Sedative Hypnotics

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Chapter 165

Sedative Hypnotics



Barbiturates are discussed in do-it-yourself suicide manuals and were implicated in the high-profile deaths of Marilyn Monroe, Jimi Hendrix, Abbie Hoffman, and Margaux Hemingway as well as in the mass suicide of 39 members of the Heaven’s Gate cult in 1997. Although barbiturates are still useful for seizure disorders, they rarely are prescribed as sedatives, with the availability of safer alternatives, such as benzodiazepines. Mortality from barbiturate poisoning declined from approximately 1500 deaths per year in the 1950s to only two fatalities in 2009.1

Barbiturates are addictive, producing physical dependence and a withdrawal syndrome that can be life-threatening. Whereas tolerance to the mood-altering effects of barbiturates develops rapidly with repeated use, tolerance to the lethal effects develops more slowly, and the risk of severe toxicity increases with continued use.

Principles of Disease

Barbiturates depress the activity of all excitable cells, especially those in the central nervous system (CNS), by enhancing the activity of γ-aminobutyric acid (GABA), the major central inhibitor. In acute overdose, barbiturates decrease neural transmission in autonomic ganglia, the myocardium, and the gastrointestinal tract and also inhibit the response to acetylcholine at the neuromuscular junction.

The GABAA receptor is a protein complex found on postsynaptic membranes in the CNS. Structurally, it consists of several distinct receptor sites surrounding a chloride ion (Cl) channel (Fig. 165-1). GABA opens the chloride channel. The resulting flow of Cl into the cell increases the negative resting potential, hyperpolarizing and stabilizing the membrane. There are separate receptor sites for barbiturates and for benzodiazepines and a third site that binds GABA, ethanol, and meprobamate. Although barbiturates and ethanol can directly increase Cl conductance, benzodiazepines require the presence of GABA to affect Cl flow, which may account for the relative safety of benzodiazepines in comparison with barbiturates.

Barbiturates produce dose-related depressive effects ranging from mild sedation to coma and fatal respiratory arrest. In the early stages of intoxication, some patients experience euphoria. Barbiturates have no analgesic effect and can paradoxically increase the reaction to pain at low doses.

Barbiturates act directly on the medulla to produce respiratory depression. In therapeutic doses, this respiratory depression mimics that of normal sleep. Starting with doses approximately three times therapeutic, the neurogenic, chemical, and hypoxic respiratory drives are progressively suppressed. Because airway reflexes are not inhibited until general anesthesia is achieved, laryngospasm can occur at low doses.

Therapeutic oral doses of barbiturates produce only mild decreases in pulse and blood pressure, similar to sleep. With toxic doses, more significant hypotension occurs from direct depression of the myocardium along with pooling of blood in a dilated venous system. Peripheral vascular resistance is usually normal or increased, but barbiturates interfere with autonomic reflexes, which then do not adequately compensate for the myocardial depression and decreased venous return. Barbiturates can precipitate severe hypotension in patients whose compensatory reflexes are already maximally stimulated, such as those with heart failure or hypovolemic shock. Barbiturates also decrease cerebral blood flow and intracerebral pressure. Although hypnotic doses of barbiturates do not affect gastric emptying, higher doses can decrease gastrointestinal smooth muscle tone and peristaltic contractions and delay gastric emptying.

Barbiturates are classified according to their onset and duration of action (Box 165-1): ultra-short acting (onset immediate after intravenous dose, duration minutes), short acting (onset 10-15 minutes after oral dose, duration 6-8 hours), intermediate acting (onset 45-60 minutes, duration 10-12 hours), and long acting (onset 1 hour, duration 10-12 hours). Only long-acting preparations have anticonvulsant effects in doses that do not cause sedation. Short- and intermediate-acting preparations are almost completely metabolized to inactive metabolites in the liver, whereas 25% of a phenobarbital (long-acting) dose is excreted unchanged through the kidney. Because phenobarbital is a weak acid (pKa 7.2), alkalinization of the urine will increase the amount of drug present in ionized form, minimizing tubular reabsorption and increasing drug clearance. Short- and intermediate-acting barbiturates are not significantly affected by pH changes in this range.

Barbiturates cross the placenta, with fetal levels approaching those of the mother. They are also excreted in low concentration in breast milk. Use during pregnancy is associated with birth defects (category D).

Clinical Features

Mild barbiturate toxicity mimics ethanol intoxication. It is manifested with drowsiness, slurred speech, ataxia, unsteady gait, nystagmus, emotional lability, and impaired cognition.

In severe acute intoxication, CNS depression progresses from stupor to deep coma and respiratory arrest. Although pupils are usually normal or small and reactive, concomitant hypoxia can cause pupils to be fixed and dilated. Corneal and gag reflexes may be diminished or absent, muscle tone flaccid, and deep tendon reflexes diminished or absent. Flexor (decorticate) and extensor (decerebrate) posturing can occur in patients comatose from barbiturate intoxication. These neurologic signs are variable and do not always correlate with severity of intoxication or depth of coma. A fluctuating level of consciousness is commonly seen. High barbiturate levels depress gastrointestinal motility, delaying drug absorption. As the drug is metabolized and blood levels drop, peristalsis and drug absorption may increase, causing drug levels to rise.

