Sedative-hypnotics are central nervous system depressants that possess sedative and hypnotic effects. Excessive doses can result in anesthesia, affecting the entire body, including the medulla. A single large dose ingestion can lead to acute sedative-hypnotic poisoning, while chronic misuse of hypnotics may cause tolerance and dependence, eventually leading to chronic poisoning. Abrupt cessation or dose reduction may result in withdrawal syndrome.
Etiology
Before 1950, barbiturates were commonly used as sedative-hypnotics, later replaced by benzodiazepines. Currently, sedative-hypnotic drugs are categorized into the following groups:
Benzodiazepines
These include:
- Long-acting drugs (half-life > 30 hours): Chlordiazepoxide, diazepam, flurazepam.
- Intermediate-acting drugs (half-life 6–30 hours): Alprazolam, oxazepam, temazepam.
- Short-acting drugs (half-life < 6 hours): Triazolam.
Barbiturates
These include:
- Long-acting drugs (duration of action: 6–8 hours): Barbital, phenobarbital (Luminal).
- Intermediate-acting drugs (duration of action: 3–6 hours): Pentobarbital, amobarbital, butabarbital.
- Short-acting drugs (duration of action: 2–3 hours): Secobarbital, thiopental sodium.
Non-barbiturate, non-benzodiazepine drugs (intermediate to short acting)
Examples include chloral hydrate, glutethimide (Doriden), methaqualone (Quaalude), and meprobamate (Miltown).
Phenothiazines (antipsychotic drugs)
Antipsychotic medications are used to treat various psychiatric disorders and symptoms. They are also known as major tranquilizers or neuroleptic agents. Based on differences in side-chain structure, they are divided into three types:
- Aliphatic group: e.g., chlorpromazine.
- Piperidine group: e.g., thioridazine.
- Piperazine group: e.g., perphenazine, fluphenazine, and trifluoperazine.
Pathogenesis
Pharmacokinetics
Sedative-hypnotics are lipid-soluble, and their absorption, distribution, protein binding, metabolism, excretion, onset time, and duration of action are related to their lipid solubility. Drugs with higher lipid solubility can easily cross the blood-brain barrier, act on the central nervous system more rapidly, and have shorter durations of action, thus being categorized as short-acting drugs.
Mechanisms of Toxicity
Benzodiazepines
The central nervous system depressant effects of benzodiazepines are associated with the enhancement of GABAergic neurotransmission. On the postsynaptic membrane, there exists a macromolecular complex consisting of benzodiazepine receptors, GABA receptors, and chloride ion channels. Benzodiazepines bind to the GABA receptor complex, increasing the affinity of GABA for its receptor, which opens the associated chloride ion channels, thereby enhancing GABA-mediated postsynaptic inhibition. In addition to central nervous system depression, benzodiazepines may also depress the cardiovascular system, with elderly individuals displaying increased sensitivity to these drugs.
Barbiturates
The effects of barbiturates on GABAergic neurons are similar to those of benzodiazepines. However, due to differences in their distribution within the central nervous system, their mechanisms of action differ. Benzodiazepines act selectively on the limbic system, affecting emotions and memory. Barbiturates have a more widespread distribution and inhibit the central nervous system primarily by suppressing the pyruvate oxidase system. Barbiturates primarily disrupt the ascending activating system of the reticular formation, causing disturbances in consciousness. Barbiturate-induced central nervous system depression follows a dose-response relationship, progressing with increasing doses from sedation to hypnosis and even anesthesia. High doses of barbiturates may depress the medullary respiratory center, resulting in respiratory failure, or suppress the vasomotor center, leading to peripheral vasodilation and shock.
Non-barbiturate, Non-benzodiazepine Drugs
The effects of these sedative-hypnotic drugs on the central nervous system are comparable to those of barbiturates.
Phenothiazines
Phenothiazines primarily act on the reticular formation, alleviating symptoms of anxiety, tension, hallucinations, delusions, and pathological thought processes. Their effects stem from the suppression of central nervous system dopamine receptors, which reduces catecholamine production. These drugs also inhibit the vasomotor and vomiting centers of the brainstem, block α-adrenergic receptors, and possess antihistaminic and anticholinergic properties.
