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Benzodiazepines

Benzodiazepines

Definition

Benzodiazepines are medicines that help relieve nervousness, tension, and other symptoms by slowing the central nervous system.

Purpose

Benzodiazepines are a type of antianxiety drugs. While anxiety is a normal response to stressful situations, some people have unusually high levels of anxiety that can interfere with everyday life. For these people, benzodiazepines can help bring their feelings under control. The medicine can also relieve troubling symptoms of anxiety, such as pounding heartbeat, breathing problems, irritability, nausea, and faintness.

Physicians may sometimes prescribe these drugs for other conditions, such as muscle spasms, epilepsy and other seizure disorders, phobias, panic disorder, withdrawal from alcohol, and sleeping problems. However, this medicine should not be used every day for sleep problems that last more than a few days. If used this way, the drug loses its effectiveness within a few weeks.

Description

The family of antianxiety drugs known as benzodiazepines includes alprazolam (Xanax), chlordiazepoxide (Librium), diazepam (Valium), and lorazepam (Ativan). These medicines take effect fairly quickly, starting to work within an hour after they are taken. Benzodiazepines are available only with a physician's prescription and are available in tablet, capsule, liquid, or injectable forms.

Recommended dosage

The recommended dosage depends on the type of benzodiazepine, its strength, and the condition for which it is being taken. Doses may be different for different people. Check with the physician who prescribed the drug or the pharmacist who filled the prescription for the correct dosage.

Always take benzodiazepines exactly as directed. Never take larger or more frequent doses, and do not take the drug for longer than directed. If the medicine does not seem to be working, check with the physician who prescribed it. Do not increase the dose or stop taking the medicine unless the physician says to do so. Stopping the drug suddenly may cause withdrawal symptoms, especially if it has been taken in large doses or over a long period. People who are taking the medicine for seizure disorders may have seizures if they stop taking it suddenly. If it is necessary to stop taking the medicine, check with a physician for directions on how to stop. The physician may recommend tapering down gradually to reduce the chance of withdrawal symptoms or other problems.

Precautions

Seeing a physician regularly while taking benzodiazepines is important, especially during the first few months of treatment. The physician will check to make sure the medicine is working as it should and will note unwanted side effects.

People who take benzodiazepines to relieve nervousness, tension, or symptoms of panic disorder should check with their physicians every two to three months to make sure they still need to keep taking the medicine.

Patients who are taking benzodiazepines for sleep problems should check with their physicians if they are not sleeping better within 7-10 days. Sleep problems that last longer than this may be a sign of another medical problem.

People who take this medicine to help them sleep may have trouble sleeping when they stop taking the medicine. This effect should last only a few nights.

Some people, especially older people, feel drowsy, dizzy, lightheaded, or less alert when using benzodiazepines. The drugs may also cause clumsiness or unsteadiness. When the medicine is taken at bedtime, these effects may even occur the next morning. Anyone who takes these drugs should not drive, use machines or do anything else that might be dangerous until they have found out how the drugs affect them.

Benzodiazepines may also cause behavior changes in some people, similar to those seen in people who act differently when they drink alcohol. More extreme changes, such as confusion, agitation, and hallucinations, also are possible. Anyone who starts having strange or unusual thoughts or behavior while taking this medicine should get in touch with his or her physician.

KEY TERMS

Anxiety Worry or tension in response to real or imagined stress, danger, or dreaded situations. Physical reactions, such as fast pulse, sweating, trembling, fatigue, and weakness may accompany anxiety.

Asthma A disease in which the air passages of the lungs become inflamed and narrowed.

Bronchitis Inflammation of the air passages of the lungs.

Central nervous system The brain and spinal cord.

Chronic A word used to describe a long-lasting condition. Chronic conditions often develop gradually and involve slow changes.

Emphysema An irreversible lung disease in which breathing becomes increasingly difficult.

Epilepsy A brain disorder with symptoms that include seizures.

Glaucoma A condition in which pressure in the eye is abnormally high. If not treated, glaucoma may lead to blindness.

Myasthenia gravis A chronic disease with symptoms that include muscle weakness and sometimes paralysis.

Panic disorder A disorder in which people have sudden and intense attacks of anxiety in certain situations. Symptoms such as shortness of breath, sweating, dizziness, chest pain, and extreme fear often accompany the attacks.

Phobia An intense, abnormal, or illogical fear of something specific, such as heights or open spaces.

Porphyria A disorder in which porphyrins build up in the blood and urine.

Porphyrin A type of pigment found in living things.

Seizure A sudden attack, spasm, or convulsion.

Sleep apnea A condition in which a person temporarily stops breathing during sleep.

Withdrawal symptoms A group of physical or mental symptoms that may occur when a person suddenly stops using a drug to which he or she has become dependent.