The life threat in severe barbiturate toxicity is respiratory depression. Because respirations can be rapid but shallow, the degree of hypoventilation may not be apparent on clinical examination, and pulse oximetry or capnography may be needed to detect the ventilation compromise.

Hypotension is common in patients with severe intoxication, along with a normal or increased heart rate. Barbiturate overdose is associated with noncardiogenic pulmonary edema. Altered pulmonary capillary permeability can be caused by hypoperfusion, hypoxia, or a direct effect of the drug. Pneumonia may be delayed.

Barbiturate withdrawal syndrome includes tremors, hallucinations, seizures, and delirium (similar to the delirium tremens of ethanol withdrawal). However, severe withdrawal occurs only after dependence on short- or intermediate-acting barbiturates (e.g., pentobarbital, secobarbital, amobarbital, or butalbital). Because these drugs are not commonly used, this syndrome is now very rare.

Diagnostic Strategies

The therapeutic level of phenobarbital is 15 to 40 µg/mL (65-172 µmol/L). A serum level greater than 50 µg/mL can be associated with coma, especially in a patient who is not a chronic user. Levels greater than 80 µg/mL are potentially fatal. Serial phenobarbital levels can monitor effectiveness of treatment. Other than phenobarbital, barbiturates have high volumes of distribution, so serum levels do not accurately reflect CNS concentrations or correlate with clinical severity. A positive urine screen establishes only exposure to a barbiturate but does not prove that the drug is present in toxic amounts and should not be relied on to explain decreased mental status.

Chest radiographs can detect noncardiogenic pulmonary edema or pneumonia. Computed tomography of the head may be helpful in comatose patients with evidence of trauma, focal neurologic signs, papilledema, or uncertain diagnosis to detect other causes of stupor and coma.

Because the electroencephalogram may be silent as a result of barbiturate overdose, no patient should be declared “brain dead” if barbiturates are present at therapeutic levels or higher.


Because barbiturates have no specific antidote, the key to management of these patients is supportive care, particularly with respect to the cardiovascular and respiratory systems. Severely intoxicated patients are unable to protect their airway and have decreased ventilatory drive. Supplemental oxygen may suffice for patients with mild to moderate overdose, but intubation is often required. Long-term induced paralysis is rarely necessary, and additional sedation usually is unnecessary for mechanical ventilation. Careful fluid replacement should maintain a systolic blood pressure above 90 mm Hg and adequate urine output. Patients should be monitored for fluid overload and pulmonary edema. Active warming should be initiated if the rectal temperature is below 30° C.

Gastrointestinal Decontamination and Enhanced Elimination

Gastric emptying by lavage is not indicated. For large overdoses, there is evidence that clearance of phenobarbital is markedly increased with multidose activated charcoal (MDAC).2 One dosage for MDAC is 25 g every 2 hours in an adult; the pediatric dose is 0.5 g/kg every 2 hours. If vomiting occurs, a smaller dose or antiemetics should be used. MDAC can also be administered slowly through a nasogastric tube. Contraindications to MDAC include an unprotected airway and gastrointestinal obstruction or perforation. Decreased peristalsis can result in constipation with MDAC and is a relative contraindication to MDAC.2 Although MDAC may shorten the duration of the intoxication, there is no evidence for improved outcome over supportive care, and supportive care without administration of activated charcoal is also an acceptable approach.

Although alkalinization of the urine with sodium bicarbonate has been recommended in the past, a nonrandomized study suggested that MDAC alone is most effective at increasing the drug’s clearance.3 The authors of that study hypothesize that alkalinization may interfere with the ability of the drug to diffuse across intestinal mucosa from the blood into the gut. A recent comprehensive review concluded that there is no role for urine alkalinization in acute barbiturate poisoning.4

Hemodialysis is rarely needed but may increase clearance of phenobarbital in the presence of renal or cardiac failure, acid-base or electrolyte abnormalities, unstable cardiorespiratory status, or inadequate response to less invasive measures. Because phenobarbital is 40 to 60% protein bound, hemoperfusion was advocated over hemodialysis; however, newer high-efficiency dialyzers using high blood flow rates provide drug clearance greater than that achieved by hemoperfusion.5 Unfortunately, there are insufficient data to determine the true risk-benefit ratio of hemodialysis in acute barbiturate overdose.4



Before 1950, treatment options for anxiety were limited. Whereas meprobamate, first synthesized in 1950, ultimately proved no safer than the barbiturates, its commercial success inspired the development of other nonbarbiturate anxiolytics. With chlordiazepoxide in 1960 and diazepam in 1963, benzodiazepines emerged as the principal agents for the treatment of anxiety. Cardiac effects and fatalities from pure benzodiazepine overdose are rare, and respiratory depression is less than with barbiturates. In addition, drug-drug interactions involving benzodiazepines are uncommon.

Benzodiazepines remain among the most widely prescribed class of drugs (Table 165-1) and are the most common prescription drugs used in suicide attempts. Fortunately, most benzodiazepine overdoses follow a relatively benign clinical course. Children make up 10% of benzodiazepine overdose cases.

