Anxiolytics nonbenzodiazepines

OFFICIAL NAMES Minor tranquilizers (sedative-hyp-notics/anxiolytics)/Nonbenzodiazepines Zaleplon (Sonata) zolpidem (Ambien) Buspirone (BuSpar)... 

Nonbenzodiazepine Benzodiazepine Receptor Ligands. The simultaneous discovery of the molecular target for the BZs, the GABA /BZ receptor complex, by two teams of workers (34,35) resulted ia the identification of a number of atypical or anxioselective anxiolytics that, whereas not having the BZ pharmacophore, interacted direcdy with the central BZ receptor. The anxioselective nature of such agents was considered to be... 

B.4.2.2 Nonbenzodlazeptnes GG-NPD was used by Kivisto et al. (1999) to quantitate the nonbenzodiazepine anxiolytic buspirone and its major metabolite, l-(2-pyrimidinyl)-piperazine, using separate extraction methods and separate assays. The hmit of quantification in plasma for both compounds was 0.2 ng/mL, which makes this assay useful for pharmacokinetic studies of this compound (Kivisto et al., 1999). A rapid, simple method for analysis of buspirone in rat brain requiring a single extraction step followed by GC-NPD has also been described (Lai. et al., 1997). 

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. 

Buspirone (Buspar). The first nonsedating, nonbenzodiazepine specifically introduced as an anxiolytic, buspirone is FDA approved for the treatment of GAD. This medication acts as a partial agonist at the postsynaptic serotonin (5HT)-1A receptor. Like the antidepressants, buspirone has a delayed onset of action and effectively relieves the intrapsychic symptoms of GAD. Devoid of the muscle-relaxing properties of benzodiazepines, buspirone does not as effectively relieve the physical symptoms of GAD. Buspirone is not effective in the treatment of depression. Furthermore, its utility for the treatment of anxiety disorders other than GAD appears to be limited. 

Buspirone. A nonbenzodiazepine anxiolytic, buspirone is an effective treatment for generalized anxiety disorder but not other anxiety disorders. There are as yet no published controlled studies of buspirone for PTSD, though a small open label series suggested it might be effective for the core symptoms of PTSD. In the absence of more definitive evidence regarding its effectiveness, we do not routinely use buspirone when treating PTSD. 

Related hypnotics that also act at benzodiazepine receptors are the newer agents zolpidem, a imida-zopyridine, zaleplon a pyrazolopyrimidine and the cyclopyrrolone zopiclone. Zopiclone might have a role for the treatment of benzodiazepine addiction. In patients in whom zopiclone was substituted for a benzodiazepine for 1 month and then itself abmptly terminated, improved sleep was reported during the zopiclone treatment, and withdrawal effects were absent on discontinuation of zopiclone. A series of non-sedating anxiolytic drugs derived from the same structural families as the above mentioned nonbenzodiazepines, have been developed, such as alpi-dem and pagoclone. 

Zolpidem is an imidazopyridine, with a chemical structure of N,N,6-trimethyl-2-(4-methylphenyl)-imidazo [ 1,2-alpha] -pyridine-3-acetamine hemitartrate (Salva and Costa, 1995). This nonbenzodiazepine sedative hypnotic was first released in Europe, and then introduced in the United States in 1993 (Hobbs et ah, 1996). Zolpidem has a strong sedative effect that seems to preclude its use as an anxiolytic. It has only weak anticonvulsant effects (Salva and Costa, 1995 Hobbs et ah, 1996). 

Buspirone is a nonbenzodiazepine anxiolytic that has recently been tested as an anti-ADHD treatment for children. Buspirone has a high affinity to 5-HTi re-... 

Buspirone is a nonbenzodiazepine anxiolytic serotonin 5-HTia partial agonist that may have a role in reducing anxiety, flashbacks, and insomnia (Wells et al., 1991), although no controlled studies of this agent have been published in childhood populations. 

This section describes the partial agonists and the nonbenzodiazepine drugs that act at the benzodiazepine receptor. What these drugs have in common is that their development has been driven by the search for effective anxiolytics that do not have the adverse effects of sedation, amnesia, ataxia, interaction with alcohol, or the problems of tolerance, dependency, and withdrawal seen with classic benzodiazepines. These problems have been addressed by the development of partial agonists, subtype-selective ligands, and other drugs, the cyclopyrrolones, which do not seem to cause these problems. 

Pazinaclone. Pazinaclone is a nonbenzodiazepine partial agonist. Animal work has shown that it has anxiolytic and anticonvulsant activity. Pazinaclone does not, however, produce the sedative, muscle relaxant, or motor coordination effects seen with diazepam (Waka and Fukada 1991). Phase II clinical trials are currently under way in the United States, Europe, and Japan, which have so far demonstrated that it is well tolerated and seems to cause significantly less sedation than do benzodiazepines (Uchiumi et al. 1992). 

