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Benzodiazepines

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What are benzodiazepines, and how do they work?

Benzodiazepines are a class of drugs primarily used for treating anxiety, but they also are effective in treating several other conditions. The exact mechanism of action of benzodiazepines is not known, but they appear to work by affecting neurotransmitters in the brain, chemicals that nerves release in order to communicate with other nearby nerves. One of these neurotransmitters is gamma-aminobutyric acid (GABA), a neurotransmitter that suppresses the activity of nerves. Scientists believe that excessive activity of nerves may be the cause of anxiety and other psychological disorders, and benzodiazepines reduce the activity of nerves in the brain and spinal cord by enhancing the effects of GABA.

For what conditions are benzodiazepines used?

Benzodiazepines are used for treating:

  • anxiety and panic
  • seizures (convulsions), and
  • insomnia or trouble sleeping.

They also are used for:

Are there differences between benzodiazepines?

Benzodiazepines differ in how quickly they start working, how long they continue to work, and for what they are most commonly prescribed.

  • Diazepam (Valium) and clorazepate (Tranxene) have fast onsets of action and usually start working within 30 to 60 minutes.
  • Oxazepam (Serax) has a slow onset, and lorazepam (Ativan), alprazolam (Xanax), and clonazepam (Klonopin) have intermediate onsets of action.
  • Clorazepate (Tranxene), midazolam (Versed), and triazolam (Halcion) are short-acting agents with durations of action of 3 to 8 hours.
  • Alprazolam (Xanax), lorazepam (Ativan), estazolam (Prosom), and temazepam (Restoril) are intermediate-acting agents with durations of action of 11 to 20 hours.
  • Chlordiazepoxide (Librium), clonazepam (Klonopin), diazepam (Valium), flurazepam (Dalmane), and quazepam are long-acting agents with duration of action of 1 to 3 days.

Although most benzodiazepines are used interchangeably, some are most commonly used for certain conditions.

  • Alprazolam (Xanax), chlordiazepoxide (Librium), chlorazepate (Tranxene), diazepam (Valium), lorazepam (Ativan), and midazolam are used for anxiety disorders.
  • Clonazepam (Klonopin), clorazepate (Tranxene), lorazepam (Ativan), clobazam (Onfi), and diazepam (Valium) are used for seizure disorders.
  • Estazolam (Prosom), flurazepam (Dalmane), quazepam (Doral), temazepam (Restoril), and triazolam (Halcion) are used for insomnia or trouble sleeping.
  • Midazolam (Versed), lorazepam (Ativan), and diazepam (Valium) are used in anesthesia.
  • Diazepam (Valium) also is used for muscle relaxation.
  • Chlordiazepoxide (Librium) is used for alcohol withdrawal.

What are the side effects of benzodiazepines?

The most common side effects associated with benzodiazepines are:

Other side effects include:

  • transient drowsiness commonly experienced during the first few days of treatment,
  • a feeling of depression,
  • loss of orientation,
  • headache,
  • sleep disturbance,
  • confusion,
  • irritability,
  • aggression,
  • excitement, and
  • memory impairment.

All benzodiazepines can cause physical dependence. Suddenly stopping therapy after a few months of daily therapy may be associated with withdrawal symptoms which include a feeling of loss of self-worth, agitation, and insomnia. If benzodiazepines are taken continuously for longer than a few months, stopping therapy suddenly may produce seizures, tremors, muscle cramping, vomiting, and sweating. In order to avoid withdrawal symptoms, the dose of benzodiazepines should be tapered slowly.

With which drugs do benzodiazepines interact?

All benzodiazepines cause excessive sedation when combined with other medications that slow the brain's processes (for example, alcohol, barbiturates, narcotics, and tranquilizers). The elimination of some benzodiazepines (for example, alprazolam [Xanax] and diazepam [Valium]) is reduced by drugs that slow elimination of drugs in the liver (for example, ketoconazole [Nizoral, Xolegel], valproic acid [Depakene, Stavzor], cimetidine [Tagamet], and fluoxetine [Prozac]). Reduced elimination may result in increased blood concentrations and side effects from the affected benzodiazepines. Antacids may reduce the rate of absorption of benzodiazepines from the intestine. Separating the administration of antacids and benzodiazepines by several hours may prevent this interaction.

What are some examples of benzodiazepines?

