Market, benzodiazepines

Benzodiazepines have a low risk for abuse in anxiety disorder patients without a history of alcohol or other substance abuse. Among the benzodiazepines there may be a spectrum of abuse liability, with drugs that serve as prodrugs for desmethyldiazepam (e.g., clorazepate), slow-onset agents (e.g., oxazepam), and partial agonists (e.g., abecarnil) having the least potential for abuse. However, there is no currently marketed benzodiazepine or related drug that is free of potential for abuse. 

Clobazam is not available in the USA but is marketed in most countries and is widely used in a variety of seizure types. It is a 1,5-benzodiazepine (other marketed benzodiazepines are 1,4-benzodiazepines) and reportedly has less sedative potential than benzodiazepines marketed in the USA. Whether the drug has significant clinical advantages is not clear. It has a half-life of 18 hours and is effective at dosages of 0.5-1 mg/kg/d. It does interact with some other antiseizure drugs and causes adverse effects typical of the benzodiazepines efficacy, in some patients, is limited by the development of tolerance. 

Partial agonists at benzodiazepine receptors As discussed for general anxiolytic agents in Chapter 8, the partial benzodiazepine agonists could be a theoretical advance over the marketed benzodiazepines. Partial agonists should have the same efficacy as full agonists but less potential for sedation, dependence, and withdrawal effects. 

Shader Rl, Greenblatt DJ. Can you provide a table of equivalences for benzodiazepines and other marketed benzodiazepine agonists J Clin Psy-chopharmacol 1997 17 331. 

In general, with the exception of the central role that benzodiazepines play in the treatment of alcohol withdrawal, the use of medications that have been approved for alcoholism rehabilitation remains very limited. A survey of nearly 1,400 addiction physicians showed that they prescribed disulfiram to only 9% of their alcoholic patients and that naltrexone was prescribed for only slightly higher proportion of patients (13%) (Market al. 2003). These tesults contrast with findings for antidepressants, which were prescribed to 44% of alcoholic patients. Although neatly all of these physicians had heatd of both disulfiram and naltrexone, their self-reported level of knowledge of these medications was much lowet than that of antidepressants. 

Medical use of benzodiazepines has been declining. Prescribing trends show an overall decline in the number of all benzodiazepine prescriptions written, with a market shift to increased prescribing of short elimination half-life agents (lorazepam, alprazolam), compared with long-elimination half-life agents (diazepam, chlordiazepoxide) (Ciraulo et al. 2004). In 2001, alprazolam was the most widely prescribed benzodiazepine (Ciraulo et al. 2004), and it also was the most widely prescribed psychiatric medication in that year for mood and anxiety disorders (Stahl 2002). 

Tricyclic antidepressants are not licensed for use in the anxiety disorders, so in theory the SSRIs should not be compared with them in cost-effectiveness terms. The SSRIs and venlafaxine are supplanting benzodiazepines as the latter s long-term problems become more appreciated. The SSRIs will take an increasing proportion of the market. However, in comparison with the overall costs of the anxiety disorders, this drug expenditure can be justified. Further cost-offset and cost-effectiveness studies will help hammer this point home. 

Marketed compounds display well-known efficacy in inducing sleep onset, but many fail in the maintenance of sleep throughout the night due to short half-lives. On the other hand, longer acting compounds, such as the benzodiazepines, elicited significant next-day adverse effects. Therefore, the balance between sustained efficacy and adequate pharmacokinetic profile remains to be solved. 

The most commonly used therapies for anxiety and depression are selective serotonin reuptake inhibitors (SSRIs) and the more recently developed serotonin noradrenaline reuptake inhibitors (SNRIs). SSRIs, which constitute 60% of the worldwide antidepressant and antianxiety market, are frequently associated with sexual dysfunction, appetite disturbances and sleep disorders. Because SSRIs and SNRIs increase 5-HT levels in the brain, they can indirectly stimulate all 14 serotonergic receptor subtypes [2,3], some of which are believed to lead to adverse side effects associated with these drugs. Common drugs for short-term relief of GAD are benzodiazepines. These sedating agents are controlled substances with addictive properties and can be lethal when used in combination with alcohol. The use of benzodiazepines is associated with addiction, dependency and cognitive impairment. 

