interfering with normal locomotion and can decrease rigidity in patients with cerebral palsy. In contrast to effects in animals, there is only a limited selectivity in human beings. Clonazepam in nonsedative doses does cause muscle relaxation, but diazepam and most other benzodiazepines do not. Tolerance occurs to the muscle relaxant and ataxic effects of these drugs.

Experimentally, benzodiazepines inhibit some types of seizure activity. Clonazepam, nitrazepam, and nordazepam have more selective anticonvulsant activity than most other benzodiazepines. Benzodiazepines also suppress ethanol-withdrawal seizures in human beings. However, the development of tolerance to the anticonvulsant effects has limited the usefulness of benzodiazepines in the treatment of recurrent seizure disorders (see Chapter 19).

Only transient analgesia is apparent in humans after intravenous administration of benzodiazepines. Such effects actually may involve the production of amnesia. Unlike barbiturates, benzodiazepines do not cause hyperalgesia.

Effects on the Electroencephalogram and Sleep Stages

The effects of benzodiazepines on the waking electroencephalogram (EEG) resemble those of other sedative-hypnotic drugs. Alpha activity is decreased, but there is an increase in low-voltage fast activity. Tolerance occurs to these effects.

Most benzodiazepines decrease sleep latency, especially when first used, and diminish the number of awakenings and the time spent in stage 0 (a stage of wakefulness). Time in stage 1 (descending drowsiness) usually is decreased, and there is a prominent decrease in the time spent in slow-wave sleep (stages 3 and 4). Most benzodiazepines increase the time from onset of spindle sleep to the first burst of rapid-eye-movement (REM) sleep. The time spent in REM sleep usually is shortened, but the number of cycles of REM sleep cycles usually is increased, mostly late in the sleep time. Zolpidem and zaleplon suppress REM sleep to a lesser extent and thus may be superior to benzodiazepines for use as hypnotics.

Benzodiazepine administration typically increases total sleep time, largely because of increased time spent in stage 2 (the major fraction of non-REM sleep). The effect is greatest in subjects with the shortest baseline total sleep time. Despite the increased number of REM cycles, the number of shifts to lighter sleep stages (1 and 0) and the amount of body movement are diminished. Nocturnal peaks in the secretion of growth hormone, prolactin, and luteinizing hormone are not affected. During chronic nocturnal use of benzodiazepines, the effects on the various stages of sleep usually decline within a few nights. With discontinuation of drug, the pattern of drug-induced changes in sleep parameters may "rebound," with an increase in the amount and density of REM sleep. If the dosage has not been excessive, patients usually will note only a shortening of sleep time rather than an exacerbation of insomnia.

Benzodiazepine use usually imparts a sense of deep or refreshing sleep. It is uncertain to which effect on sleep parameters this feeling can be attributed. As a result, variations in the phar-macokinetic properties of individual benzodiazepines appear to be much more important determinants of their effects on sleep than are any potential differences in their pharmacodynamic properties.

Molecular Targets for Benzodiazepine Actions in the CNS Benzodiazepines likely exert most of their effects by interacting with inhibitory neurotransmitter receptors directly activated by GABA. Benzodiazepines act at GABAa (ionotropic) receptors (but not at GABAb [metabotropic] receptors [GPCRs]) by binding to a specific site that is distinct from that of GABA binding. Unlike barbiturates, benzodiazepines do not activate GABAA receptors directly but rather require GABA to express their effects; i.e., they only modulate the effects of GABA. Benzodiazepines and related compounds can act as agonists, antagonists, or inverse agonists at the benzodiazepine-binding site on GABAA receptors. Agonists at the benzodiazepine-binding site shift the GABA concentration-response curve to the left, increasing the amount of chloride current generated by GABAA-receptor activation; inverse agonists shift the curve to the right, reducing the effect of given concentration of GABA. Both these effects are blocked by antagonists at the benzodiazepine-bind-ing site. A pure antagonist (e.g., flumazenil) acting alone at this binding site does not affect GABAA-receptor function but can reverse the effects of high doses of benzodiazepines. The behavioral and electrophysiological effects of benzodiazepines also can be reduced or prevented by prior treatment with antagonists at the GABA-binding site (e.g., bicuculline).

