Mechanism of Action and Clinical Uses
Benzodiazepines interact with specific receptors in the central nervous system, particularly in the cerebral cortex. It enhances the inhibitory effects of various neurotransmitters. Benzodiazepines are used for preoperative medication, intravenous sedation, intravenous induction of anesthesia, and suppression of seizure activity (Table 2.2).
Benzodiazepines are unique among the group of intravenous anesthetics in that their action can readily be terminated by administration of their selective antagonist flumazenil (intravenous administration of 0.2 mg/min until reaching the desired degree of reversal. The usual total dose is 0.6-1.0 mg). The synergistic effects between benzodiazepines and other drugs, especially opioids and propofol, facilitate better sedation and analgesia. However, the combination of these drugs also enhances their respiratory depression and may lead to airway obstruction or apnea.
Their most desired effects are anxiolysis and anterograde amnesia (form of memory loss relating to the things that happen after a traumatic event), which are extremely useful for premedication. Benzodiazepines are commonly administered orally, intramuscularly, and intravenously to provide sedation or induction of general anesthesia. Diazepam and lorazepam are well absorbed from the gastrointestinal tract, with peak plasma levels usually achieved in 1 and 2 h, respectively. Oral midazolam has been popular for pediatric premedication.
Table 2.2 Uses and Doses of Commonly Used Benzodiazepines
|Agent||Duration of Action||Use||Route||Dose (mg/kg)|
|Diazepam||Long lasting||Premedication||Oral||0.2 - 0.5|
|Sedation||IV||0.04 - 0.2|
|Induction||IV||0.3 - 0.6|
|Midazolam||Short lasting||Premedication||IM||0.07 - 0.15|
|Sedation||IV||0.01 - 0.1|
|Induction||IV||0.1 - 0.4|
|IM||0.03 - 0.05|
|Sedation||IV||0.03 - 0.04|
Intramuscular injection of diazepam is painful and unreliable. In contrast, midazolam and lorazepam are well absorbed after intramuscular injection, with peak levels achieved in 30 and 90 min, respectively. Induction of general anesthesia with midazolam requires intravenous administration of the drug. Sites of clearance are liver and kidney.
Effects on Organ Systems and Side Effect
The benzodiazepines display minimal cardiovascular depressant effects even at induction doses. Arterial blood pressure, cardiac output, and peripheral vascular resistance usually decline slightly, whereas heart rate sometimes rises. Midazolam tends to reduce blood pressure and peripheral vascular resistance more than diazepam. Changes in heart rate variability during midazolam sedation suggest decreased vagal tone (i.e., drug-induced vagolytic).Respiratory
Benzodiazepines depress the ventilatory response to co2. This depression is usually insignificant unless the drugs are administered intravenously or in association with other respiratory depressants. Although apnea may be less common after benzodiazepine induction than after barbiturate induction, even small intravenous doses of diazepam and midazolam have resulted in respiratory arrest. Ventilation must be monitored in all patients receiving intravenous benzodiazepines, and resuscitation equipment must be immediately available.Cerebral
Benzodiazepines reduce cerebral oxygen consumption, cerebral blood flow, and intracranial pressure but not to the extent of the barbiturates do. They are very effective in preventing and controlling grand mal seizures. The anti anxiety, amnesic, and sedative effects seen at low dose progress to stupor and unconsciousness at induction doses. Compared with thiopental, induction with benzodiazepines is associated with a slower loss of consciousness and a longer recovery.
- Cimetidine binds to cytochrome P-450 and reduces the metabolism of diazepam.
- Erythromycin inhibits metabolism of midazolam and causes a 2- to 3-fold prolongation and intensification of its effects.
- Heparin displaces diazepam from protein-binding sites and increases the free drug concentration (200% increases after 1000 units of heparin).
- The combination of opioids and diazepam markedly reduces arterial blood pressure and peripheral vascular resistance. This synergistic interaction is particularly pronounced in patients with ischemic or valvular heart disease.
- Benzodiazepines reduce the minimum alveolar concentration of volatile anesthetics as much as 30%.
- Ethanol, barbiturates, and other central nervous system depressants potentiate the sedative effects of the benzodiazepines.