Continuing Education Activity

Anxiolytics and sedative-hypnotics are widely consumed at home and in a hospital setting. This activity reviews the most commonly used agents of these classes, their potential toxicity, and therapies for toxicity. It focuses on the main factors relevant to anxiolytic and sedative-hypnotic medication toxicity and how a multidisciplinary approach can potentiate or mitigate this result.

Objectives:

• Identify the epidemiology of anxiolytic and hypnotic-sedative use and related toxicity.

• Evaluate how common pharmaceutical interactions, pathological states, and the metabolism of anxiolytics and sedative-hypnotics impact toxicity.

• Differentiate the management options available for anxiolytic and sedative-hypnotic toxicity.

• Communicate some interprofessional team strategies for improving care coordination to improve anxiolytic and hypnotic-sedative toxicity outcomes.

Introduction

Anxiolytics are a class of medications aimed at treating patients with panic disorders, generalized anxiety, and various other uses. Sedatives (hypnotics) are a class of drugs used in different situations ranging from treating insomnia to treating someone connected to a mechanical ventilator. Both of these medications have broad uses in various conditions and are effective when used at proper dosages and under the guidance of trained medical professionals. However, these drugs also run the risk of misuse and abuse, which could lead to unwanted and potentially fatal consequences. This topic focuses on the following drug families: benzodiazepines (BZD), nonbenzodiazepine receptor agonists, opiates, melatonin agonists, antidepressants, antipsychotics, anticonvulsants, barbiturates, and antihistamines. These medications have varying mechanisms of action but generally exert their most significant effect on the central nervous system.

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 using a 3A4 inhibitor like fluvoxamine, which inhibits the metabolism of alprazolam, thus causing a build-up of levels in the bloodstream and causing sedation. The use of opioids and BZD is another cause of accidental toxicity. Finally, the use of BZD barbiturates with alcohol to enhance the intoxication can result in unintended respiratory depression and death.

Epidemiology

The more commonly abused anxiolytic is the BZD class of medications. There is less data available for other drugs mentioned in this topic; however, BZD misuse was most common amongst younger adults. Adults aged 18 to 49 were accountable for the highest rate of misuse. However, adults aged 50 to 65 were most often prescribed BZD.[1] The lifetime prevalence of anxiolytic and sedative use disorders (including BZD, 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 concurrent illicit drug use disorder. 

Risk factors associated with anxiolytic and sedative toxicity include:

• Caucasian
• Female
• Uninsured
• Unemployed
• Panic symptoms
• Other psychiatric symptoms
• Alcohol abuse or dependence
• Cigarette use
• Illicit drug use
• History of IV drug use[3] 

Pathophysiology

The mechanisms of action of some medications discussed in this topic 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. 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 channel opening frequency and time.[4] However, nonbenzodiazepine receptor agonists have a different chemical structure than BZDs, and they selectively target 1 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 difference between toxicity between mood stabilizers except based on case fatality where multiple drug poisonings were considered. Carbamazepine was over twice as likely 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 are reviewed below. BZD toxicity coming from an overdose of oral BZDs rarely causes 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. These behaviors include 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 than other sleep medications. 

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 presents 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 (eg, 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, 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, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic symptoms (DRESS). They are rare adverse effects, but it is important to be aware of these potential consequences.

Evaluation

In evaluating patients for anxiolytics or sedative toxicity, much of the examination is guided by history and physical examination. If possible, it is important to determine from the patient or a witness 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 evaluate 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 benefit appropriate patients. Toxicological screening can give providers a definitive diagnosis when history is not readily available. 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

Multiple treatment modalities are 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 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.[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 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 to 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 at risk of developing torsades de pointes. Additionally, immediate non-synchronized electric defibrillation is indicated for patients with hemodynamic instability.

As stated before, TCA toxicity begins with the evaluation of ABCs and 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 2 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. It should be administered intravenously but can be administered nasally, subcutaneously, or intramuscularly. 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 can include 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

Ultimately, the prognosis depends on several factors, including but not limited to duration, dosage, and intervention. Early toxicity has a good and manageable prognosis if identified and treated. 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.

Deterrence and Patient Education

Identification and treatment of those who are at risk for suicidal attempts help to decrease the risk of death from anxiolytic or sedative toxicity. Therapy for those individuals with close monitoring can be extremely helpful in avoiding these complications. Proper use and patient education about these medications can help to ensure the appropriate and safe use of these medications as intended.

Enhancing Healthcare Team Outcomes

Rapid identification of those with life-threatening toxicity could ultimately save someone's life. Proper monitoring, correct usage, and medication adherence can help to decrease the risk of toxicity with these medications. Seeking help from trained professionals with experience in appropriately using these drugs can lead to substantial positive patient outcomes. However, misuse, improper monitoring, and delay in seeking care can lead to overdoses and potentially fatal outcomes.