Chemistry and Structure-Activity Relationships

The structures of the pharmacologically active 1,4-benzodiazepines are shown in Figure 13-1 and Table 13-1. All benzodiazepines currently available in the United States are derived from the basic molecule shown in Table 13-1, to which are added various substituent groups. Slight modifications of the basic structure have produced triazolobenzodiazepines (e.g., alprazolam, triazolam) and imidazobenzodiazepines (e.g., midazolam).

FIGURE 13-1 Structural formulas of chlordiazepoxide, the first benzodiazepine used clinically; midazolam, an imidazobenzodiazepine; and the triazolobenzodiazepines alprazolam and triazolam. Triazolam is derived from alprazolam by the addition of a chlorine atom on the ortho position of the phenyl group. Estazolam is formed from alprazolam by removal of the methyl group of the triazolo ring (not shown).

All benzodiazepines with psychopharmacologic activity have an electronegative group at R₇. A chlorine atom seems to confer optimal activity, whereas bromo and nitro substitutions are only weakly anxiolytic. A nitro moiety at R₇ enhances antiseizure properties, however, as illustrated by clonazepam, which is used as an anticonvulsant. Hydrogen or methyl groups at R₇ significantly reduce pharmacologic activity. Substitution at position 5 with any group other than a phenyl ring also reduces activity. Halogenation at R₂′ increases potency; larger alkyl substitutions decrease it. Substitution on the nitrogen at R₁ with a methyl group enhances activity, as do methyl or hydrogen groups at R₃. A biosynthetic pathway for the in vivo formation of diazepam-like benzodiazepines has been proposed.⁷ Whether synthesis occurs naturally is unknown, but benzodiazepines are found in a variety of foods.⁶⁹

Mechanism of Action

Perhaps the most exciting and significant advance in the understanding of anxiety and the mechanism of action of benzodiazepines occurred with the discovery of specific benzodiazepine binding sites in the brain and the understanding that these were in some way linked to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). As shown schematically in Figure 13-2, when the GABA receptor is activated, the Cl⁻ channel opens, allowing Cl⁻ influx, membrane hyperpolarization, and neuronal inhibition. Benzodiazepines, by interacting at high-affinity benzodiazepine binding sites on the GABA receptor complex, facilitate GABA action. Although devoid of direct GABA-mimetic effects, benzodiazepines increase inhibitory neurotransmission resulting from GABA. Although the exact mechanism by which benzodiazepines accomplish their effect is not fully delineated, it is known that they increase the frequency at which Cl⁻ channels open in response to GABA.⁶⁰ GABA inhibition (chiefly postsynaptic inhibition) is enhanced by benzodiazepines, and any transmitter system modulated by this inhibitory drive is inhibited to a greater extent in the presence of benzodiazepines.

FIGURE 13-2 Schematic of the γ-aminobutyric acid (GABA)_A receptor complex illustrating the sites of action of benzodiazepine agonists, antagonists, and GABA. The benzodiazepine receptor is coupled to the GABA_A receptor so that its activation facilitates (denoted by the plus sign) the action of GABA on the Cl⁻ ionophore. Increased Cl⁻ influx leads to hyperpolarization (i.e., inhibition) of the neuron. Benzodiazepine antagonists inhibit the binding of benzodiazepines. Inverse agonists inhibit the constitutive activity of the benzodiazepine-GABA_A receptor complex by binding to the benzodiazepine receptor. Also illustrated is the picrotoxin site, which, when acted on by picrotoxin, antagonizes (minus sign) the influx of Cl⁻ and can lead to convulsions.

(Adapted from Dubovsky SL: Generalized anxiety disorder: new concepts and psychopharmacologic therapies, J Clin Psychiatry 51[suppl 1]:3-10, 1990.)

