Sedatives include benzodiazepines, barbiturates, and related drugs. High doses can cause decreased level of consciousness and respiratory depression, which may require intubation and mechanical ventilation. Chronic users may have a withdrawal syndrome of agitation and seizures, so dependence is managed by slow tapering with or without substitution (ie, with pentobarbital or phenobarbital).
The therapeutic benefit of sedatives is well-established, but their value in alleviating stress and anxiety is also probably the reason that they are abused so frequently. Abused anxiolytics and sedatives include benzodiazepines, barbiturates, and other drugs taken to promote sleep.
Pathophysiology of Sedative Toxicity
Benzodiazepines and barbiturates bind gamma-aminobutyric acid (GABA)-A receptors, increase the affinity of the receptor to GABA, and promote inhibitory neurotransmitter effects.
Хронічні ефекти
Patients taking high doses of sedatives frequently have difficulty thinking, slow speech (with some dysarthria), decreased comprehension, poor memory, faulty judgment, narrowed attention span, and emotional lability. In susceptible patients, psychologic dependence on the drug may develop rapidly. The extent of physical dependence is related to dose and duration of use. For example, pentobarbital 200 mg/day taken for many months may not induce significant tolerance, but 300 mg/day for > 3 months or 500 to 600 mg/day for 1 month may induce a withdrawal syndrome when the drug is stopped.
Tolerance and tachyphylaxis develop irregularly and incompletely; thus, considerable behavioral, mood, and cognitive disturbances persist, even in regular users, depending on the dosage and the drug’s pharmacodynamic effects. Some cross-tolerance exists between alcohol and sedatives, especially drugs that act on GABA-A receptors. Barbiturates and alcohol are similar in the dependence, withdrawal symptoms, and chronic intoxication they cause. Physiologic dependence develops over weeks to months in chronic users.
Вагітність
Teratogenicity has been associated with benzodiazepine use during pregnancy, but the evidence is inconclusive. Prolonged use of barbiturates during pregnancy can cause barbiturate withdrawal in the neonate. Perinatal use of benzodiazepines also may cause neonatal withdrawal syndrome or toxicity (eg, apnea, hypothermia, hypotonia). Phenobarbital increases the risk of congenital malformation in the fetus (1). Meprobamate, a nonbenzodiazepine anxiolytic, can also cause neonatal withdrawal.
Довідковий матеріал щодо патофізіології
1.Veroniki AA, Cogo E, Rios P, et al: Comparative safety of anti-epileptic drugs during pregnancy: A systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med 15 (1):95, 2017. doi: 10.1186/s12916-017-0845-1
Symptoms and Signs of Sedative Toxicity
Гостра токсичність та передозування
The signs of sedative intoxication are depression of deep tendon reflexes, fine lateral-gaze nystagmus, slightly decreased alertness with coarse or rapid nystagmus, ataxia, slurred speech, and postural unsteadiness.
Increasing toxicity can cause nystagmus on forward gaze, miosis, somnolence, marked ataxia with falling, confusion, stupor, respiratory depression, and, ultimately, death. Overdose of a benzodiazepine rarely causes hypotension, and these drugs do not cause arrhythmias.
Синдром відміни
When intake of therapeutic doses of sedatives is stopped or reduced below a critical level, a self-limited mild withdrawal syndrome can ensue. After only a few weeks of use, attempts to stop using the drug can exacerbate insomnia and result in restlessness, disturbing dreams, frequent awakening, and feelings of tension in the early morning.
Withdrawal from benzodiazepines is similar to alcohol withdrawal and is occasionally life-threatening. Symptoms can include tachypnea, tachycardia, tremulousness, hyperreflexia, confusion, and seizures. Patients taking short-acting benzodiazepines develop withdrawal within 1 to 2 days from the last dose. The onset of withdrawal from long-acting benzodiazepines is several days to a week after the cessation. Withdrawal may be most severe in patients who used drugs with rapid absorption and a quick decline in serum levels (eg, alprazolam, lorazepam, triazolam). The symptoms of benzodiazepine withdrawal may fluctuate, and the intensity of the symptoms may not decrease steadily. Many people who misuse benzodiazepines have been or are heavy users of alcohol, and a delayed benzodiazepine withdrawal syndrome may complicate alcohol withdrawal.
