Mechanism of Action. Benzodiazepines appear to produce all their pharmacologic effects by facilitating the actions of GABA (do not activate the GABA_A receptors but rather enhance the affinity of the receptors for GABA) (Fig. 5-4).

Side Effects

1. Fatigue and drowsiness are the most common side effects in patients treated chronically with benzodiazepines.

2. Although effects on ventilation seem to be absent, it may be prudent to avoid these drugs in patients with chronic lung disease characterized by hypoventilation and/or decreased arterial oxygenation as they may interact with other medications to have adverse effects.

3. Decreased motor coordination and impairment of cognitive function may occur, especially when benzodiazepines are used in combination with other CNS depressant drugs.

4. Acute administration of benzodiazepines may produce transient anterograde amnesia, especially if there is concomitant ingestion of alcohol.

Drug Interactions

1. Benzodiazepines exert synergistic sedative effects with other CNS depressants including alcohol, inhaled and injected anesthetics, opioids, and ₂ agonists.

2. Anesthetic requirements for inhaled and injected anesthetics are decreased by benzodiazepines.

3. Although benzodiazepines, especially midazolam, potentiate the ventilatory depressant effects of opioids, the analgesic actions of opioids are reduced by benzodiazepines.

Midazolam has replaced diazepam for use in preoperative medication and conscious sedation. The amnestic effects of midazolam are more potent than its sedative effects (patients may be awake but remain amnestic for events and conversations such as postoperative instructions for several hours).

1. Pharmacokinetics (Table 5-3)

   1. Midazolam undergoes rapid absorption from the gastrointestinal tract and prompt passage across the blood-brain barrier.

   2. Despite this prompt passage into the brain, midazolam is considered to have a slow effect-site equilibration time (0.9 to 5.6 minutes) compared with other drugs such as propofol and thiopental. In this regard, IV doses of midazolam should be sufficiently spaced to permit the peak clinical effect to be appreciated before a repeat dose is considered.

   3. The short duration of action of a single dose of midazolam is due to its lipid solubility, leading to rapid redistribution from the brain to inactive tissue sites as well as rapid hepatic clearance.

2. Metabolism. Midazolam is rapidly metabolized by hepatic and small intestine cytochrome P450 (CYP3A4) enzymes to active and inactive metabolites (Fig. 5-5). The principal metabolite of midazolam, 1-hydroxymidazolam, has approximately half the activity of the parent compound.

3. Effects on Organ Systems

   1. Central Nervous System. Midazolam, like other benzodiazepines, produces decreases in CMRO₂ and cerebral blood flow analogous to barbiturates and propofol. Induction of anesthesia with midazolam does not prevent increases in ICP associated with direct laryngoscopy for tracheal intubation. Paradoxical excitement occurs in less than 1% of all patients receiving midazolam and is effectively treated with a specific benzodiazepine antagonist, flumazenil.

   2. Ventilation. Midazolam produces dose-dependent decreases in ventilation (patients with chronic obstructive pulmonary disease experience even greater midazolam-induced depression of ventilation). Transient apnea may occur after rapid injection of large doses of midazolam (>0.15 mg/kg IV), especially in the presence of preoperative medication that includes an opioid.

   3. Cardiovascular System. Cardiac output is not altered by midazolam, suggesting that blood pressure changes are due to decreases in systemic vascular resistance.

4. Clinical Uses

   1. Preoperative Medication. Midazolam is the most commonly used oral preoperative medication for children. Oral midazolam syrup (2 mg/mL) is effective for producing sedation and anxiolysis at a dose of 0.25 mg/kg with minimal effects on ventilation and oxygen saturation. Midazolam, 0.5 mg/kg administered orally 30 minutes before induction of anesthesia, provides reliable sedation and anxiolysis in children without producing delayed awakening.

   2. Intravenous Sedation. Midazolam in doses of 1.0 to 2.5 mg IV (onset within 30 to 60 seconds, time to peak effect 3 to 5 minutes, duration of sedation 15 to 80 minutes) is effective for sedation during regional anesthesia as well as for brief therapeutic procedures. The most significant side effect of midazolam when used for sedation is depression of ventilation. Midazolam-induced depression of ventilation is exaggerated (synergistic effects) in the presence of opioids and other CNS depressant drugs. Increasing age greatly increases pharmacodynamic variability and is associated with generally increased sensitivity to the hypnotic effects of midazolam.

