Benzodiazepine Toxicity - Symptoms, Diagnosis, and Management

Introduction

Benzodiazepine drugs are a group of psychoactive drugs which alter the central nervous system functions and cause altered consciousness, mood, perception, and behavior. They treat conditions such as seizures, insomnia, and anxiety. The widespread use and easy availability of benzodiazepine drugs have led to drug overdose and abuse. Benzodiazepines, when taken at recommended levels, are considered safe. However, toxicity and adverse health effects are observed in individuals with benzodiazepine overdose and abuse. The toxicity of benzodiazepines is aggravated when they are taken in combination with other medications (tricyclic antidepressants, opiates) and alcohol. The toxicity of benzodiazepines may cause central nervous system depression, slurred speech, lack of muscle coordination, and respiratory depression.

What Are Benzodiazepines?

Benzodiazepines are organic compounds with a benzene ring and a diazepine ring. They also contain a variable side chain that determines the drug's action duration, potency, elimination rate, and metabolic activity. Benzodiazepines mediate their action through gamma-aminobutyric acid A receptors (GABA-A) in the central nervous system. They enhance the effect of gamma-aminobutyric acid neurotransmitters (GABA) and induce hypnotic, sedative, muscle relaxant, and anti-anxiety effects. There are different types of benzodiazepines available for medical use. They differ in the rate of absorption, potency, and outcomes.

The typical examples of benzodiazepines that we use are as follows.

• Diazepam.

• Alprazolam.

• Lorazepam.

• Flurazepam.

• Clonazepam.

• Temazepam.

• Chlordiazepoxide.

• Midazolam.

• Quazepam.

• Estazolam.

What Are the Uses of Benzodiazepines?

Benzodiazepine shows anticonvulsant,sedative,and calming effects. Because of these actions, they are used for the treatment of different conditions.

It includes the following.

• Anxiety.

• Sleeping troubles.

• Panic attacks.

• Muscle relaxation.

• Bipolar disorder.

• Alcohol withdrawal symptoms.

• Nausea.

• Agitation.

• Breathlessness.

• Parasomnia.

• Delirium.

In some cases, benzodiazepines are also used as an anesthetic agent before surgical procedures.

What Is Benzodiazepine Toxicity?

Ingestion of large doses of benzodiazepines results in toxicity and adverse effects. It may occur due to accidental consumption of large amounts of the drug (acute overdose) or may be due to long-term consumption of larger quantities than recommended (chronic exposure). The most common presentation after a benzodiazepine overdose is central nervous system depression, slurred speech, impaired balance, and lack of muscle coordination. In cases of severe overdose, the symptoms may include respiratory depression and coma. Identifying the overdose and early supportive medical management may reduce the toxicity and save lives. However, severe toxicity occurs in some cases due to the combination of benzodiazepines with barbiturates, alcohol, opioids, anticonvulsants, and some antidepressant drugs, leading to severe complications and death.

During benzodiazepine overdose, the effects of gamma-aminobutyric acid (GABA) neurotransmitters on the brain receptors will be enhanced, causing central nervous system depression. The toxic effects associated with overdose occur due to severe central nervous system depression and cardiac arrest leading to coma. Harmful effects related to benzodiazepine overdose are different for each individual, depending on the drug. Benzodiazepine drugs like Temazepam and Flurazepam are frequently involved in dangerous toxic effects and death. In cases of parenteral (given by injection) formulations of benzodiazepines, toxicity occurs due to the presence of dilutant propylene glycol in the formulations. Prolonged use of Diazepam and Lorazepam in parenteral formulations may cause skin irritation, soft tissue necrosis, hypotension, hemolysis, seizure, lactic acidosis, cardiac dysfunction, and multiorgan failure.

What Are the Signs and Symptoms of Benzodiazepine Toxicity?

After an acute benzodiazepine overdose, symptoms develop within four hours. Patients initially show mild to moderate alterations in central nervous system functions.

The signs and symptoms associated with benzodiazepine overdose are the following.

1. Initial Symptoms

• Impaired balance.

• Somnolence (state of drowsiness and long periods of sleep)

• Impaired motor activities.

• Slurred speech.

• Anxiety.

• Headache.

• Behavioral changes.

• Hallucinations.

• Aggressive behavior.

• Delirium.

• Diplopia (double vision).

• Inability to create new memories (anterograde amnesia).

• Abnormal eye movements.

• Vomiting.

• Confusion.

• Thinking difficulties.

• Abnormal muscle movements.

• Nausea.

• Gastric irritations.

2. Late Symptoms

• Hypoxia (low oxygen levels in the blood).

• Bradycardia (heart rate less than 60 beats per minute).

• Hypotension (low blood pressure).

• Hypothermia (body temperature less than usual).

• Cardiac arrest.

• Seizures.

• Respiratory arrest.

• Pulmonary aspiration (entry of food, secretions, or gastric contents into the respiratory system).

• Hypotonia (reduced muscle strength).

• Coma.

How to Diagnose Benzodiazepine Toxicity?

Most cases of benzodiazepine overdose are diagnosed based on clinical presentation and history of overdose. In the case of acute poisoning, the patient may be unable to provide a proper history and supporting information due to altered mental status and consciousness. Therefore, adequate examination of the vital signs and respiration must be done as early as possible after hospital admission. The concentration of benzodiazepines in the blood can be obtained using laboratory blood tests. Techniques such as gas-liquid chromatography, thin-layer chromatography, radioimmunoassay, and mass spectrometry can measure benzodiazepine concentrations in blood.

How Can We Manage Benzodiazepine Toxicity?

• Gastric Decontamination - Gastrointestinal decontamination (gastric irrigation) using activated charcoal is not indicated in benzodiazepine toxicity due to an increased risk of aspiration. In cases of benzodiazepine overdose, gastric decontamination is recommended when benzodiazepines are taken in combination with other drugs. Otherwise, gastric lavage and benzodiazepine elimination are not effective.

• Supportive Care - It includes observation of vital signs and proper airway management. In cases of respiratory depression, intubation can be done to maintain the airway. Artificial ventilation is recommended in cases of pulmonary aspiration and severe respiratory failure. Intravenous fluids are given to the patient to maintain average fluid volume. Hypotension due to benzodiazepine toxicity can be managed with fluid resuscitation and dopamine or norepinephrine. Atropine is given to patients to increase heart rate and coronary blood circulation and treat bradycardia.

• Antidote - Flumazenil is the commonly used antidote (substances that can reduce and reverse poisoning) for benzodiazepine poisoning. They act by blocking benzodiazepine receptors. Flumazenil reverses the central nervous system depression caused by benzodiazepine toxicity. It is contraindicated in patients who are under long-term benzodiazepine medication. In some cases, adverse effects like seizures, cardiac arrest, and death may occur following Flumazenil administration. Hence it must be administered carefully after obtaining the patient's allergy history and expert opinion.

Conclusion

Benzodiazepines are a group of drugs used to lower brain activity and treat conditions like anxiety, seizures, and sleeplessness. Benzodiazepines are generally considered safe when ingested at tolerable levels. However, due to their widespread use and easy availability, drug overdose and abuse are common with benzodiazepines. Drug overdose may cause central nervous system toxicity and serious health effects. Therefore, proper drug doses must be followed by individuals using benzodiazepines to avoid overdose and dangerous adverse effects.