BZDs exert their therapeutic effect at specific BZD receptor sites in the central nervous system (CNS) [1]. The BZD receptor is located within the γ-aminobutyric acid-A (GABA-A) receptor supramolecular complex (GRSMC). Binding of GABA or GABA plus a BZD causes an allosteric change in the GRSMC. This results in an alteration in chloride-channel permeability, with an increase in chloride flux and hyperpolarization. GABA is an inhibitory neurotransmitter, and its receptors form an inhibitory bidirectional system with connections within many areas of the CNS. Once neurotransmission has been altered, there is a secondary effect on neurotransmitter release from the internuncial neurons. For the most part, activation of a GABA neuron leads to changes in dopamine release, although norepinephrine and acetylcholine may be involved. Serotonin effect is minimal except for neurons in the dorsal raphe [2]. Activation of GRSMC by a BZD potentiates synaptic GABA-mediated inhibition [3,4]. The GRSMCs are located throughout the brain and the spinal cord area. The BZD receptors are categorized as omega 1, omega 2, and omega 3. Each of the omega subtypes tends to cluster in particular areas of the CNS [2,5,6,7]. The omega-1 subtype predominates in the sensorimotor cortex and is predominantly sedative–hypnotic. The omega-2 subtype is concentrated in the limbic areas of the brain with mainly anxiolytic and anticonvulsant properties [2,3].

BZD absorption from the gastrointestinal (GI) tract depends on the properties and pharmaceutical formulation of each drug. Peak levels occur within 3 hours post-ingestion; intramuscular absorption can be erratic and delayed. Duration of action is dependent on the lipophilicity of each compound; the more
lipophilic, the shorter the duration of action. BZDs are highly protein-bound (85% to 99%). Their volume of distribution depends on lipid solubility and varies from 0.26 to 0.58 L per kg for chlordiazepoxide to 0.95 to 2.00 L per kg for diazepam. BZDs are metabolized by hepatic microsomal oxidation (N-dealkylation) and then glucuronidation [8,9]. They can be classified on the basis of elimination half-life (Table 143.2).

Fatality from pure BZD overdose is rare. Toxicity may vary between individual agents. Alprazolam overdose was found to result in more frequent intensive care unit admission, mechanical ventilation, and flumazenil use than other benzodiazepines [10]. A retrospective review of 1,239 overdose cases from one medical examiner’s office revealed only two deaths solely related to diazepam overdose [11]. In chronic abusers, rapid clinical recovery after BZD overdose is believed to result from adaptation or tolerance to the depressant effect [12].

Overdose commonly occurs as a part of polydrug ingestions. BZDs alone produce slurred speech, lethargy, ataxia, nystagmus, and coma. Loss of deep tendon reflexes and apnea are unusual except with a massive overdose. There are rare case reports of coma, cardiac arrest, acute respiratory distress syndrome, and pulmonary edema [12,13,14,15]. Abrupt cessation of BZDs after long-term use may result in a withdrawal syndrome [16,17] (see Chapter 145).

Recommended laboratory studies include serum electrolytes, blood urea nitrogen, creatinine, and glucose. Because BZDs may be involved in polydrug overdoses, serum acetaminophen levels and a 12-lead electrocardiogram (ECG) results should
also be obtained. Creatine phosphokinase (CPK), urine analysis, arterial blood gas, imaging studies, serum salicylate concentrations, and lumbar puncture should be obtained as clinically indicated. Quantitative BZD levels are not useful in the clinical management of overdose cases.

The most important aspect of BZD overdose management is supportive care. Airway management should precede all interventions, and intubation is indicated if the patient cannot adequately maintain spontaneous ventilation or protect the airway. Vascular access should be established. The patient should be placed on continuous pulse oximetry and cardiac monitoring. Activated charcoal (1 g per kg) may be considered in awake patients if the presentation is within 1 hour of ingestion, but there is currently no evidence to suggest that administration changes outcome following simple BZD overdose and may in fact be harmful in patients who subsequently become sedated if the airway is unprotected. Charcoal administration is often not practical as many adult patients, presenting with deliberate self-poisoning, do so more than 2 hours post-ingestion [18]. Additionally, the risks of charcoal administration in a sedated patient with isolated benzodiazepine ingestion must be weighed against the low risk of morbidity and mortality seen with this type of poisoning. There is no evidence to suggest that repeat-dose charcoal enhances BZD elimination [19].