Phenothiazines have broad clinical applications, with chlorpromazine being the most commonly used. When administered orally, their intestinal absorption is highly variable. These drugs tend to inhibit intestinal motility, causing them to remain in the intestines for extended periods. After absorption, they are widely distributed in body tissues, with the highest concentrations in the brain and lungs. They are primarily metabolized in the liver and are excreted mostly in the form of glucuronides or sulfur compounds. The excretion rate is slow, with a half-life of 10–20 hours, and effects lasting several days.
Tolerance, Dependence, and Withdrawal Syndrome
All sedative-hypnotics have the potential to cause tolerance and dependence, which can result in withdrawal syndromes. The precise mechanisms underlying these phenomena remain incompletely understood. Long-term use of benzodiazepines leads to a reduction in benzodiazepine receptors, contributing to tolerance. Abrupt discontinuation after prolonged benzodiazepine use creates withdrawal syndromes due to upregulation of benzodiazepine receptor density. Barbiturates, non-barbiturates, and ethanol exhibit even greater potential for developing tolerance, dependence, and withdrawal syndromes.
Clinical Manifestations
Acute Poisoning
Barbiturate Poisoning
Significant doses of barbiturates can lead to central nervous system (CNS) depression. The severity of symptoms correlates with the ingested dose:
- Mild poisoning: Symptoms include drowsiness, emotional instability, reduced attention, memory impairment, ataxia, slurred speech, unsteady gait, and nystagmus.
- Severe poisoning: Progressive CNS depression, ranging from drowsiness to deep coma. Respiratory depression manifests as slow and shallow breathing, potentially culminating in respiratory arrest. Additional symptoms may include hypotension or shock, reduced muscle tone, absent tendon reflexes, and bullous skin lesions. Prolonged coma may lead to complications such as pneumonia, pulmonary edema, cerebral edema, and renal failure.
Benzodiazepine Poisoning
The CNS depressant effects of benzodiazepines are generally mild. Typical symptoms include drowsiness, dizziness, vertigo, fatigue, slurred speech, blurred consciousness, and ataxia. Severe symptoms, such as prolonged deep coma and respiratory suppression, are rare and typically occur in the presence of co-ingestion of other sedative-hypnotics or alcohol.
Non-Barbiturate, Non-Benzodiazepine Poisoning
Although the symptoms of this group are similar to barbiturate poisoning, they display unique characteristics:
- Chloral hydrate poisoning: Patients exhibit a characteristic pear-like odor on their breath, with initial pupil constriction followed by dilation in later stages. Additional complications include arrhythmias, pulmonary edema, liver and kidney damage, and coma.
- Glutethimide poisoning: Consciousness disturbances may fluctuate periodically. The effects on the circulatory system are prominent, including hypotension and shock. Anticholinergic symptoms, such as pupil dilation, may also occur.
- Methaqualone poisoning: Significant respiratory depression and pyramidal tract signs may occur.
- Meprobamate poisoning: Symptoms closely resemble barbiturate poisoning, frequently accompanied by hypotension.
Phenothiazine Poisoning
The most common presentation involves extrapyramidal reactions, which can be classified into three types:
- Parkinsonian syndrome: Symptoms resembling tremor paralysis.
- Akathisia: Inability to sit still.
- Acute dystonic reactions: Symptoms include torticollis, difficulty swallowing, and jaw clenching.
Patients allergic to chlorpromazine-class drugs may experience severe complications, such as exfoliative dermatitis, agranulocytosis, and cholestatic hepatitis, even at therapeutic doses, sometimes resulting in death. It is generally recognized that acute toxic reactions may occur at doses of 2–4 g. Due to the pronounced anticholinergic effects of these drugs, symptoms often include tachycardia, hyperthermia, and reduced intestinal motility. Antagonism of α-adrenergic receptors can result in vasodilation and hypotension. Quinidine-like membrane-stabilizing effects and myocardial suppression may lead to arrhythmias, as well as ECG changes, such as prolonged PR and QT intervals and altered ST segments and T waves. Overdoses may also produce extrapyramidal symptoms, coma, and respiratory depression, although generalized seizures are rare.
Chronic Poisoning
Chronic poisoning may develop in individuals who habitually abuse large quantities of hypnotics. Symptoms often include mild signs of intoxication accompanied by distinct psychiatric symptoms, which primarily manifest in the following three areas.
