Anxiolytics tolerance

The CCK system shares one property with the opioid system, ie, the existence of selective nonpeptide antagonists. These include aspedicine, a natural benzodiazepine (136), and Devazepide (L-364,718 MK-329) (137). Selective, potent peptide antagonists for CCK, eg, Cl-988 and PD 134308, have been developed that maybe useful as anxiolytics and as dmgs which increase the analgesic effect of morphine but at the same time prevent morphine tolerance (138) (see Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

Pharmacodynamic tolerance to the psychomotor effects of benzodiazepines has been demonstrated after single or multiple doses (File 1985 Greenblatt and Shader 1978 Rosenberg and Chiu 1985). Pharmacodynamic tolerance to the anxiolytic effect (over a 6-month period) has not been demonstrated (Rickels et al. 1983), and clinical experience supports the view that many patients with anxiety disorders require long-term therapy with benzodiazepines or alternative antianxiety agents. An important clinical consequence of tolerance to sedative effects is observed in benzodiazepine overdoses, when patients may initially be... 

In the case of chronic processes, the patient can, at any time, take the decision to stop the treatment, as a reaction to changes in price or other variables. Whereas the econometric technique for analysing the demand for pharmaceuticals for acute processes is that of discrete choice models, here we will apply duration or survival models. In addition, the technology of drags for chronic diseases can have non-constant returns to scale. For example, the consumption of anxiolytics raises the tolerance and reduces the effect, resulting in an increase in the necessary dose. 

Zolpidem, chemically unrelated to benzodiazepines or barbiturates, acts selectively at the y-aminobutyric acidA (GABAA)-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. It is comparable in effectiveness to benzodiazepine hypnotics, and it has little effect on sleep stages. Its duration is approximately 6 to 8 hours, and it is metabolized to inactive metabolites. Common side effects are drowsiness, amnesia, dizziness, headache, and GI complaints. Rebound effects when discontinued and tolerance with prolonged use are minimal, but theoretical concerns about abuse exist. It appears to have minimal effects on next-day psychomotor performance. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Cases of psychotic reactions and sleep-eating have been reported. 

Catania MA, Firenzuoli F, Crupi A, Mannucd C, Caputi AP, Calapai G (2003) Hypericum perforatum attenuates nicotine withdrawal signs in mice. Psychopharmacology 169 186-189 Cheeta S, Irvine EE, Kenny PJ, File SE (2001) The dorsal raphd nucleus is a crucial structure mediating nicotine s anxiolytic effects and the development of tolerance and withdrawal responses. Psychopharmacology 155 78-85... 

The word "tolerability" is perhaps a little clumsy but it describes accurately what is assessed, namely how well the drug is tolerated by those to whom it is administered. This last qualification is necessary because there are many instances in which a drug is better tolerated or less well tolerated by young healthy volunteers than by patients. For example, anxiolytics and tricyclic antidepressants are usually far better tolerated by patients with depression than by healthy volunteers. However, healthy volunteer studies generally provide useful information about tolerability even if it may under- or overestimate tolerability in patients. Many adverse reactions wiU be directly related to the known pharmacological activity of the drug and are therefore predictable. 

The longstanding use in some countries of hydroxyzine, a centrally-acting Hi-histamine receptor antagonist, is supported by positive findings in controlled trials in GAD (Ferreri and Hantouche 1998 Lader and Scotto 1998). Hydroxyzine promotes sleep and its anxiolytic effects have an early onset. Although it causes sedation, tolerance to this effect often occurs and effects on psychomotor performance are smaller than with benzodiazepines (de Brabander and Deberdt 1990). It is well-tolerated and withdrawal effects have not been reported. Although the evidence for its efficacy is not large, hydroxyzine provides an option for some patients with GAD for whom standard treatments are unsuitable. 

Dunn R, Reed TA, Copeland PD, Frye CA (1998) The nitric oxide synthase inhibitor 7-nitroindazole displays enhanced anxiolytic efficacy without tolerance in rats following subchronic administration. Neuropharmacology 37 899-904 Freeman AR, Westphal J, Norris G, Roggero B, Webb P, Freeman K (1997) Efficacy of ondansetron in the treatment of generalized anxiety disorder. Depress Anxiety 5 140-141... 

Long-term use is not recommended in most children and adolescents, but when it does occur, patients may develop tolerance to many of the side effects, particularly sedation. Tolerance does not appear to develop toward the anxiolytic effects, and the vast majority of patients do not require escalating doses once a therapeutic effect is found (Lader, 1987 Hobbs et al., 1996). 