Because benzodiazepines work on the central nervous system, they may add to the effects of alcohol and other drugs that slow down the central nervous system, such as antihistamines, cold medicine, allergy medicine, sleep aids, medicine for seizures, tranquilizers, some pain relievers, and muscle relaxants. They may also add to the effects of anesthetics, including those used for dental procedures. These effects may last several days after treatment with benzodiazepines ends. The combined effects of benzodiazepines and alcohol or other CNS depressants (drugs that slow the central nervous system) can be very dangerous, leading to unconsciousness or, rarely, even death. Anyone taking benzodiazepines should not drink alcohol and should check with his or her physician before using any CNS depressants. Taking an overdose of benzodiazepines can also cause unconsciousness and possibly death. Anyone who shows signs of an overdose or of the effects of combining benzodiazepines with alcohol or other drugs should get immediate emergency help. Warning signs include slurred speech or confusion, severe drowsiness, staggering, and profound weakness.

Some benzodiazepines may change the results of certain medical tests. Before having medical tests, anyone taking this medicine should alert the health care professional in charge.

Children are generally more sensitive than adults to the effects of benzodiazepines. This sensitivity may increase the chance of side effects.

Older people are more sensitive than younger adults to the effects of this medicine and may be at greater risk for side effects. Older people who take these drugs to help them sleep may be drowsy during the day. Older people also increase their risk of falling and injuring themselves when they take these drugs.

Special conditions

People with certain medical conditions or who are taking certain other medicines can have problems if they take benzodiazepines. Before taking these drugs, be sure to let the physician know about any of these conditions:

ALLERGIES. Anyone who has had unusual reactions to benzodiazepines or other mood-altering drugs in the past should let his or her physician know before taking the drugs again. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.

PREGNANCY. Some benzodiazepines increase the likelihood of birth defects. Using these medicines during pregnancy may also cause the baby to become dependent on them and to have withdrawal symptoms after birth. When taken late in pregnancy or around the time of labor and delivery, these drugs can cause other problems in the newborn baby, such as weakness, breathing problems, slow heartbeat, and body temperature problems.

BREASTFEEDING. Benzodiazepines may pass into breast milk and cause problems in babies whose mothers taken the medicine. These problems include drowsiness, breathing problems, and slow heartbeat. Women who are breastfeeding their babies should not use this medicine without checking with their physicians.

OTHER MEDICAL CONDITIONS. Before using benzodiazepines, people with any of these medical problems should make sure their physicians are aware of their conditions:

  • current or past drug or alcohol abuse
  • depression
  • severe mental illness
  • epilepsy or other seizure disorders
  • swallowing problems
  • chronic lung disease such as emphysema, asthma, or chronic bronchitis
  • kidney disease
  • liver disease
  • brain disease
  • glaucoma
  • hyperactivity
  • myasthenia gravis
  • porphyria
  • sleep apnea

USE OF CERTAIN MEDICINES. Taking benzodiazepines with certain other drugs may affect the way the drugs work or may increase the chance of side effects.

Side effects

The most common side effects are dizziness, light-headedness, drowsiness, clumsiness, unsteadiness, and slurred speech. These problems usually go away as the body adjusts to the drug and do not require medical treatment unless they persist or they interfere with normal activities.

More serious side effects are not common, but may occur. If any of the following side effects occur, check with the physician who prescribed the medicine as soon as possible:

  • behavior changes
  • memory problems
  • difficulty concentrating
  • confusion
  • depression
  • seizures (convulsions)
  • hallucinations
  • sleep problems
  • increased nervousness, excitability, or irritability
  • involuntary movements of the body, including the eyes
  • low blood pressure
  • unusual weakness or tiredness
  • skin rash or itching
  • unusual bleeding or bruising
  • yellow skin or eyes
  • sore throat
  • sores in the mouth or throat
  • fever and chills

Patients who take benzodiazepines for a long time or at high doses may notice side effects for several weeks after they stop taking the drug. They should check with their physicians if these or other trouble-some symptoms occur:

  • irritability
  • nervousness
  • sleep problems

Other rare side effects may occur. Anyone who has unusual symptoms during or after treatment with benzodiazepines should get in touch with his or her physician.

Interactions

Benzodiazepines may interact with a variety of other medicines. When this happens, the effects of one or both of the drugs may change or the risk of side effects may be greater. Anyone who takes benzodiazepines should let the physician know all other medicines he or she is taking. Among the drugs that may interact with benzodiazepines are:

  • Central nervous system (CNS) depressants such as medicine for allergies, colds, hay fever, and asthma; sedatives; tranquilizers; prescription pain medicine; muscle relaxants; medicine for seizures; sleep aids; barbiturates; and anesthetics.

Medicines other than those listed above may interact with benzodiazepines. Be sure to check with a physician or pharmacist before combining benzodiazepines with any other prescription or nonprescription (over-the-counter) medicine.

Resources

OTHER

"Medications." National Institute of Mental Health Page. 1995. http://www.nimh.nih.gov.

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"Benzodiazepines." Gale Encyclopedia of Medicine, 3rd ed.. . Encyclopedia.com. 20 Aug. 2017 <http://www.encyclopedia.com>.

