CHAPTER 45
BENZODIAZEPINES
James R. Roberts, M.D.
John A. Tafuri, M.D.
The first commercially marketed benzodiazepine was accidentally synthesized in 1955 by Roche Laboratories in Nutley, New Jersey, but the scope of its pharmacologic properties and its clinical applications were not appreciated until 1957. That drug, chlordiazepoxide (Librium), was noted to possess clinically effective sedative, hypnotic, and anticonvulsant properties. When it became available in 1960 it ushered in an era of widespread benzodiazepine use that persists today. Diazepam, perhaps the best known and most commercially successful of all the benzodiazepines, was synthesized in 1959 and marketed as Valium in 1963. Since that time, over 3000 benzodiazepines have been developed, over 120 have been tested for biologic activity, and 28 are currently in clinical use throughout the world. Thirteen benzodiazepines are approved for use in the United States (Table 45-1). Benzodiazepines have varying sedative, hypnotic, amnestic, anxiolytic, anticonvulsant, and muscle relaxant properties. Alprazolam, a newer benzodiazepine, may also have significant antidepressant activity. Individual drugs are FDA approved and marketed for specific indications on the basis of these characteristics, although current evidence indicates that all benzodiazepines are effective for the treatment of anxiety and insomnia.
Since their introduction, the benzodiazepines have enjoyed a meteoric rise in popularity and have largely replaced other sedative-hypnotics. Their extraordinary acceptance in clinical medicine has been based on their safety, efficacy, minimal side effects, low addiction potential, and the medical and public demand for sedative and anxiolytic agents. It has been estimated that 500 million people worldwide have taken benzodiazepines during the last 25 years.7 The prevalence of benzodiazepine use in the United States in 1979 and 1981 was estimated to be 11 and 13 per cent, respectively. However, long-term use (greater than 1 year) occurs in only 1 to 2 per cent of adults in the general population.9-l9
Worldwide sales of benzodiazepines exceed 1 billion dollars per year. Annual prescriptions for benzodiazepines in the United States peaked in 1972 at 77 million, but use has subsequently declined by almost one third, largely because of widespread negative publicity and concern over their potential misuse, abuse, and long-term side effects.1 Despite these concerns, benzodiazepines remain extremely popular, accounting for 5 of the 50 most frequently prescribed drugs in the United States in 1987. Xanax (alprazolam) is currently the most widely used benzodiazepine and is the fourth most prescribed drug in the United States. Halcion (triazolam), Valium (diazepam), and Ativan (lorazepam) are also frequently prescribed, ranking 18th, 19th, and 34th, respectively. (Fig. 45-1).
Because of their widespread availability, benzodiazepines are also among the most frequently misused drugs. Many investigators, however, emphasize that dependence and abuse by the general population are largely overstated by the media and are minor compared with alcohol, cocaine, or opiate abuse.
It has been estimated that 40 to 50 per cent of drug abusers also use benzodiazepines. As a class, benzodiazepines are not powerful euphoriants and are therefore not frequently abused primarily. Secondary drug abuse is common, however, usually in the form of self-medication to decrease the adverse side effects of stimulants or hallucinogens, to ameliorate the unpleasant symptoms of withdrawal from more highly addictive substances, or to substitute for the drug of primary dependence when it is not available.
Diazepam is the fourth most common drug involved in drug-related visits to the emergency department, mainly as a consequence of intentional overdose. Since the selection of a drug for overdose is highly influenced by its availability, it is not surprising that benzodiazepines are commonly taken in overdse. Data from the National Data Collection System of the American Association of Poison Control Centers System showed that benzodiazepines had the highest number of toxic exposures in patients over 17 years of age, both as a single agent and in combination with other drugs and alcohol. In contrast to the sedative-hypnotic drugs they replaced, benzodiazepines are less addictive, possess less potential for abuse, and are remarkably safe.
