Benzodiazepines

The basic chemical structure of the benzodiazepines consists of a benzene ring coupled to a seven-member heterocyclic structure containing two nitrogens (diazepine) at positions 1 and 4. Of the 2,000 benzodiazepines that have been synthesized, approximately 15 clinically useful compounds are on the market in the United States.

Benzodiazepines are a group of medicines which are sometimes used to treat anxiety.

Benzodiazepines also possess muscle relaxant activity. Their pharmacology is discussed in Chapter 30. Diazepam (Valium) has been used for control of flexor and extensor spasms, spinal spasticity, and multiple sclerosis. The muscle relaxant effect of the benzodiazepines may be mediated by an action on the primary afferents in the spinal cord, resulting in an increased level of presynaptic inhibition of muscle tone. Polysynaptic reflexes are inhibited.The most troublesome side effect is drowsiness, which is dose dependent. Tolerance to both the therapeutic effects and the side effects develops.

The benzodiazepines constitute the most commonly used group of anxiolytics and sedative–hypnotics. Since the first member of this group, chlordiazepoxide, was introduced, many congeners have been marketed. Most of these drugs possess anxiolytic, sedative–hypnotic, and anticonvulsant properties. Thus, the clinical indications for specific benzodiazepines are not absolute. and their uses overlaps considerably.

For details of the chemistry and SARs of the BZDs, see thediscussion of anxiolytic sedative–hypnotic drugs. Amongthe current clinically useful drugs, the structural features associatedwith anticonvulsant activity are identical with thoseassociated with anxiolytic sedative–hypnotic activity.

The benzodiazepines bind with high affinity to specific macromolecules within the central nervous system. These benzodiazepine-binding sites (receptors) are closely associated with the receptors for γ-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the mammalian brain. Benzodiazepines potentiate GABAergic neurotransmission in essentially all areas of the central nervous system. This enhancement is thought to occur indirectly at the postsynaptic GABAA receptor complex.
The functional significance of this drug–receptor interaction is that the receptor complex regulates the entrance of chloride into the postsynaptic cells. The increase in chloride conductance mediated by GABA is intensified by the benzodiazepines. This facilitation of GABA-induced chloride conductance results in greater hyperpolarization of these cells and therefore leads to diminished synaptic transmission.
Another chemical class of sedative–hypnotic drugs, the barbiturates, also binds to receptors associated with the GABA–chloride ionophore, but these drugs appear to prolong rather than intensify GABA’s effects. Fig. 24.4 shows the presumed drug receptor–GABA– chloride ionophore relationship.
In addition to the clinically useful benzodiazepines, which act as agonists at the benzodiazepine receptor, at least two other types of ligands also interact with this binding site. These are the benzodiazepine receptor antagonists and the inverse agonists. For example, flumazenil (Romazicon) is a receptor antagonist that selectively blocks the effects of other benzodiazepines at their binding sites; it has clinical application in the treatment treatment of benzodiazepine overdose and in the reversal of benzodiazepine-induced sedation. The inverse agonists are compounds that interact with benzodiazepine receptors and decrease, rather than increase, GABAmediated changes. They also can antagonize the effects of benzodiazepine agonists and when administered alone, can be anxiogenic and proconvulsant.

The benzodiazepines, when given by slow IV infusion to induce anesthesia, have minimal influences on the cardiovascular and respiratory systems. Thus, they may be logical substitutes for barbiturates in poor-risk patients who cannot tolerate cardiovascular depression. In other respects, they appear pharmacologically similar to the barbiturates. IV administration causes unconsciousness without analgesia; skeletal muscle relaxation is inadequate for intubation or short surgical procedures. Consequently, when these characteristics of anesthetic management are desired, benzodiazepines must be coadministered with appropriate analgesic drugs and neuromuscular blocking agents.
The popularity of the benzodiazepines as an anesthetic supplement in cardiac surgery is related to their amnesic potential.They can ensure unawareness during the initial period, when the anesthetics are being diluted in the fluid of the bypass circuit. Lorazepam is often chosen for this purpose because it is longer acting and more potent than either midazolam or diazepam. Benzodiazepine administration may cause amnesia even when used in doses that do not produce unconsciousness. Antegrade amnesia may occur with the doses that are used to relieve preoperative anxiety.

Although it is widely claimed that the benzodiazepine drugs have a specific calming or anxiolytic effect, their most prominent and easily quantifiable action is central nervous system depression. In very low therapeutic doses, this depression manifests as relief of anxiety that is often accompanied by a feeling of sluggishness or drowsiness. As the dose is increased, the degree of depression is intensified such that muscle relaxation, hypnosis and a more intense central nervous system depression occur. This depression is related to the ability of these drugs to facilitate the inhibitory actions of GABA.
A significant advantage of the benzodiazepines over other central nervous system depressants (e.g., the barbiturates) is that they possess a much greater separation between the dose that produces sleep and the dose that produces death. This increased margin of safety has been one of the major reasons benzodiazepines have largely replaced the barbiturates and other types of sedative– hypnotics in the treatment of anxiety and insomnia. In addition, benzodiazepine administration is associated with few side effects.