"Benzodiazepines." Gale Encyclopedia of Medicine, 3rd ed.. . Encyclopedia.com. (August 20, 2017). http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/benzodiazepines

"Benzodiazepines." Gale Encyclopedia of Medicine, 3rd ed.. . Retrieved August 20, 2017 from Encyclopedia.com: http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/benzodiazepines

Benzodiazepines

Benzodiazepines

Definition

Benzodiazepines are medicines that help relieve nervousness, tension, and other symptoms by slowing the central nervous system .

Purpose

Benzodiazepines are a type of antianxiety drugs. While anxiety is a normal response to stressful situations, some people have unusually high levels of anxiety that can interfere with everyday life. For these people, benzodiazepines can help bring their feelings under control. The medicine can also relieve troubling symptoms of anxiety, such as pounding heartbeat, breathing problems, irritability, nausea, and faintness.

Physicians may sometimes prescribe these drugs for other conditions, such as muscle spasms, epilepsy and other seizure disorders, phobias, panic disorder, withdrawal from alcohol, and sleeping problems. However, this medicine should not be used every day for sleep problems that last more than a few days. If used this way, the drug loses its effectiveness within a few weeks.

Benzodiazepines should not be used to relieve the nervousness and tension of normal everyday life.

Description

The family of antianxiety drugs known as benzodiazepines includes alprazolam (Xanax), chlordiazepoxide (Librium), diazepam (Valium), and lorazepam (Ativan). These medicines take effect fairly quickly, starting to work within an hour after they are taken. Benzodiazepines are available only with a physician's prescription and are available in tablet, capsule, liquid, or injectable forms.

Recommended dosage

The recommended dosage depends on the type of benzodiazepine, its strength, and the condition for which it is being taken. Doses may be different for different people. Check with the physician who prescribed the drug or the pharmacist who filled the prescription for the correct dosage.

Always take benzodiazepines exactly as directed. Never take larger or more frequent doses, and do not take the drug for longer than directed. If the medicine does not seem to be working, check with the physician who prescribed it. Do not increase the dose or stop taking the medicine unless the physician says to do so. Stopping the drug suddenly may cause withdrawal symptoms, especially if it has been taken in large doses or over a long period. People who are taking the medicine for seizure disorders may have seizures if they stop taking it suddenly. If it is necessary to stop taking the medicine, check with a physician for directions on how to stop. The physician may recommend tapering down gradually to reduce the chance of withdrawal symptoms or other problems.

Precautions

Seeing a physician regularly while taking benzodiazepines is important, especially during the first few months of treatment. The physician will check to make sure the medicine is working as it should and will note unwanted side effects.

People who take benzodiazepines to relieve nervousness, tension, or symptoms of panic disorder should check with their physicians every two to three months to make sure they still need to keep taking the medicine.

Patients who are taking benzodiazepines for sleep problems should check with their physicians if they are not sleeping better within 7-10 days. Sleep problems that last longer than this may be a sign of another medical problem.

People who take this medicine to help them sleep may have trouble sleeping when they stop taking the medicine. This effect should last only a few nights.

Some people, especially older people, feel drowsy, dizzy, lightheaded, or less alert when using benzodiazepines. The drugs may also cause clumsiness or unsteadiness. When the medicine is taken at bedtime, these effects may even occur the next morning. Anyone who takes these drugs should not drive, use machines, or do anything else that might be dangerous until they have found out how the drugs affect them.

Benzodiazepines may also cause behavior changes in some people, similar to those seen in people who act differently when they drink alcohol. More extreme changes, such as confusion, agitation, and hallucinations , also are possible. Anyone who starts having strange or unusual thoughts or behavior while taking this medicine should get in touch with his or her physician.

Because benzodiazepines work on the central nervous system, they may add to the effects of alcohol and other drugs that slow down the central nervous system, such as antihistamines, cold medicine, allergy medicine, sleep aids, medicine for seizures, tranquilizers, some pain relievers, and muscle relaxants. They may also add to the effects of anesthetics, including those used for dental procedures. These effects may last several days after treatment with benzodiazepines ends. The combined effects of benzodiazepines and alcohol or other CNS depressants (drugs that slow the central nervous system) can be very dangerous, leading to unconsciousness or, rarely, even death. Anyone taking benzodiazepines should not drink alcohol and should check with his or her physician before using any CNS depressants. Taking an overdose of benzodiazepines can also cause unconsciousness and possibly death. Anyone who shows signs of an overdose or of the effects of combining benzodiazepines with alcohol or other drugs should get immediate emergency help. Warning signs include slurred speech or confusion, severe drowsiness, staggering, and profound weakness.

Some benzodiazepines may change the results of certain medical tests. Before having medical tests, anyone taking this medicine should alert the health care professional in charge.

Children are generally more sensitive than adults to the effects of benzodiazepines. This sensitivity may increase the chance of side effects.