Benzodiazepine receptors are found in the brains of all mammalian species, birds, amphibians, reptiles, and higher fishes. Benzodiazepine receptors are linked to a specific GABA receptor subtype, the GABA_A receptor (see Figure 13-2). Figure 13-3 provides further details on binding domains associated with the GABA_A receptor. Historically, GABA receptors have been classified into two subtypes: the Cl⁻ channel–linked GABA_A receptors and the G protein–linked GABA_B receptors. Benzodiazepine-sensitive GABA_A receptors are activated by GABA agonists, such as muscimol (a hallucinogen), and blocked by GABA antagonists, such as picrotoxin and bicuculline (convulsants).⁷² GABA_B receptors are benzodiazepine and bicuculline insensitive and are activated by baclofen, a centrally acting muscle relaxant.

FIGURE 13-3 Arrangement of allosteric binding domains on the γ-aminobutyric acid (GABA)_A receptor complex. The complex is composed of five unique subunits. Multiple receptor subtypes are possible on the basis of different combinations of the subunits. Binding sites for picrotoxin (a convulsant), barbiturates, GABA, and benzodiazepines are presented for illustrative purposes. In addition, distinct binding sites for other chemical agents have been identified (shown as blank areas). The figure does not identify which receptor subunits are involved in the binding of each drug.

(Adapted from Sieghart W: GABA_A receptors: ligand-gated Cl⁻ ion channels modulated by multiple drug-binding sites, Trends Pharmacol Sci 13:446-450, 1992.)

The benzodiazepine receptor—along with the GABA_A receptor, a barbiturate receptor, the Cl⁻ channel, and binding domains for other drugs—forms a single macromolecular complex. Similar to GABA receptors, benzodiazepine receptors are heterogeneous; there are at least three types: type 1 (BZ₁), type 2 (BZ₂), and the “peripheral type” benzodiazepine receptor. The presence of BZ₁ and BZ₂ receptor types is apparently determined by the subunit composition of the GABA_A macromolecular complex. The BZ₁ receptor may be linked to sleep, whereas the BZ₂ receptor may be linked to cognition and motor function. High-affinity benzodiazepine binding sites are found on specific subunits of the GABA_A receptor complex, which, as shown in Figure 13-4, is a pentamer composed of several glycoprotein subunits (α, β, γ). This organization is analogous to the organization of the nicotinic receptor. As illustrated in Figure 13-4, which depicts the most common form of GABA_A receptor complex in the rat brain, a γ subunit is necessary (but insufficient) for benzodiazepine binding and pharmacologic effects.⁵⁶ Cloning experiments have shown that there are multiple subtypes of α, β, and γ subunits,³³ which provide a basis for GABA receptor heterogeneity.^13,49

FIGURE 13-4 Structural model of the γ-aminobutyric acid (GABA)-benzodiazepine (BZ) receptor complex. The arrangement of the subunits (α, β, γ) forms the Cl⁻ channel. GABA binding sites are illustrated at the two analogous interfaces between the α and β subunits. The BZ binding site is associated with the interface of the α and γ subunits.

(Adapted from Zorumski CF, Isenberg KE: Insights into the structure and function of GABA-benzodiazepine receptors: ion channels and psychiatry, Am J Psychiatry 148:162-173, 1991.)

The heterogeneity of receptor subunits may offer an explanation for the diverse pharmacologic effects (antianxiety, anticonvulsant, sedative, and skeletal muscle relaxant) of benzodiazepines. Determination of the molecular basis of receptor heterogeneity may eventually facilitate the development of benzodiazepines with a greater degree of selectivity in producing each of these effects. At present, none of the clinically available antianxiety benzodiazepines shows selectivity for either BZ₁ or BZ₂ receptors, although the hypnotic benzodiazepine quazepam is likely selective for the BZ₁ receptor.⁵⁰ Zolpidem and zaleplon, two nonbenzodiazepines selective for the BZ₁ receptor, are discussed later in this chapter.

The heterogeneous nature of GABA_A receptors may explain some of the differences in clinical profile between benzodiazepines and barbiturates. In contrast to benzodiazepines, barbiturates increase the duration (but not the frequency) of opening of Cl⁻ channels activated by GABA and in high concentrations promote Cl⁻ conductance even in the absence of GABA. Variations of GABA_A receptor responses to benzodiazepines and barbiturates in specific CNS areas may be another factor contributing to their respective pharmacologic profiles.

