Anxiolytics and Sedative-Hypnotics Toxicity

Etiology

The most common etiologies for anxiolytic and sedative toxicity include but are not limited to improper dosing, misuse/abuse, or drug-drug interactions. An example of improper dosing would be the use of diazepam 5 to 10 mg in an older person with liver disease in which the drug slowly builds up in their system to give toxic side effects like sedation and falls.  Another example would be the use of a 3A4 inhibitor like fluvoxamine, where fluvoxamine inhibits the metabolism of alprazolam, thus causing a build-up of levels in the bloodstream, causing sedation. The use of opioids and benzodiazepines is another cause of accidental toxicity.  Finally, the use of benzodiazepines or barbiturates with alcohol to enhance the intoxication can result in unintended respiratory depression and death.

Epidemiology

The more commonly abused anxiolytic is the benzodiazepine class of medications. There are less data available for other drugs mentioned in this article; however, benzodiazepine misuse was most common amongst younger adults.  Adults aged 18 to 49 were accountable for the highest rate of misuse. Though adults aged 50 to 65 were most often prescribed benzodiazepines.[1] The lifetime prevalence of anxiolytic and sedative use disorders (including benzodiazepines, barbiturates, etc.) in the United States was estimated to be 1.0 and 1.1 percent.[2] The prevalence of anxiolytic and sedative use disorder in the USA was estimated to be 0.16% of the total population and 6% of individuals with concomitant illicit drug use disorder. 

Risk factors associated with anxiolytic and sedative toxicity include [3]:

• White race
• Female sex
• Uninsured
• Unemployed
• Panic symptoms
• Other psychiatric symptoms
• Alcohol abuse or dependence
• Cigarette use
• Illicit drug use
• History of IV drug use

Pathophysiology

The mechanisms of action of some of the medications discussed in this article appear below. Toxicity related to these drugs would involve having more than the recommended amount of the drug in a patient's system at a given time, leading to adverse outcomes.

Benzodiazepines (BZDs) and barbiturates are gamma-aminobutyric acid type A (GABA-A) receptor agonists. GABA-A receptors are major neurotransmitter inhibitors in the central nervous system. They are ligand-gated chloride ion channels causing an influx of chloride ions into the cell. BZDs and barb increase GABA's inhibitory effect increasing the frequency and time of channel openings.[4]

Nonbenzodiazepine receptor agonists have a different chemical structure compared to BZDs, however, and they selectively target one type of GABA-A receptor. 

Melatonin agonists target melatonin receptors MT and MT (with slight affinity to MT)  in the suprachiasmatic nucleus within the hypothalamus.

Antihistamines target H1 receptors in the gastrointestinal, blood vessel, and respiratory tracts. 

Opiates act on multiple receptors, both centrally and peripherally. They appear to release dopamine by enhancing GABA disinhibition of dopamine release.  However, the mu receptor (opioids affect mu, kappa, and sigma) is responsible for pain relief and euphoria, but also respiratory depression, so opioid overdose results in respiratory depression, coma, and death. 

Antidepressants and antipsychotics cause sedation, usually through antihistamine H1 blockade. They can also cause toxicity with other sedatives by drug-drug pharmacokinetic interaction. Anticonvulsants usually enhance GABA neurotransmission and cause sedation via this mechanism and also can cause pharmacokinetic interactions.

Toxicokinetics

In a study comparing BZDs and non-BZDs used in self-poisoning, researchers found temazepam and zopiclone/zolpidem to be more likely to have a fatal outcome compared to diazepam.[5]

In a study comparing the toxicity of mood stabilizers and antipsychotics, looking at case fatality and fatal toxicity in self-poisoning, researchers found little differences between toxicity between mood stabilizers except based on case fatality where multiple drug poisonings were considered. Carbamazepine was over twice as like to result in death compared to lithium. Clozapine was more likely to result in death compared to chlorpromazine. Risperidone was less toxic compared to chlorpromazine.[6]

History and Physical

The toxidrome associated with the various anxiolytics or sedative-hypnotics depends on the type of medication leading to toxicity. Some of the various toxidromes will be reviewed below. 