STRUCTURE
The benzodiazepines are organic bases (Figs. 45-1 and 45-2). All benzodiazepines share a structure composed of a six-membered benzene ring which is attached to a seven-membered diazepine ring with a benzene ring substituted at the number five position. Specific benzodiazepines are formed by varying the substitutions at the R,1 R2, R3, R4, R7, and R’2 positions. Despite the myriad benzodiazepine compounds available, all derivatives can be expected to have similar qualitative pharmacologic and clinical effects when adjusted for differences in potency.However, various compounds have significant differences in onset and duration of action and metabolism, which theoretically makes them more suitable for certain indications.
PHARMACOKINETICS
Absorption
Although some benzodiazepines form water-soluble salts at acidic pH, at physiologic pH all are moderately to highly lipid-soluble molecules that are rapidly and completely absorbed from the proximal small bowel (Table 45-2). Significant differences in lipid solubility affect the rate of gastrointestinal absorption and subsequent distribution. Highly lipophilic benzodiazepines (diazepam, flurazepam, midazolam) are rapidly absorbed, and less lipophilic compounds (oxazepam, temazepam) are more slowly absorbed.
The parent forms of two benzodiazepines, clorazepate and prazepam, do not reach the circulation of the system in clinically significant amounts. The active metabolite is formed in the gastrointestinal tract or liver prior to systemic absorption and appears in the serum as desmethyldiazepam. Desmethyldiazepam is rapidly formed from clorazepate after acid hydrolysis within the stomach and is slowly formed from prazepam after first-pass metabolism in the liver.
The rate of oral absorption may be influenced by several factors other than lipid solubility. Absorption is enhanced by taking the drugs on an empty stomach or by the coingestion of alcohol, and is slowed by the coadministration of food35, 36 or aluminum- or magnesium hydroxide-containing antacids. Absorption also may be altered by manipulating the pharmaceutical preparation, such as slow-release diazepam (Valium CR).
Benzodiazepine absorption from intramuscular (IM) injection is variable. Lorazepam and midazolam are the only benzodiazepines adequately 
absorbed following intramuscular administration. Chlordiazepoxide absorption is particularly slow and erratic, and plasma concentration may not peak for 6 to 12 hours. Diazepam is inconsistently absorbed after intramuscular administration. Serum levels of both chlordiazepoxide and diazepam are more rapidly achieved by the oral route than by intramuscular administration.
Following absorption, benzodiazepines are more than 70 per cent protein bound, but the degree of protein binding varies significantly. Protein binding is greatest with diazepam (99 per cent) and least with alprazolam (70 per cent). Only unbound drug is available to cross the blood-brain barrier and interact at CNS receptors. Drug concentrations in the CSF are generally 2 to 4 per cent of plasma levels, or roughly parallel to the concentration of free drug in the plasma. Increased protein binding decreases the concentration of free drug in equilibrium with sites of action and elimination, causing a decrease in intensity of effects and slowing the drug’s rate of elimination. Hypoalbuminemia increases the concentration of active drug and may increase clinical effects. There is little or no glomerular filtration of protein-bound benzodiazepines.
Distribution
Following gastrointestinal absorption or intravenous administration, benzodiazepines are rapidly distributed to highly perfused organs, particularly the central nervous system. All benzodiazepines are widely distributed, and tissue concentrations within the brain, liver, and spleen typically exceed that of the serum. The volume of distribution of various benzodiazepines ranges from 0.3 to 5.5 liters per kg. Benzodiazepines are lipophilic and quickly penetrate the blood-brain barrier via passive diffusion to reach their sites of action within the CNS. Since the penetration into the CNS is rapid, the onset of clinical effects is limited more by the rate of systemic absorption of individual compounds rather than by their rate of distribution.
Pharmacologically, the serum and CNS are termed the “central compartment” of drug distribution. Following initial distribution within this compartment, benzodiazepines are slowly redistributed to more poorly perfused sites (such as adipose tissue and muscle), collectively termed the “peripheral compartment.” Highly lipid-soluble benzodiazepines will undergo more rapid and tensive redistribution.