The benzodiazepine-insensitive GABA_B receptors coupled to G proteins are associated with a decrease in Ca⁺⁺ conductance and an increase in K⁺ conductance and could be expected to cause pharmacologic effects when stimulated or antagonized. GABA_B receptors are less widely distributed than GABA_A receptors but are found in high concentrations in the cerebral cortex and cerebellum. Subtypes of GABA_B receptors may exist. GABA_B receptors have not been studied as extensively as GABA_A receptors, but they may participate in blood pressure regulation⁶¹ in addition to muscle activity and offer a potential site for therapeutic drug action.

The existence of subclasses of benzodiazepine receptors suggests that some agents, with specific activity for individual receptor subtypes, may be more selective than others in terms of their pharmacologic profile. Whether this selectivity results in significant clinical differences is an open question.¹⁴ Quazepam, a long-acting benzodiazepine hypnotic, produces sedation, but seems to have little ataxic effect and may cause less tolerance than other benzodiazepines. Autoradiographic studies have shown selective binding of quazepam to BZ₁ receptors,³¹ which may account for sedation with minimal muscle relaxant effects. Of all currently available benzodiazepines, only quazepam, one of its active metabolites (1-oxoquazepam), and possibly the antianxiety agent halazepam have selectivity for the BZ₁ receptor subtype. These benzodiazepines differ chemically from other benzodiazepines by having a trifluoroethyl substituent (see Table 13-1), which may be responsible for BZ₁ selectivity. Selective activity at the BZ₁ receptor has not been associated with any special clinical benefit of quazepam, however, compared with other benzodiazepines for treating insomnia.

Another potential effect of benzodiazepines is on the “peripheral-type” benzodiazepine receptor, now known as the mitochondrial translocator protein. These peripheral benzodiazepine binding sites, which can be pharmacologically differentiated from central BZ₁ and BZ₂ receptors, have been found not only in the periphery (kidney, lung), but also in the brain. In the CNS, they are most prevalent on glial cells. Their functions include cholesterol transport into mitochondria with the resulting increase in steroid synthesis. The activity of this transporter seems to have important effects in certain brain disorders.

Although the pharmacologic actions of benzodiazepines are closely tied to GABA receptors, numerous other neurotransmitters, including glycine, norepinephrine, and 5-hydroxytryptamine (5-HT), have been suggested to play a role in their action. An interaction between GABA and 5-HT has been shown experimentally with diazepam and tryptaminergic anxiolytics.³⁶ This finding is interesting in light of the mechanism of action of the nonsedating antianxiety agent buspirone (see later), a 5-HT_1A partial agonist.

Pharmacologic Effects

Benzodiazepines have clinically useful antianxiety, sedative-hypnotic, amnestic, anticonvulsant, and skeletal muscle relaxant properties. Benzodiazepines previously were thought to differ pharmacologically only in terms of their pharmacokinetics. Although differences in pharmacokinetic properties explain many of their clinical differences, certain benzodiazepines seem to have unique properties.¹⁷ Alprazolam has documented antidepressant and antipanic properties, and diazepam may be more selective as a skeletal muscle relaxant than other benzodiazepines. Diazepam is the only benzodiazepine approved for the treatment of skeletal muscle spasm and spasticity of CNS origin.

Absorption, Fate, and Excretion

The pharmacokinetics of individual benzodiazepines differ, and there is a wide range in speed of onset and duration of action among these compounds. Benzodiazepines frequently are classified according to their elimination half-life, as illustrated in Table 13-2; however, the elimination half-life of a given drug is only one factor affecting its clinical profile. The rates of drug absorption and tissue distribution and redistribution are often important factors in determining onset and duration of clinical effects after short-term administration. Additionally, there is a wide variation in drug half-lives among patients.

After oral administration, most benzodiazepines are rapidly absorbed and highly bound to plasma protein. Lorazepam, oxazepam, prazepam, and temazepam are more slowly absorbed. Peak blood concentrations are generally obtained in 1 to 3 hours. The lipid solubility of these compounds differs significantly, however, so that a highly lipid-soluble drug such as diazepam exerts its effect more rapidly, whereas lorazepam, which is less lipid-soluble, has a slower onset of action even after systemic absorption. Diazepam also accumulates in body fat because of its lipophilic properties, and it is slowly eliminated from these stores. This characteristic partially accounts for the prolonged half-life of diazepam, which can range from 1 to 4 days.

