Benzodiazepines
Benzodiazepines
Definition
Benzodiazepines belong to a class of drugs with sedative and hypnotic properties. The principal use of this class of drugs is to produce drowsiness and enable sleep, although they are among the most commonly prescribed drugs for producing anti-anxiety effects. Benzodiazepines are also widely prescribed for muscle spasticity, convulsive disorders, pre-surgical sedation, involuntary movement disorders, and detoxification from alcohol and other substances. The action of benzodiazepines result is primarily from effects on the central nervous system. However, the benzodiazepines are not simply neuronal depressants, they have a complex pharmacological profile such that the clinical usefulness of individual drugs varies widely.
Description
While the selectivity of unique benzodiazepine drugs allows them to have therapeutic potential for various conditions, this class of drugs has a common sedative profile. The sedative properties of benzodiazepines progress through a continuum from sedation to hypnosis to stupor. The sedation component is associated with memory impairment and retrograde amnesia for events that occur while under the effects of the drug. Benzodiazepines increase total sleep time. Benzodiazepine use is associated with refreshing sleep even though not all stages of sleep are affected equally. Other effects of benzodiazepines that can be produced at non-sedative doses are muscle relaxation, anti-seizure activity, and analgesia. The anti-anxiety effects of benzodiazepines relieve the excessive or exaggerated debilitating generalized worry about everyday life events.
Mechanism of action
Benzodiazepines affect a key neurotransmitter in the brain called gamma-amino butyric acid (GABA). This neurotransmitter has an inhibitory effect on neurons. Benzodiazepines enhance the affinity of the recognition site on the GABA receptor for GABA, resulting in an increase in GABA-mediated inhibition. Activation of the GABA receptor complex is thought to be responsible for producing the therapeutic anti-anxiety effects of benzodiazepines and for mediating many of the side effects of these drugs.
In addition to benzodiazepines, other drugs affect the GABA receptor complex, which serves as a primary site of action of benzodiazepines, barbiturates, and other sedative-hypnotics, such as alcohol. Benzodiazepines and barbiturates act on separate binding sites on the receptor to enhance the inhibitory action of GABA. They do so by altering the receptor so that it has a greater binding affinity for GABA. Ethanol modifies the receptor by altering its membrane environment so that it has increased affinity for GABA and the other sedative-hypnotic drugs. Benzodiazepines, barbiturates, and ethanol all have related actions on a common receptor type (GABA receptors), which explains their pharmacologic synergy and the therapeutic benefit of benzodiazepines in alcohol detoxification.
Side effects
Benzodiazepines are central nervous system depressants, and the major side effects of these drugs are an extension of their actions. However, paradoxical effects such as increased anxiety, hostility, irritability, vivid dreams, psychoses, and confusion have been reported as side effects of this class of drugs. Other acute side effects include skin rash, nausea, headache, vertigo, and irregular menses. Long-term treatment can result in both tolerance (a decrease in efficacy to a repeated dose) and dependence (real or perceived reliance on the drug to function).
Tolerance to all of the actions of benzodiazepines can develop. Tolerance to the hypnotic effects develops rapidly, which is beneficial against daytime anxiety but makes management of insomnia difficult. Initial relief of insomnia is followed by a gradual loss of efficacy. Tolerance to the anxiolytic effect develops more slowly than tolerance to the hypnotic effects, but benzodiazepines often lose their efficacy after four to six months of regular use. Benzodiazepine therapy is often continued to suppress withdrawal symptoms. Dosage escalation maintains tolerance and dependence, and patients may have difficulty discontinuing drug therapy. Thus, after long-term use of benzodiazepines (or ethanol), there is a decrease in the efficacy of GABA receptors, presumably as a result of tolerance. When benzodiazepines or ethanol are abruptly discontinued, this decreased inhibitory neurotransmission is unmasked, leading to withdrawal symptoms such as anxiety, insomnia, autonomic hyperactivity (for example, increased heart rate and dilated pupils), and, possibly, seizures. Withdrawal symptoms emerge with rapid dose reduction or abrupt discontinuation of the drug.
KEY TERMS
Barbiturate —General neuronal depressant.
Central nervous system —The brain and spinal cord.
Gamma amino butyric acid (GABA) —A chemical messenger in the brain that provides neuronal inhibition.
Hypnotic —A drug that produces drowsiness and facilitates the onset and maintenance of sleep.
Neurotransmitters —Chemical messengers that transmit signals between nerves.
Sedative —A drug that decreases activity and calms the recipient.
Long-term use of benzodiazepines may also result in psychologic dependence or “overreliance” on the drug, including a loss of self-confidence and drug-seeking behavior. Patients may be reluctant to discontinue the drug because of anticipatory anxiety.
Interactions
Additive effects with other central nervous system depressants (for example, barbiturates, or ethanol) are the primary drug interactions observed with benzodiazepines.
Resources
BOOKS
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., Text rev. Washington, D.C.: American Psychiatric Association, 2000.
Doble, Adam, Ian Martin, and David J. Nutt. Calming the Brain: Benzodiazepines and Related Drugs from Laboratory to Clinic. London: Taylor and Francis, 2004.
Hardman, Joel Griffith, Lee E. Limbird, and Alfred G. Gilman. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill, 2001.
Andrew J. Bean, PhD