The benzodiazepines utilized in anesthesia include midazolam (Versed), diazepam (Valium), and lorazepam (Ativan) all of which exert their sedative and hypnotic effects by enhancing GABA transmission (an inhibitory neurotransmitter). The most commonly used perioperative benzodiazepine is midazolam which has an elimination half-life of 3 h. With a typical sedative IV dose of 1–2 mg, the clinical effect typically lasts for 20–30 min owing to redistribution. Benzodiazepines are used for sedation, anxiolysis, and amnesia. A beneficial side effect of these drugs is their anticonvulsant activity, which can help raise the seizure threshold in susceptible patients (e.g. patients receiving nerve blocks are at risk for local anesthetic toxicity). Benzodiazepines do not provide analgesia and can be very long-acting when used in large doses. This is why benzodiazepines are usually used jointly with other agents during the course of an anesthetic.

Some patients, particularly children, are so anxious that the anesthesiologist deems it prudent to administer a benzodiazepine for anxiolysis prior to entering the operating room. Midazolam (0.25–0.5 mg/kg orally in children) can be administered in these situations. It is important to remember that loss of balance and respiratory depression can occur after administration of benzodiazepines (particularly when combined with opioids). Patients given a benzodiazepine preoperatively should not be allowed to ambulate without assistance, and should always be monitored.

Intraoperatively, benzodiazepines can be used for sedation in instances where the patient does not receive a general anesthetic (often referred to as monitored anesthesia care, or MAC), or to provide sedation and/or amnesia as part of a balanced anesthetic technique. The amnestic properties of benzodiazepines are particularly useful in patients with poor hemodynamic status, who may not tolerate enough inhaled anesthetic agent to ensure complete unconsciousness.

If a patient becomes oversedated, or exhibits delayed emergence from general anesthesia, and the cause is suspected to be due to benzodiazepines, flumazenil (Romazicon) can be administered. Flumazenil is a pharmacologic antagonist which acts at the benzodiazepine receptor and effectively reverses the sedation from benzodiazepines. The drug is titrated in boluses of 0.1 mg every 5 min in adults. Because flumazenil only lasts about an hour and causes or produces incomplete reversal of respiratory depression, resedation can occur after administration (especially when used with diazepam, which has a half-life of approximately 20 h).

Commonly used opioids include morphine, hydromorphone (Dilaudid), fentanyl and its derivatives, and meperidine (Demerol). These drugs provide sedation and analgesia, but do not provide reliable amnesia. They act on receptors in the brain (periaqueductal gray area) and spinal cord (substantia gelatinosa) via the mu (μ), kappa (κ), and delta (δ) receptors by mimicking endogenous endorphins. Opioid receptor activation is considered to lead to neurotransmitter inhibition via inhibition of acetylcholine and substance P release. Table 4.1 shows opioid receptor subtypes and effects.

IV opioids are the primary means by which pain is controlled for surgical patients. While short-acting opioids such as fentanyl and its derivatives are used mainly for pain control intraoperatively, longer-acting opioids such as morphine, hydromorphone, or meperidine are usually used for postoperative pain. In addition to varying durations of action, it is their degree of binding to different opioid receptors and consequent side effect profiles that help in choosing the appropriate opioid for each patient and situation. Table 4.2 shows the relative dose, time to peak effect, and duration for the most commonly used IV opioids.

Fentanyl is a rapid-acting synthetic opioid which is about 100 times more potent than morphine. It is often given (dose 50–150 mcg for a 70 kg adult) during the induction of anesthesia to blunt the sympathetic response during intubation. It can cause apparent chest wall rigidity in high doses (1000 mcg), which in rare cases may impair or prevent adequate ventilation.

Sufentanil and Alfentanil are both analogues of fentanyl. When compared with sufentanil and fentanyl, alfentanil is an ultra short-acting opioid (5–10 min), about 25 % as potent as fentanyl, but has significantly faster onset than fentanyl (1–2 min). Sufentanil is approximately 5–10 times more potent than fentanyl. Both opioids may be used for induction and maintenance of anesthesia.

Morphine is the least lipid-soluble opioid and the most likely agent to accumulate in the presence of renal failure. It can cause bradycardia and histamine release in some patients. Morphine has a slower peak onset (30 min) when compared with fentanyl. Along with hydromorphone , morphine is the most commonly used long-acting opioid for postoperative pain control. Usually, either 5–15 mg of morphine or 1–2 mg of hydromorphone is given during a typical general anesthetic case.

Meperidine is structurally similar to atropine (may increase heart rate) and is metabolized to an active agent, normeperidine. It has useful antishivering properties and may be used postoperatively for this effect. It can accumulate in patients with renal failure leading to oversedation and/or seizures, and can cause release of histamine. It should be avoided in patients on type A monoamine oxidase inhibitors, as it may lead to hyperthermia, seizures, and even death. There is a well-known case involving the death of a patient named Libby Zion who received meperidine, although she had been taking phenelzine (Nardil), a type A MAO inhibitor. This error was found to result from overworked physicians who overlooked the drug reaction and ultimately led to the 80 h workweek limitation for residents.

Remifentanil has a potency similar to fentanyl, but is much shorter-acting (context sensitive half-time is about 4 min). It is broken down by nonspecific plasma esterases, and does not accumulate in patients after prolonged infusion, or in patients with renal or hepatic failure. It is almost always used as a continuous infusion, but can also be given as a bolus to facilitate intubation or nerve blocks.

Figure 4.1 shows how the context-sensitive half-time is a function of the length of time that the agent is administered. For opioids that exhibit accumulation (i.e., fentanyl), the context-sensitive half-time increases markedly with long durations of administration. Opioids which are enzymatically degraded as fast as they are administered (i.e., remifentanil) do not show this effect.

Opioids can be used alone for sedation cases but have several dose-dependent adverse side effects. Consequently, opioids are more commonly used in combination with other agents for MAC cases or as part of a balanced general anesthetic.

The major adverse side effect of opioids is respiratory depression. This is due to both a decrease in the hypoxic drive to breathe, and an increase in the apneic threshold (the CO₂ level above which patients are stimulated to breathe). If a patient is nonresponsive and/or hypoventilating from opioid overdose, this effect can be reversed with naloxone (Narcan, 0.04–0.4 mg every 2 min) which antagonizes mu receptors. Other adverse side effects of opioids include pruritus, bradycardia, arterial and venous vasodilation, nausea and vomiting, urinary retention, miosis, muscle rigidity (mainly with fentanyl), and decreased gastric motility/constipation.