True or false? low doses of cns depressants can cause sedative effects and relaxation.

RELEVANT PHYSIOLOGY

Many of the drugs used in the practice of anesthesia, including sedatives, exert their effects through the modification of chemical transmission in the CNS. Central synaptic mechanisms are basically similar to those occurring in the periphery; however, the complexity of interneuronal connections in the brain makes the prediction of drug effects far more difficult. A large number of neurotransmitters have been identified in the CNS, including:

glutamate

γ-aminobutyric acid (GABA)

glycine

noradrenaline (norepinephrine)

dopamine

5-hydroxytryptamine

acetylcholine

histamine.

Abstract

Sedatives are central nervous system (CNS) depressant drugs primarily used as sleep-inducing hypnotics, anxiolytics, muscle relaxants, and anticonvulsants. The most frequently prescribed sedatives include the benzodiazepines, non-benzodiazepine sedative hypnotics, barbiturates, and muscle relaxants. Other medications, such as the antihistamine diphenhydramine, can also be used for their general sedative properties. The use of sedatives often begins with a prescription to treat insomnia, anxiety, or muscular pain, and abuse develops for their sedative-hypnotic effects resulting in increased dosage without medical advice or continued use after the insomnia, anxiety, or pain has subsided.

Sedatives

Sedatives such as benzodiazepines can be used to help induce sleep at the appropriate hour in the new time zone but may cause residual drowsiness on awakening. The shorter-acting sedatives, such as zolpidem or temazepam, are less likely to produce such a ‘hangover’, but certain individuals will have untoward effects.26 Whether the sedatives have any specific effect on the internal clock remains unclear. GABA type A receptors exist in the suprachiasmatic nuclei, so benzodiazepines may have some direct effect, but animal studies are inconclusive and there are no data on humans. Concern has been raised over the use of any sedative while still on a plane, as a sedated sleeper may be less mobile and more prone to deep venous thrombosis (the same, of course, applies to alcohol). The AAMS guidelines recommend the short-term use of sedatives as optional, with cautions that side-effects are a concern and that although sleep onset is improved, there is no evidence to support improvement of daytime symptoms of jet lag.

B General Anesthesia vs. Sedatives

Sedatives (sometimes referred to as hypnotics) are substances designed to depress the central nervous system to induce anxiolysis and increase sleepiness (Wisden, Yu, & Franks, 2017). Often, sedatives can induce a state similar to natural NREM sleep, characterized by increased delta oscillations, reduced respiratory rate, and lowered body temperature (Yu, Franks, & Wisden, 2018). As such, sedatives are frequently employed in clinical settings, such as intensive care units, to reduce postoperative delirium and promote sleep in an inhospitable environment (Skrobik, Duprey, Hill, & Devlin, 2018; Yu et al., 2018). While sedatives differ from general anesthesia in that it is usually possible to be aroused from a sedative state, certain sedative agents share anesthetic molecular targets (GABAA receptors) and even act as general anesthetics at elevated dosages (i.e., propofol and barbiturates) (Franks, 2008; Yu et al., 2018). Accordingly, discerning the neural mechanisms essential to exerting a sedative effect can give insight to the processes of sleep and general anesthesia. Therefore, the literature evaluating the neurobiological overlaps of specific sedative compounds and natural sleep will also be reviewed in the next section (Fig. 15.1).

2.1 PREMEDICATION

Sedatives and narcotics have a propensity to exacerbate the sleep-related apneic episodes and may impair life-saving arousal in patients with OSAHS. Benzodiazepines and barbiturates preferentially decrease neural input to the upper airway dilating muscles, leading to airway obstruction.16 Even small doses of narcotics given intravenously or epidurally can cause severe airway obstruction and apnea.17,18 Administration of a combination of sedatives and narcotics can be disastrous. Anxiolytic drugs such as midazolam should only be administered when close monitoring of the patient by appropriate personnel is possible. This means that the drug should not be given until the patient is about to enter the operating room for surgery. Because of the increased incidence of aspiration of gastric contents, an antacid and/or metoclopramide should be given to decrease the gastric acidity and volume. Glycopyrrolate to reduce oral secretions and dexametasone to reduce airway edema and nausea and vomiting are generally administered.

