Benzodiazepines

Published on 07/02/2015 by admin

Filed under Anesthesiology

Last modified 22/04/2025

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Benzodiazepines

Eric G. Cornidez, MD

Benzodiazepines promote the binding of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) to GABA_A receptors. The benzodiazepinergic enhancement of the inhibitory effect of GABA on neuronal excitability is the result of increased neuronal membrane permeability to chloride ions, leading to hyperpolarization and a less excitable state. Most of the effects of benzodiazepines (sedation, anxiolysis, muscle relaxation, anterograde amnesia, and anticonvulsant activity) are consequences of the impact of these drugs on the central nervous system. Benzodiazepines are used to treat insomnia, alcohol withdrawal, and seizures and, most importantly from the anesthesia provider’s perspective, are frequently used to provide sedation and amnesia in the perioperative setting. Major side effects can include lightheadedness, motor incoordination, confusion, and impairment of motor and mental functions. Benzodiazepines have recently been associated with the development of delirium in the intensive care unit (Table 85-1).

Table 85-1

Commonly Used Benzodiazepines

Drug	Route(s)	Common Use(s)	Comments	Half-life
Midazolam	Oral, IV, IM	Anesthetic premedication	Rapid onset	2.5
Temazepam	Oral	Insomnia	Short-term therapy	8.8
Alprazolam	Oral	Anxiety	Withdrawal symptoms may be especially severe	11.2-16.3
Lorazepam	Oral, IV, IM	Anxiety; anesthetic premedication, alcohol withdrawal	Metabolized solely by conjugation	14
Clonazepam	Oral	Seizure disorders; adjunctive treatment in acute mania and certain movement disorders	Tolerance	20-50
Diazepam	Oral, IV, IM, rectal	Anxiety, status epilepticus, skeletal muscle relaxation; anesthetic premedication	Decreases metabolism of cytochrome P-450–dependent drugs.	30-60

IM, Intramuscular; IV, intravenous.

Midazolam

Midazolam is a short-acting water-soluble benzodiazepine with sedative, anxiolytic, amnesic, and anticonvulsant properties. It may be given orally, intravenously, intramuscularly, or intranasally. Because of its rapid and reliable onset of action and short half-life and because it can be administered orally, midazolam is frequently used in the pediatric and adult perioperative setting to provide preoperative anxiolysis, conscious sedation during surgery, and induction or supplementation of general anesthesia.

Pharmacology

Midazolam causes virtually no local irritation after injection and can be mixed with other drugs commonly used as premedication agents. Its onset of action is among the fastest in its group (intravenous [IV], 1-5 min; intramuscular [IM], 15 min; oral [PO], 15 min). Similar to diazepam, it is highly bound to plasma proteins (95% protein binding). Rapid redistribution from the brain to other tissues and rapid metabolism by the liver account for the short duration of action.

Metabolism

Midazolam is hydroxylated and conjugated in the liver to two active derivatives that are renally excreted, and, therefore, patients in renal failure have prolonged pharmacodynamic effects. The elimination half-life of midazolam is 1 to 4 h and is prolonged with cirrhosis, congestive heart failure, obesity, and advanced age; similarly, as mentioned, the half-life of the metabolites is prolonged in patients with renal failure.

Effects on organ systems

Cardiovascular system

An intravenously administered 0.2-mg/kg dose of midazolam produces an increase in heart rate and decrease in blood pressure similar to that of an induction dose of thiopental (3-4 mg/kg). Hypotension is more common in pediatric patients or patients with hemodynamic instability and is more prominent when the patient also has received opioids because of synergism between the opioids and benzodiazepines.

Respiratory system

Ventilation is depressed by 0.015 mg/kg of midazolam, especially in patients with chronic obstructive pulmonary disease. Transient apnea may occur, especially when large doses of midazolam are given in conjunction with opioids.

Central nervous system

The administration of midazolam results in dose-related decreases in cerebral blood flow and cerebral O₂ consumption. As do most benzodiazepines, midazolam may impair physical, mental, or both physical and mental abilities. Patients should be advised not to participate in activities that require mental alertness and rapid physical response time (e.g., driving) for at least 24 h after receiving midazolam.

Placenta

Midazolam crosses the placenta and enters the fetal circulation. Its effects on the fetus are not known; however, studies have demonstrated a teratogenic risk when midazolam is administered to pregnant patients early in pregnancy.

Diazepam

Diazepam is a water-insoluble benzodiazepine used to treat acute alcohol withdrawal and seizures; to provide preoperative anxiolysis, intravenous sedation, and skeletal muscle relaxation; and for maintenance of general anesthesia. The safety and efficacy of diazepam in children younger than 2 years of age has not been studied.