Flumazenil (Romazicon, Anexate) is a BZD antagonist that binds to the GRSMC omega-1 and -2 subtypes, competitively inhibiting BZD binding and thereby reversing BZD sedative and anxiolytic effects [20]. It may also reverse BZD-induced respiratory depression, obviating the need for intubation, but this effect is inconsistent. It does not fully reverse the amnestic effects of BZDs. Patients may appear awake and alert, but subsequent recall (e.g., of instructions) may be poor [21,22].

For most patients with pure benzodiazepine poisoning, supportive care with attention to airway and ventilatory status is all that is required to manage their overdose. It is uncommon for patients to require administration of flumazenil to treat sedation alone. This agent should never be considered in place of airway intervention in compromised patients. Adverse drug events associated with flumazenil use include anxiety, nausea, agitation, and crying. It should be avoided in patients who are suspected to be BZD-tolerant [23]. Flumazenil may precipitate an abrupt withdrawal syndrome with potential for seizures in these patients. This may occur after short-term use of benzodiazepines [24]. Flumazenil should also be avoided in patients with polypharmacy overdoses in whom reversal of BZD effect may unmask the epileptogenic effects of the other drugs (e.g., cyclic antidepressants, isoniazid, and cocaine). Flumazenil is contraindicated in patients with electrocardiographic evidence of cyclic antidepressant toxicity (e.g., prolonged QRS duration), as this finding is associated with a high risk of seizures [25]. Patients with a history of epilepsy are also at increased risk for seizures. Flumazenil has been suggested for both diagnostic purposes in undifferentiated coma and therapeutic purposes. Despite this, its role and indications remain unclear in the management of the BZD-poisoned patient [23]. Flumazenil does not reduce hospital length of stay or need for high-dependency monitoring. If administering flumazenil, the initial dose should be 0.05 to 0.1 mg. This can be repeated at 30-second intervals. In general, if there has not been any response after a total dose of 1 to 2 mg, the diagnosis of benzodiazepine poisoning is unlikely. In the uncommon situation where it may be used to reverse toxicity in deliberate self-poisoning, the aim is to titrate a flumazenil dose such that the patient is moderately drowsy and easily aroused, and not to have the patient completely awake, alert, and keen to self-discharge from hospital. Because flumazenil has a short half-life (approximately 50 minutes), it may be administered as an infusion in severe BZD poisoning, in a similar fashion to naloxone in severe opioid poisoning [26]. Seizures that result from flumazenil therapy may require treatment with large doses of BZDs or barbiturates (e.g., thiopental or phenobarbital).

Treatment of BZD withdrawal is similar to that for barbiturates and other nonbarbiturate sedative–hypnotics (see later discussion here and Chapter 145).

Barbiturates depress the activity of all excitable tissues. They enhance GABA postexcitatory inhibition at the nerve terminal and appear to have a binding site on the GRSMC, leading to increased chloride flux. The CNS is most sensitive, with skeletal and smooth muscle depression evident at higher doses.

Barbiturates are available in all forms, although most toxicity results from ingestion. Barbiturates are divided into groups based on their duration of action. Ultra-short–acting barbiturates are highly lipid soluble and rapidly partition into the CNS, with subsequent redistribution to all tissues. When parenterally administered, they have rapid onset with less than 1-hour duration of effect; their predominant role is in induction of anesthesia.

Short- and intermediate-acting barbiturates are intermediate in lipid solubility and are used as anxiolytics and sedatives. Long-acting barbiturates have relatively low lipid solubility and are mainly used as anticonvulsants. Systemic toxicity tends to be a function of the drug’s elimination half-life (Table 143.3).