11.6.3 TDM of Sedatives and Analgesics in Critically Ill Patients

Sedatives and analgesics are frequently administered to patients in the ICU to provide pain relief for pre- and postsurgical procedures, promote relaxation, relieve anxiety and physical stress, induce sleep, and reduce mobility and agitation. Sedatives that are commonly utilized include benzodiazepines, opioids, and barbiturates [61]. These drugs may also be utilized for analgesia, in addition to nonsteroidal antiinflammatory antibodies. TDM can be utilized to reduce the risk of adverse effects, such as constipation and fatality caused by respiratory depression, hepatotoxicity, nephrotoxicity, portal hypertension, and GI bleeding. However, therapeutic guidelines are not well established [62]. The response to therapy of drugs that are extensively metabolized by the liver can also be impacted by liver disease. For example, the bioavailability of opioid therapy can vary in patients with chronic liver disease or combined hepatorenal diseases and can induce encephalopathy in critically ill patients [62,63].

Adjuvant Cerebroprotectants

Sedatives such as short-acting benzodiazepines, propofol, barbiturates, and paralytics can be used judiciously to help control ICP. However, barbiturates have many side effects, including depression of the cardiorespiratory and immune systems. Consequently, they are used for the acute situation of intractably elevated ICP when the mass effect is likely to resolve relatively quickly. Additional brain protection from hypothermia is promising and under investigation. Anticonvulsants have no direct effect on ICP, but are recommended in selected patients with mass lesions, when a seizure could suddenly increase ICP and cause clinical deterioration.

Sedation and Neuromuscular Blockade

Sedatives and analgesics may be useful to reduce struggling and exacerbation of elevated ICP, promote optimal ventilation, alleviate pain, and allow for adequate nursing care. Sedation may reduce cerebral metabolic activity and prevent seizures. Potential adverse effects of sedation are hypotension, which can exacerbate poor cerebral perfusion, and obscuration of the neurologic examination.

Neuromuscular blockade may aid in the management of TBI patients by promoting ease of ventilation, reducing ICP, and stopping metabolic demands from skeletal muscle. Complications of neuromuscular blockade include an increased risk of pneumonia, cardiovascular depression, immobilization stress (if used with inadequate sedation), unnoticed seizure activity, and prolonged paralysis/myopathy.

Sedatives and Anxiolytics

Sedatives and anxiolytics are administered infrequently to pregnant patients because they increase risks of sedation and respiratory depression in both mother and newborn, especially when used with opioids. Sedatives and anxiolytics were used more frequently in the past to diminish the adverse motivational-affective component of labor pain. Examples of such drugs are barbiturates and benzodiazepines.

Diazepam and midazolam are benzodiazepines used as anxiolytic agents in obstetrics. They rapidly cross the placenta, yielding approximately equal maternal and fetal blood levels within minutes of IV administration (Cree et al, 1973). In addition, the neonate has a limited ability to excrete diazepam, so the drug and its active metabolite may persist in significant amounts in the neonate for up to 1 week (Scher et al, 1972). Diazepam can result in neonatal hypotonia, lethargy, and hypothermia when used in large maternal doses (30 mg) (Cohen et al, 1993). However, when it is used in small doses (2.5 to 10 mg IV), minimal sedation and hypotonia have been observed (McAllister, 1980). Midazolam has a shorter duration of activity, but rapidly crosses the placenta and is associated with neonatal hypotonia in larger doses. The use of benzodiazepines remains somewhat controversial, but these agents can reduce maternal anxiety and are useful for treating convulsions associated with local anesthetic toxicity or eclampsia. However, all benzodiazepines are amnestics, and therefore may not be appropriate in many childbirth situations, depending on the desires of the parturient.

Sedatives

Sedatives do not possess any analgesic qualities. They are often used in early labor to reduce anxiety, augment the analgesic effects of narcotics, and decrease the nausea often associated with narcotics. Barbiturates, phenothiazines, and benzodiazepines are examples. The last two classes are not commonly used because of their many maternal and neonatal risks.102–104 Promethazine (Phenergan) is an antiemetic and is the most widely used sedative in labor. It rapidly crosses the placenta and has no known antagonist. In large or small doses combined with opioids, promethazine can depress the fetus for long periods of time. When used carefully with an opioid such as morphine in prodromal labor, however, promethazine may promote therapeutic rest for the patient. In some institutions, zolpidem, a sleep aid, is alternately given for therapeutic rest.