Benzodiazepines drug tolerance

Unlike benzodiazepines, buspirone is not associated with sedative or abuse problems, but some clinicians have observed that bus-pirone s anxiolytic properties do not appear to be as potent as those of benzodiazepines, particularly in patients who have previously received a benzodiazepine. Because buspirone is not sedating and has no psychomotor effects, it has a distinct advantage over benzodiazepines when optimal alertness and motor performance are necessary. Response to buspirone occurs in approximately 2-4 weeks. Buspirone does not show cross-tolerance with benzodiazepines and other sedative or hypnotic drugs such as alcohol, barbiturates, and chloral hydrate. Therefore, buspirone does not suppress benzodiazepine withdrawal symptoms. In anxious patients who are taking a benzodiazepine and who require a switch to buspirone, the benzodiazepine must be tapered gradually to avoid withdrawal symptoms, despite the fact that the patient is receiving buspirone. 

The barbiturates were formerly the mainstay of treatment used to sedate the patient or to induce and maintain sleep. Today, they have been largely replaced by the benzodiazepines, mainly because barbiturates induce tolerance, drug-metabolizing enzymes, physical dependence, and very severe withdrawal symptoms. Foremost is their ability to cause coma in toxic doses. Certain barbiturates, such as the very short-acting thiopental, are still used to induce anesthesia (see p. 115). 

Greenblatt DJ, Shader RI Dependence, tolerance, and addiction to benzodiazepines clinical and pharmacokinetic considerations. Drug Merab Rev 8 13-28, 1978... 

Assess patients for improvement of anxiety symptoms and for return to baseline occupational, social, and interpersonal functioning. With effective treatment, the patient should have no or minimal symptoms of anxiety or depression. While drug therapy is being initiated, evaluate patients more frequently to ensure tolerability and response. Increase the dose in patients exhibiting a partial response after 2 to 4 weeks on an antidepressant or 2 weeks on a benzodiazepine. Individualize the duration of treatment because some patients require up to one year of treatment.27... 

Secobarbital exhibits the same pharmacologic properties as other members of the barbiturate class. Most nonmedical use is with short-acting barbiturates, such as secobarbital. Although there may be considerable tolerance to the sedative and intoxicating effects of the drug, the lethal dose is not much greater in addicted than in normal persons. Tolerance does not develop to the respiratory effect. The combination of alcohol and barbiturates may lead to fatalities because of their combined respiratory depressive effects. Similar outcomes may occur with the benzodiazepines. Severe withdrawal symptoms in epileptic patients may include grand mal seizures and delirium. 

Haefely, W., Biological basis of drug-induced tolerance, rebound, and dependence. Contribution of recent research on benzodiazepines, Pharmacopsychiatry, 19, 353-361,1986. 

Changes have also been reported to occur in the sub-unit composition of the GABA-A receptor following chronic exposure to barbiturates, neurosteroids, ethanol and benzodiazepine agonists. These changes may underlie the development of tolerance, physical dependence and the problems which are associated with the abrupt withdrawal of such drugs. 

The activity of benzodiazepines may be terminated when the drug is removed from the benzodiazepine receptor site and diffuses into peripheral adipose tissue sites and then metabolized in the liver, or when there is a decrease in the sensitivity of the benzodiazepine receptors following chronic exposure to the drug (termed acute tolerance). The rate of development of acute tolerance appears to vary with the different benzodiazepines, making it difficult to relate the changes in therapeutic response to the changes in plasma concentration. 

Benzodiazepines are the drugs of choice for status epilepticus (see above) however, development of tolerance renders them less suitable for long-term therapy. Clonazepam is used for myoclonic and atonic seizures. Clobazam, a 1,5-benzodiazepine exhibiting an increased anticonvulsant/seda-tive activity ratio, has a similar range of clinical uses. Personality changes and paradoxical excitement are potential side effects. 

Drug and alcohol dependent patients Use with caution in patients with alcoholism and other drug dependencies due to the increased frequency of benzodiazepine tolerance and dependence observed in these patient populations. 

However, adverse effects also include dependence and thus drug abuse. Tolerance develops within 3 months for anxiety. However considerable interindividual variability exists for the development of this tolerance. Benzodiazepines have very little effect on respiration which is not seen with sedative doses. In cases involving benzodiazepine intoxication, respiratory assistance has only been needed in patients who had also taken another CNS depressants. 

The current state on the pharmacotherapy of anxiety disorders is summarized by J.R. Nash and D.J. Nutt. The recent shift in clinical practice towards the use of antidepressants, particularly SSRIs, for the first-fine treatment of anxiety disorders is supported by research evidence from randomized controlled trials. It is only in recent years that drugs acting via GABA neurotransmission have been supplanted as first-line treatments, and new drugs in this class with improved tolerability compared to the benzodiazepines are likely to be marketed in the near future. 

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