A Textbook of Clinical Pharmacology and Therapeutics

short-term use, as it causes intense withdrawal

phenomena and dependence.

• Diazepamormidazolami.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
   diazepaminintralipidis 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 evi-

dence 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 audi-

tory hallucinations, paranoia, feelings of unreality, deperson-

alization, 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 seda-

tive actions of alcohol, histamine (H 1 ) antagonists and other

hypnotics.

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. Buspironeis 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 pur-
poses. Compounds with a short half-life tend to be used as hyp-
notics, 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 phar-
macological treatment of insomnia and anxiety. Clonazepamis
believed to be more anticonvulsant than other members of the
group at equi-sedating doses. Benzodiazepines bind to specific
binding sites in the GABAAreceptor–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