Clinical Toxicology of Sedative-Hypnotics

CLINICAL TOXICOLOGY OF SEDATIVE-HYPNOTICS

Direct Toxic Actions

Many of the common adverse effects of sedative-hypnotics result from dose-related depression of the central nervous system. Relatively low doses may lead to drowsiness, impaired judgment, and diminished motor skills, sometimes with a significant impact on driving ability, job performance, and personal relationships. Sleep driving and other somnambulistic behavior with no memory of the event has occurred with the sedative-hypnotic drugs used in sleep disorders, prompting the Food and Drug Administration in 2007 to issue warnings of this potential hazard. Benzodiazepines may cause a significant dose-related anterograde amnesia; they can significantly impair ability to learn new information, particularly that involving effortful cognitive processes, while leaving the retrieval of previously learned information intact. This effect is utilized for uncomfortable clinical procedures, eg, endoscopy, because the patient is able to cooperate during the procedure but amnesic regarding it afterward. The criminal use of benzodiaz-epines in cases of “date rape” is based on their dose-dependent amnestic effects. Hangover effects are not uncommon following use of hypnotic drugs with long elimination half-lives. Because elderly patients are more sensitive to the effects of sedative-hypnotics, doses approximately half of those used in younger adults are safer and usually as effective. The most common reversible cause of confu-sional states in the elderly is overuse of sedative-hypnotics. At higherdoses, toxicity may present as lethargy or a state of exhaustion or, alternatively, as gross symptoms equivalent to those of ethanol intoxication. The physician should be aware of variability among patients in terms of doses causing adverse effects. An increased sensitivity to sedative-hypnotics is more common in patients with cardiovascular disease, respiratory disease, or hepatic impairment and in older patients. Sedative-hypnotics can exacerbate breathing problems in patients with chronic pulmonary disease and in those with symptomatic sleep apnea.

Sedative-hypnotics are the drugs most frequently involved in deliberate overdoses, in part because of their general availability as very commonly prescribed pharmacologic agents. The benzodiaz-epines are considered to be safer drugs in this respect, since they have flatter dose-response curves. Epidemiologic studies on the incidence of drug-related deaths support this general assumption—eg, 0.3 deaths per million tablets of diazepam prescribed versus 11.6 deaths per million capsules of secobarbital in one study. Alprazolam is purportedly more toxic in overdose than other benzodiazepines. Of course, many factors other than the specific sedative-hypnotic could influence such data—particularly the presence of other central nervous system depressants, including ethanol. In fact, most serious cases of drug overdosage, intentional or accidental, do involve polypharmacy; and when combinations of agents are taken, the practical safety of benzodiazepines may be less than the foregoing would imply.

The lethal dose of any sedative-hypnotic varies with the patient and the circumstances . If discovery of the ingestionis made early and a conservative treatment regimen is started, the outcome is rarely fatal, even following very high doses. On the other hand, for most sedative-hypnotics—with the exception of benzodiazepines and possibly the newer hypnotic drugs that have a similar mechanism of action—a dose as low as ten times the hypnotic dose may be fatal if the patient is not discovered or does not seek help in time. With severe toxicity, the respiratory depres-sion from central actions of the drug may be complicated by aspiration of gastric contents in the unattended patient—an even more likely occurrence if ethanol is present. Cardiovascular depression further complicates successful resuscitation. In such patients, treatment consists of ensuring a patent airway, with mechanical ventilation if needed, and maintenance of plasma volume, renal output, and cardiac function. Use of a positive ino-tropic drug such as dopamine, which preserves renal blood flow, is sometimes indicated. Hemodialysis or hemoperfusion may be used to hasten elimination of some of these drugs.