BZD toxicity coming from an overdose of oral BZDs rarely cause toxicity unless co-ingested with another agent.[7] The most common presentation of BZD toxicity consists of CNS depression with hemodynamically stable vital signs. These patients are often arousable and capable of contributing to history taking though drowsy. Of note, most intentional overdoses with BZDs occur with ethanol co-ingestion. Clinically the patient may appear to have slurred speech, ataxia, and depressed mentation, especially if co-ingested with another form of sedative. Isolated overdoses involving oral BZDs rarely lead to respiratory failure; however, when combined with other sedatives, it may be encountered. Severe toxicity can manifest in a stuporous or comatose patient. 

NonBZD hypnotics generally have a similar presentation in the event of toxicity. However, this class of medications is more often associated with complex-sleep related behaviors. Complex-sleep related behaviors include events such as sleepwalking, sleep-driving, eating, and other behaviors that can be completed while not fully awake. These effects were more common with zolpidem, zaleplon, and eszopiclone compared to other medications used for sleep. 

Overdoses associated with SSRI/SNRIs rarely cause death or serious injury.[8][9][10] Nearly all fatal overdoses involve the co-ingestion of another substance or massive quantities. There is a possibility of serotonin syndrome, which results from the overstimulation of central and peripheral serotonin receptors. Generally, this will present in a patient with anxiety, agitation, delirium, diaphoresis, tachycardia, hypertension, hyperthermia, gastrointestinal distress, tremor, muscle rigidity, myoclonus, and hyperreflexia.[9] Notably, bupropion and venlafaxine can precipitate seizures when ingested at toxic levels. Status epilepticus is rare in an overdose of these drugs.

TCA overdose presents with mental status change, including sedation, confusion, delirium, or hallucination. There may be cardiac conduction delays, arrhythmias, hypotension, and anticholinergic toxicity (e.g., hyperthermia, flushing, pupillary dilation.) Patients may initially present normally and then deteriorate rapidly due to the variable absorption kinetics involved in TCAs.

Opiate Toxicity can present with depressed mental status, depressed respiratory rate, decreased tidal volumes, decreased bowel sounds/movements, and/or miotic pupils.  Normal pupil examination does not exclude a diagnosis of opiate toxicity. Heart rate ranges from bradycardia to tachycardia. Hypotension may be present. Hypotension would result from histamine release. Hypothermia may be present due to impaired thermogenesis or environmental exposure. 

There are a large number of antiseizure drugs that can cause sedation and potential toxicity. The most severe reactions to these medications as a whole could include suicidality and severe skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). They are rare adverse effects, but important to be aware of these potential consequences.

Evaluation

In evaluating patients for anxiolytics or sedative toxicity, much of the examination will be guided by history and physical examination. It is important to determine from the patient or a witness, if possible, what drug the patient ingested to tailor treatment. History is often unreliable in patients who intentionally ingested medication in an attempt to commit suicide.[11][12] The ability to provide history may also be limited to the drug's potential sedating and mind-altering effects. Signs and symptoms must be correlated with the patient's story as well. Attempts to gain information from witnesses, paramedics, etc., should be made to help determine the patient's exposure.[11]

Physical examination should consist of an evaluation of the patient's mental status, vital signs, and pupillary assessment. Looking for signs of physiologic excitation vs. depression or mixed effects can help to determine the potential intoxicant. Looking for signs such as odor, pupillary exam, neuromuscular abnormalities, mental status changes, skin changes, temperature changes, blood pressure, heart rate changes, and respiratory changes can help establish a potential diagnosis.  

Electorcardiology may provide diagnostic and prognostic information. It is especially important to pay attention to the QRS and QTc intervals. Many anxiolytics or sedative medications can prolong the QRS interval, potentially leading to lethal arrhythmias. Some antipsychotic drugs can block potassium efflux again, leading to prolonged QT intervals. Toxin-induced QRS interval prolongation occurs in TCA poisoning, and immediate action is necessary. 

Radiographic studies are beneficial for appropriate patients.

Toxicological screening can give a definitive diagnosis to providers when history is not readily available. These can be urinary, serum, or bodily fluid based testing can provide further detail. However, false positives can occur. Co-ingestion with other medications is common and proper workup would include testing for co-intoxicants.

