Barbiturates general anesthetic

Although most anesthetics are achiral or are adininistered as racemic mixture, the anesthetic actions are stereoselective. This property can define a specific, rather than a nonspecific, site of action. Stereoselectivity is observed for such barbiturates as thiopental, pentobarbital, and secobarbital. The (3)-enantiomer is modestly more potent (56,57). Additionally, the volatile anesthetic isoflurane also shows stereoselectivity. The (3)-enantiomer is the more active (58). Further evidence that proteins might serve as appropriate targets for general anesthetics come from observations that anesthetics inhibit the activity of the enzyme luciferase. The potencies parallel the anesthetic activities closely (59,60). 

Pharmacological Profiles of Anxiolytics and Sedative—Hypnotics. Historically, chemotherapy of anxiety and sleep disorders rehed on a wide variety of natural products such as opiates, alcohol, cannabis, and kawa pyrones. Use of various bromides and chloral derivatives ia these medical iadications enjoyed considerable popularity early ia the twentieth century. Upon the discovery of barbiturates, numerous synthetic compounds rapidly became available for the treatment of anxiety and insomnia. As of this writing barbiturates are ia use primarily as iajectable general anesthetics (qv) and as antiepileptics. These agents have been largely replaced as treatment for anxiety and sleep disorders. 

Although PCP was developed as an anesthetic, its profile as an anesthetic is very different from typical general anesthetics of the CNS-depressant class (Domino 1964). Nonetheless, PCP has a number of behavioral and pharmacological effects similar to those of depressants such as the barbiturates (Balster and Wessinger 1983). PCP has profound motor effects, as evidenced by effects on rotorod performance and similar measures (Kalir et al. 1969 ... 

The GABA-gated chloride ion channel is modulated by several classes of drugs that bind to allosteric sites on the receptor complex the benzodiazepines, barbiturates and related intravenous general anesthetics such as etomidate and propofol, as well as anesthetic steroids and endogenous neurosteroids. It appears that some types of GABAa receptor are directly enhanced by ethanol and volatile general anesthetics (Fig. 16-2) [7,8,20]. 

Behaviorai effects Opioids produce sedation, but not as profoundly as CNS depressants like barbiturates or general anesthetics. A person administered an opioid is generally lethargic but arousable. 

Unlike barbiturates, benzodiazepine derivatives administered orally lack a general anesthetic action cerebral activity is not globally inhibited (respiratory paralysis is virtually impossible) and autonomic functions, such as blood pressure, heart rate, or body temperature, are unimpaired. Thus, benzodiazepines possess a therapeutic margin considerably wider than that of barbiturates. 

In surgical practice, two barbiturates are primarily used thiopental and methohexital. However, it should be stated that barbiturates are hypnotics, and at therapeutic doses has a very weak analgesic and muscle relaxant effect, which general anesthetics must possess. 

Since general anesthetics are related to a variety of classes of chemical compounds, there is no general pattern that exists between their chemical structure and their activity. Particular patterns only exist for different groups of compounds (barbiturates, benzodiazepines, etc.). 

Figure 4.12 The GABA-A channel functions as a receptor for many multiple different drug classes, including benzodiazepines (e.g., diazepam) and barbiturates (e.g., phenobarbital). There is also a steroid-binding site on the GABA-A channel which may be useful in the future design of general anesthetics.

Estazolam potentiates the CNS depressant effects of phenothiazines, narcotics, antihistamines, MAOIs, barbiturates, alcohol, general anesthetics, and TCAs. Use with cimetidine, disulfiram, oral contraceptives, and isoniazid may diminish hepatic metabolism and result in increased plasma concentrations of estazolam and increased CNS depressant effects. Fleavy smoking (more than 20 cigarettes/day) accelerates estazolam s clearance. Theophylline antagonizes estazolam s pharmacological effects. 

Triazolam potentiates the CNS depressant effects of phenothiazines, narcotics, antihistamines, MAOIs, barbiturates, alcohol, general anesthetics, and antidepressants. Use with cimetidine and disulfiram may increase triazolam s plasma concentration. 

SAFETY PROFILE Poison by ingestion, intraperitoneal, rectal, subcutaneous, and intravenous routes. Human systemic effects by intraarterial route acute arterial occlusion by rectal route respiratory depression, body temperature decrease, general anesthetic. An experimental teratogen. Experimental reproductive effects. An intravenous anesthetic. When heated to decomposition it emits toxic fumes of NOx and Na20. See also PENTOTHAL and BARBITURATES. 

As noted under the heading of general anesthetics, there are other allosteric sites that recognize re.spectively. neuro-.stcroids. barbiturates, inhalation anesthetics, alcohols and the phenol Diprivan (.separate sites). The convuLsants picro-toxin and pcntylenetetrazole have definite binding sites on GABA receptors. 

Intravenous anesthetics are also relatively lipid-soluble, which helps account for their rapid onset. This high degree of lipid solubility allows them to rapidly cross the blood-brain barrier and partition into the brain. Barbiturates such as thiopental and methohexitol and the nonbarbiturates etomidate and propofol are often used to induce anesthesia, but only propofol is commonly used today as a general anesthetic by continuous infusion, thus only propofol will be discussed. 

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