Clinical Pharmacology and Therapeutics

108 HYPNOTICS AND ANXIOLYTICS
• Desensitization can be useful when severe anxiety
develops in well-recognized situations (e.g. agoraphobia,
arachnophobia, etc.). Anxiolytic drugs are sometimes
given intermittently and with a flexible-dose scheme in
such situations.
• Benzodiazepines are the anxiolytics normally used where
pharmacological therapy is indicated. Buspirone is as
effective as and less hypnotic than the benzodiazepines,
but has slower onset.
• β-Blockers are sometimes useful in patients with
prominent symptoms, such as palpitations or tremor.
• Tricyclic antidepressants may be effective in anxiety and
in preventing panic attacks.
• Monoamine oxidase inhibitors (used only by specialists)
can be useful for treating anxiety with depression, phobic
anxiety, recurrent panic attacks and obsessive-compulsive
disorders.
• Individual panic attacks are usually terminated by
benzodiazepines, which may have to be supplemented
with short-term treatment with phenothiazines (e.g.
chlorpromazine).
• If hyperventilation is the principal ‘trigger’, advice on
controlled breathing exercises can be curative.
DRUGS USED TO TREAT SLEEP DISTURBANCES
AND ANXIETY
The distinction between hypnotics and anxiolytics is rather
arbitrary, and the same classes of drugs are used for both purposes.
Compounds with a short half-life tend to be used as hypnotics,
because they cause less ‘hangover’ effects; longer half-life
drugs tend to be used as anxiolytics, since a longer duration of
action is generally desirable in this setting. Benzodiazepines
are used for the short-term alleviation of anxiety, but should
not be used long term, where antidepressants (Chapter 20) are
usually the treatment of choice.
BENZODIAZEPINES
These drugs are anxiolytic, anticonvulsant muscle relaxants
that induce sleepiness; they remain drugs of choice for the pharmacological
treatment of insomnia and anxiety. Clonazepam is
believed to be more anticonvulsant than other members of the
group at equi-sedating doses. Benzodiazepines bind to specific
binding sites in the GABA A receptor–chloride channel complex
in the brain, and facilitate the opening of the channel in the
presence of GABA; this increases hyperpolarization-induced
neuronal inhibition.
Examples
• Diazepam – used as an anxiolytic, because of its long
half-life.
• Temazepam – used as a hypnotic, because of its short
half-life.
• Lorazepam – potent short half-life benzodiazepine.
Should generally be avoided for more than very
short-term use, as it causes intense withdrawal
phenomena and dependence.
• Diazepam or midazolam i.v. before procedures such as
endoscopy, cardioversion and operations under local
anaesthesia. Early short-lived high peak blood levels are
accompanied by anterograde amnesia.
Cautions
• respiratory failure;
• breast-feeding;
• previous addiction.
Adverse effects
• drowsiness;
• confusion;
• paradoxical disinhibition and aggression.
Adverse effects of intravenous diazepam include:
1. Cardiovascular and respiratory depression (uncommon).
Patients with chronic lung disease, and those who have
been previously given other central depressant drugs are
at risk.
2. Local pain following i.v. injection. An emulsion of
diazepam in intralipid is less irritating to the vein.
Intra-arterial benzodiazepine can cause arterial spasm
and gangrene.
Drug dependence, tolerance and withdrawal
Benzodiazepine dependence is usually caused by large doses
taken for prolonged periods, but withdrawal states have
arisen even after limited drug exposure. Pharmacological evidence
of tolerance may develop within three to 14 days. The
full withdrawal picture can manifest within hours of the last
dose for the shorter-acting drugs, or may develop over up to
three weeks with the longer-duration benzodiazepines.
Withdrawal syndrome includes a cluster of features including
frank anxiety and panic attacks. Perceptual distortions (e.g.
feelings of being surrounded by cotton wool), visual and auditory
hallucinations, paranoia, feelings of unreality, depersonalization,
paraesthesiae, sweating, headaches, blurring of
vision, dyspepsia and influenza-like symptoms can occur.
Depression and agoraphobia are also common. The syndrome
may persist for weeks. Withdrawal from benzodiazepines in
patients who have become dependent should be gradual. If
this proves difficult, then an equivalent dose of a long-acting
benzodiazepine should be given as a single night-time dose
instead of shorter-acting drugs. The dose should then be
reduced in small fortnightly steps. Psychological support is
important.
Drug interactions
Pharmacodynamic interactions with other centrally acting drugs
are common, whereas pharmacokinetic interactions are not.
Pharmacodynamic interactions include potentiation of the sedative
actions of alcohol, histamine (H 1 ) antagonists and other
hypnotics.