Approved benzodiazepines in the United States include:

  • alprazolam (Xanax)
  • chlordiazepoxide (Librium)
  • clonazepam (Klonopin)
  • clorazepate (Tranxene)
  • diazepam (Valium)
  • estazolam (Prosom)
  • flurazepam (Dalmane)
  • lorazepam (Ativan)
  • midazolam (Versed)
  • oxazepam (Serax)
  • temazepam (Restoril)
  • triazolam (Halcion)
  • quazepam (Doral)

What are the dangers of benzodiazepine addiction?

Two serious concerns of benzodiazepine therapy are the potential for abuse and the development of physical dependence. Although intentional abuse of prescription benzodiazepines is relatively uncommon in the general population, it should be used more cautiously in individuals with a history of drug abuse as they are at the greatest risk for seeking benzodiazepines to experience a "high." Benzodiazepines are rarely the sole drug of abuse, and abusers usually combine benzodiazepines with other drugs to increase the effect. For example, benzodiazepines are combined with certain opioids, a class of strong prescription pain relievers, to enhance the euphoric effects. Among abusers, diazepam (Valium) and alprazolam (Xanax) are most popular due to their rapid onset. For most patients, use of a benzodiazepine for a period of several months does not seem to cause issues of addiction, tolerance, or difficulties in stopping the medication when it is no longer needed. However, several months of use significantly increases the risk for addiction, tolerance, and appearance of withdrawal symptoms with dose reduction or termination of therapy.

Abusers are at higher risk for side effects including confusion, slurred speech, seizures or convulsions, severe drowsiness or coma, shakiness, slow heartbeat, difficulty breathing, and severe weakness. Benzodiazepine addicts also have a higher risk for developing dementia, an illness affecting the brain that causes gradual memory loss and problems with language and motor skills, in the long term.

The dangers of benzodiazepine addiction are many. Fatal cases of overdose have been reported with the use of benzodiazepines. Each year benzodiazepine overdose contributes to a significant number of trips to the emergency room and hospital admissions. The antidote for benzodiazepine overdose is flumazenil (Romazicon). To treat benzodiazepine overdose, flumazenil is injected rapidly into the vein.

What are the dangers of benzodiazepine withdrawal?

When benzodiazepine treatment is stopped abruptly, patients may develop withdrawal symptoms. Factors that increase the risk and severity of withdrawal symptoms include high doses and long term benzodiazepine use. Additionally, withdrawal symptoms tend to occur earlier with benzodiazepines with short elimination half-lives.

Common symptoms of benzodiazepine withdrawal include anxiety, trouble sleeping, restlessness, muscle tension, and irritability. Less commonly, patients may also experience nausea, malaise, blurred vision, sweating, nightmares, depression, muscle coordination problems,tremors, and muscle twitching or spasms. In rare cases, hallucinations, delusions, seizures, and ringing in the ears may also occur. Risk of withdrawal seizures is higher with high benzodiazepine dose, long treatment duration, and concurrent use of medications that lower the seizure threshold. Prompt recognition and treatment of benzodiazepine withdrawal is crucial as this condition may be life threatening. Benzodiazepine withdrawal is treated with intravenous (injected into the vein) benzodiazepines such as diazepam (Valium) which tends to work over a longer period of time.

REFERENCES:

Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2009.

DiPiro et al. Pharmacotherapy: A Pathophysiologic Approach, 9th edition. Chapter 53: Anxiety Disorders I; Generalized Anxiety, Panic, and Social Anxiety Disorders. Access Pharmacy [online].

DiPiro et al. Pharmacotherapy: A Pathophysiologic Approach, 9th edition. Chapter 48: Substance-Related Disorders I; Over and Depressants, Stimulants, and Hallucinogens. Access Pharmacy [online].

Greller H et al. Benzodiazepine poisoning and withdrawal. UpToDate. Last updated Oct 30, 2014.

Hoffman, Robert S., et al. "Antidotes in Depth." Goldfrank's Toxicologic Emergencies, 10e. Eds. Robert S. Hoffman, et al. New York, NY: McGraw-Hill, 2015. n. pag. AccessPharmacy. Web. 21 Feb. 2015.

Mihic, S. John, and R. Adron Harris. "Chapter 17. Hypnotics and Sedatives." Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. Eds. Laurence L. Brunton, et al. New York, NY: McGraw-Hill, 2011. n. pag. AccessPharmacy. Web. 21 Feb. 2015.

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