Duration of Action
Benzodiazepine activity is terminated by at least three mechanisms. Two of these are pharmacokinetic and the third involves a functional change of the benzodiazepine receptor. The rate of redistribution of drug from the central compartment (CNS) to the peripheral compartment is the most important determinant of duration of clinical effect. The second mechanism responsible for the duration of action is hepatic metabolism and renal excretion. The third mechanism is acute tolerance or acute adaptation, terms used to describe the clinical observation that benzodiazepine receptors appear to become less sensitive to drug effects with continued exposure.
Redistribution
It may seem paradoxic that a drug’s measured plasma half-life does not predict its duration of action, but such is the case with benzodiazepines. The duration of action of benzodiazepines is a 
function of the CNS elimination half-life. The most lipophilic benzodiazepines have the shortest duration of action in the CNS because they are rapidly and extensively redistributed. They have the longest calculated plasma half-lives following redistribution because they remain in clinically inactive peripheral storage compartments (fat, muscle) for prolonged periods of time. Drugs that are less lipophilic have shorter plasma half-lives yet a longer duration of action, because redistribution from the CNS to the peripheral compartment is more limited and occurs more slowlv. The rapid egress of highly lipid-soluble benzodiazepines from the central compartment to the peripheral compartment results in a duration of action of less than their respective plasma half-lives might suggest. This is illustrated by comparing the clinical anticonvulsant activity of lorazepam and diazepam. Lorazepam (half-life: 10 to 20 hours), a drug of relatively low lipophilicity, has more prolonged antiseizure activity than the highly lipophilic diazepam (half life: 20 to 70 hours). The benzodiazepine midazolam is extremely lipophilic and also rapidly biotransformed by the liver. It has an extremely short duration of action because both redistribution and metabolism contribute significantly to the termination of clinical effects and plasma clearance.(Table 45-3).
Metabolism
Hepatic biotransformation via oxidation or conjugation accounts for virtually all benzodiazepine metabolism and clearance in humans (Fig. 45-3). Hepatic metabolism can be divided into two phases: Phase I metabolism consists of oxidative pathways, either aliphatic hydroxylation by the cytochrome P450 enzyme system or N-dealkylation. Phase I biotransformation produces pharmacologically active metabolites or intermediates. Phase II metabolism consists of hepatic conjugation of hydroxyl and amino groups to form inactive glucuronides, sulfates, and acetylated compounds that are rapidly excreted in the urine. Hepatic metabolism differs among benzodiazepines, and compounds may undergo both Phase I and Phase II metabolism (diazepam, chlordiazepoxide, flurazepam, halazepam, clorazepate, prazepam, triazolam, alprazolam, midazolam, and clonazepam) or only Phase II metabolism (lorazepam, oxazepam, and temazepam).
Phase I oxidation is termed a “susceptible pathway” since the rate of activity may be altered by several factors. Phase I metabolism is inhibited or decreased by increasing age, pre-existing liver disease (including cirrhosis or hepatitis), or the coadministration of estrogens, isoniazid, disulfiram, phenytoin, alcohol, or cimetidine. Phase I metabolism is stimulated or induced by cigarette smoking37 or by the chronic administration of substances that induce the cytochrome P-450 system, such as phenobarbital and alcohol. Benzodiazepines are very weak inducers of hepatic microsomal 61 systems and do not significantly alter their own metabolism.
Phase II conjugation is considered a “nonsusceptible pathway” since those factors that alter benzodiazepine oxidation usually have little or no effect on conjugation. Agents undergoing Phase II metabolism may be preferred in patients with liver impairment, in the elderly, or in the presence of drugs that affect Phase I hepatic metabolism. Since the therapeutic indices of all benzodiazepines are very large, it is unclear whether the effects of higher blood concentrations resulting from decreased metabolism are clinically significant.
