if
combined with other CNS depressants.
Benzodiazepines have at least some abuse potential, although
their capacity for abuse is considerably below that of other classical
sedative- hypnotic agents. When these agents are abused, it is generally
in a multi- drug abuse pattern. In fact, the primary reason for
misuse of these agents often is failed attempts to control anxiety.
Tolerance to the anxiolytic effects develops with chronic administration,
with the result that some patients escalate the dose of benzodiazepines
over time. Ideally, benzodiazepines should be used for short
periods of time and in conjunction with other medications (e.g.,
SSRIs) or evidence- based psychotherapies (e.g., cognitive behavioral
therapy for anxiety disorders).
SSRIs and the SNRI venlafaxine are first- line treatments for
most types of anxiety disorders, except when an acute drug effect is
desired; fluvoxamine is approved only for obsessive- compulsive disorder.
As for their antidepressant actions, the anxiolytic effects of
these drugs become manifest following chronic treatment. Other
drugs with actions on serotonergic neurotransmission, including trazodone,
nefazodone, and mirtazapine, also are used in the treatment
of anxiety disorders. Details regarding the pharmacology of these
classes of were presented earlier.
Both SSRIs and SNRIs are beneficial in specific anxiety conditions
such as generalized anxiety disorder, social phobias,
obsessive- compulsive disorder, and panic disorder. These effects
appear to be related to the capacity of serotonin to regulate the activity
of brain structures such as amygdala and locus coeruleus that are
thought to be involved in the genesis of anxiety. Interestingly, the
SSRIs and SNRIs often will produce some increases in anxiety in the
short- term that dissipate with time. Therefore, the maxim “start low
and go slow” is indicated with anxious patients; however, many
patients with anxiety disorders ultimately will require doses that
are about the same as those required for the treatment of depression.
Anxious patients appear to be particularly prone to severe
discontinuation reactions with certain medications such as venlafaxine
and paroxetine; therefore, slow off- tapering is required.
Buspirone is used in the treatment of generalized anxiety disorder
(Goodman, 2004). Like the SSRIs, buspirone requires chronic
treatment for effectiveness. Also, like the SSRIs, buspirone lacks many
of the other pharmacological effects of the benzodiazepines: it is not
an anticonvulsant, muscle relaxant, or sedative, and it does not impair
psychomotor performance or result in dependence. Buspirone is primarily
effective in the treatment of generalized anxiety disorder, but
not for other anxiety disorders. In fact, patients with panic disorder
often note an increase in anxiety acutely following initiation of buspirone
treatment; this may be the result of the fact that buspirone
causes increased firing rates of the locus coeruleus, which is thought
to underlie part of the pathophysiology of panic disorder.
CLINICAL SUMMARY
Mood and anxiety disorders are the most common psychiatric illnesses
and are encountered frequently by clinicians in all disciplines.
Depression represents a spectrum of conditions with a range of severity
and a high frequency of co morbidities. Depressive conditions
range from mild, self- limiting conditions to extremely severe illnesses
that can include a high suicidal potential, psychosis, and serious functional
impairment. Whereas the likelihood of receiving treatment for
depression or anxiety has improved, problems remain with regard to
duration, dosing, and adherence to treatment. Unfortunately, persons
with depressive or anxiety disorders continue to suffer considerable
delays in diagnosis and adequate treatment. Prominently used agents
inhibit transmitter reuptake via SERT and NET.
Current antidepressant and anxiolytic treatment strategies are
imperfect. Many patients have significant residual symptoms after pharmacotherapy.
Fortunately, antidepressant/anxiolytic drug development
is expanding beyond standard 5-HT and NE uptake inhibitors. New
antidepressant medications include triple (5-HT, NE, and DA)
413
CHAPTER 15
DRUG THERAPY OF DEPRESSION AND ANXIETY DISORDERS