Pharmacology

Because of its insolubility in water, diazepam is dissolved in propylene glycol and sodium benzoate; the solution may cause pain when injected using an IV or IM route. Diazepam is taken up rapidly into the brain because of its high lipid solubility and then redistributed extensively to other tissues. Its oral form has absorption of 85% to 100%, making it more reliable than IM administration. Diazepam is highly protein bound; therefore, diseases associated with hypoalbuminemia may increase its effects.

Metabolism

Diazepam is metabolized by hepatic microsomal enzymes, producing two main metabolites, desmethyldiazepam and oxazepam. Desmethyldiazepam is slightly less potent than diazepam and is metabolized more slowly, contributing to sustained effects. Elimination half-life ranges from 21 to 37 h in healthy persons, increases progressively with age, and increases markedly in the presence of cirrhosis. The elimination half-life of nordazepam is 48 to 96 h.

Effects on organ systems

Cardiovascular system

Diazepam given in IV doses of 0.3 to 0.5 mg/kg results in mild reductions in blood pressure, peripheral vascular resistance, and cardiac output. Occasionally, hypotension will occur after even small doses of diazepam.

Respiratory system

Diazepam causes a decreased slope of the ventilatory response to CO_2, but the CO₂ response curve is not shifted to the right, as it is after opioid administration. Occasionally, small doses of diazepam may result in apnea.

Skeletal muscle

Diazepam reduces skeletal muscle tone through its action on spinal internuncial neurons.

Anticonvulsant activity

Diazepam (0.1 mg/kg) abolishes seizure activity in status epilepticus and alcohol withdrawal, although the effect is short-lived. It also increases the threshold for local anesthetic-induced seizure activity.

Placenta

Diazepam crosses the placenta easily. An increased risk of congenital malformations has been associated with the use of diazepam during pregnancy.

Lorazepam

Lorazepam is a relatively long-acting benzodiazepine that is a more potent amnesic than is diazepam or midazolam. The cardiovascular, ventilatory, and neuromuscular blocking effects of lorazepam resemble those of diazepam and midazolam. Its elimination half-life is 10 to 20 h. Lorazepam is used clinically for preoperative sedation and anterograde amnesia but is seldom used for induction of anesthesia or IV sedation because of its slow onset.

Pharmacology

The onset of action depends on the route of administration: IV, 5 min; IM, 20 to 30 min; PO, 30 to 60 min.

Metabolism

Lorazepam is metabolized by hepatic microsomal enzymes to inactive compounds, which are then eliminated in urine. The elimination half-life ranges from 10.5 h in older children or adults, to approximately 16 h in the elderly, to 40 h in neonates. Because its metabolites are inactive, the use of lorazepam is recommended over midazolam for patients in the intensive care unit who require anxiolysis for longer than 24 h.

Other benzodiazepines

The benzodiazepines oxazepam (Serax), clonazepam (Klonopin), flurazepam (Dalmane), temazepam (Restoril), triazolam (Halcion), and quazepam (Doral) are used most commonly to treat insomnia or anxiety. Though these drugs are not typically used in the perioperative setting, patients may present for anesthesia who may be taking these medications; therefore, clinicians will need to consider the actions of these drugs when formulating an anesthetic plan.

Benzodiazepine antagonist

Flumazenil

Flumazenil is a specific antagonist of the central nervous system effects of benzodiazepine because it binds to specific sites on the GABA_A receptor, where it competitively inhibits the binding of the neurotransmitter, GABA, to this receptor. Flumazenil is eliminated almost entirely by hepatic metabolism to inactive products, and its clinical effects usually last 30 to 60 min. Therefore, flumazenil may need to be readministered after 30 min should sedation reappear. Small incremental doses are preferable to a single bolus: 1 mg of flumazenil given over 1 to 3 min should abolish most effects of therapeutic doses of benzodiazepines. Patients suspected of having a benzodiazepine overdose should respond to a cumulative dose of 1 to 5 mg of flumazenil administered over 2 to 10 min. Should the sedated patient not respond to 5 mg of flumazenil, a cause of sedation other than benzodiazepines should be investigated. Some clinicians have successfully used flumazenil to reverse some of the sequelae of hepatic encephalopathy.

Tolerance, dependence, and withdrawal

Tolerance to the anxiolytic effect of benzodiazepines is controversial. Even though most patients who chronically use benzodiazepines report experiencing decreased drowsiness over a few days, they do not convincingly demonstrate a tolerance to the impairment of some measures of psychomotor performance (e.g., visual tracking). On the other hand, tolerance has been demonstrated to the anticonvulsant, neuromuscular blocking, and ataxic effects of benzodiazepines. Dependence on benzodiazepines has been shown to occur. Abrupt discontinuation of benzodiazepines after prolonged administration of high doses may result in symptoms of withdrawal (one third of patients in the intensive care unit who receive benzodiazepines for 7 days or longer have been reported to exhibit signs of withdrawal) such as dysphoria, irritability, sweating, tremors, unpleasant dreams, and temporary intensification of insomnia or anxiety.

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