Anesthetics barbiturates

MacDonald, R.L. and Barker, J.L., Anticonvulsant and anesthetic barbiturates different postsynaptic action in cultured mammalian neurons, Neurology, 29, 432-4-11, 1979. 

The barbiturates were used extensively in the past as hypnotic sedatives, but have been replaced by the much safer benzodiazepine derivatives. They do continue to be used as anesthetics and as anticonvulsants. The primary mechanism of action of barbiturates is to increase inhibition through the GABA system. Anesthetic barbiturates also decrease excitation via a decrease in calcium conductance. 

Toxicants may have three effects on pulse rate bradycardia (decreased rate), tachycardia (increased rate), and arrhythmia (irregular pulse). Alcohols may cause either bradycardia or tachycardia. Amphetamines, belladonna alkaloids, cocaine, and tricyclic antidepressants (see imi-primine hydrochloride in Figure 6.12) may cause either tachycardia or arrhythmia. Toxic doses of digitalis may result in bradycardia or arrhythmia. The pulse rate is decreased by toxic exposure to carbamates, organophosphates, local anesthetics, barbiturates, clonidine, muscaric mushroom toxins, and opiates. In addition to the substances mentioned above, those that cause arrhythmia are arsenic, caffeine, belladonna alkaloids, phenothizine, theophylline, and some kinds of solvents. 

Phenobarbital is used to treat seizures, and thiopental is used as an IV anesthetic. Barbiturates induce deep CNS depression at high doses, and there is no antidote. 

Amobarbital, a barbiturate, is used as a sedative to treat insomnia and as a preanesthetic medication. The barbiturates were used extensively in the past as hypnotic-sedatives but have been replaced by the much safer benzodiazepine derivatives (see Table 9). They do continue to be used as anesthetics (e.g., thiopental) and anticonvulsants (e.g., phenobarbital). The primary mechanism of action of barbiturates is to increase inhibition through the gamma-aminobutyric acid (GABA) system (see Figure 50). Anesthetic barbiturates also decrease excitation via a decrease in calcium conductance. The most commonly used barbiturates are thiopental (Pentothal), methohexital (Brevital), secobarbital (Seconal), pentobarbital (Nembutal), amobarbital (Amytal), and phenobarbital (Luminal). 

Cardiovascular The anesthetic barbiturates produce dose-dependent decreases in blood pressure that are due primarily to vasodilation, particularly venodUation, and to a lesser degree to a direct decrease in cardiac contractility. Typically, heart rate increases as a compensatory response to a lower blood pressure, although barbiturates also blunt the baroreceptor reflex. 

Respiratory Barbiturates are respiratory depressants. Induction doses of thiopental decrease minute ventilation and tidal volume with a smaller and inconsistent decrease in respiratory rate reflex responses to hypercarbia and hypoxia are diminished by anesthetic barbiturates at higher doses or in the presence of other respiratory depressants such as opiates, apnea can result. With the exception of uncommon anaphylactoid reactions, these drugs have little effect on bronchomotor tone and can be used safely in asthmatics. 

Intravenous anesthetics Barbiturates Thiopental Thiamylal, methohexital... 

The MAOIs interfere with the hepatic metabolism of many prescription and nonprescription (over-the-counter) drugs and may potentiate the actions of their pharmacological effects (i.e., cold decongestants, sympathomimetic amines, general anesthetics, barbiturates, and morphine). 

Drugs implicated 3-Lactams other antibacterials NMBDs some NSAIDs quinolones mAbs proton pump inhib s P-Lactams quinine quinidine sulfonamides NSAIDs procainamide gold carbamazepine propylthiouracil ticlopidine P-Lactams ciprofloxacin sulfonamides lincomycin tetracycline NSAIDs carbamazepine allopurinol gold methyldopa mAbs NSAIDs p-lactams othCT antibiotics anti-convulsants antimalarials local anesthetics barbiturates quinolones dapsone... 

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). 

Methohexital [18652-93-2] (Brevital), C 4H gN202, (2) is a barbiturate iv anesthetic iaduction agent that has a slightly faster onset than thiopentone and less accumulation. The recovery from anesthesia is also slightly faster and better. However, iaduction is associated with an iacreased iacidence of excitatory phenomena. Methohexital also causes respiratory and cardiovascular depression and is unstable ia solution, necessitating reconstitution before use (99). 

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. 

Combinations of barbiturates and benzodiazepine tranquilizers or even antihistaminergics having sedative properties are sometimes used. Furthermore, infusion of anesthetics can be used to provide long-term anesthesia for intensive care medicine. The antagonist flumazenil (18) is available to reverse the effects of anesthetics of the benzodiazepine class. 

The ultra-short-acting barbiturates include methohexital sodium (Brevi-tal) and thiopental sodium (Pentothal). These agents are used as anesthetics and are administered intravenously. Barbiturates with short-to-intermediate duration of action are used for their sedative-hypnotic effect in the treatment of anxiety. These medications include amobarbital (Amytal), butabarbital (Butisol), sodium pentobarbital (Nembutal), and secobarbital (Seconal). 

Respiratory drive and rhythm are depressed by barbiturates. Coughing, sneezing, hiccupping, and laryngospasm may occur during anesthesia with barbiturates. Sedative ot hypnotic doses of barbiturates teduce heatt tate and blood pressure to levels found in normal sleep. Anesthetic doses produce more pronounced effects. Barbiturates cross the placenta when used in labor, they can cause respiratoty depression in neonates. Anesthetic doses dectease force and frequency of uterine contractions among pregnant women. 

Hypnotics. Common hypnotics are thiopental, propofol, midazolam, etomidate, ketamine and inhaled anesthetics. The incidence of hypersensitivity reactions with thiopental is rare. Recently, thiopental was involved in less than 1% of allergic reactions in France [9]. Ever since Cremophor EL, used as a solvent for some non-barbiturate hypnotics, has been avoided, many previously reported hypersensitivity reactions have disappeared. In the last French surveys, reactions to propofol accounted for less than 2.5% of allergic reactions, and reactions to midazolam, etomidate or ketamine appear to be really rare [9]. Finally, no immune-mediated immediate hypersensitivity reaction involving isoflurane, desflurane or sevoflurane has been reported despite their wide use. 

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 ... 

GABA, and molecules that act at GABA-A receptors, have been classically recognized as hypnotics (i.e. benzodiazepines) and anesthetics (i.e. barbiturates). Benzodiazepine (BZD) receptors, a modulatory site on the GABA-A receptor, were... 

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]. 

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