A therapeutic alternative for treatment of anxiety and depression is the use of 5-HT1A agonists. Azapirones comprise the major class of 5-HT1A agonists of which buspirone (Buspar [4]) is the only FDA-approved 5-HT1A selective agonist (relative to the other 13 serotonin receptor subtypes) for anxiety currently on the US market (Scheme 19.1). Buspirone has shown efficacy in randomized controlled trials of GAD for which it was approved [5-7]. Unlike benzodiazepines, buspirone is not addictive... 

Benzodiazepines. The benzodiazepines were developed in the 1950s and introduced into the U.S. market in the 1960s. They have found a variety of uses including the treatment of several anxiety disorders, insomnia, seizure disorders, alcohol withdrawal, surgical anesthesia, and others. The benzodiazepines have also been used to calm agitated patients and are therefore useful during the acute treatment phase of bipolar mania. 

Azapirones. Though several azapirones have been developed and tested in the laboratory setting, only one, bnspirone (Bnspar), is currently on the market. Buspirone is the first nonsedating, nonbenzodiazepine anxiolytic, other than the antidepressants described earlier. It has no dependence or addictive liability and is not lethal in overdose. Buspirone is also devoid of many of the problems of the benzodiazepines such as sedation, motor impairment, addiction, physical dependence, or withdrawal. Yet, doubts remain in the minds of many practitioners regarding the effectiveness of buspirone. This will be discussed in more detail later in this chapter. 

The benzodiazepines that have been most commonly marketed as sedative-hypnotics include temazepam (Restoril), estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), and triazolam (Halcion). Of these five, temazepam is the most easily metabolized and eliminated. Therefore, temazepam is preferred for elderly and medically ill patients to minimize the risk of drug accumulation. 

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. 

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. 

The basic chemical structure of the benzodiazepines consists of a benzene ring coupled to a seven-member heterocyclic structure containing two nitrogens (di-azepine) at positions 1 and 4 (Fig. 30.1). Of the 2,000 benzodiazepines that have been synthesized, approximately 15 clinically useful compounds are on the market in the United States (Table 30.1). 

Benzodiazepines are very important drugs from a turnover point of view. A large number of these compounds has been synthesized, developed and marketed (about thirty have been launched), a dozen of which contain fluorine atoms. Specific clinical indications for each compound do not result from a difference in the mechanism but from the pharmacokinetic and pharmacodynamic behavior of each one. 

During the early twentieth century the barbiturates were used in children and adolescents for their sedative and hypnotic effects however, their safety profile and propensity to cause physical dependence led scientists in search of safer anxiolytics. The development of animal models of behavioral disorders facilitated the formulation of drugs with more specific central nervous system (CNS) effects. In 1959, chlordiazepoxide (Librium) was the first benzodiazepine (BZ) to receive a patent. It entered the market in 1960, followed by diazepam (Valium) in 1963. Today, over 35 BZs have been formulated and over 10 are available in the United States (Ballenger, 1995 Hobbs et ah, 1996). 

Zolpidem. Zolpidem is an imidazolopyridine that, like CL 218,872, binds with high affinity to aip2Y2 receptors. In contrast to CL 218,872, zolpidem differentiates within benzodiazepine type 11 receptors in that it displays a 20-fold reduced affinity at 02 2 2 rid otjpjyj receptors, but shows nearly no affinity to 0C5P2y2 receptors (Pritchett and Seeburg 1990). Zolpidem is also unusual in that it has sedative activity at lower doses than those producing anxiolytic, muscle relaxant, and anticonvulsant effects and is consequently marketed for night sedation. 

Zopiclone. Zopiclone is a full agonist that has been shown to have sedative properties in experimental animals and to be a potent hypnotic in humans. It has a short duration of action and minimal effects on sleep architecture, which means that it has few residual effects on waking. It appears to cause less tolerance and problems on withdrawal than the classic benzodiazepines and is currently marketed as a hypnotic. 

Some 25 anxiolytics and hypnotics are marketed at present the best known of these are listed in Table 1.10. Here, again., there are striking differences between the doses of these products, which can be explained m the same way as for antipsychotics. The benzodiazepine derivatives and related compounds show few qualitative differences nevertheless, the time effect features, i.e. the timing of onset of action and peak action as well as duration of action, mean that it is sensible to use different products for different purposes. 

---