Clinical pharmacology: sedative-hypnotic drugs

1. Clinical pharmacology of sedative-
hypnotics
Domina Petric, MD

2. Clinical uses of sedative-hypnotics
Relief of anxiety
Insomnia
Sedation and amnesia before and during medical and surgical procedures
Treatment of epilepsy and seizure states
As a component of balanced anesthesia (intravenous administration)
For control of ethanol or other sedative-hypnotic withdrawal states
For muscle relaxation in specific neuromuscular disorders
As diagnostic aids or for treatment in psychiatry

3. Treatment of anxiety states
The psychic awareness of anxiety is accompanied by enhanced
vigilance, motor tension and autonomic hyperactivity.
Anxiety is often secondary to organic disease states, such as
myocardial infarction, angina pectoris and gastrointestinal ulcers.
Secondary anxiety states (situational anxiety) results from
circumstances that may have to be dealt with only once or a few
times, for example, anticipation of frightening medical or dental
procedures, family illness…
Secondary anxiety is usually self-limiting, but the short-term use of
sedative-hypnotics may be appropriate.
The use of sedative-hypnotics prior to surgery or some unpleasant
medical procedure is rational and proper.

4. Treatment of anxiety states
Excessive or unreasonable anxiety about life circumstances
(generalized anxiety disorder, GAD), panic disorders and
agoraphobia can also be treated with these drugs,
sometimes in conjunction with psychotherapy.
The benzodiazepines are used for the management of acute
anxiety states and for rapid control of panic attacks.
Benzodiazepines are also used, but much less commonly, in
the long-term management of GAD and panic disorders.
Alprazolam is used in the treatment of panic disorders and
agoraphobia.

5. The choice of benzodiazepines for the treatment of
anxiety is based on:
Rapid onset of action.
Relatively high therapeutic index.
Availability of flumazenil for treatment of overdose.
A low risk of drug interactions based on liver enzyme induction.
Minimal effects on cardiovascular or autonomic functions.

6. Treatment of anxiety states
Disadvantages of the benzodiazepines include the risk of
dependence, depression of CNS functions and amnestic effects.
The benzodiazepines exert additive CNS depression when
administered with other drugs, including ethanol.
In the treatment of generalized anxiety disorders and certain
phobias, newer antidepressants like selective serotonin reuptake
inhibitors (SSRIs) and serotonin-norepinephrine reuptake
inhibitors (SNRIs) are considered today drugs of first choice.
SSRIs and SNRIs have a slow onset of action and limited
effectiveness in acute anxiety states.

7. Treatment of anxiety states
Sedative-hypnotics should be used with appropriate caution.
A dose should be prescribed that does not impair mentation or motor
functions during walking hours.
Some patients may tolerate the drug better if most of the daily dose is
given at bedtime, with smaller doses during the day.
Prescriptions should be written for short periods (less than 2 months).
The physician should assess the efficacy of therapy from the patient´s
subjective responses.
Combinations of antianxiety agents should be avoided.
Patients taking sedatives should avoid the consuption of alcohol and
the concurrent use of OTC medications containing antihistaminic or
anticholinergic drugs.

8. Treatment of sleep problems
Sleep disorders are common and often result from
inadequate treatment of underlying medical conditions or
psychiatric illness.
True primary insomnia is rare.
Nonpharmacologic therapies:
 diet and exercise
 avoiding stimulants before retiring
 ensuring a comfortable sleeping environment
 retiring at a regular time each night

9. Treatment of sleep problems
In some cases patient will need a sedative-hypnotic for a limited
period.
The abrupt discontinuance of many drugs in this class can lead to
rebound insomnia.
Benzodiazepines can cause a dose-dependent decrease in both REM
and slow-wave sleep.
The newer hypnotics zolpidem, zaleplon and eszopiclone are less
likely to change sleep patterns.
The drug selected should be one that provides sleep of fairly rapid
onset (decreased sleep latency) and sufficient duration, with
minimal hangover effects: drowsiness, dysphoria, mental or motor
depression the following day.

10. Treatment of sleep problems
Daytime sedation is more common with benzodiazepines that
have slow elimination rates, like lorazepam, and those that are
biotransformed to active metabolites, like flurazepam and
quazepam.
If benzodiazepines are used nightly, tolerance can occur, which
may lead to dose increases by the patient to produce the
desired effect.
Anterograde amnesia occurs to some degree with all
benzodiazepines used for hypnosis.
Favorable clinical features of zolpidem, zaleplon and eszopiclone
include rapid onset of activity and modest day-after
psychomotor depression with few amnestic effects.

11. Treatment of sleep problems
Zolpidem is available in a biphasic release formulation
that provides sustained drug levels for sleep
maintenance.
Zaleplon acts rapidly.
Because of its short half-life, zaleplon has value in the
management of patients who awaken early in the sleep
cycle.
Zaleplon and eszopiclone (despite its relatively long half-
life) appear to cause less amnesia and day-after
somnolence than zolpidem or benzodiazepines.

12. Warning
The failure of insomnia to remit after 7-10
days of treatment may indicate the presence
of a primary psychiatric or medical illness
that should be evaluated.
Long-term use of hypnotics is an
irrational and dangerous medical
practice!!!

13. Sedation drugs and doses
Drug Dosage
Alprazolam 0,25-0,5 mg 2-3 times daily
Buspirone 5-10 mg 2-3 times daily
Chlordiazepoxide 10-20 mg 2-3 times daily
Clorazepate 5-7,5 mg twice daily
Diazepam 5 mg twice daily
Halazepam 20-40 mg 3-4 times daily
Lorazepam 1-2 mg once or twice daily
Oxazepam 15-30 mg 3-4 times daily
Phenobarbital 15-30 mg 2-3 times daily

14. Drugs and doses for hypnosis
Drug Dosage at bedtime
Chloral hydrate 500-1000 mg
Estazolam 0,5-2 mg
Eszopiclone 1-3 mg
Lorazepam 2-4 mg
Quazepam 7,5-15 mg
Secobarbital 100-200 mg
Temazepam 7,5-30 mg
Triazolam 0,125-0,5 mg
Zaleplon 5-20 mg
Zolpidem 5-10 mg

15. Other therapeutic uses
For sedative and possible amnestic effects during medical or
surgical procedures, as well as for premedication prior to
anesthesia, oral formulations of shorter-acting drugs are
preferred.
Long-acting drugs, chlordiazepoxide, diazepam and phenobarbital,
are administered in progressively decreasing doses to patients
during withdrawal from physiologic dependence on ethanol or
other sedative-hypnotics.
Parenteral lorazepam is used to suppress the symptoms of delirium
tremens.
Meprobamate and the benzodiazepines are frequently used as
central muscle relaxants.

16. Other therapeutic uses
Psychiatric uses of benzodiazepines other than
treatment of anxiety states include:
• initial management of mania
• control of drug-induced hyperexcitability states
(phencyclidine intoxication)
Sedative-hypnotics are also used occasionally as
diagnostic aids in neurology and psychiatry.

17. Literature
Katzung, Masters, Trevor.
Basic and clinical
pharmacology.