Altered Consciousness and Hypomanic States
Short-term agitation or clouded consciousness may develop. Symptoms include increased speech excitability, euphoria, fatigue, tremors, slurred speech, and unsteady gait.
Cognitive Impairment
Significant declines in memory, calculation ability, and comprehension are observed, along with reduced capacity for work and learning.
Personality Changes
Patients may lose their sense of initiative and exhibit a diminished sense of responsibility toward family and society.
Withdrawal Syndrome
Individuals with long-term, high-dose use of sedative-hypnotics may experience withdrawal syndrome when abruptly discontinuing or rapidly reducing the dosage. The syndrome is primarily characterized by increased autonomic nervous system excitability and varying degrees of neurological and psychiatric disturbances.
Mild Cases
Within a day or several days after the last dose, symptoms such as anxiety, irritability, insomnia, headache, anorexia, fatigue, and tremors may arise. Peak symptoms occur 2–3 days after discontinuation, including nausea, vomiting, and muscle spasms.
Severe Cases
Seizures may occur within 1–2 days of abrupt discontinuation (in some cases, seizures may present 7–8 days later). Other symptoms may include hallucinations, delusions, disorientation, high fever, and delirium, with recovery occurring over several days to three weeks. These symptoms tend to appear in individuals consuming doses exceeding five times the therapeutic amount for over a month. Severity is greater when higher doses are used over a prolonged period and treatment is abruptly discontinued.
Withdrawal symptoms are more frequent, earlier in onset, and more severe in individuals abusing barbiturates. Such patients are prone to epileptiform seizures and hypomanic states. In contrast, those abusing benzodiazepines exhibit later onset symptoms, likely due to slower elimination of intermediate metabolites, and tend to have milder withdrawal symptoms, primarily characterized by anxiety and insomnia.
Laboratory Tests
Drug Concentration Analysis in Blood, Urine, and Gastric Contents
Evaluation of drug levels in these samples is useful for diagnostic reference. However, serum benzodiazepine concentrations are of limited utility in determining toxicity severity due to variations in metabolic half-lives and individual drug clearance rates.
Blood Biochemistry Tests
Measurement of blood glucose, blood urea nitrogen, creatinine, and electrolytes is recommended.
Arterial Blood Gas Analysis
Assessment of blood gas levels aids in evaluating respiratory and metabolic status.
Diagnosis
Acute Poisoning
A history of ingesting large doses of sedative-hypnotics, along with symptoms like altered consciousness, respiratory depression, and hypotension. Sedative-hypnotics or their metabolites can be detected in gastric contents, blood, or urine.
Chronic Poisoning
Long-term abuse of large amounts of hypnotics is associated with symptoms such as mild ataxia and psychiatric manifestations.
Withdrawal Syndrome
Withdrawal symptoms including tremors, anxiety, insomnia, delirium, psychotic manifestations, and epileptiform seizures develop after abrupt cessation or rapid dose reduction following prolonged abuse of sedative-hypnotics.
Differential Diagnosis
Sedative-hypnotic poisoning must be differentiated from the following conditions:
Acute Poisoning and Other Causes of Altered Consciousness
Assessment of prior history of primary hypertension, epilepsy, diabetes, liver disease, renal disease, or exposure to toxins such as carbon monoxide, alcohol, or organic solvents is essential. Examination for head trauma, fever, meningeal irritation signs, hemiplegia, or cyanosis is also critical. A differential diagnosis can be made based on clinical presentation and relevant laboratory evaluations.
Chronic Poisoning and Bipolar Disorder
Patients with chronic poisoning exhibiting hypomanic states often experience fatigue, tremors, and unsteady gait. A history of drug use aids in differentiation.
Withdrawal Syndrome and Neurological or Psychiatric Disorders
Primary epilepsy is characterized by a history of seizures. Schizophrenia and alcohol intoxication may present with tremors and delirium; however, a prior history of these conditions or a history of alcohol abuse helps to distinguish these cases.
Treatment
Treatment of Acute Poisoning
Maintaining Vital Organ Function in Comatose Patients
Maintaining airway patency
For patients in deep coma, tracheal intubation should be used to secure the airway while ensuring oxygen supply and effective ventilation.