Older people are more sensitive than younger adults to the effects of this medicine and may be at greater risk for side effects. Older people who take these drugs to help them sleep may be drowsy during the day. Older people also increase their risk of falling and injuring themselves when they take these drugs.

Special conditions

People with certain medical conditions or who are taking certain other medicines can have problems if they take benzodiazepines. Before taking these drugs, be sure to let the physician know about any of these conditions:

ALLERGIES Anyone who has had unusual reactions to benzodiazepines or other mood-altering drugs in the past should let his or her physician know before taking the drugs again. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.

PREGNANCY Some benzodiazepines increase the likelihood of birth defects. Using these medicines during pregnancy may also cause the baby to become dependent on them and to have withdrawal symptoms after birth. When taken late in pregnancy or around the time of labor and delivery, these drugs can cause other problems in the newborn baby, such as weakness, breathing problems, slow heartbeat, and body temperature problems.

Women who are pregnant or who may become pregnant should not use benzodiazepines unless their anxiety is so severe that it threatens their pregnancy. Any woman who must take this medicine while pregnant should be sure to thoroughly discuss its risks and benefits with her physician.

BREAST-FEEDING Benzodiazepines may pass into breast milk and cause problems in babies whose mothers take the medicine. These problems include drowsiness, breathing problems, and slow heartbeat. Women who are breast-feeding their babies should not use this medicine without checking with their physicians.

OTHER MEDICAL CONDITIONS Before using benzodiazepines, people with any of these medical problems should make sure their physicians are aware of their conditions:

  • current or past drug or alcohol abuse
  • depression
  • severe mental illness
  • epilepsy or other seizure disorders
  • swallowing disorders
  • chronic lung disease such as emphysema, asthma, or chronic bronchitis
  • kidney disease
  • liver disease
  • brain disease
  • glaucoma
  • hyperactivity
  • myasthenia gravis
  • porphyria
  • sleep apnea

USE OF CERTAIN MEDICINES Taking benzodiazepines with certain other drugs may affect the way the drugs work or may increase the chance of side effects.

Side effects

The most common side effects are dizziness , lightheadedness, drowsiness, clumsiness, unsteadiness, and slurred speech. These problems usually go away as the body adjusts to the drug and do not require medical treatment unless they persist or they interfere with normal activities.

More serious side effects are not common, but may occur. If any of the following side effects occur, check with the physician who prescribed the medicine as soon as possible:

  • behavior changes
  • memory problems
  • difficulty concentrating
  • confusion
  • depression
  • seizures (convulsions)
  • hallucinations
  • sleep problems
  • increased nervousness, excitability, or irritability
  • involuntary movements of the body, including the eyes
  • low blood pressure
  • unusual weakness or tiredness
  • skin rash or itching
  • unusual bleeding or bruising
  • yellow skin or eyes
  • sore throat
  • sores in the mouth or throat
  • fever and chills.

Patients who take benzodiazepines for a long time or at high doses may notice side effects for several weeks after they stop taking the drug. They should check with their physicians if these or other troublesome symptoms occur:

  • irritability
  • nervousness
  • sleep problems.

Other rare side effects may occur. Anyone who has unusual symptoms during or after treatment with benzodiazepines should get in touch with his or her physician.

Interactions

Benzodiazepines may interact with a variety of other medicines. When this happens, the effects of one or both of the drugs may change or the risk of side effects may be greater. Anyone who takes benzodiazepines should let the physician know all other medicines he or she is taking. Among the drugs that may interact with benzodiazepines are:

  • central nervous system (CNS) depressants such as medicine for allergies, colds, hay fever, and asthma
  • sedatives
  • tranquilizers
  • prescription pain medicine
  • muscle relaxants
  • medicine for seizures
  • sleep aids
  • barbiturates
  • anesthetics

Medicines other than those listed above may interact with benzodiazepines. Be sure to check with a physician or pharmacist before combining benzodiazepines with any other prescription or nonprescription (over-the-counter) medicine.

Resources

OTHER

"Medications." National Institute of Mental Health Page. 1995 <http://www.nimh.nih.gov>.

Nancy Ross-Flanigan

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"Benzodiazepines." Gale Encyclopedia of Neurological Disorders. . Encyclopedia.com. 20 Aug. 2017 <http://www.encyclopedia.com>.

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"Benzodiazepines." Gale Encyclopedia of Neurological Disorders. . Retrieved August 20, 2017 from Encyclopedia.com: http://www.encyclopedia.com/science/encyclopedias-almanacs-transcripts-and-maps/benzodiazepines

Benzodiazepines

BENZODIAZEPINES

The benzodiazepines were introduced into clinical practice in the 1960s for the treatment of anxiety and sleep disorders. Members of this class of drug were classified initially as minor tranquilizers although this term has fallen into disfavor. These agents have proven to be safe and effective alternatives to older Sedative-Hypnotic agents such as Barbiturates, Chloral Hydrate, glutethimide, and carbamates. Benzodiazepines are widely prescribed drugs, with 8.3 percent of the U.S. population reporting medical use of these agents in 1990.

