Tolerance development barbiturates

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. 

Many CNS depressants have some liability for dependence. This is typically greater with barbiturates, but lesser with benzodiazepines, and perhaps nonexistent in many antiseizure medications. CNS depressants produce tolerance when administered chronically, where increasingly larger doses are required to sustain the same level of effect. Further, a cross-tolerance often develops, where the tolerance is generalized to other CNS depressants. For example, a person with an ethanol tolerance will also display some tolerance to barbiturates. The therapeutic index tends to decrease as tolerance increases, so that the difference between an effective and toxic dose diminishes. Thus, tolerance to CNS depressants is accompanied by a smaller safety margin. 

Tolerance to many of the effects of the depressants develops. Unlike opioids, barbiturate and benzodiazepine tolerance develops slowly. Also, tolerance is incomplete in some instances or does not influence some pharmacological effects. One such exception is the lack of tolerance to barbiturate lethality. The lethal dose in a tolerant individual is not much different from that of the general population. Cross-tolerance develops to some degree between the depressant classes of drugs. 

Barbiturates overdosing may occur readily. Since tolerance develops to the behavioral effects but not to the respiratory effects, increasing the dosage may result in death. Also, because of amnesia-causing effects, people forget that they took their medication and may proceed to take additional doses, which may lead to respiratory depression and death. 

One major reason for the movement away from the medical use of barbiturates involves tolerance and dependence. Tolerance develops fairly rapidly to many effects of the barbiturates. Whereas a given dose may be effective at inducing sleep for a while, if the drug is used regularly the patient soon may require a higher dose in order to sleep. If doses escalate too much and regular use persists, the patient will experience an abstinence syndrome when he or she attempts to withdraw from barbiturates. The symptoms of the barbiturate withdrawal syndrome are similar to those of alcohol— shakes, perspiration, confusion, and in some cases full-blown delirium tremens (DTs) (see Chapter 9)—but convulsions and seizures are more likely to occur in barbiturate... 

Tolerance and abstinence may develop with any of the barbiturates. It has been reported that abrupt withdrawal of secobarbital (given 0.8-2.2 g/d for 6 weeks) causes both minor symptoms (tremors, anorexia, insomnia, and apprehension) and major symptoms (seizures, delirium, and hypothermia) that can persist for up to 2 weeks after discontinuation. Tolerance to barbiturates can develop within 2 weeks of treatment because of induction of hepatic microsomal enzymes (2). 

Barbiturates are rarely used today, and when barbiturate treatment is initiated, it should be restricted to 2 weeks because of the risk of tolerance developing. 

Chlorpromazine produces a tranquihty characterized by a detached serenity without depression of mental faculties or clouding of consciousness. It depresses the CNS selectively by reducing input directed to the reticular formation through collaterals arriving from the sensory pathways. Chlorpromazine-induced sedation differs from that caused by barbiturates in that the patient can be easily aroused. In practice, the more sedative neuroleptics are often prescribed for agitated, overactive patients, and the less sedative agents are used for apathetic, withdrawn patients. However, sedation is not necessary for its antipsychotic property for two reasons (1) tolerance develops to the sedative effects, and (2) fluphenazine, prochlorperazine, and trifluoperazine are excellent neuroleptics that lack pronounced sedative effects. 

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... 

Secobarbital exhibits the same pharmacologic properties as other members of the barbiturate class. Most nonmedical use is with short-acting barbiturates, such as secobarbital. Although there may be considerable tolerance to the sedative and intoxicating effects of the drug, the lethal dose is not much greater in addicted than in normal persons. Tolerance does not develop to the respiratory effect. The combination of alcohol and barbiturates may lead to fatalities because of their combined respiratory depressive effects. Similar outcomes may occur with the benzodiazepines. Severe withdrawal symptoms in epileptic patients may include grand mal seizures and delirium. 

The side effects of barbiturates include sedation, poor physical coordination, and impaired mental performance. They also potentiate the intoxicating effects of alcohol. Barbiturates can be extremely dangerous in overdose, causing anesthesia, coma, and even death. In addition, barbiturates can cause dangerous suppression of breathing in patients with sleep apnea or other respiratory disorders. With repeated use over just a few weeks, physical dependence and tolerance to their effects can develop, leading to increasing doses to maintain the desired therapeutic effect. If a... 

Barbiturates. The first barbiturate, barbital, was introduced at the turn of the 20th century. Hundreds of others, including phenobarbital and pentobarbital, were later developed. The barbiturates were a highly successful class of medications as it became clear that they treated not only alcohol withdrawal but seizure disorders, anxiety, and insomnia as well. By the 1960s, however, the barbiturates were largely surpassed by the benzodiazepines. The newer benzodiazepines act in a similar fashion and provide much the same therapeutic benefit but are significantly safer and easier to tolerate. 

Like the barbiturates, the benzodiazepines make it easier to fall asleep and to stay asleep through the night. However, they also suppress REM sleep, which can lead to REM rebound when they are discontinued. Tolerance to their sleep-promoting effects often develops after chronic use. Some long-acting benzodiazepines, such as flurazepam (Dalmane), are associated with pronounced hangover effects in the morning and are therefore problematic as sedative-hypnotics. Others, with a short-to-intermediate dnration of action, are more desirable as hypnotics. 

Changes have also been reported to occur in the sub-unit composition of the GABA-A receptor following chronic exposure to barbiturates, neurosteroids, ethanol and benzodiazepine agonists. These changes may underlie the development of tolerance, physical dependence and the problems which are associated with the abrupt withdrawal of such drugs. 

Pharmacodynamic tolerance, probably on the basis of down-regulation of receptors, develops more rapidly to the effects of barbiturates on mood and sedation than to the anticonvulsant and lethal action. This results in a marked decrease in therapeutic index and the ratio of LD50 and ED50 can approach 1. Furthermore, barbiturates induce P450 enzymes and thus increase their own metabolism resulting in time dependent pharmacokinetic behavior. 

Geriatric Considerations - Summary Because barbiturates have a low therapeutic window, a wide range of drug interactions, rapid development of tolerance, and great potential for abuse and dependence, these agents are not recommended for use in older adults. 

Cross tolerance is development of tolerance to pharmacologically related drugs e.g. morphine and barbiturates. 

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. 

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