   3. Induction of Anesthesia. Anesthesia can be induced by administration of midazolam, 0.1 to 0.2 mg/kg IV, over 30 to 60 seconds. Onset of unconsciousness (synergistic interaction) is facilitated when a small dose of opioid (fentanyl, 50 to 100 μg IV or its equivalent) precedes the injection of midazolam by 1 to 3 minutes. In healthy patients receiving small doses of benzodiazepines, the cardiovascular depression associated with these drugs is minimal. When significant cardiovascular responses occur, it is most likely a reflection of benzodiazepine-induced peripheral vasodilation.

   4. Maintenance of Anesthesia. Midazolam may be administered to supplement opioids, propofol, and/or inhaled anesthetics during maintenance of anesthesia (anesthetic requirements for volatile anesthetics are decreased in a dose-dependent manner by midazolam).

   5. Postoperative Sedation. Long-term IV administration of midazolam (loading dose 0.5 to 4 mg IV and maintenance dose 1 to 7 mg per hour IV) to produce sedation in intubated patients results in relative saturation of peripheral tissues with midazolam and clearance from the systemic circulation becomes less dependent on redistribution into peripheral tissues and more dependent on hepatic metabolism. The concomitant administration of analgesic doses of opioids greatly decreases the needed dose of midazolam and results in a more rapid recovery from sedation following discontinuation of the IV infusion of midazolam. Emergence time from midazolam infusion is increased in elderly patients, obese patients, and in the presence of severe liver disease.

   6. Paradoxical vocal cord motion is a cause of nonorganic upper airway obstruction and stridor that may manifest postoperatively (midazolam 0.5 to 1 mg IV may be an effective treatment).

Diazepam is a highly lipid-soluble benzodiazepine with a more prolonged duration of action compared with midazolam. Because of the beneficial aspects of midazolam pharmacology, parenteral diazepam is seldom used as part of current anesthetic regimens (see Table 5-3).

Lorazepam is a more potent sedative and amnesic than midazolam and diazepam, whereas its effects on ventilation, the cardiovascular system, and skeletal muscles resemble those of other benzodiazepines.

Oxazepam is a pharmacologically active metabolite of diazepam (duration of action is slightly shorter than that of diazepam because oxazepam is converted to pharmacologically inactive metabolites).

Alprazolam has significant anxiety-reducing effects in patients with primary anxiety and panic attacks (may be an alternative to midazolam for preoperative medication).

Clonazepam is a highly lipid-soluble benzodiazepine that is well absorbed after oral administration and is particularly effective in the control and prevention of seizures, especially myoclonic and infantile spasms.

Flurazepam is used exclusively to treat insomnia (30 mg orally to adults produces a hypnotic effect in 15 to 25 minutes and lasts 7 to 8 hours).

Temazepam is an orally active benzodiazepine administered exclusively for the treatment of insomnia. Despite the relatively long elimination half-time, temazepam, as used to treat insomnia, is unlikely to be accompanied by residual drowsiness the following morning.

Triazolam is an orally absorbed benzodiazepine that is effective in the treatment of insomnia. Marked anterograde amnesia has developed when this drug has been self-administered in attempts to facilitate sleep when traveling through several time zones.

Flumazenil is a specific and exclusive benzodiazepine antagonist with a high affinity for benzodiazepine receptors, where it exerts minimal agonist activity (prevents or reverses, in a dose-dependent manner, all the agonist effects of benzodiazepines).

1. Dose and Administration

   1. The dose of flumazenil should be titrated individually to obtain the desired level of consciousness. The recommended initial dose is 0.2 mg IV (8 to 15 μg/kg IV), which typically reverses the CNS effects of benzodiazepine agonists within about 2 minutes. If required, further doses of 0.1 mg IV (to a total of 1 mg IV) may be administered at 60-second intervals.

   2. The duration of action of flumazenil is 30 to 60 minutes, and supplemental doses of the antagonist may be needed to maintain the desired level of consciousness. An alternative to repeated doses of flumazenil to maintain wakefulness is a continuous low-dose infusion of flumazenil, 0.1 to 0.4 mg per hour.

   3. The administration of flumazenil to patients being treated with antiepileptic drugs for control of seizure activity is not recommended as it could precipitate acute withdrawal seizures.

2. Side Effects. Flumazenil-induced antagonism of excess benzodiazepine agonist effects is not followed by acute anxiety, hypertension, tachycardia, or neuroendocrine evidence of a stress response in postoperative patients.