BASIC PHARMACOLOGY

All benzodiazepines produce similar pharmacologic effects, although the potency for each effect may vary with individual agents. They decrease or abolish Anxiety, produce sedation, induce and maintain sleep, control certain types of seizures, and relax skeletal muscles. The basic chemical structure is shown in Figure 1.

Dissimilarity in the effects of different benzodiazepines tend to be more quantitative than qualitative in nature. Many of these differences are attributable to how benzodiazepines are absorbed, distributed, and metabolized in the body. A few benzodiazepinesclorazepate for exampleare pro-drugs; that is, they become active only after undergoing chemical transformation in the body. The extent to which a benzodiazepine is soluble in fatlike substancesthat is, the degree to which it is lipophilicdetermines the rate at which it crosses the tissue barriers that protect the brain. Drugs that are highly lipophilic such as Diazepam (Valium) rapidly enter and then leave the brain. Benzodiazepines are metabolized in the body in a number of ways (see Table 1). Many benzodiazepines are transformed in the liver into compounds that possess pharmacologic activity similar to that of the originally administered drug. Diazepam, prazepam, and halazepam are all converted to the active metabolite desmethyldiazepam, which is eliminated from the plasma at a very slow rate. Oxazepam (Serax) and lorazepam (Ativan), in contrast, are conjugated with glucuronide, a substance formed in the liver, to form inactive metabolites that are readily excreted into the urine.

Most of the effects that result from the administration of benzodiazepines are a consequence of the direct action of these agents on the central nervous system. Benzodiazepines interact directly with proteins that form the benzodiazepine receptor. Benzodiazepine receptors exist as part of a larger receptor complex (Figure 2). The interaction of the Neuro-Transmitter gamma-amino butyric acid (GABA) with this complex leads to the enhanced flow of chloride ions into neurons (Kardos, 1993). This complex is referred to as the GABAA receptor-chloride ion channel complex. Much of the available evidence indicates that the action of benzodiazepines involves a facilitation of the effects of GABA and similarly acting substances on the GABAA receptor complex, thus leading to an increased movement of chloride ions into nerve cells. Entry of chloride ions into neurons tends to diminish their responsiveness to stimulation by other nerve cells, and consequently substances that produce an increase in chloride flow into cells depress the activity of the central nervous system. This depressant effect becomes manifested as either sedation or sleep. Agents that increase chloride ion inflow include not only the benzodiazepines but also other central nervous system depressant agents such as Ethanol (alcohol) and the barbiturates. Benzodiazepines differ from barbiturates in that they require the release of GABA to affect the movement of chloride, whereas at higher doses barbiturates, through their own direct effects, can act to increase chloride in-flow into cells.

The GABAA receptor complex is composed of alpha, beta, and gamma subunits (Zorumski & Isenberg, 1991). Each subunit consists of a chain of twenty to thirty amino acids. Multiple subtypes of the alpha, beta, and gamma subunits have been shown to exist, and the types of subunits that form a single receptor complex appear to vary in different areas of the central nervous system. Some researchers have proposed that different drugs selectively interact with benzodiazepine receptors composed of a particular kind of α subunit, thereby leading to differences in drug effects. Although there is little evidence to support this hypothesis, future research should clarify the issue.

New compounds, such as the imidazopyridines, have been developed that act at the benzodiazepine receptor but are chemically distinct from the benzodiazepines. Zolpidem is an imidazopyridine used in clinical practice as a hypnotic agent. Other new drugs have been synthesized that can stimulate the benzodiazepine receptor but do not produce the maximal effects that result from the administration of higher doses of benzodiazepines. These drugs are classified as partial Agonists. The drug abecarnil, which belongs to the beta-carboline class of compounds, is an example of such an agent that has been used experimentally to treat anxiety.

Flumazenil is a benzodiazepine derivative that has no activity of its own but acts to antagonize the actions of benzodiazepines at the benzodiazepine receptor. It is used to reverse the effects of these drugs during anesthesia or in benzodiazepine overdoses. Other compounds, including some of the beta-carbolines such as methyl-beta-carboline-3-carboxylate, act on the benzodiazepine receptor to produce effects that are opposite to those of benzodiazepines (Kardos, 1993; Zorumski & Isenberg, 1991). Administration of these inverse agonists can lead to the appearance of anxiety and convulsions.