Withdrawal from barbiturates is also similar to alcohol withdrawal. In people who chronically take in large doses of barbiturates, as well as in those who stop or decrease the dosage abruptly, a potentially life-threatening withdrawal syndrome similar to delirium tremens may occur. Occasionally, even after properly managed withdrawal over 1 to 2 weeks, a seizure may occur. Without treatment, withdrawal of a short-acting barbiturate can cause the following:
Within the first 12 to 20 hours: Increasing restlessness, tremulousness, and weakness
By the 2nd day: More prominent tremulousness, sometimes increased deep tendon reflexes, and increased weakness
During the 2nd and 3rd days: Seizures (in 75% of patients who were taking ≥ 800 mg/day), sometimes progressing to status epilepticus and death
From the 2nd to the 5th day: Delirium, insomnia, confusion, frightening visual and auditory hallucinations, and often hyperpyrexia and dehydration
Diagnosis of Sedative Toxicity
Usually a clinical diagnosis
Diagnosis of sedative intoxication is usually made clinically. Drug levels can be measured for some drugs (eg, phenobarbital), but typically hospital laboratories cannot measure levels of most sedatives. Benzodiazepines and barbiturates are usually included in routine immunoassay-based qualitative urine drug screens. However, detecting drugs on such screening tests may not reflect the patient's condition and usually does not alter clinical management; even if the results are positive, if patients do not have a clear history of sedative ingestion, other causes of the patient's symptoms should be ruled out.
Treatment of Sedative Toxicity
Supportive care
Rarely flumazenil for benzodiazepines
Sometimes urine alkalinization and/or activated charcoal for barbiturates
Токсична дія та передозування
Acute intoxication generally requires nothing more than supportive care, including monitoring the airway, respirations, and cardiovascular status. If ingestion was within 1 hour, the gag reflex is preserved, and the patient can protect the airway, 50 g of activated charcoal may be given to reduce further absorption; however, this intervention has not been shown to reduce morbidity or mortality and is no longer routinely recommended. However, multidose activated charcoal is suggested to enhance elimination because of enterohepatic circulation of phenobarbital, although studies supporting positive clinical outcome is lacking. Occasionally, intubation and mechanical ventilation are required.
The benzodiazepine receptor antagonist flumazenil can reverse sedation and respiratory depression secondary to benzodiazepine overdose. Dose is 0.2 mg IV given over 30 seconds; 0.3 mg may be given after 30 seconds, followed by 0.5 mg every 1 minute to total 3 mg. However, its clinical usefulness is not well-defined because most people who overdose on benzodiazepines recover with only supportive care, and occasionally flumazenil precipitates seizures.
Contraindications to flumazenil include long-term benzodiazepine use (because flumazenil may precipitate withdrawal), an underlying seizure disorder, presence of twitching or other motor abnormalities, a concomitant epileptogenic drug overdose (especially of tricyclic antidepressants), and cardiac arrhythmias. Because many of these contraindications are usually unknown in overdoses, flumazenil is best reserved for patients with respiratory depression during a medical procedure (ie, when medical history is clearly known).
If phenobarbital overdose is diagnosed, urine alkalinization with sodium bicarbonate may enhance excretion. Some studies report successful treatment of high-dose phenobarbital overdose by hemodialysis (1).
Urinary alkalinization is accomplished by adding 150 mEq (150 mmol) sodium bicarbonate diluted in 1 liter D5W and infused at a rate of 1 to 1.5 liters per hour. Urinary pH should be maintained as close to 8 as possible for effective alkalinization.
Синдром відміни та детоксикація
Severe acute withdrawal of sedatives requires hospitalization for close monitoring of withdrawal symptoms, preferably in an intensive care unit, and use of appropriate doses of IV benzodiazepines. Oral benzodiazepines may be used if withdrawal symptoms are mild.
One approach for managing sedative dependence is to withdraw the drug on a strict schedule while monitoring signs of withdrawal. Often, switching to a long-acting drug, which is easier to taper, is better. The timing of dose reduction depends on the presence and severity of withdrawal symptoms.
Довідковий матеріал щодо лікування
1. Hoyland K, Hoy M, Austin R, et al: Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep 2013: bcr2013010011, 2013. doi: 10.1136/bcr-2013-010011
Додаткова інформація
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
Findtreatment.gov: Listing of licensed US providers of treatment for substance use disorders