Page 406 - Basic _ Clinical Pharmacology ( PDFDrive )

392 SECTION V Drugs That Act in the Central Nervous System

Meprobamate and the benzodiazepines have frequently been depressants, including ethanol. In fact, most serious cases of drug
used as central muscle relaxants, though evidence for general overdosage, intentional or accidental, do involve polypharmacy;
efficacy without accompanying sedation is lacking. A possible and when combinations of agents are taken, the practical safety of
exception is diazepam, which has useful relaxant effects in skeletal benzodiazepines may be less than the foregoing would imply.
muscle spasticity of central origin (see Chapter 27). The lethal dose of any sedative-hypnotic varies with the patient
Psychiatric uses of benzodiazepines other than treatment of and the circumstances (see Chapter 58). If discovery of the inges-
anxiety states include the initial management of mania and the tion is made early and a conservative treatment regimen is started,
control of drug-induced hyperexcitability states (eg, phencyclidine the outcome is rarely fatal, even following very high doses. On the
intoxication). Sedative-hypnotics are also used occasionally as other hand, for most sedative-hypnotics—with the exception of
diagnostic aids in neurology and psychiatry. benzodiazepines and possibly the newer hypnotic drugs that have
a similar mechanism of action—a dose as low as 10 times the hyp-
CLINICAL TOXICOLOGY OF notic dose may be fatal if the patient is not discovered or does not
SEDATIVE-HYPNOTICS seek help in time. With severe toxicity, the respiratory depression
from central actions of the drug may be complicated by aspiration
of gastric contents in the unattended patient—an even more likely
Direct Toxic Actions occurrence if ethanol is present. Cardiovascular depression further
Many of the common adverse effects of sedative-hypnotics result complicates successful resuscitation. In such patients, treatment
from dose-related depression of the CNS. Relatively low doses may consists of ensuring a patent airway, with mechanical ventilation
lead to drowsiness, impaired judgment, and diminished motor skills, if needed, and maintenance of plasma volume, renal output, and
sometimes with a significant impact on driving ability, job perfor- cardiac function. Use of a positive inotropic drug such as dopa-
mance, and personal relationships. Sleep driving and other somnam- mine, which preserves renal blood flow, is sometimes indicated.
bulistic behavior with no memory of the event have occurred with the Hemodialysis or hemoperfusion may be used to hasten elimina-
sedative-hypnotic drugs used in sleep disorders, prompting the FDA tion of some of these drugs (see Table 58–2).
in 2007 to issue warnings of this potential hazard. Benzodiazepines Flumazenil reverses the sedative actions of benzodiazepines, and
may cause a significant dose-related anterograde amnesia; they can those of eszopiclone, zaleplon, and zolpidem, although experience
significantly impair ability to learn new information, particularly with its use in overdose of the newer hypnotics is limited. How-
that involving effortful cognitive processes, while leaving the retrieval ever, its duration of action is short, its antagonism of respiratory
of previously learned information intact. This effect is utilized for depression is unpredictable, and there is a risk of precipitation of
uncomfortable clinical procedures, eg, endoscopy, because the patient withdrawal symptoms in long-term users of benzodiazepines. Con-
is able to cooperate during the procedure but amnesic regarding it sequently, the use of flumazenil in benzodiazepine overdose remains
afterward. The criminal use of benzodiazepines in cases of “date rape” controversial and must be accompanied by adequate monitoring
is based on their dose-dependent amnestic effects. Hangover effects and support of respiratory function. The extensive clinical use of
are not uncommon following use of hypnotic drugs with long elimi- triazolam has led to reports of serious CNS effects including behav-
nation half-lives. Because elderly patients are more sensitive to the ioral disinhibition, delirium, aggression, and violence. However,
effects of sedative-hypnotics, doses approximately half of those used behavioral disinhibition may occur with any sedative-hypnotic
in younger adults are safer and usually as effective. The most common drug, and it does not appear to be more prevalent with triazolam
reversible cause of confusional states in the elderly is overuse of sedative- than with other benzodiazepines. Disinhibitory reactions during
hypnotics. At higher doses, toxicity may present as lethargy or a state benzodiazepine treatment are more clearly associated with the use
of exhaustion or, alternatively, as gross symptoms equivalent to those of very high doses and the pretreatment level of patient hostility.
of ethanol intoxication. The physician should be aware of variability Adverse effects of the sedative-hypnotics that are not referable
among patients in terms of doses causing adverse effects. An increased to their CNS actions occur infrequently. Hypersensitivity reac-
sensitivity to sedative-hypnotics is more common in patients with tions, including skin rashes, occur only occasionally with most
cardiovascular disease, respiratory disease, or hepatic impairment and drugs of this class. Reports of teratogenicity leading to fetal defor-
in older patients. Sedative-hypnotics can exacerbate breathing prob- mation following use of certain benzodiazepines have resulted
lems in patients with chronic pulmonary disease and in those with in FDA assignment of individual benzodiazepines to either cat-
symptomatic sleep apnea. egory D or X in terms of pregnancy risk. Most barbiturates are
Sedative-hypnotics are the drugs most frequently involved in FDA pregnancy category D. Eszopiclone, ramelteon, suvorexant,
deliberate overdoses, in part because of their general availability as zaleplon, and zolpidem are category C, while buspirone is a cat-
very commonly prescribed pharmacologic agents. The benzodiaz- egory B drug in terms of use in pregnancy. Because barbiturates
epines are considered to be safer drugs in this respect, since they enhance porphyrin synthesis, they are absolutely contraindicated in
have flatter dose-response curves. Epidemiologic studies on the inci- patients with a history of acute intermittent porphyria, variegate
dence of drug-related deaths support this general assumption—eg, porphyria, hereditary coproporphyria, or symptomatic porphyria.
0.3 deaths per million tablets of diazepam prescribed versus 11.6
deaths per million capsules of secobarbital in one study. Alprazolam Alterations in Drug Response
is purportedly more toxic in overdose than other benzodiazepines.
Of course, many factors other than the specific sedative-hypnotic Depending on the dosage and the duration of use, tolerance
could influence such data—particularly the presence of other CNS occurs in varying degrees to many of the pharmacologic effects