Benzodiazepines: Pharmacology and Actions (PDF)

FIGURE 5.9 Etomidate, but not thiopental, is associated with decreases in the plasma concentrations of cortisol. Mean ± standard deviation. *P < .05 compared with thiopental. Reprinted with permission from Fragen RJ, Shanks CA, Molteni A, et al. Effects of etomidate on hormonal responses to surgical...

FIGURE 5.9 Etomidate, but not thiopental, is associated with decreases in the plasma concentrations of cortisol. Mean ± standard deviation. *P < .05 compared with thiopental. Reprinted with permission from Fragen RJ, Shanks CA, Molteni A, et al. Effects of etomidate on hormonal responses to surgical stress. Anesthesiology. 1984;61(6):652-656. Copyright © 1984 American Society of Anesthesiologists, Inc. Allergic Reactions The incidence of allergic reactions following administration of etomidate is very low.136 When reactions have occurred, it is difficult to separate the role of etomidate from other concomitantly administered drugs (neuromuscular blocking drugs) that are more likely to evoke histamine release than etomidate. Benzodiazepines Benzodiazepines are drugs that exert, in slightly varying degrees, five principal pharmacologic effects: anxiolysis, sedation, anticonvulsant actions, spinal cord–mediated skeletal muscle relaxation, and anterograde amnesia (acquisition or encoding of new information).137 The amnestic potency of benzodiazepines is greater than their sedative effects resulting in a longer duration of amnesia than sedation. Stored information (retrograde amnesia) is not altered by benzodiazepines.138 Benzodiazepines do not produce adequate skeletal muscle relaxation for surgical procedures nor does their use influence the required dose of neuromuscular blocking drugs. The frequency of anxiety and insomnia in clinical practice combined with the efficacy of benzodiazepines has led to widespread use of these drugs. For example, it is estimated that 4% of the population uses “sleeping pills” sometime during a given year, and 0.4% of the population uses hypnotics for more than a year.139 Although benzodiazepines are effective for the treatment of acute insomnia, their use for management of chronic insomnia is decreasing as their impact on cognitive function and mortality have emerged.140 Compared with barbiturates, benzodiazepines have fewer tendencies to produce tolerance, less potential for abuse, a greater margin of safety, and elicit fewer and less serious drug interactions. Unlike barbiturates, benzodiazepines do not induce hepatic microsomal enzymes. Benzodiazepines are intrinsically far less addicting than opioids, cocaine, amphetamines, or barbiturates. Midazolam is the most commonly used benzodiazepine in the perioperative period. Furthermore, the context-sensitive half-times for diazepam and lorazepam are prolonged; therefore, only midazolam is likely to be used for prolonged administration when prompt recovery is desired. However, the longer context-sensitive half-time of lorazepam makes this drug an attractive choice to facilitate sedation of patients in critical care environments. Unlike other drugs administered IV to produce CNS effects, benzodiazepines, as a class of drugs, are unique in the availability of a specific pharmacologic antagonist, flumazenil. Structurally, benzodiazepines are similar and share many active metabolites. The duration of action of benzodiazepines is not linked to receptor events but rather is determined by the rate of metabolism and elimination. Importantly, benzodiazepines do not produce enzyme induction. Mechanism of Action Benzodiazepines appear to produce all their pharmacologic effects by facilitating the actions of GABA.141 Benzodiazepines do not activate the GABAA receptors but rather enhance the affinity of the receptors for GABA (Figure 5.10).142 As a result of increased affinity for GABA, there is a greater probability of chloride channel openings, resulting in increased chloride conductance and hyperpolarization of the postsynaptic cell membrane. The postsynaptic neurons are thus rendered more resistant to excitation. This resistance to excitation is presumed to be the mechanism by which benzodiazepines produce anxiolysis, sedation, anterograde amnesia, alcohol potentiation, and anticonvulsant and skeletal muscle relaxant effects. FIGURE 5.10 Model of the γ-aminobutyric acid (GABA) receptor forming a chloride channel. Benzodiazepines (benzo) attach selectively to α subunits and are presumed to facilitate the action of the inhibitory neurotransmitter GABA on α subunits. Reprinted with permission from Möhler H, Richards JG. The benzodiazepine receptor: a pharmacologic control element of brain function. Eur J Anaesthesiol Suppl. 