Flumazenil reverses the sedative actions of benzodiazepines, and those of eszopiclone, zaleplon, and zolpidem, although experi-ence with its use in overdose of the newer hypnotics is limited. However, its duration of action is short, its antagonism of respira-tory depression is unpredictable, and there is a risk of precipitation of withdrawal symptoms in long-term users of benzodiazepines . Consequently, the use of flumazenil in benzodiaz-epine overdose must be accompanied by adequate monitoring and support of respiratory function. The extensive clinical use of tri-azolam has led to reports of serious central nervous system effects including behavioral disinhibition, delirium, aggression, and vio-lence. Although behavioral disinhibition may occur with any sedative-hypnotic drug, it does not appear to be more prevalent with triazolam than with other benzodiazepines. Disinhibitory reactions during benzodiazepine treatment are more clearly associ-ated with the use of very high doses and the pretreatment level of patient hostility.

Adverse effects of the sedative-hypnotics that are not referable to their central nervous system actions occur infrequently. Hypersensitivity reactions, including skin rashes, occur only occa-sionally with most drugs of this class. Reports of teratogenicity leading to fetal deformation following use of certain benzodiaz-epines have resulted in FDA assignment of individual benzodiaz-epines to either category D or X in terms of pregnancy risk. Most barbiturates are FDA pregnancy category D. Eszopiclone, ramelt-eon, zaleplon, and zolpidem are category C, while buspirone is a pregnancy category B drug. Because barbiturates enhance porphy-rin synthesis, they are absolutely contraindicated in patients with a history of acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, or symptomatic porphyria.

Alterations in Drug Response

Depending on the dosage and the duration of use, tolerance occurs in varying degrees to many of the pharmacologic effects of sedative-hypnotics. However, it should not be assumed that the degree of tolerance achieved is identical for all pharmacologic effects. There is evidence that the lethal dose range is not altered significantly by the long-term use of sedative-hypnotics. Cross-tolerance between the different sedative-hypnotics, including ethanol, can lead to an unsatisfactory therapeutic response when standard doses of a drug are used in a patient with a recent history of excessive use of these agents. However, there have been very few reports of tolerance development when eszopiclone, zolpidem, or zaleplon was used for less than 4 weeks.

With the long-term use of sedative-hypnotics, especially if doses are increased, a state of dependence can occur. This may develop to a degree unparalleled by any other drug group, includingthe opioids. Withdrawal from a sedative-hypnotic can have severeand life-threatening manifestations. Withdrawal symptoms range from restlessness, anxiety, weakness, and orthostatic hypotension to hyperactive reflexes and generalized seizures. Symptoms of withdrawal are usually more severe following discontinuance of sedative-hypnotics with shorter half-lives. However, eszopiclone, zolpidem, and zaleplon appear to be exceptions to this, because withdrawal symptoms are minimal following abrupt discontinu-ance of these newer short-acting agents. Symptoms are less pro-nounced with longer-acting drugs, which may partly accomplish their own tapered withdrawal by virtue of their slow elimination. Cross-dependence, defined as the ability of one drug to suppress abstinence symptoms from discontinuance of another drug, is quite marked among sedative-hypnotics. This provides the ration-ale for therapeutic regimens in the management of withdrawal states: Longer-acting drugs such as chlordiazepoxide, diazepam, and phenobarbital can be used to alleviate withdrawal symptoms of shorter-acting drugs, including ethanol.

Drug Interactions

The most common drug interactions involving sedative-hypnotics are interactions with other central nervous system depressant drugs, leading to additive effects. These interactions have some therapeutic usefulness when these drugs are used as adjuvants in anesthesia practice. However, if not anticipated, such interactions can lead to serious consequences, including enhanced depression with concomitant use of many other drugs. Additive effects can be predicted with concomitant use of alcoholic beverages, opioid analgesics, anticonvulsants, and phenothiazines. Less obvious but just as important is enhanced central nervous system depression with a variety of antihistamines, antihypertensive agents, and antidepressant drugs of the tricyclic class.

Interactions involving changes in the activity of hepatic drug-metabolizing enzyme systems have been discussed.