Anxiety
Anxiety disorders are among the most common forms of psychiatric illness. Anxiety often accompanies other psychiatric disease and such medical illnesses as angina pectoris, gastrointestinal disorders, and hypertension.Anxiety that results from fear caused by an acute illness or a stressful event, such as a divorce or the loss of a loved one, is usually self-limiting and can be of relatively short duration. Other disorders that have anxiety as a component are not necessarily associated with a life event, and may persist for considerable periods, even throughout the individual’s life.
Both acute and chronic anxiety can be treated with benzodiazepines, although it is anticipated that for most anxiety disorders counseling will also play an important role. Benzodiazepines employed in the treatment of anxiety should be used in the lowest effective dose for the shortest duration so that they will provide maximum benefit to the patient while minimizing the potential for adverse reactions. For most types of anxiety, none of the benzodiazepines is therapeutically superior to any other. Choice of a particular agent is usually made on the basis of pharmacokinetic considerations. A benzodiazepine with a long half-life should be considered if the anxiety is intense and sustained. A drug with a short half-life may have advantages when the anxiety is provoked by clearly defined circumstances and is likely to be of short duration.
Insomnia
All of the benzodiazepines will produce sedative– hypnotic effects of sufficient magnitude to induce sleep, provided that the dose is high enough. However, the aim in the treatment of sleep disorders is to induce sleep that is as close as possible to natural sleep so that the patient falls asleep quickly, sleeps through the night, and has sleep of sufficient quality to awake refreshed.
Extensive sleep studies have been conducted with a variety of sedative–hypnotic drugs, and all of these drugs appear to alter the normal distribution of rapid eye movement (REM) and non-REM sleep. Most of the older sedative–hypnotic agents markedly depress REM sleep. In contrast, when the benzodiazepines are used in appropriate doses, they depress REM sleep to a much smaller extent. As with treatment of anxiety, the choice of a particular benzodiazepine to treat a sleep disturbance is again generally based on pharmacokinetic criteria. While longer-acting compounds may ensure that a patient will sleep through the night, they also may cause cumulative effects resulting in daytime sluggishness or drug hangover. Shorter-acting compounds avoid the hangover problem, but their use may be associated with early awakening and an increase in daytime anxiety.

Several benzodiazepines are used in the management of epileptic seizures, although only a few are approved for the treatment of seizure disorders in the United States. Since the benzodiazepines share many properties, they will be discussed as a class; individual members will be mentioned for specific indications.
The primary action of the benzodiazepines as anticonvulsants is to enhance inhibition through their interaction with the GABAA receptor at the benzodiazepine binding site. However, there appears to be an additional action of benzodiazepines: blocking voltage-dependent sodium channels. This effect is not seen at usual doses but is likely a factor in their use in the treatment of status epilepticus.
Benzodiazepines are well absorbed, and the oral route is preferred in most situations. In the treatment of status epilepticus, the preferred route is usually intravenous. Benzodiazepines are extensively metabolized by the microsomal drug-metabolizing system; frequently an active compound is broken down to another agent that is also active pharmacologically. This is the reason for the long duration of action of several benzodiazepines.
The benzodiazepines have many clinical indications and are discussed in Chapters 25, 30, 35, and 40. As AEDs, they have their major usefulness in the treatment of absence, myoclonic, and atonic seizures and in the emergency treatment of status epilepticus.
Drowsiness occurs readily and unfortunately is usually a problem at therapeutic doses. The other limiting side effect of the benzodiazepines is the rapid development of tolerance to their anticonvulsant effects.
Although all of the benzodiazepines are similar, certain ones are employed more for the treatment of seizure disorders. Clonazepam was the first benzodiazepine approved in the United States specifically for the treatment of convulsive disorders. Clonazepam is a very long acting compound with potent anticonvulsant activity. Unfortunately, sedation and tolerance tend to limit its usefulness. Drooling and hypersalivation may be troublesome in children and in infants.