1988;2:15-24. Copyright © 1988 European Society of Anaesthesiology. Benzodiazepines interact with a site located between the α and γ subunits of the GABAA receptor. The γ subunit is required for benzodiazepine binding. The α1- and α5-containing GABAA receptors are important for sedation, whereas anxiolytic activity is due to interaction with α2 and α5 subunit–containing receptors.143,144 The α1-containing GABAA receptors are the most abundant receptor subtypes accounting for approximately 60% of GABAA receptors in the brain. The α2 subunits have more restricted expression, principally in the hippocampus and amygdala. The α5-containing GABAA receptors are principally extrasynaptic and are responsible for modulation of the resting membrane potential. This anatomic distribution of receptors is consistent with the minimal effects of these drugs outside the CNS (minimal circulatory effects). In the future, it may be possible to design benzodiazepines that selectively activate specific GABAA receptor types to produce anxiolysis without sedation. The GABAA receptor is a large macromolecule that contains physically separate binding sites (principally α, β, and γ subunits) not only for GABA and the benzodiazepines but also barbiturates, etomidate, propofol, steroids, and alcohol. Acting on a single receptor at different binding sites, the benzodiazepines, barbiturates, and alcohol can produce synergistic effects to increase GABAA receptor–mediated inhibition in the CNS. This property explains the pharmacologic synergy of these substances and, likewise, the risks of combined overdose, which can produce life-threatening CNS depression. This synergy is also the basis for pharmacologic cross-tolerance between these different classes of drugs and is consistent with the clinical use of benzodiazepines as the first-choice drugs for detoxication from alcohol. Conversely, benzodiazepines have a built-in ceiling effect that prevents them from exceeding the physiologic maximum of GABA inhibition. The low toxicity of the benzodiazepines and their corresponding clinical safety is attributed to this limitation of their effect on GABAergic neurotransmission. Differences in the onset and duration of action among commonly administered benzodiazepines reflect differences in potency (receptor binding affinity), lipid solubility (ability to cross the blood–brain barrier and redistribute to peripheral tissues), and pharmacokinetics (uptake, distribution, metabolism, and elimination). All benzodiazepines are highly lipid soluble and are highly bound to plasma proteins, especially albumin. Hypoalbuminemia owing to hepatic cirrhosis or chronic renal failure may increase the unbound fraction of benzodiazepines, resulting in enhanced clinical effects produced by these drugs. Following oral administration, benzodiazepines are highly absorbed from the gastrointestinal tract, and after IV injection, they rapidly enter the CNS and other highly perfused organs. Nucleoside Transporter Systems Benzodiazepines decrease adenosine degradation by inhibiting the nucleoside transporter, which is the principal mechanism whereby the effect of adenosine is terminated through reuptake into cells.145 Adenosine is an important regulator of cardiac function (reduces cardiac oxygen demand by slowing heart rate and increases oxygen delivery by causing coronary vasodilation), and its physiologic effects convey cardioprotection during myocardial ischemia. Electroencephalogram The effects of benzodiazepines on the EEG resemble those of barbiturates in that α activity is decreased and low-voltage rapid β activity is increased. This shift from α to β activity occurs more in the frontal and rolandic areas with benzodiazepines, which, unlike the barbiturates, do not cause posterior spread. In common with barbiturates, however, tolerance to the effects of benzodiazepines on the EEG does not occur. Midazolam, in contrast to barbiturates and propofol, is unable to produce an isoelectric EEG. Side Effects Fatigue and drowsiness are the most common side effects in patients treated chronically with benzodiazepines. Sedation that could impair performance usually subsides within 2 weeks in patients chronically treated with benzodiazepines. Patients should be instructed to ingest benzodiazepines before meals and in the absence of antacids because meals and antacids may decrease absorption from the gastrointestinal