Clinical pharmacology of sedative-hypnotics Domina Petric, MD

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

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.

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.

Relatively high therapeutic index. 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.

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.

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.

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

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.

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.

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.

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!!!

Sedation drugs and doses 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

Drugs and doses for hypnosis 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

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.

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.

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