GABAa Receptor-Mediated Electrical Events: In Vivo Properties

The remarkable safety of the benzodiazepines is likely related to the fact that their effects in vivo depend on the presynaptic release of GABA; in the absence of GABA, benzodiazepines have no effects on GABAA receptor function. Although barbiturates also enhance the effects of GABA at low concentrations, they directly activate GABA receptors at higher concentrations, which can lead to profound CNS depression (see below). Further, the behavioral and sedative effects of benzodiazepines can be ascribed in part to potentiation of GABA-ergic pathways that serve to regulate the firing of neurons containing various monoamines (see Chapter 12). These neurons are known to promote behavioral arousal and are important mediators of the inhibitory effects of fear and punishment on behavior. Finally, inhibitory effects on muscular hypertonia or the spread of seizure activity can be rationalized by potentiation of inhibitory GABA-ergic circuits at various levels of the neuraxis.

Molecular Basis for Benzodiazepine Regulation of GABAa Receptor-Mediated Electrical Events

The enhancement of GABA-induced chloride currents by benzodiazepines results primarily from an increase in the frequency of bursts of chloride channel opening produced by submaximal amounts of GABA. Inhibitory synaptic transmission measured after stimulation of afferent fibers is potentiated by benzodiazepines at therapeutically relevant concentrations. Measurements of GABAa receptor-mediated currents indicate that benzodiazepines shift the GABA concentration-response curve to the left without increasing the maximum current evoked with GABA, consistent with a model in which benzodiazepines exert their major actions by increasing the gain of inhibitory neurotransmission mediated by GABAA receptors. Some data are difficult to reconcile with the hypothesis that actions at GABAa receptors mediate all effects of benzodiazepines. Low concentrations of benzodiazepines that are not blocked by bicuculline or picrotoxin induce depressant effects on hippocampal neurons; the induction of sleep in rats by benzodiazepines also is insensitive to bicuculline or picrotoxin but is prevented by flumazenil. At higher (hypnotic/amnesic) concentrations, actions of the benzodiazepines may involve other mechanisms, including inhibition of the uptake of adenosine and the resulting potentiation of its actions as a neuronal depressant, as well as the GABA-independent inhibition of Ca2+ currents, Ca2+-dependent neurotransmitter release, and tetrodotoxin-sensitive Na+ channels.

The macromolecular complex containing GABA-regulated chloride channels also may be a site of action of general anesthetics, ethanol, inhaled drugs of abuse, and certain metabolites of endogenous steroids.

RESPIRATION Hypnotic doses of benzodiazepines are without effect on respiration in normal adult subjects, but special care must be taken in the treatment of children and individuals with impaired hepatic function (e.g., alcoholics). At higher doses, such as those used for preanesthetic medication or for endoscopy, benzodiazepines slightly depress alveolar ventilation and cause respiratory acidosis as the result of a decrease in hypoxic rather than hypercapnic drive; these effects are exaggerated in patients with chronic obstructive pulmonary disease (COPD), and alveolar hypoxia and/or CO2 narcosis may result. These drugs can cause apnea during anesthesia or when given with opioids. Patients severely intoxicated with benzodiazepines only require respiratory assistance when they also have ingested another CNS-depressant drug, most commonly ethanol.

In contrast, hypnotic doses of benzodiazepines may worsen sleep-related breathing disorders by adversely affecting control of the upper airway muscles or by decreasing the ventilatory response to CO2. The latter effect may cause hypoventilation and hypoxemia in some patients with severe COPD, although benzodiazepines may improve sleep and sleep structure in some instances. In patients with obstructive sleep apnea (OSA), hypnotic doses of benzodiazepines may exaggerate the impact of apneic episodes on alveolar hypoxia, pulmonary hypertension, and cardiac ventricular load. Caution should be exercised with patients who snore regularly: partial airway obstruction may be converted to OSA under the influence of these drugs.

CARDIOVASCULAR SYSTEM The cardiovascular effects of benzodiazepines are minor in normal subjects except in severe intoxication. In preanesthetic doses, all benzodiazepines decrease blood pressure and increase heart rate.

GI TRACT Despite anecdotal reports that benzodiazepines improve a variety of "anxiety-related" GI disorders, there is a paucity of evidence. Diazepam markedly decreases nocturnal gastric acid secretion in human beings, but other agents are considerably more effective in acid-peptic disorders (see Chapter 36).

ABSORPTION, FATE, AND EXCRETION The physicochemical and pharmacokinetic properties of the benzodiazepines affect their clinical utility. All have high lipid-water distribution coefficients in the nonionized form; nevertheless, lipophilicity varies more than 50-fold according to the polarity and electronegativity of various substituents.