THERAPEUTIC USE

Benzodiazepines are used for a variety of therapeutic purposes. Anxiety is the experience of fear that occurs in a situation where no clear threat exists. Numerous studies have demonstrated that anxiety disorders, including generalized anxiety disorder and many phobias, can be treated effectively with benzodiazepines. Panic disorder is a psychiatric illness in which patients experience intense sporadic attacks of anxiety often accompanied by the avoidance of open spaces and other places or objects that are associated with panic. High-potency benzodiazepines such as alprazolam (Xanax) or clonazepam (Klonopin) can prevent the occurrence of panic attacks in patients suffering from panic disorder. Flurazepam (Dalmane), triazolam (Halcion), and the other benzodiazepines listed in Table 1 are used in the treatment of insomnia and other sleep disorders. All rapidly acting benzodiazepines marketed in the United States have hypnotic effects. Classification of a benzodiazepine as a hypnotic is often more a marketing strategy than it is a decision based on pharmacologic differences among the class of drugs.

Status epilepticus is a seizure or a series of seizures that occurs over an extended period of time. This condition can lead to irreversible brain damage and is often successfully managed by the intravenous infusion of diazepam. Clonazepam is used either alone or in combination with other anticonvulsant medications to treat absence seizure and other types of seizure disorders. Clorazepate is used to control some types of partial seizuresthat is, seizures that occur in a limited area of the brain. The increase in central nervous system excitability, seizures, and anxiety that may appear during alcohol withdrawal can be treated with any benzodiazepine. Midazolam (Versed) is a benzodiazepine that is rapidly metabolized in the body and is used to help induce anesthesia during surgical procedures. The skeletal-relaxant properties of benzodiazepines make them useful for the treatment of back pain due to muscle spasms.

ADVERSE EFFECTS

Benzodiazepines have proven to be exceptionally safe agents. The dose at which these agents are lethal tends to be exceedingly high. Fatalities are more apt to occur when these drugs are taken in combination with other central nervous system depressant agents such as ethanol. Sedation is a common adverse effect associated with benzodiazepine use. Light-headedness, confusion, and loss of motor coordination may all result following the administration of benzodiazepines. Memory impairment may be detected in individuals treated with benzodiazepines, and this effect may prove to be particularly troublesome to Elderly patients who are experiencing memory-related problems. Psychomotor impairment can be hazardous to individuals when they are driving. This problem can be exacerbated in individuals who consume ethanol while they are being treated with benzodiazepines. Hypnotic agents that are converted into active metabolites that are slowly eliminated from the body, such as flurazepam, may produce residual daytime effects that can impair tasks such as driving. The adverse effects of benzodiazepines on performance tend to be more of a problem in elderly people than in younger individuals. Patients with cirrhosis, a liver degenerative disease, are also more likely to experience benzodiazepine toxicity than are those with normal liver function. The appearance of the adverse effects associated with benzodiazepine administration in both elderly people and in cirrhotic patients can be minimized by treating them with agents such as oxazepam and lorazepam, which tend not to accumulate in the blood because they are excreted rapidly into the urine as glucuronide conjugates.

A small number of patients may exhibit paradoxical reactions when they are treated with benzodiazepines (Rall, 1990). These may include low-level anxiety, restlessness, depression, paranoia, hostility, and rage. Sleep patterns may be disrupted by benzodiazepine administration, and nightmares may increase in frequency. Benzodiazepines suppress two stages of the sleep cyclethe stage of deepest sleep, stage IV, and the rapid eye movement (REM) stage in which dreaming occurs.

TOLERANCE AND PHYSICAL DEPENDENCE

Tolerance to a drug involves either a decrease in the effect of a given dose of a drug during the course of repeated administration of the agent or the need to increase the dose of a drug to produce a given effect when it is administered repeatedly. Chronic treatment of animals with benzodiazepines leads to a reduction in potency of these agents as enhancers of chloride ion uptake. These effects at the cellular level are paralleled by the appearance of tolerance to the sedative effects of benzodiazepines. Tolerance also develops to the impairment of motor coordination that is produced by these drugs. Limited evidence suggests that the antianxiety effects of benzodiazepines may not diminish with time, or at the very least that benzodiazepines retain their effectiveness as antianxiety agents for several months.

Physical Dependence results from adaptive changes in the nervous system that may be related to the development of tolerance. Dependence of this sort can be detected by the appearance of a characteristic abstinence or Withdrawal syndrome when chronic administration of a drug is either abruptly discontinued or after the administration of an antagonist to the drug that has been taken for a prolonged period of time (Ciraulo & Greenblatt, in press). Individuals who are treated chronically with benzodiazepines may exhibit signs and symptoms of withdrawal when the administration of these drugs is discontinued. Minor symptoms of withdrawal include Anxiety, insomnia, and nightmares. Less common and more serious symptoms include psychosis, death, and generalized seizures. Signs of withdrawal may become evident twenty-four hours after the discontinuation of a benzodiazepine that is rapidly eliminated from the blood. Peak abstinence symptoms may not appear until two weeks after discontinuation of a benzodiazepine that is removed from the body slowly. Some of the symptoms that appear after benzodiazepine treatment is discontinued may be due to the recurrence of the anxiety disorder for which the drug had been originally prescribed.