Harto N, Branconnier RJ Clinical profile of gepirone, a nonbenzodiazepine anxiolytic. Psychopharmacol Bull 24 154-160, 1988... 

Robinson DR, Shrotriya RC, Alms DR, et al Treatment of panic disorder nonbenzodiazepine anxiolytics, including buspirone. Psychopharmacol Bull 25 21-26, 1989... 

Kastenholz KV, Crimson ML. Buspirone, a novel nonbenzodiazepine anxiolytic. Clin Pharm 1984 3 600-607. 

Insomnia is a common comorbid condition with depression, and frequently is made worse by antidepressants, particularly the SSRIs. When insomnia persists despite adequate evaluation and attempts to reduce it by other approaches, it is often necessary to use a concomitant sedative-hypnotic, especially a short-acting nonbenzodiazepine with rapid onset such as zaleplon or zolpidem. At times a benzodiazepine sedative hypnotic such as triazolam or temazepam may be necessary. If anxiety persists during the day and cannot be otherwise managed, it may be necessary to add an anxiolytic benzodiazepine such as alprazolam or clonazepam. Use of sedative-hypnotics and anxiolytics should be short-term whenever possible. 

The fundamental neurobiological importance of the GABA A receptor is underscored by observations that even more receptor sites exist at or near this complex (Fig. 8—20). This includes receptor sites for nonbenzodiazepine sedative-hypnotics such as zolpidem and zaleplon, for the convulsant drug picrotoxin, for the anticonvulsant barbiturates, and perhaps even for alcohol. This receptor complex is hypothetically responsible in part for mediating such wide-ranging CNS activities as seizures, anticonvulsant drug effects, and the behavioral effects of alcohol, as well as the known anxiolytic, sedative-hypnotic, and muscle relaxant effects of the benzodiazepines. 

Nonbenzodiazepine anxiolytic. Busprione (Bu-Spar) is the first in a class of drugs that specifically work as anxiolytics. In addition to exerting no sedative effect, this medication poses few of the disadvantages associated with the benzodiazepines—such as physical or psychological dependency—and does not significantly interact with most other compounds. 

Buspirone is structurally unrelated to other anxiolytics and was the first nonbenzodiazepine to demonstrate efficacy in GAD. Its mode of action is unclear, although we know it suppresses 5HT neurotransmission through a selective activation of the inhibitory presynaptic 5HT1 -reactor. Buspirone has a tl of 7 h, and is metabolised in the liver it has an active metabolite that may accumulate over weeks. Twice daily dosing is suitable, with the usual range being 15-30 mg/d p.o., maximum 45 mg/d. 

MOA Nonbenzodiazepine hypnotic but binds to benzodiazepine omega-1 receptor in vitro. No musde relaxant anxiolytic or anticonvuisant effects. 

Buspirone is a nonbenzodiazepine anxiolytic that lacks anticonvulsant, muscle relaxant, hypnotic, motor impairment, and dependence properties. It is considered to be a second-line agent for GAD because of inconsistent reports of efficacy, delayed onset of effect (i.e., 2 weeks or longer), and lack of efficacy for other potential comorbid depressive and anxiety disorders (e.g., panic disorder or SAD). " ... 

Zolpidem and zaleplon are nonbenzodiazepines that bind to the BZ, receptors and therefore are more specific hypnotics. Buspirone is an anxiolytic that does not work through the GABA system. It is nonsedating and does not cause dependence but takes a week or two to show antianxiety effects. 

Porter RH, Jaeschke G, Spooren W et al (2005) Fenobam a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther 315 711-721... 

Compound 24 is a gamma-aminobutyric acid (GABA) receptor modulator that interacts with the GABA-A sub-type which is, in turn, the same locale where the classical benzodiazepine anxiolytics are also thought to interact (diazepam or Valium being a common benzodiazepine structure shown above as 57). Although 24 is classed as a nonbenzodiazepine sedative-hypnotic because it has... 

Using molecular biological techniques, point mutations of the a subunits have revealed that the sedative effects of the benzodiazepines likely result from an Interaction with the ai subunit, whereas the anxiolytic effects result from an interaction at the 02 subunit (27,28), as shown in Figure 15.10 and Table 15.3. Nonbenzodiazepine receptor agonists, such as the sedative-hypnotics indiplon, zaleplon, zolpicone, and zolpidem (see Chapter 19), are ai subunit-preferring ligands, as shown in Table 15.3 (29). 

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