Sedative-hypnotic drugs tolerance

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

Glutethimide (3-ethyl-3-phenyl-2,6-piperidinedione) is a sedative-hypnotic drug that is now rarely used therapeutically because of wide variation in gastrointestinal absorption, fast development of pharmacodynamic tolerance, a fairly severe discontinuation syndrome, and potential for abuse. Reports of... 

Nontolerant individuals who consume alcohol in large quantities develop typical effects of acute sedative-hypnotic drug overdose along with the cardiovascular effects previously described (vasodilation, tachycardia) and gastrointestinal irritation. Since tolerance is not absolute, even chronic alcoholics may become severely intoxicated if sufficient alcohol is consumed. 

Longer-term difficulties associated with benzodiazepine use for insomnia come from observations that many patients develop tolerance for these agents, so that they stop working after a week or two. To avoid this, patients must take a sleeping pill only a few times within several days, or for only about 10 days in a row followed by several days or weeks with no drug treatment. Furthermore, if patients persist in taking benzodiazepines as sedative-hypnotics for several weeks to months, there can be a withdrawal syndrome once the medications are stopped, particularly if they are stopped suddenly. This is discussed in further detail in Chapter 13. 

Drug combinations Probably the most common combination treatment is concomitant use of an SSRI and a benzodiazepine, especially on initiation of treatment (Fig. 9—6). The benzodiazepines (especially alprazolam and clonazepam) not only appear to act synergistically to increase the onset of therapeutic action and perhaps even boost the efficacy of SSRIs, but they also appear to block the anxiogenic actions of the SSRIs and lead to better tolerability as well as the ability to attain therapeutic dosing levels for the SSRIs. Sometimes sedative-hypnotics such as zale-plon or zolpidem are required in addition to an SSRI, especially on initiation of SSRI treatment. 

Barbiturates (a class of drugs with more effective sedative-hypnotic effects) replaced bromides in 1903. Depending on the dose, frequency, and duration of use, however, tolerance, physical dependence, and psychological dependence on barbiturates can occur relatively rapidly. With the development of tolerance, the margin of safety between the effective dose and the lethal dose becomes very narrow. That is, in order to obtain the same level of intoxication, the tolerant abuser may raise his or her dose to a level that can produce coma and death. 

Regular use of the sedative-hypnotics may result in tolerance—the need for increasing doses to achieve the same effect. Within two to four weeks, tolerance can develop to the sedative effect of minor tranquilizers taken at night for sleep. Thus, these drugs are not usually used prescribed for more than a few days at a time. 

Clinical studies showed that elderly patients are more sensitive to drugs such as sedatives, hypnotics, and analgesics. The most extensive studies show a decrease in responsiveness to /3-adrenoreceptors, stimulants, and blockers. Hypothermia is poorly tolerated by the elderly, as their body temperature regulation is impaired. 

Finally, some people metabolize alcohol more rapidly than others and so can handle larger doses. This may be genetically determined if so, some people could inherit a tendency to become alcoholic. People who drink alcohol regularly metabolize it faster than people who do not, and won t be affected by doses that nondrinkers would certainly feel. This is tolerance, and it develops quickly to alcohol and other sedative-hypnotics. Alcoholics show very high tolerance to the drug they can even survive doses of alcohol that would kill nondrinkers. Other people may have lower than normal abilities to metabolize alcohol. Some Japanese, for example, have an inborn biochemical quirk that causes them to get drunk on doses of wine or liquor that would hardly affect most Americans or Europeans. 

Cross-tolerance means that tolerance to any sedative-hypnotic drug will extend to other drugs in the same class. Cross-dependency means that use of any drug in this class, or any opioid drug will enhance the effects and abusers may turn to other drugs in either category to either supplement their drugs of choice or stand in for them if they are not readily available. 

Benzodiazepines show less tendency to tolerance and dependency than other older sedative-hypnotic drugs, especially barbiturates. Also, benzodiazepines produce less abuse potential. 

Despite the advantages of benzodiazepines compared with other sedative-hypnotic drugs, tolerance and dependency do occur. Rebound insomnia may also occur either during each night of treatment with benzodiazepines or during withdrawal of treatment extended for several days. Cessation of benzodiazepines may also lead to recurrence of the original symptoms or even to transient worsening. 

The effects of benzodiazepines on the waking electroencephalogram (EEC) resemble those of other sedative-hypnotic drugs. Alpha activity is decreased but there is an increase in low-voltage fast activity. Tolerance occurs to these effects. 

Tolerance and dependence Tolerance occurs mainly as a result of CNS adaptation but may be partly caused by an increased rate of ethanol metabolism. There is cross-tolerance to other sedative-hypnotic drugs. Both psychologic and physical dependence are marked, the latter demonstrated by an abstinence syndrome that occurs if a chronic user abruptly discontinues ethanol intake. 

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