Many benzodiazepines are converted to pharmacologically active metabolites that have long half-lives (Figure 13-5). Clorazepate and prazepam are nearly completely converted (in the stomach and liver) to the long-acting metabolite desmethyldiazepam (nordazepam) before they enter the systemic circulation. Desmethyldiazepam is a metabolite of many other benzodiazepines, including chlordiazepoxide, diazepam, and halazepam. Flurazepam is also converted to active metabolites in its first pass through the liver. Generally, the products of phase I metabolism are eventually conjugated with glucuronic acid and inactivated and excreted in the urine and feces. Because the half-lives of the different active metabolites vary considerably, the overall duration of the pharmacologic effect of benzodiazepines also varies considerably. Oxazepam and lorazepam are not converted to active metabolites but are directly conjugated and excreted. These drugs are eliminated rapidly and may be especially useful in patients who have a deficiency in hepatic microsomal enzymes resulting from liver disease or other reasons.

FIGURE 13-5 Metabolism of benzodiazepines. Drugs available for clinical use appear in bold type. With the exception of the prodrugs clorazepate and prazepam, only the glucuronide conjugates are inactive.

Alprazolam and triazolam, containing a fused triazolo ring, undergo α-hydroxylation on the methyl group of the ring. This reaction is mediated through hepatic CYP3A4 isoenzymes, and the subsequent conversion to the glucuronide occurs rapidly in the case of triazolam and accounts for the short duration of action of the drug. Alprazolam and triazolam also undergo 4-hydroxylation of the benzodiazepine ring and then conjugation to the glucuronide. Midazolam, which contains a fused imidazo ring, is quickly metabolized in a similar manner. Midazolam has a rapid onset of action, a high metabolic clearance, a rapid rate of elimination, and a short duration of action. Termination of CNS activity is a result of peripheral redistribution and metabolic transformation. It is converted into several metabolites that have little pharmacologic activity; however, because of extensive first-pass metabolism, the α-hydroxy metabolite may contribute to the sedative effect when midazolam is given orally to children.

The poor oral bioavailability of triazolam, alprazolam, and midazolam of approximately 50% is believed to be due to CYP3A4 metabolism in the gut wall and hepatic first-pass metabolism. Triazolam’s availability is improved when administered sublinqually.³² Inhibition of CYP3A4 metabolism by coadministration of itraconazole, erythromycin, or grapefruit juice can significantly increase maximum blood concentrations and the area under the curves of these short-acting benzodiazepines.²⁷

Many benzodiazepines are biotransformed to long-acting metabolites. These metabolites, which accumulate with repeated administration, are the cause of lingering residual effects. An active metabolite of flurazepam and quazepam, N-desalkylflurazepam, which accounts for some of the activity of quazepam and nearly all the activity of flurazepam, has an elimination half-life of 50 to 100 hours. In sleep laboratory studies, it has been shown that flurazepam does not reach full effectiveness until the second or third consecutive night of intake. Quazepam decreases sleep latency and facilitates sleep maintenance after a single dose.

Temazepam has a half-life of about 13 hours, and only a very small amount of oxazepam is formed as a metabolite; estazolam has a similar half-life and forms a short-lived active metabolite. Triazolam, with a mean half-life of 2.9 hours, is converted to metabolites that, although active, are rapidly eliminated. Because of their short durations of action, temazepam and triazolam do not generally accumulate even with repeated nightly use. Triazolam is indicated for patients who have difficulty falling asleep but who stay asleep when sleep ensues.

Adverse Effects and Drug Interactions

Drowsiness is the most common side effect of benzodiazepines. The drowsiness may not be an unwanted reaction, but rather a therapeutic benefit in anxiety states that cause insomnia. Other signs and symptoms of dose-dependent CNS depression include ataxia, incoordination, dysarthria, confusion, apathy, muscle weakness, dizziness, and somnolence. Elderly individuals (>65 years old) seem to be particularly susceptible and individuals with a history of alcohol or barbiturate abuse seem to be particularly resistant to the gross CNS depressant properties of benzodiazepines.