Table 165-1



Principles of Disease

Benzodiazepines produce sedative, hypnotic, anxiolytic, and anticonvulsant effects by enhancing the inhibitory actions of GABA. Binding of a benzodiazepine to a specific benzodiazepine receptor potentiates GABA effects on the chloride channel at the GABAA receptor, increasing intracellular flux of chloride ions and hyperpolarizing the cell. The net effect is a diminished ability of the nerve cell to initiate an action potential, inhibiting neural transmission.

Three unique benzodiazepine receptors exist, distributed variably throughout the central and peripheral nervous systems. Classic benzodiazepines are nonselective, producing a broad range of clinical effects. Newer benzodiazepines interact selectively with a single receptor subtype to achieve a desired result, such as sedation, while minimizing unwanted effects.


Benzodiazepines are rapidly absorbed orally. Intramuscular use of chlordiazepoxide and diazepam is limited by erratic absorption, but lorazepam and midazolam are predictably absorbed after intramuscular injection. After absorption, benzodiazepines distribute readily and rapidly penetrate the blood-brain barrier. In plasma, benzodiazepines are highly protein bound.6

All benzodiazepines are metabolized in the liver. Oxazepam, temazepam, and lorazepam are directly conjugated to an inactive, water-soluble glucuronide metabolite that is excreted by the kidney. Other benzodiazepines must first be converted by the hepatic cytochrome P450 system. Chlordiazepoxide, diazepam, flurazepam, and clorazepate are metabolized to active derivatives that are then slowly conjugated and excreted. The long elimination half-lives of these intermediates can cause accumulation in the body with repeated dosing. Triazolam, alprazolam, and midazolam are converted to hydroxylated intermediates that are active, but because they are so rapidly conjugated and excreted, they do not contribute significantly to the drug’s overall effect.6

Cytochrome P450 processes may be significantly impaired in elderly patients or those with liver disease, leading to prolonged elimination of some benzodiazepines. Coingestion of drugs that also undergo cytochrome P450 metabolism (e.g., cimetidine, ethanol) also prolongs the half-lives of these benzodiazepines, but the clinical significance of these interactions is unclear.7

Clinical Features

CNS depression is common in patients with benzodiazepine poisoning and ranges from mild drowsiness to coma. Respiratory depression is due mainly to upper airway obstruction and increased upper airway resistance from loss of muscle tone rather than central apnea. Significant respiratory depression is rare but can be seen with large oral overdoses or during intravenous conscious sedation, particularly when the benzodiazepine is combined with an opioid such as fentanyl.7 Hypotension is uncommon. Other potential complications include aspiration pneumonia and pressure necrosis of skin and muscles.

Most children have symptoms within 4 hours of benzodiazepine ingestion. Ataxia is the most common sign of toxicity, occurring in 90% of patients. Respiratory depression occurs in less than 10% of pediatric cases, and hypotension has not been reported.

Prolonged or high-dose infusions of certain benzodiazepine preparations have been associated with the development of lactic acidosis. Metabolism of the propylene glycol diluent in diazepam and lorazepam intravenous solutions by alcohol dehydrogenase produces lactate, which can accumulate and cause acidosis severe enough to require intervention. Patients with renal or hepatic insufficiency are at increased risk for this complication.8

Diagnostic Strategies

Any patient with altered mental status should have a blood glucose level rapidly determined. Qualitative immunoassays for benzodiazepines in urine are available but do not aid management decisions. Most of these tests detect only benzodiazepines that are metabolized to oxazepam glucuronide; therefore, clonazepam, lorazepam, midazolam, and alprazolam are not detected on many urine drug screens.9 Serum drug concentrations are not routinely available and do not correlate with clinical severity. A lack of alcohol odor or a negative breathalyzer or blood ethanol test result suggests benzodiazepine or another sedative as a possible cause.

The benzodiazepine antagonist flumazenil should not be routinely administered to patients with coma of unknown origin or suspected benzodiazepine overdose, either for diagnostic or for therapeutic purposes.10 Any possibility of concomitant tricyclic overdose contraindicates flumazenil use.



Flumazenil, a nonspecific competitive antagonist of the benzodiazepine receptor, can reverse benzodiazepine-induced sedation after general anesthesia, procedural sedation, and confirmed benzodiazepine overdose, but it is not recommended for the routine reversal of sedative overdose in the ED. Although theoretic benefits of flumazenil use include cost savings and avoidance of procedures and tests such as endotracheal intubation and lumbar puncture, several studies have not been able to demonstrate an actual benefit.12 Seizures and cardiac dysrhythmias can occur after flumazenil administration, and fatalities have been reported. Flumazenil use can precipitate acute withdrawal in patients who are dependent on benzodiazepines. Similarly, this antidote is hazardous when it is given to patients who have coingested seizure-causing drugs (such as cocaine or a tricyclic antidepressant) because of loss of the benzodiazepine’s protective anticonvulsant properties. Coingestants that cause dysrhythmias, such as carbamazepine and chloral hydrate, may increase the likelihood of cardiac effects. Other risk factors are summarized in Box 165-2

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