Tolerance and Withdrawal

Pharmacodynamic tolerance to barbiturates develops over weeks to months, whereas pharmacokinetic tolerance occurs in a period of days. At maximum tolerance, the dosage of a barbiturate may be six times the original dosage. 

Pentobarbital withdrawal may involve a distal region of the chromosome 1 in the mouse (Buck et al. 1999), a site that may be identical to that associated with alcohol withdrawal. This finding suggests that common genes may be involved in both ethanol and pentobarbital dependence. 

Anorexia and vomiting Postural faintness, orthostatic hypotension 

There are three common protocols for barbiturate detoxification. In all approaches, the goal is to prevent the occurrence of major symptoms and to minimize the development of intolerable minor symptoms. The first procedure is based on protocols described by several authors (Ewing and BakeweU 1967 Isbell 1950 Wilder 1968) (see Table 3 ). The first step is to determine the severity of tolerance. If the patient is intoxicated, no additional barbiturate should be given until the symptoms of intoxication have resolved. If there is substantial evidence or strong suspicion of chronic barbiturate use, it is not necessary or desirable to wait until withdrawal symptoms appear. A 200-mg oral dose of pentobarbital may be given on an empty stomach to a 

Symptoms after test dose Estimated 24-hour Estimated 24-hour 

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Diagnostic criteria for inhalant use disorders in DSM-IV-TR are similar to those in the International Classification of Diseases, Tenth Revision (ICD-10) (World Health Organization 1992). These criteria include biological, cognitive, and behavioral dimensions. The DSM-IV-TR diagnosis of inhalant dependence is given when three or more of the seven criteria are present (see Table 8-2). The first criteria to be considered here are tolerance and withdrawal. These phenomena are considered to be forms of adaptation to chronic administration of these compounds and were discussed extensively earlier in this chapter. 

Another way to conceptualize drug problems is to examine psychological versus physical dependence on a substance. Psychological dependence is defined by beliefs A person thinks he or she needs the substance in order to cope. Physical dependence, on the other hand, is defined by actual physical changes related to drug use that may result in withdrawal symptoms and tolerance. However, to confuse matters, recreational users also may experience tolerance and withdrawal, so it is important to be careful when using these distinctions to define whether a person has a drug problem. 

Houtsmuller EJ, Walsh SL, Schuh KJ, Johnson RE, Stitzer ML, Bigelow GE. (1998). Dose-response analysis of opioid cross-tolerance and withdrawal suppression during LAAM maintenance. J Pharmacol Exp Ther. 285(2) 387-96. 

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... 

With respect to veterinary medicines, the US-FDA establishes tolerances to include a safety factor to assure that the drug will have no harmful effects on consumers of the food product. The US-FDA first determines the level at which the dmg does not produce any measurable effect in laboratory animals. From this, the US-FDA determines an acceptable daily intake (ADI), and the drug tolerance and withdrawal times are then determined so that the concentrations of dmg residues in edible tissues are below the ADI. Depending on the dmg, safety factors of between 100-fold to 2000-fold are included in the calculations used to set the tolerances. 

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. 

Kendler, K. S. and C. A. Prescott. Caffeine intake, tolerance, and withdrawal in women a population-based twin study. Am J Psychiatry 1999 156(2) 223-228. 

Tolerance and withdrawal symptoms milder than with opiates... 

Alprazolam has caused a lower incidence of drowsiness, light-headedness and depression than diazepam. Alprazolam, like other benzodiazepines, has the potential for the development of tolerance and withdrawal symptoms, although the incidence is lower than that seen with other benzodiazepines. Alprazolam s potential for drug dependence is less in comparison to other benzodiazepines. 

The development of tolerance and withdrawal would be unlikely at therapeutic doses. 

We may or may not want to say that the rat is addicted to brain stimulation, which produces craving but not tolerance and withdrawal symptoms. Yet the syndrome described in the passage is one that matches a widespread view of the behavior of addicts. Compare, for instance, the rat in front of the aversive grid with a habitual drunkard as described by a nineteenth-century pioneer in the study of alcohol, Benjamin Rush "When strongly urged, by one of his friends, to leave off drinking, he said, Were a keg of rum in one comer of a room, and were... 

ADDICTION Physical dependence on a drug characterized by tolerance and withdrawal. 

Evidence of long-term effectiveness, tolerance, and withdrawal effects... 

Dependence refers to any one or the combination of cognitive, behavioral, and physical symptoms that indicate that the individual continues to use the substance in spite of significant harm or life problems. Typically a person who has substance dependence also experiences tolerance and withdrawal, as well as compulsive use and drug-seeking behavior. 

When considering the issnes of alcohol tolerance and withdrawal, it is usefnl to review what is expected for the normal person in response to varions blood alcohol levels (BALs) ... 

Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal... 

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