Elderly and young patients occasionally respond to benzodiazepines with excitement rather than depression. Excitatory CNS effects may include an increased incidence of nightmares, hyperactivity, insomnia, irritability, agitation, and rage and hostility. Because these responses differ from what would be expected of a CNS depressant, they have been termed paradoxic reactions. A paradoxic decrease in seizure threshold, particularly in patients with grand mal epilepsy, has also been observed, even though diazepam is used in acute treatment of status epilepticus. These unusual occurrences of what seems to be a CNS excitatory action may be a disinhibitory effect similar to that observed with alcohol.

Benzodiazepines cause changes in normal sleep patterns. Patients seem to adapt quickly to the nonspecific CNS depression of benzodiazepines. Nonetheless, daytime sedation after a nighttime dose, referred to as “hangover,” is a common side effect, especially of long-acting benzodiazepines. This residual effect may be beneficial in some cases, but undesirable in others.

Adverse effects of benzodiazepines other than those referable to the CNS depressant actions are usually more irritating than life-threatening. Allergic reactions to benzodiazepines usually manifest as minor skin rashes. Because injectable formulations of diazepam contain propylene glycol and ethyl alcohol solvents, intramuscular and intravenous administration can cause local pain, phlebitis, and thrombosis. Phlebitis is more likely to occur if a vein in the hand or wrist is used and may be more common after repeated injections, especially in heavy smokers, elderly individuals, and women taking oral contraceptives. With the introduction of the water-soluble benzodiazepine midazolam, the occurrence of venous complications and pain at the injection site has diminished.

Tolerance and psychological dependence develop frequently with benzodiazepines, but true physical dependence is less common. Nevertheless, the abuse potential of benzodiazepines should not be ignored.⁵¹ Tolerance to the sedative-hypnotic effects of benzodiazepines is slower to develop with longer acting agents. In cases of physical dependence, the severity of withdrawal depends on the dose of the drug being used and the drug’s half-life. Rapid discontinuation of benzodiazepines, especially short-acting compounds, can lead to symptoms of withdrawal. Often these symptoms are nearly identical to the symptoms for which treatment was initiated, including anxiety, irritability, insomnia, and fatigue. The symptoms become more severe with high doses and prolonged treatment. Withdrawal can be minimized by reducing the dosage very gradually (≤10% per day over 10 to 14 days) or by the use of longer acting compounds. Withdrawal from lower doses is usually not life-threatening, and symptoms last no longer than 2 weeks. Withdrawal from high doses may be life-threatening because of accompanying convulsions.

Mechanisms involved in the development of tolerance are unknown, but the long-term administration of benzodiazepines to animals causes downregulation of benzodiazepine receptors,⁴⁰ which could be a contributing factor. Diazepam has been particularly popular as a drug of abuse. Because of the strong binding of diazepam to tissue constituents, it is not rapidly removed by dialysis or diuresis in patients with acute overdose. Flumazenil, a benzodiazepine antagonist (described later), can reverse benzodiazepine overdose. Flumazenil can precipitate withdrawal in benzodiazepine-dependent patients, however.

Some short-acting benzodiazepines are especially amnestic; triazolam also causes confusional states and delusions. Because of the prominence of these adverse CNS effects, the United States and several European countries have removed the 0.5 mg tablet form of triazolam from the market. The U.S. Food and Drug Administration (FDA) also approved labeling for triazolam that recommended use only for short-term (7 to 10 days) treatment of insomnia, emphasized the need to monitor patients for bizarre behavioral side effects, and set new limits on the maximum dosage. Triazolam is abused more frequently than either temazepam or flurazepam, probably because of its more rapid absorption.

Despite these problems, one of the major advantages of benzodiazepines compared with other sedatives is their high margin of safety. Death is rare in cases of overdose and is usually the result of a combination of drugs (especially alcohol) with benzodiazepines. The few deaths associated with the use of a benzodiazepine alone have primarily involved elderly patients, very young children, massive iatrogenic overdosing, or suicides.