Treatment / Management

There are multiple treatment modalities available for patients with toxicity from anxiolytics and sedatives. The first priority is to ensure the patient is hemodynamically stable, with specific attention paid to the airway, breathing, and circulation. Endotracheal intubation and subsequent mechanical ventilation are often necessary for patients at significant risk for respiratory failure and, ultimately, cardiopulmonary arrest. 

Treatment should be targeted to the sedative, most likely causing the toxicity. Most treatments will involve supportive care and monitoring for deterioration. However, treatment for specific anxiolytics or sedatives exists. Some treatments are listed below.

BZD toxicity treatment mostly consists of supportive care and close monitoring unless the toxicity is severe. Airway protection is of the utmost importance. Endotracheal intubation, supplemental oxygen, and continuous cardiac monitoring should start for severe overdoses. End-tidal CO2 monitoring can be useful to monitor those at risk of hypoventilation. Decontamination with activated charcoal is NOT recommended in isolated BZD overdose as it can precipitate aspiration. The antidote flumazenil is a nonspecific competitive antagonist for the BZD receptor. It can reverse BZD-induced sedation following general anesthesia, procedural sedation, or overdose.[13][14] However, its use is controversial as flumazenil can precipitate withdrawal seizures in patients who have developed a tolerance for BZDs. The risk only increases with co-ingestion with other medications that have pro-convulsant properties occurred.[15] Caution and special consideration are necessary before administering flumazenil to patients who have a chronic use of BZDs. If chronic use is not present, the risk of precipitating a withdrawal seizure is less, and likely flumazenil's use would be safe. 

SSRI/SNRI treatment involves monitoring for signs and symptoms of serotonin syndrome, seizures, cardiac conduction abnormalities, and QT interval prolongation. BZDs can be given or those with signs of serotonin syndrome or seizures. Sodium bicarbonate is an option for those with cardiac toxicity. Magnesium sulfate intravenously can be given to those with the risk of developing torsades de pointes. Additionally, immediate non-synchronized electric defibrillation is indicated for patients with hemodynamic instability.

TCA toxicity, as stated before, begins with the evaluation of ABCs as well as hemodynamics. Sodium bicarbonate is the initial treatment for cardiac toxicity in patients who have overdosed on TCAs and is indicated in patients who develop a widening of the QRS interval >100 msec or ventricular arrhythmia. Additionally, BZDs should be administered if the patient develops seizures. Gastrointestinal decontamination may be a consideration with the use of activated charcoal. Unless bowel obstruction, ileus, or perforation is suspected, the use of activated charcoal is recommended within two hours of ingestion. 

Opiate toxicity has become an epidemic in the United States. As mentioned above, these patients require special monitoring of ABCs. If opiate toxicity is suspected, naloxone, which is a short-acting opiate antagonist, can be administered to reverse the effects of the opiates. Preferably it should be administered intravenously but can be administered nasally, subcutaneously, or intramuscularly as well. However, absorption time is different in those methods compared to intravenously. 

Consultation with poison control can further assist in the management of these drug toxicities. 

Differential Diagnosis

The differential can be broad as most patients presenting with the toxicity of anxiolytics or sedatives are obtunded and unable to contribute to a meaningful history. Additionally, if the patient overdosed intentionally, history becomes less reliable. It is important to consider all causes of mental status changes in patients presenting with signs of toxicity. Differential diagnosis is broad and can consist of metabolic, structural, or infectious causes. Hypoglycemia is commonly seen as a potential cause of altered mental status and is easy to rule out with a point-of-care test.

Prognosis

anagableUltimately prognosis will depend on several factors, including but not limited to duration, dosage, and intervention. If identified and treated, early toxicity will have a good prognosis and is manageable. However, a delay in care or a substantial dosage of the intoxicant can lead to a prognosis that may be extremely poor.

Complications

Complications can be minimal to lethal. If treated early, there should be minimal to no long-term complications from an acute overdose. If the overdose leads to secondary complications such as cerebral ischemia, cardiac ischemia, or otherwise, the effects may be permanent.