Several benzodiazepines are biotransformed to active metabolites that contribute to their pharmacologic activity. In some cases the metabolites possess half-lives that far exceed those of the parent compound. In such instances, persistent clinical effects are more likely a consequence of the metabolic products than of the parent compound itself. Flurazepam has a plasma metabolic half-life of 1 to 4 hours, but its pharmacologically active metabolite , desalkylflurazepam , has a serum half-life of 45 to 300 hours. The primary metabolite of diazepam, desmethyldiazepam, is also pharmacologically active, and its half-life exceeds that of diazepam. Theoretically, benzodiazepines with long elimination half-lives or active metabolites may accumulate in the body with repeated dosing, resulting in excess sedation or significant performance-impairing effects. However, significant adaptation or tolerance usually offsets the effect of increasing serum level, and cumulative toxicity is uncommon.
Tolerance
Tolerance develops rapidly to the sedative but not the anxiolytic effects of benzodiazepines. Tolerance to the anticonvulsant and muscle relaxation properties of benzodiazepines has not been extensively studied. It is speculated that tolerance is a result of a biologic adaptation of the benzodiazepine receptor complex to constant concentrations of drug. Thus, even if the benzodiazepine concentration within the CNS is constant the sedative effects are decreased with time. Some patients can tolerate the equivalent of 400 to 500 mg of diazepam per day yet still be awake and functional. Other factors that may influence tolerance include the “drug experience” or “drug sophistication” phenomenon that occurs in patients familiar with pharmacologic actions of the medication. It appears that the tolerance phenomenon occurs with all benzodiazepines.
MECHANISM OF ACTION
Benzodiazepines appear to produce their sedative, hypnotic, anxiolytic, and anticonvulsant actions by binding to specific pharmacologic receptors in the central nervous system (Fig. 45-4). These high-affinity binding sites are stereospecific for all benzodiazepines and do not bind narcotics, barbiturates, or other sedative hypnotics. Benzodiazepine receptors are most concentrated in the cerebral cortex but are also found in the cerebellum, amygdala, hippocampus, hypothalamus, and spinal cord. Receptors have also been identified outside the CNS, although peripheral receptors do not appear to have significant physiologic effects. The molecular receptor for the benzodiazepine molecule is a glycoprotein located on the lipid membranes of both neural and glial cells. It is speculated that there are at least two classes of benzodiazepine receptor believed to mediate different specific effects. Type I receptors predominate in the cerebellar cortex, and both type I and type II receptors are found in the cerebral cortex and hippocampus. Type I receptors are postulated to mediate anxiolytic effects, and type II receptors mediate the sedative and other actions of benzodiazepines. No endogenous ligand or neurotransmitter for these receptors has been identified. Benzodiazepine receptors are not influenced by norepinephrine acetylcholine, dopamine, histamine, or serotonin.
DRUG INTERACTION
As a group, the benzodiazepines have little or no propensity to sign)ficantly augment or inhibit the activity of most other drugs. This lack of interaction is one reason why benzodiazepines have all but replaced barbiturates as the standard sedative-hypnotics. Probablv the most sign)ficant drug interaction occurs in the presence of alcohol or other CNS depressants and accounts for the ability of benzodiazepines to enhance the sedation produced by these substances.
The specific mechanism of benzodiazepine interaction with ethanol is complex and not completely understood. The combination is generally believed to produce additive effects rather than actual potentiation as defined in the true pharmacologic sense. The CNS effects are extremely variable and have not been quantified, but the ability of benzodiazepines to enhance the detrimental effects of ethanol on psychomotor skills (e.g., automobile driving) is well documented. Alcohol induced liver injury tends to decrease the metabolism of benzodiazepines, but the clinical effect depends on the specific benzodiazepine and is difficult to predict. For example, in alcoholics, the elimination half-life of chlordiazepoxide is longer and the clearance slower, but clearance of the major active metabolite, desmethyldiazepoxide, is increased.
A number of other drugs have been reported to have a possible interaction with various benzodiazepines, but many of these interactions are poorly studied and remain theoretical, unconfirmed, or without clinical significance.