Benzodiazepines cross the placental barrier. During the first trimester, long-term use of these drugs has been associated with increased fetal malformations, including cleft lip and cleft palate in humans. There is no clear estimate of the risk after single-dose use. All benzodiazepines are classified as pregnancy category D except triazolam, which is pregnancy category X. It is generally agreed that these drugs should be avoided during pregnancy.⁴³ The frequent use of benzodiazepines during late pregnancy may lead to withdrawal in the neonate. Large doses of benzodiazepines given to mothers during labor and delivery may result in respiratory depression, hypotonia, and hypothermia in neonates.

Drug interactions associated with anxiolytic and sedative drugs used in dentistry are listed in Table 13-3. The therapeutic index for benzodiazepines is normally so large that wide ranges of dosing recommendations and blood concentrations do not significantly affect their safety and efficacy. Plasma concentrations after a given dose may normally vary such that a minor shift in elimination from drug interactions is unlikely to result in an overdose. In healthy subjects taking no other medications, plasma concentrations 3 hours after a single 15 mg dose of diazepam have been reported to range from 20 µg/mL to 260 µg/mL.³⁸ A drug interaction that causes a 20% increase in diazepam plasma concentrations is unlikely to have significant toxicity. Most healthy patients can tolerate small variations in a drug’s absorption or metabolism that are caused by coadministration of another drug. Combining sedatives is problematic. The combination of ethanol with a benzodiazepine is an important source of serious toxicity.⁶³

TABLE 13-3 Adverse Drug Interactions: Anxiolytics and Sedative-Hypnotics

CNS, Central nervous system.

Rifampin induces metabolic enzymes in the gut and liver responsible for the metabolism of diazepam, midazolam, and triazolam. A 96% reduction in the bioavailability of midazolam has been reported.² Triazolam is so rapidly and effectively metabolized in the gut that peak plasma concentrations are only 12% of normal.⁶⁸ This interaction is one of the most pronounced alterations in drug kinetics ever reported. The almost complete loss of triazolam bioavailability and subsequent efficacy is quite significant and warrants use of an alternative anxiolytic, such as oral oxazepam, nitrous oxide inhalation, or an intravenous agent. The anticonvulsant carbamazepine can also induce hepatic enzymes for the oxidative metabolism of benzodiazepines such as alprazolam, triazolam, and midazolam.³ Decreased benzodiazepine plasma concentrations and greatly reduced sedative effects after oral administration of these agents may occur. This interaction may be important in medicine because of loss of seizure control. A loss of sedative efficacy in dentistry may also occur. Benzodiazepines that are metabolized solely through glucuronidation, such as oxazepam, are suitable alternative agents for sedation in these situations.

The Ca⁺⁺ channel blockers verapamil and diltiazem have been shown to inhibit the CYP3A isozymes required for the metabolism of triazolam and midazolam. In controlled clinical trials, a 2-day regimen of these drugs decreased the metabolism and increased the bioavailability of midazolam and triazolam administered orally. Peak blood concentrations were increased twofold to threefold and were associated with increased sedation and performance deficits.¹ Avoidance of this combination is recommended, particularly in elderly patients known to be sensitive to benzodiazepines.

Cimetidine also inhibits the oxidative metabolism of certain benzodiazepines, such as triazolam and alprazolam. Half-life increases of 30% to 63% have been reported.¹⁸ Metabolism of diazepam may also be delayed. An increased and prolonged level of sedation after oral administration may occur because of the decreased first-pass metabolism.⁵² Benzodiazepines that are metabolized directly to the glucuronide conjugate (e.g., oxazepam) are not affected. Similarly, the antimicrobials erythromycin and clarithromycin and the azole antifungals ketoconazole and itraconazole are potential inhibitors of the hepatic isozymes required for oxidative metabolism of these benzodiazepines. By decreasing the first-pass effect and improving bioavailability, triazolam blood concentrations may increase threefold.⁶⁷ The antiviral agents indinavir, nelfinavir, and ritonavir inhibit hepatic oxidative enzymes required for metabolism of many benzodiazepines. These significant pharmacokinetic drug interactions could potentially cause oversedation and respiratory depression.

