Barbiturates tolerance

Barbiturates induce hepatic microsomal drug-metabolizing enzymes resulting in an increased degradation of barbiturates, ultimately leading to barbiturate tolerance. 

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. 

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... 

Decrease baroreflex sensitivity Decrease -receptor response Decrease 2 -receptor response Increase sensitivity to barbiturates Decrease glucose tolerance... 

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. 

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. 

Barbiturates additional 5-7 days Pentobarbital tolerance test initial detoxification at B3... 

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. 

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... 

Historically, the treatment of alcohol use disorders with medication has focused on the management of withdrawal from the alcohol. In recent years, medication has also been used in an attempt to prevent relapse in alcohol-dependent patients. The treatment of alcohol withdrawal, known as detoxification, by definition uses replacement medications that, like alcohol, act on the GABA receptor. These medications (i.e., barbiturates and benzodiazepines) are cross-tolerant with alcohol and therefore are useful for detoxification. By contrast, a wide variety of theoretical approaches have been used to reduce the likelihood of relapse. This includes aversion therapy and anticraving therapies using reward substitutes and interference approaches. Finally, medications to treat comorbid psychiatric illness, in particular, depression, have also been used in attempts to reduce the likelihood of relapse. 

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. 

Benzodiazepines. Like the barbiturates, benzodiazepines bind to the GABA receptor and are therefore cross-tolerant with alcohol. As a result, they also make suitable replacement medications for alcohol and are widely used for alcohol detoxification. Theoretically, any benzodiazepine can be used to treat alcohol withdrawal. However, short-acting benzodiazepines such as alprazolam (Xanax) are often avoided because breakthrough withdrawal may occur between doses. Intermediate to long-acting benzodiazepines including chlordiazepoxide (Librium), diazepam (Valium), oxazepam (Serax), lorazepam (Ativan), and clonazepam (Klonopin) are more commonly utilized. 

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. 

Carbromal (Uradal, Adalin.) 1 mole of a-bromo-a-ethyl butyryl bromide is mixed with dry urea (1 mole) and heated on a steam bath for several hours. Precautions must be taken to keep steam and atmospheric H2O from the reaction vessel. Cool, allow to solidify, wash with H2O, and recrystallize from alcohol. Dose (sedative) 300 to 500 mg, (hypnotic) 700 to 950 mg, mp 116-118°. This drug is less potent than the barbiturates, but it is less toxic, extremely well tolerated, has a wide margin of safety, and acts rapidly. 

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. 

Tolerance may occur which means that the effect of some AEDs may wear off with time (benzodiazepines, barbiturates, vigabatrin). There are exceptional cases where refractory epilepsy escapes... 

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. 

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. 

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