Maintaining blood pressure
Hypotension caused by acute poisoning is often due to vasodilation. Blood volume should be replenished through fluid infusion, and if ineffective, a moderate dose of dopamine [10–20 μg/(kg·min) as a reference dose] may be considered.
Cardiac monitoring
Antiarrhythmic medications may be administered if arrhythmias occur.
Promoting consciousness recovery
For patients with acute altered consciousness of unknown origin, the administration of glucose, vitamin B1, and naloxone may be considered.
Removal of Toxins
Gastric lavage
Activated charcoal
Effective for adsorbing a variety of sedative-hypnotic drugs. Multidose activated charcoal can be considered in cases of barbiturate poisoning.
Alkalization of urine and diuresis
Treatment with furosemide and alkalized urine is only effective for long-acting barbiturate poisoning and not for phenothiazine poisoning.
Blood purification
Hemodialysis and hemoperfusion may enhance the clearance of phenobarbital and phenothiazines. These methods can be considered for critically ill patients, particularly those with concurrent heart failure, kidney failure, acid-base imbalances, electrolyte abnormalities, or progressive deterioration. Given that barbiturates have a high protein-binding rate, hemoperfusion is the preferred option. Blood purification techniques have limited utility in benzodiazepine poisoning.
Specific Antidotes
There are no specific antidotes for barbiturate and phenothiazine poisoning.
Flumazenil, a benzodiazepine receptor antagonist, can competitively inhibit benzodiazepine receptors, blocking the central nervous system effects of benzodiazepines. Dosage: 0.2 mg intravenous injection over 30 seconds. If no response is observed, 0.3 mg may be administered, followed by 0.5 mg every minute if needed, up to a maximum dose of 3 mg. Flumazenil is contraindicated in patients concurrently using medications that may induce seizures (e.g., tricyclic antidepressants), those with physical dependence on benzodiazepines, individuals using benzodiazepines to control seizures, and patients with increased intracranial pressure.
Symptomatic Treatment
The treatment of most sedative-hypnotic poisonings, particularly phenothiazine poisoning, primarily involves symptomatic and supportive measures. In phenothiazine poisoning with hypotension, blood volume should be replenished to maintain blood pressure. If necessary, α-receptor agonists such as norepinephrine or phenylephrine can be considered. Vasopressors with β-receptor agonist effects, such as epinephrine, isoproterenol, and dopamine, should be avoided even in small doses, as their β-receptor activation may exacerbate hypotension by promoting peripheral vasodilation.
Specialist Consultation
Psychiatric consultation is advised.
Treatment of Chronic Poisoning
Gradual Reduction of Sedative-Hypnotic Doses
Medication doses should be reduced gradually and ultimately discontinued.
Psychological Support
Psychiatric consultation and psychotherapy may be necessary.
Treatment of Withdrawal Syndrome
The principle of withdrawal syndrome treatment is to administer sufficient doses of sedative-hypnotics to control symptoms, then gradually reduce the dosage and discontinue the medication. This is done by substituting short-acting drugs with long-acting ones, such as diazepam or phenobarbital. The same drug class may be used, or an alternative class may be substituted.
Diazepam 10–20 mg or phenobarbital 1.7 mg/kg can be administered intramuscularly every hour until withdrawal symptoms subside. The total dose given is then calculated as the daily dose, divided into 3–4 oral doses. Once the patient stabilizes for two days, the dosage is progressively reduced. Before each dose reduction, the patient’s condition should be observed. If symptoms such as nystagmus, ataxia, or slurred speech are not present, a 5%–10% reduction in dosage may be implemented. Complete withdrawal is typically achieved within 10–15 days.
If delirium occurs, intravenous diazepam may be used to calm the patient.
Prognosis
Patients with mild poisoning often recover without the need for treatment. Moderate poisoning resolves within 24–48 hours with careful care and appropriate treatment. Severe poisoning may require 3–5 days for the patient to regain consciousness. The mortality rate is below 5%.
Prevention
Prescribing, administering, and storing sedative-hypnotics should be strictly controlled. Medications should be use with caution in individuals with unstable emotions or mental disorders. Drug dependence must be avoided. Long-term users of large doses of hypnotics, including epilepsy patients on prolonged phenobarbital therapy, should not abruptly discontinue these medications. Gradual dose reductions are essential.