All benzodiazepines are absorbed completely, with the exception of clorazepate; this drug is decarboxylated rapidly in gastric juice to W-desmethyldiazepam (nordazepam), which subsequently is absorbed completely. Some benzodiazepines (e.g.,prazepam and flurazepam) reach the systemic circulation only in the form of active metabolites.

Drugs active at the benzodiazepine receptor may be divided into four categories based on their elimination half-lives: (1) ultrashort acting; (2) short-acting (t1/2 <6 hours): triazolam, the non-benzodiazepine zolpidem (t1/2 ~2 hours), and zopiclone (t1/2 = 5-6 hours); (3) intermediate-acting (t1/2 = 6-24 hours): estazolam and temazepam; and (4) long-acting (t1/2 >24 hours): flurazepam, diazepam, and quazepam.

The extent of binding of benzodiazepines and their metabolites to plasma proteins correlates with lipid solubility and ranges from -70% (alprazolam) to nearly 99% (diazepam). The concentration in the cerebrospinal fluid is approximately equal to the concentration of free drug in plasma. There is rapid uptake of benzodiazepines into the brain and other highly perfused organs after intravenous administration (or oral administration of a rapidly absorbed compound), followed by redistribution into tissues that are less well perfused (e.g., muscle and fat). Redistribution is most rapid for drugs with the highest lipid solubility. In the regimens used for nighttime sedation, the rate of redistribution sometimes can have a greater influence than the rate of biotransformation on the duration of CNS effects. Redistribution kinetics of lipophilic benzodiazepines (e.g., diazepam) is complicated by enterohepatic circulation. The volumes of distribution of the benzodiazepines are large and in many cases are increased in elderly patients. These drugs cross the placental barrier and are secreted into breast milk.

The benzodiazepines are metabolized extensively by CYPs, particularly CYP 3A4 and 2C19. Some benzodiazepines (e.g., oxazepam) are conjugated directly. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, and grapefruit juice are inhibitors of CYP 3A4 and can affect the metabolism of benzodiazepines. Because active metabolites of some benzodi-azepines are biotransformed more slowly than are the parent compounds, the duration of action of many benzodiazepines bears little relationship to the t1/2 of elimination of the drug that has been administered (e.g., the t1/2 of flurazepam in plasma is -2 hours, but that of a major active metabolite W-desalkylflurazepam is -50 hours). Conversely, the rate of biotransformation of agents that are inactivated by the initial reaction is an important determinant of their duration of action; these agents include oxazepam, lorazepam, temazepam, triazolam, and midazolam. Metabolism of the benzodiazepines occurs in three major stages. In general terms, the substituent at position 1 (or 2) of the diazepine ring is rapidly removed or modified to form metabolites that frequently are biologically active; then position 3 is more slowly hydroxylated, yielding derivatives that are generally active; finally the 3-OH compounds are conjugated with glucuronic acid to inactive products.

Because benzodiazepines do not significantly induce the synthesis of hepatic CYPs, chronic benzodiazepine administration usually does not result in the accelerated metabolism of benzodi-azepines or other substances. Cimetidine and oral contraceptives inhibit W-dealkylation and 3-hydroxylation of benzodiazepines, as do ethanol, isoniazid, and phenytoin to a lesser degree. These reactions usually are reduced to a greater extent in elderly patients and in patients with chronic liver disease than are those involving conjugation.

An ideal hypnotic agent would have a rapid onset of action when taken at bedtime, a sufficiently sustained action to facilitate sleep throughout the night, and no residual action by the following morning. Triazolam theoretically fits this description most closely. Because of the slow rate of elimination of desalkylflurazepam, flurazepam (or quazepam) might seem to be unsuitable for this purpose. In practice, there appear to be some disadvantages to the use of agents that have a relatively rapid rate of disappearance, including the early-morning insomnia that is experienced by some patients and a greater likelihood of rebound insomnia on drug discontinuation. With careful selection of dosage, flurazepam and other benzodiazepines with slower rates of elimination than triazolam can be used effectively.

Therapeutic Uses

The therapeutic uses and routes of administration of individual benzodiazepines marketed in the U.S. are summarized in Table 16-2. Note that most benzodiazepines can be used interchangeably. Benzodiazepines used as anticonvulsants have a long t1/2, and rapid entry into the brain is required for efficacy in treatment of status epilepticus. A short elimination t1/2 is desirable for hypnotics,

Names, Routes of Administration, and Therapeutic Uses of Benzodiazepines


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