Antagonists

Benzodiazepine antagonists are important therapeutic compounds that have the potential to reverse the effects of benzodiazepines. They have no intrinsic activity of their own but do not reverse constitutive benzodiazepine receptor activity. Flumazenil (Figure 13-6) is currently the only benzodiazepine receptor antagonist approved by the FDA.

FIGURE 13-6 Structural formula of flumazenil.

Flumazenil has clinical application in managing benzodiazepine overdose and in hastening recovery from benzodiazepine sedation or anesthesia after diagnostic procedures or minor surgery. Although certain precautions must be observed, flumazenil may allow for a shorter monitoring period after surgery and earlier discharge of the patient.²⁰ Flumazenil has been used successfully in reversing benzodiazepine-induced coma, but whether it should be given routinely to comatose patients when the cause of the coma is unknown is unclear. The routine use of flumazenil is not recommended in cases of mixed drug overdose, airway obstruction, or seizure disorders. Flumazenil may increase the risk of cardiac arrhythmias and seizures in patients who have overdosed with tricyclic antidepressants.²² Ventricular arrhythmias have also been precipitated by flumazenil in patients with chloral hydrate overdose.⁵⁵

Flumazenil administered intravenously can generally reverse benzodiazepine-induced sedation in 1 to 2 minutes. Reversal of benzodiazepine sedation by flumazenil may last for several hours. In a study in which patients were sedated with midazolam before dental extraction, flumazenil significantly improved patient assessment regarding state of alertness compared with placebo controls (Figure 13-7) only for the first 30 minutes.⁸ The duration of action of flumazenil (elimination half-life of 45 to 75 minutes) is likely to be shorter than that of a benzodiazepine agonist. Other studies have also noted that the duration of action of flumazenil is shorter than that of midazolam and that sedation and respiratory depression may recur.²⁰ Flumazenil is not a substitute for careful postoperative monitoring.

FIGURE 13-7 Reversal of midazolam sedation by flumazenil in patients undergoing a surgical dental extraction. Flumazenil or placebo was administered after intravenous midazolam and dental extraction. Differences between flumazenil and control groups were significant at the P < .05 level for the 5-, 15-, and 30-minute time periods. The dashed line represents the flumazenil group; the solid line represents the midazolam alone.

(Adapted from Clark MS, Lindenmuth JE, Jafek BW, et al: Reversal of central benzodiazepine effects by intravenous flumazenil, Anesth Prog 38:12-16, 1991.)

Another cautionary note is the possibility of flumazenil precipitating withdrawal in patients who are dependent on the benzodiazepines. Signs of benzodiazepine withdrawal include flushes, agitation, tremor, and seizures. Resedation with a benzodiazepine or barbiturate may be required in these circumstances. Although some studies suggest the amnesia from benzodiazepines is reversed by flumazenil, this is not consistently observed.⁹

General Therapeutic Uses

Not everyone requires pharmacotherapy for anxiety, fear, and apprehension; anxious states are often brought on by a series of events that eventually pass, allowing the anxiety to subside. Pharmacotherapy is indicated only when anxiety becomes chronic, or when it interferes with the individual’s functioning. Benzodiazepines and other antianxiety agents are not curative; they merely treat the symptoms of anxiety. The patient then copes more effectively with the situation or responds more favorably to psychotherapy or other pharmacotherapy.

Approximately 35% of patients with a generalized anxiety disorder show marked improvement with benzodiazepines, 40% are moderately improved, and 25% remain unresponsive.¹⁵ These antianxiety agents are useful in the treatment of acute anxiety resulting from transient stress that is environmental, physical, or psychological in origin. For the treatment of long-standing anxiety, benzodiazepines ideally should be used only with appropriate psychotherapy. Sometimes benzodiazepines are prescribed inappropriately and with too little supervision. Despite concerns about the abuse potential of benzodiazepines, patients who have no prior history of drug abuse are unlikely to be at risk. Table 13-4 lists benzodiazepines and other drugs used for the management of acute anxiety.

TABLE 13-4 Preparations for Treatment of Anxiety