Barbiturates are well absorbed from the GI tract; serum levels and symptoms are detectable within 30 minutes, and their peak effect occurs by 4 hours. Barbiturates are variably metabolized by the liver, with most of the highly lipid-soluble group excreted after glucuronidation. The longer-acting barbiturates rely more on urinary excretion for elimination (phenobarbital, 25% to 33%; barbital, 95%; primidone, 15% to 42%; phenylethylmalonamide a metabolite of primidone, 95%) [28]. As they are weak acids, renal elimination can be enhanced by urinary alkalinization. The kinetics of barbiturate elimination are mixed: first order at low concentrations and zero order at high ones [29]. Therapeutic serum drug levels are 10 to 40 μg per mL for phenobarbital and 1 to 5 μg per mL for the short-acting barbiturates. Toxic dosages are in the range of 6 to 10 g for the long-acting barbiturates and 3 to 6 g for the short-acting ones. Most patients demonstrate some degree of sedation with levels of 8 mg per kg. Tolerance rapidly develops, and chronic users may require 5 to 10 times the normal dose for sedation. Depending on the degree of tolerance, drug levels associated with coma range from 80 to 120 μg per mL for phenobarbital and 15 to 50 μg per mL for short-acting agents. Other sedatives (e.g., ethanol) have an additive effect and can result in toxicity at lower doses and blood concentrations [30].

The most common toxic scenario results from accidental or intentional oral barbiturate ingestion by a seizure patient or family member. Barbiturates may be involved in polypharmacy overdoses, particularly butalbital, a component of several common headache medications (e.g., Fiorinal).

Most patients present with some degree of sedation, which is evident within 30 minutes after ingestion of the agent. This may rapidly progress to coma, respiratory collapse, and hypotension. The patient may be mildly hypothermic from loss of autonomic function and decrease in overall muscle activity. The CNS depression is generalized, although there are many reports of focal findings [30,31]. Cardiovascular collapse with severe hypotension is believed to be due to direct myocardial suppression and vascular dilation, an indicator of serious toxicity. Dysrhythmias are rare. The gut becomes atonic, producing delayed absorption or ileus, which may then progress to bowel necrosis. Bullous skin lesions over pressure points occur in 6% of patients within 24 hours of ingestion [32,33]. The lesions are tense clean bullae surrounded by erythema, and the bullae fluid has detectable amounts of barbiturate. The presence of bullae is not pathognomonic for barbiturate poisoning. Bullae formation has also been reported following other sedative–hypnotics, tricyclic antidepressants, methadone, and carbon monoxide poisoning. Crystalluria has been reported [34].

Withdrawal symptoms may occur after 1 to 2 months of chronic use. Symptoms usually present after 2 to 7 days of abstinence or four to five elimination half-lives. Agitation, hyperreflexia, anxiety, and tremor are the most common symptoms, followed by confusion and hallucinations. In early withdrawal, up to 75% of patients experience seizures. Barbiturate withdrawal seizures appear to be more severe than ethanol withdrawal seizures. Transplacental tolerance occurs, with neonatal irritability noted for months after birth [35].

Serum phenobarbital concentration should be determined in situations where phenobarbital or primidone overdose is suspected. However, results of other serum barbiturate concentrations are generally not available in a clinically meaningful time. Recommended laboratory studies include complete blood cell count, serum electrolytes, blood urea nitrogen, creatinine, glucose, and liver function tests. Because barbiturates may be involved in polydrug overdoses, serum acetaminophen concentration, to exclude occult ingestion, and an ECG should also be obtained. CPK, urine analysis, arterial blood gas, imaging studies, and lumbar puncture should be obtained as clinically indicated.

The most important aspect of barbiturate overdose management is supportive care. Early airway management is imperative, as up to 40% of patients may suffer from pulmonary aspiration. Frequent monitoring of all vital signs, including rectal temperature, is indicated. Vascular access should be obtained. The patient should be placed on continuous pulse oximetry and cardiac monitoring. A single dose of activated charcoal (1 g per kg) should be considered in large ingestions with appropriate airway protection.

Multiple-dose activated charcoal (MDAC) and urinary alkalinization can enhance the elimination of phenobarbital and possibly other barbiturates [36,37,38]. In a human volunteer study, MDAC was superior to urinary alkalinization in enhancing elimination of intravenously administered phenobarbital [39]. MDAC is recommended for all barbiturate overdoses, and urinary alkalinization is recommended for those involving long-acting agents such as phenobarbitone.