Most adverse effects associated with use of the benzodiazepines are related to their ability to produce central nervous system depression.These include drowsiness, excessive sedation, impaired motor coordination, confusion, and memory loss.These effects are most troublesome during the initial week or two of treatment. Subsequently, the patient becomes tolerant and these effects produce less difficulty. Although for most individuals these symptoms are mild, patients should be cautioned against engaging in potentially dangerous tasks such as operating machinery or driving a car during the initial treatment period. Less common adverse effects include blurred vision, hallucinations, and paradoxical reactions consisting of excitement, stimulation, and hyperactivity.Also, a variety of gastrointestinal complaints occur, and blood dyscrasias have been reported, but these are rare. Benzodiazepine administration during pregnancy, delivery, or lactation has the potential to have adverse effects on the fetus or newborn.
As with other central nervous system depressants, the effects of benzodiazepines are additive with those of ethanol. Patients should be warned that ethanolcontaining beverages may produce a more profound depression when taken simultaneously with a benzodiazepine.
One of the major reasons for the popularity of the benzodiazepines is their relative safety. Overdoses with the benzodiazepines occur commonly, but fatal toxic occurrences are rare. Fatal intoxications are more likely in children, in individuals with respiratory difficulties, and in individuals who have consumed another central nervous system depressant, such as alcohol. After an overdose, the patient begins a deep sleep that may last for 24 to 48 hours, depending on the dose. However, even with large overdoses, the patient can usually still be aroused.

Midazolam (Versed), diazepam (Valium), and lorazepam (Ativan) are benzodiazepine derivatives that are useful in anesthesia. Midazolam is the most popular of these agents for the induction of anesthesia. Its popularity is related to its aqueous solubility and to its short duration of action, which permits a prompt return of psychomotor competence. Unlike midazolam, lorazepam and diazepam are not water soluble and must be formulated in propylene glycol; the latter is irritating to the vasculature on parenteral administration.
Benzodiazepines are useful as orally administered premedications. They are also used intravenously in doses that produce conscious sedation rather than hypnosis. Sedated patients tolerate unpleasant procedures (e.g., wound repair, bronchoscopy, angiography) while maintaining cardiorespiratory function and the ability to respond to tactile stimulation or verbal commands.
Midazolam has a shorter half-life (t_1/2β = 1.3–2.2 hours) than either diazepam (t_1/2β = 30 hours) or lorazepam and is not converted in the liver to active metabolites, as is diazepam. Thus, use of midazolam results in a more rapid return to psychomotor competence. Doses may need to be lowered by at least 30% in older patients and in those premedicated with opioids or other sedative drugs.

When used with other sedative–hypnotics or alcohol, the benzodiazepines will produce additive central nervous system depression.
Many benzodiazepines are metabolized by the cytochrome P450 (CYP) enzyme designated CYP3A4. CYP3A4 is inhibited by grapefruit juice and by drugs such as ketoconazole, itraconazole, nefazodone, erythromycin, and ritonavir. Coadministration of these substances along with a benzodiazepine may result in intensification and prolongation of the benzodiazepine effect. Conversely, rifampin, carbamazepine, and phenytoin can induce the CYP3A4 enzyme, and therefore their coadministration can reduce the therapeutic effect of the benzodiazepines.

Benzodiazepines are usually given orally and are well absorbed by this route. Since the benzodiazepines are weak bases, they are less ionized in the relatively alkaline environment of the small intestine, and therefore, most of their absorption takes place at this site. For emergency treatment of seizures or when used in anesthesia, the benzodiazepines also can be given parenterally. Diazepam and lorazepam are available for intravenous administration.
The distribution of the benzodiazepines from blood to tissues and back again is a dynamic process with considerable influence on the onset and duration of the therapeutic effects produced by these compounds. Those having greater lipid solubility tend to enter the central nervous system more rapidly and thus tend to produce their effects more quickly. Several of the benzodiazepines have therapeutic effects that are much shorter in duration than would be predicted based on their rates of metabolism and excretion; redistribution away from the central nervous system is of primary importance in terminating their therapeutic effects.
Although tissue redistribution of benzodiazepines may be an important means of terminating the actions of selected members of this class of drugs, many benzodiazepines do undergo extensive biotransformation. Metabolism takes place both by dealkylation and conjugation reactions. In many instances, dealkylation can result in the formation of pharmacologically active compounds. Indeed, most clinically available benzodiazepines are converted in the liver to one or more active metabolites. In several cases the active metabolites have a much longer half-life than the parent compound. In one case, acid hydrolysis in the stomach converts an inactive compound (clorazepate) to an active drug (nordazepam).The water-soluble metabolites of the benzodiazepines are excreted primarily in the urine.
Since most of the benzodiazepines do undergo biotransformation, it is possible that changes in liver function may alter the duration of the therapeutic effect produced by these drugs. Despite the fact that few clinical studies have demonstrated serious toxicities associated with benzodiazepine administration in individuals with compromised liver function, prudence in the use of these compounds in the elderly and in individuals with liver disease seems advisable.
One of the great disadvantages associated with many of the sedative and hypnotic drugs (e.g., barbiturates, propanediol carbamates), which have now largely been replaced by the benzodiazepines, is the fact that those drugs are very effective inducers of hepatic drugmetabolizing enzymes. Since the benzodiazepines are only weak inducers of hepatic microsomal enzymes, they cause relatively few clinically significant drug interactions related to metabolism of other drugs.