In animals, the severity of withdrawal can be directly related to the dose and length of time of administration of a benzodiazepine. This kind of relationship has been harder to demonstrate in clinical studies. Many patients who are treated with benzodiazepines for prolonged periods of time may experience at least some symptoms of withdrawal, but most of these individuals should not be viewed as benzodiazepine "addicts" because they have relied on their medications for medical reasons, have taken the medications as directed by their physicians, and will not continue to compulsively seek out benzodiazepines once their prescribed course of treatment with these medications has been discontinued. The intensity of abstinence symptoms that may be seen in patients who are physically dependent on benzodiazepines can be markedly reduced if patients are allowed to gradually taper off their medications. There may be a risk of physical withdrawal from benzodiazepines in some patients who abruptly stop the medication following as few as four weeks after treatment. Patients who discontinue taking rapidly metabolized hypnotic drugs such as triazolam may be at risk for experiencing rebound insomnia, even if they have been under treatment for a few days to one week. Serious problems associated with benzodiazepine withdrawal are more likely to be a problem for patients who have been treated with high doses of these medications for four or more months.

ABUSE AND DEPENDENCE

Although no consensus exists as to the definition of drug addiction, diagnostic criteria for drug abuse and dependence have been developed by both the American Psychiatric Association and the World Health Organization. Drug abuse can be viewed as the use of a pharmacological substance in a manner that is not consistent with existing medical, social, or legal standards and practice. Alternatively, drug abuse has been defined in the Diagnostic and Sta-Tistical Manual of Mental Disorders of the APA as involving a "maladaptive pattern of substance use manifested by recurrent and significant adverse consequences related to repeated use" (American Psychiatric Association, 1994). Abuse of drugs may involve the use of drugs for recreational purposesthat is, drugs are administered to experience their mood-elevating (euphoric) effects. For some individuals, self-administration of drugs for these purposes may lead to compulsive drug-seeking behavior and other extreme forms of drug-controlled behavior. These behavior patterns may become further reinforced by the effects of withdrawal symptoms that dependent individuals attempt to reduce by the administration of the abused agent. The APA specifies that individuals can be classified as being drug dependent if they exhibit signs of drug tolerance, symptoms of withdrawal, cannot control their drug use, feel compelled to use a drug, and/or continue to use a substance even if the consequences of this use may prove harmful to them (American Psychiatric Association, 1994).

Abuse of drugs may sometimes represent self-medication. Cocaine and Amphetamine users sometimes rely on benzodiazepines to relieve the jitteriness that may result from the administration of Psychomotor Stimulants. Some abusers of benzodiazepines may be medicating themselves with these agents to treat preexisting conditions of anxiety and Depression.

The Abuse Liability of benzodiazepinesthat is, the likelihood that they will be misusedhas been assessed in studies of the tendency of either human beings or animals to administer these agents to themselves and studies of the subjective effects that result from the administration of different benzodiazepines. When provided access to cocaine and other psychomotor stimulants, animals will consistently self-administer these agents at high rates over time. Primates will intravenously self-administer benzodiazepines at moderate rates that are below those observed for the administration of Barbiturates or Cocaine. This finding and the results of a number of additional animal studies indicate that the benzodiazepines have a lower abuse liability than do the barbiturates or the psychomotor stimulants (Ciraulo & Greenblatt, in press).

Individuals with a history of sedative-hypnotic abuse will self-administer triazolam and diazepam (Roache & Griffiths, 1989). In contrast, normal volunteers do not prefer diazepam to placebo. Subjective responses to drugs can be assessed through the use of instruments such as the Addiction Research Center Inventory-Morphine Benzedrine Group Scale and the Profile of Moods States that help to standardize the reports of subjects concerning their drug-induced experiences. Investigations in which subjective responses of normal subjects to benzodiazepine administration have been assessed indicate that these agents tend not to produce mood elevations in normal populations. On the other hand, individuals with a history of either alcoholism or sedative-hypnotic abuse are more likely to experience euphoria after the administration of a single dose of either diazepam or other benzodiazepines. Adult children of alcoholics experience mood elevation after the ingestion of either alprazolam or diazepam, thus suggesting that these individuals may have a predisposition to benzodiazepine abuse.

Studies suggest that benzodiazepines are less likely to be abused than the barbiturates, opiates, or psychomotor stimulants, but that they carry more risk for abuse than do medications such as the antianxiety agent buspirone or drugs that have sedating effects such as the antihistamine diphenhydramine (Preston et al., 1992). There also may be differences among the benzodiazepines themselves. Some authorities believe that diazepam has greater abuse liability than halazepam, oxazepam, chlordiazepoxide, or clorazepate, although others believe that there is little difference among them. Diazepam, lorazepam, alprazolam, and triazolam all produce mood effects that are similar to those of known drugs of abuse. The rate at which these drugs reach the brain after administration may be a major determining factor in the onset of euphoria or pleasant effects associated with abuse. Inferences about abuse potential are made on the basis of subjective effects and self-administration in drug abusers and alcoholics. Many experts question the applicability of these findings to the general population.