tract. Chronic administration of benzodiazepines does not adversely affect systemic blood pressure, heart rate, or cardiac rhythm. Although effects on ventilation seem to be absent, it may be prudent to avoid these drugs in patients with chronic lung disease characterized by hypoventilation and/or decreased arterial oxygenation as they may interact with other medications to have adverse effects. Decreased motor coordination and impairment of cognitive function may occur, especially when benzodiazepines are used in combination with other CNS depressant drugs. Acute administration of benzodiazepines may produce transient anterograde amnesia, especially if there is concomitant ingestion of alcohol. For example, there have been reports of profound amnesia in travelers who have ingested triazolam combined with alcohol to facilitate sleep on airline flights.146 Drug Interactions Benzodiazepines exert synergistic sedative effects with other CNS depressants including alcohol, inhaled and injected anesthetics, opioids, and α2 agonists. Anesthetic requirements for inhaled and injected anesthetics are decreased by benzodiazepines. Although benzodiazepines, especially midazolam, potentiate the ventilatory depressant effects of opioids, the analgesic actions of opioids are reduced by benzodiazepines.147,148 Indeed, antagonism of benzodiazepine effects with flumazenil results in enhanced analgesic effects of opioids. In patients receiving long-term opioid therapy for chronic pain, all-cause mortality is significantly higher in those receiving opioids and benzodiazepines concurrently.149 Hypothalamic-Pituitary-Adrenal Axis Benzodiazepine-induced suppression of the hypothalamic-pituitary-adrenal axis is supported by evidence of suppression of cortisol levels in treated patients.150 In animals, alprazolam produces dose-dependent inhibition of adrenocorticotrophic hormone and cortisol secretion.151 This suppression is enhanced compared with other benzodiazepines and may contribute to the unique efficacy of alprazolam in the treatment of major depression. Dependence Even therapeutic doses of benzodiazepines may produce dependence as evidenced by the onset of physical or psychologic symptoms after the dosage is decreased or the drug is discontinued. Symptoms of dependence may occur after more than 6 months of use of commonly prescribed low-potency benzodiazepines. It is misleading to consider dependence as evidence of addiction in the absence of inappropriate drug-seeking behaviors. Withdrawal symptoms (irritability, insomnia, tremulousness) have a time of onset that reflects the elimination half-time of the drug being discontinued. Typically, symptoms of withdrawal appear within 1 to 2 days for short-acting benzodiazepines and within 2 to 5 days for longer acting drugs. Aging Aging and liver disease affect glucuronidation less than oxidative metabolic pathways. Lorazepam, oxazepam, and temazepam are metabolized only by glucuronidation and have no active metabolites. For this reason, these benzodiazepines may be preferentially selected in elderly patients over benzodiazepines, such as diazepam, and that is metabolized by hepatic microsomal enzymes to form active metabolites. Elderly patients may also be intrinsically sensitive to benzodiazepines, suggesting that the enhanced response to these drugs that occurs with aging has pharmacodynamic as well as pharmacokinetic components. Long-term benzodiazepine administration may accelerate cognitive decline in elderly patients. Benzodiazepine withdrawal symptoms in the elderly include confusion. Postoperative confusion is more common in elderly long-term benzodiazepine users (daily use for >1 year) than in short-term users or nonusers of benzodiazepines.152 Platelet Aggregation Benzodiazepines may inhibit platelet-activating factor–induced aggregation resulting in drug-induced inhibition of platelet aggregation. Midazolaminduced inhibition of platelet aggregation may reflect conformational changes in platelet membranes.153 Although benzodiazepines significantly inhibit platelet aggregation in vitro, they do not appear to affect the risk of hemorrhagic complications in patients with severe, chemotherapy-induced thrombocytopenia154; the clinical significance of benzodiazepine-induced inhibition of platelet aggregation in the surgical arena is unclear. Midazolam Midazolam is a water-soluble benzodiazepine with an imidazole ring in its structure that accounts for stability in aqueous solutions and rapid metabolism.155 This benzodiazepine has replaced diazepam for use in