Anesthesia/anesthetics benzodiazepines

Benzodiazepines have the capacity to produce a calming effect and to cause anterograde amnesia, in which the patient cannot recall events that took place for some time after the drug was administered. Benzodiazepine-induced sedation and amnesia are deemed useful in the preparation of patients for anesthesia, surgery, and other frightening or unpleasant medical and dental procedures and diagnostic tests. Midazolam is a frequently used anesthetic benzodiazepine (see Chapter 25). 

Combinations of barbiturates and benzodiazepine tranquilizers or even antihistaminergics having sedative properties are sometimes used. Furthermore, infusion of anesthetics can be used to provide long-term anesthesia for intensive care medicine. The antagonist flumazenil (18) is available to reverse the effects of anesthetics of the benzodiazepine class. 

Further, the removal of benzodiazepine sensitivity in a selective a subunit in a mouse using the gene knockin technique has established that the al subunit plays a major role in the sedative and amnesiac effects of benzodiazepines, part of the anticonvulsant effect and little of the anxiolytic effect the latter effects are more importantly mediated by the a2 subunit [5, 6], The 0 subunit selectivity for the drugs loreclezole (an anxiolytic) and etomidate (an anesthetic) allowed determination that a single residue in the M2 domain could account for this selectivity (02 = 03 >01). When a mouse knockin selectively removed the etomidate sensitivity of the 02 subunit, the animals showed reduced sensitivity to sedative effects of etomidate but no reduction of the true anesthetic effects. In contrast, mutation of the 03 subunit to negate etomidate sensitivity of that subunit alone resulted in a mouse with no sensitivity to the anesthesia produced by etomidate. This proved that the GABA receptor is the target of at least this one anesthetic (etomidate) and, furthermore, that the specific locations in the brain of 03 subunits are important for anesthetic action, while the... 

Midazolam is a rapidly metabolized benzodiazepine (p. 228) that is used for induction of anesthesia. The longer-acting lorazepam is preferred as adjunct anesthetic in prolonged cardiac surgery with cardiopulmonary bypass its am-nesiogenic effect is pronounced. 

In anesthesia drugs from several groups are used as premedication. Pre-anesthetic medication can decrease the anesthetic doses which otherwise would be required to induce anesthesia and so decrease the risk for adverse effects. Pre-anesthetic medication will increase the rate of induction of anesthesia and can reduce pre-operative pain and anxiety. Drugs include benzodiazepines for sedation and their muscle relaxant properties, opiates for pain relieve and anticholinergics or histamine Hi receptor antagonists against nausea and vomiting. Neuroleptics are also used as premedication for their antiemetic effects. 

Benzodiazepines—including diazepam, lorazepam, and midazolam—are used intravenously in anesthesia (see Chapter 25), often in combination with other agents. Not surprisingly, benzodiazepines given in large doses as adjuncts to general anesthetics may contribute to a persistent postanesthetic respiratory depression. This is probably related to their relatively long half-lives and the formation of active metabolites. However, such depressant actions of the benzodiazepines are usually reversible with flumazenil. 

Recovery is sufficiently rapid with most intravenous drugs to permit their use for short ambulatory (outpatient) surgical procedures. In the case of propofol, recovery times are similar to those seen with sevoflurane and desflurane. Although most intravenous anesthetics lack antinociceptive (analgesic) properties, their potency is adequate for short superficial surgical procedures when combined with nitrous oxide or local anesthetics, or both. Adjunctive use of potent opioids (eg, fentanyl, sufentanil or remifentanil see Chapter 31) contributes to improved cardiovascular stability, enhanced sedation, and perioperative analgesia. However, opioid compounds also enhance the ventilatory depressant effects of the intravenous agents and increase postoperative emesis. Benzodiazepines (eg, midazolam, diazepam) have a slower onset and slower recovery than the barbiturates or propofol and are rarely used for induction of anesthesia. However, preanesthetic administration of benzodiazepines (eg, midazolam) can be used to provide anxiolysis, sedation, and amnesia when used as part of an inhalational, intravenous, or balanced anesthetic technique. 

In contrast to the barbiturates, benzodiazepines do not produce an anesthetized state. They may be used as a preanesthetic in order to lessen anxiety, to be followed by a barbiturate and then the general anesthesia gas such as halothane. 

Several drugs are used intravenously, alone or in combination with other drugs, to achieve an anesthetic state (as components of balanced anesthesia) or to sedate patients in intensive care units who must be mechanically ventilated. These drugs include the following (1) barbiturates (thiopental, methohexital) (2) benzodiazepines (midazolam, diazepam) (3) opioid analgesics (morphine, fentanyl, sufentanil, alfentanil, remifentanil) (4) propofol (5) ketamine and (6) miscellaneous drugs (droperidol, etomidate, dexmedetomidine). Figure 25-2 shows the structures of... 

Adjunctive use of potent opioids (eg, fentanyl and related compounds) contributes cardiovascular stability, enhanced sedation, and profound analgesia. Other intravenous agents such as the benzodiazepines (eg, midazolam, diazepam) have slower onset and recovery features and are rarely used for induction of anesthesia. However, preanesthetic administration of benzodiazepines can be used to provide a basal level of sedation and amnesia when used in conjunction with other anesthetic agents. 

General anesthetics are rarely given alone. In addition to the analgesic agents just mentioned, benzodiazepines (midazolam, Versed diazepam, Valium ) are commonly used as adjuncts for the relief of anxiety, amnesia, and sedation prior to induction of anesthesia. Neuromuscular blockers (e.g., succinylcholine or pancuronium) can also be administered during the induction of anesthesia to relax skeletal muscles. 

The anesthetic effect of (+)-etomidate subsides within a few minutes owing to redistribution of the drug. Etomidate can provoke myoclonic movements that can be prevented by premedication with a benzodiazepine or an opioid. Because it has little effect on the autonomic nervous system, it is suitable for induction in combination anesthesia. Etomidate inhibits cortisol synthesis in subanesthetic doses and can therefore be used in the long-term treatment of adrenocortical overactivity (Cushing disease). 

As the dose of a benzodiazepine is increased, sedation progresses to hypnosis and then to stupor. The clinical literature often refers to the anesthetic effects and uses of certain benzodiazepines, but the drugs do not cause a true general anesthesia because awareness usually persists, and relaxation sufficient to allow surgery cannot be achieved. However, at preanesthetic doses, there is amnesia for events subsequent to administration of the drug, possibly creating the illusion of previous anesthesia. 

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