Studies that accurately reflect the extent of benzodiazepine abuse in the United States are not available. A survey of American households produced by the National Institute on Drug Abuse suggested that the nonmedical use of tranquilizers was not a major health problem (Ciraulo & Greenblatt, in press). Only 2.4 percent of individuals between the ages of 18 and 24 and 1.3 percent of survey respondents who were older than 26 reported using tranquilizers for nonmedical purposes. This type of survey does not take into account benzodiazepine usage among groups such as homeless people, prisoners, and migrant workers, and so it cannot convey a complete picture of how benzodiazepines are misused at the nationwide level (Cole & Chiarello, 1990).

Benzodiazepines are frequently used by individuals who abuse other drugs, but they are rarely used as either initial or primary drugs of abuse. Benzodiazepine abusers often take these drugs in combination with other agents. In Scotland, drug abusers have often injected temazepam in combination with the Opioid drug Buprenorphine (Ruben & Morrison, 1992). Large percentages of methadone-clinic patients have urine tests that are positive for benzodiazepines. Methadone-Maintenance patients have indicated that diazepam, lorazepam, and alprazolam can produce desirable pleasurable effects (Sellers et al., 1993). Whether methadone patients use benzodiazepines to increase the effects of methadone or as self-medication for anxiety is not clear.

The percentage of alcoholics admitted for treatment who also concurrently use benzodiazepines ranges between 12 to 23 percent. High rates of benzodiazepine abuse have been found in alcoholics who have experienced failure in treatment programs for alcohol abuse. Clinical experience suggests that benzodiazepine abuse occurs with the greatest frequency in alcoholics with severe dependence and in alcoholics who abuse multiple types of drugs.

Individuals with a history of either alcohol abuse or alcohol dependence often have anxiety disorders. The issue of treating alcoholics with benzodiazepines is complex because some of these patients can take the medications without abusing them or relapsing to alcohol use whereas others take them in higher than prescribed doses and find that their desire to drink alcohol is increased.

SUMMARY

A large number of benzodiazepines are available for clinical use. These agents all share a set of pharmacologic properties that result from enhanced chloride flux at the GABAA-receptor complex, which in turn results in the inhibition of neuronal activity in many regions of the central nervous system. Differences in activity among the benzodiazepines appear to be related primarily to differences in rates of absorption and metabolism, although recent research has suggested that intrinsic activity at benzodiazepine receptor subtypes also may influence drug effects. These drugs have been used extensively to treat anxiety, insomnia, seizures, and other disorders. They are safe and effective and their use has rarely been associated with irreversible adverse effects. Both physical and psychological dependence may be problematic for some individuals who are treated on a long-term basis with these agents or who have abused alcohol or other drugs.

(See also: Addiction: Concepts and Definitions ; Benzodiazepines: Complications ; Sleep, Dreaming, and Drugs )

BIBLIOGRAPHY

American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: Author.

Ciraulo, D. A., & Greenblatt, D. J. (in press). Sedative-, hypnotic-, or anxiolytic-related disorders. Baltimore: Williams & Wilkins.

Cole, J.O., & Chiarello, R. J. (1990). The benzodiazepines as drugs of abuse. Journal of Psychiatric Research, 24 (Suppl. 2), 135-144.

Kardos, J. (1993). The GABA-A receptor channel mediated chloride ion translocation through the plasma membrane: New insights from 36 Cl-ion flux measurements. Synapse, 13, 74-93.

Preston, K. L., et al. (1992). Subjective and behavioral effects of diphenhydramine, lorazepam and methocarbamol: Evaluation of abuse liability. Journal of Pharmacology and Experimental Therapeutics, 262 (2), 707-720.

Rall, T. W. (1990). Hypnotics and sedatives: Ethanol. In A. G. Gilman et al. (Eds.), Goodman and Gilman's the pharmacological basis of therapeutics, 8th ed. New York: Pergamon.

Roache, J.D., & Griffiths, R. R. (1989). Diazepam and triazolam self-administration in sedative abusers: Concordance of subject ratings, performance and drug self-administration. Psychopharmacology, 99, 309-315.

Ruben, S. M., & Morrison, C. L. (1992). Temazepam misuse in a group of injecting drug users. British Journal of Addiction, 87, 1387-1392.

Sellers, E. M., et al. (1993). Alprazolam and benzodiazepine dependence. Journal of Clinical Psychiatry, 54 (Suppl. 10), 64-75.

Zorumski, C. F., & Isenberg, K. E. (1991). Insights into the structure and function of GABA-Benzodiazepine receptors: Ion channels and psychiatry. American Journal of Psychiatry, 148, 162-173.

Domenic A. Ciraulo

Clifford Knapp

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"Benzodiazepines." Encyclopedia of Drugs, Alcohol, and Addictive Behavior. . Encyclopedia.com. 20 Aug. 2017 <http://www.encyclopedia.com>.

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