Tropisetron. The 5-FIT3 antagonist tropisetron has also been reported to be effective in the treatment of patients with generalized anxiety disorder [Lecrubier et al. 1993). The anxiolytic effect of tropisetron develops quickly, is dose dependent, and is accompanied by satisfactory tolerability and safety. The incidence of adverse events, including headache, nausea, constipation, and nervousness, is low and the severity is generally mild. The most typical adverse effects of benzodiazepine anxiolytics, such as fatigue, muscle relax-... 

In conclusion, neurosteroid-based anxiolytics with low intrinsic toxicity may represent an exciting new pharmacological development with potential advantages over existing classes of anxiolytics with regard to tolerance, dependence, and abuse liability. 

The Y -aminobutyric acid-A receptor (GABAjJ is a macromolecular complex through which a variety of ligands act. Our understanding of this receptor complex and the mechanism of action of these ligands has expanded rapidly over recent years. This is as a consequence of substantial developments in the fields of molecular biology and immunochemistry and has been fueled by the as yet elusive quest for effective anxiolytics that do not have the problems associated with the benzodiazepines, that is, adverse effects, interaction with alcohol, and the related issues of tolerance, dependency, and problems on withdrawal. 

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. 

Several partial agonists are currently in development. Some are described in this section, others are described in the sections on subtype-selective drugs and the cyclopyrrolones. The work so far has tended to show the hoped-for features of lack of adverse effects, lack of interaction with alcohol, and reduced liability to cause tolerance, in addition to being effective anxiolytics. 

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). 

Alpidem. Alpidem is an imidazopyridine partial agonist that also shows relative selectivity for the type I benzodiazepine receptor. Studies have shown an anxiolytic effect comparable with the classic benzodiazepines, but with an improved adverse effect profile [Pancheri et al. 1993). It has also been compared with buspirone in patients with generalized anxiety disorder and shown to be more rapidly effective and again to have a more favorable adverse effect profile [Legris et al. 1993). Longer-term studies with alpidem have shown that tolerance does not occur, and no significant problems of withdrawal on discontinuation were found [Chevalier et al. 1993). Alpidem was licensed in France for the treatment of anxiety but has now been suspended because of recent reports of alpidem-induced hepatic dysfunction. The reason for this is unclear, but it may be a reflection of the fact that alpidem also binds to peripheral benzodiazepine receptors, which are present in high density in the liver. 

Suriclone. Suriclone is one of the most potent of all agents known to act at the benzodiazepine receptor. Its anxiolytic effects have been clearly demonstrated in rodents (Doble et al. 1992). It has also been demonstrated to be efficacious in the treatment of generalized anxiety disorder in humans (Ansseau et al. 1991). Animal work has shown it to have fewer side effects and less potential for interacting with alcohol than do benzodiazepines. These would represent significant advantages if they were also seen in humans. Repeated doses have failed to show tolerance and do not produce the change in set point of the GABAj receptor seen with the benzodiazepines. The reason for this is unclear but may be linked to a difference in the interaction of the cyclo-pyrrolones with the receptor compared with that of the benzodiazepines. 

Use of the extended-release (XL) preparation is recommended because of increased tolerability, decreased seizure risk, and the increased ease of use associated with a once-a-day preparation. Treatment with the sustained-release (SR) or XL preparation is initiated at a dose of 150 mg, preferably taken in the morning. After 4 days, the dosage may be increased to 150 mg twice a day (SR) or 300 mg once daily in the morning (XL). Gradual dose titration helps to minimize initial anxiety and insomnia. Temporary use of anxiolytic or hypnotic agents is reasonable in some patients but generally should be limited to the first few weeks of treatment. 

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 generally excellent tolerability of these preparations has contributed greatly to the widespread use of anxiolytics. The commonest side effects (Table 1.11) are tiredness and muscle relaxation and these usually can be avoided or attenuated by reducing the dose. Ataxia and paradoxical reactions such as irritability and increased agitation occasionally arise in the elderly but are rare in younger patients. Much attention has been focused on the negative effects of benzodiazepines on memory and other cognitive functions (see Chapter 7). 

In this category of models the animal learns a performance, typically to abstain from a behavior that it would normally display according to its natural and current tendency. For example, in the so-called Vogel test a partly water-deprived and thirsty rat learns that, during a signaled period, every lick at the water spout will be followed by a mild electric foot-shock. This sequence induces anxiety and an untreated (control) animal will abstain from drinking. However, animals pretreated with anxiolytic drugs will overcome their inhibition and tolerate at least some of the shocks and drink even when punished. 

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