Therapeutically barbiturates

Life-threatening hyperkalemia after therapeutic barbiturate coma with thiopental has been described in three patients it was fatal in one (6). All the episodes occurred after the withdrawal of thiopental. Hypokalemia that is resistant to potassium replacement is common during thiopental coma and clinicians may choose to manage asjmptomatic barbiturate-induced hypokalemia expectantly in an attempt to avoid rebound hyperkalemia. 

Cairns CJ, Thomas B, Fletcher S, Parr MJ, Finfer SR. Life-threatening hyperkalaemia following therapeutic barbiturate coma. Intensive Care Med 2002 28(9) 1357-60. 

Rapid Method for the Determination of Therapeutic Barbiturate Levels in Serum Using Gas-Liquid Chromatography... 

Electrolyte balance Disturbances of potassium homeostasis rarely complicate therapeutic barbiturate coma [92 ]. 

Neil Ml, Dale MC. Hypokalaemia with severe rebound h3rperkalaemia after therapeutic barbiturate coma. Anesth Analg 2009 108(6) 1867-8. 

Benzodiazepiaes have largely replaced barbiturates and barbiturate-like agents for use as anxiolytics and sedative—hypnotics. Because benzodiazepiaes rarely produce levels of CNS depression that require therapeutic iatervention, the need for analeptics has decreased considerably. 

The thus-washed crude product is dissolved in a mixture of 12 parts of ethanol and 20 parts of benzene, with mild warming if necessary. 1 Part of sodium chloride and 1.5 parts of saturated aqueous sodium chloride solution are added to the obtained solution in ethanol-benzene, and whole thoroughly admixed. When the brine layer has settled. It is separated and the afore-described washing repeated. The clear solution is concentrated under reduced pressure until incipient formation of crystals and is then poured into 30 parts of benzene, whereupon a thick crystalline pulp is forthwith formed which, after being cooled to room temperature, is centrifuged off. The so-obtained 5-allyl-5-( 3-hydroxypropyl)-barbituric acid is dried at 70°C under reduced pressure and can be used for therapeutic purposes without further purification. Melting point 164 °C to 165°C. Yield 5 parts. 

Acetaminophen may alter blood glucose test results, causing falsely lower blood glucose values. Use with the barbiturates, hydantoins, isoniazid, and rifampin may increase the toxic effects and possibly decrease the therapeutic effects of acetaminophen. The effects of the loop diuretics may be decreased when administered with acetaminophen. Hepatotoxicity has occurred in chronic alcoholics who are taking moderate doses of acetaminophen. 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

Convulsive disorders are still a serious therapeutic problem and new agents are being actively sought. Classical therapy was based upon the barbiturates that are no longer in favor because of their many side effects and their suicide potential. Interestingly, a seemingly minor structural variation of phenobarbital (152, shown as its sodium salt) leads to an anticonvulsant of increased potency and which has less hypnotic activity. In this case, sodium phenobarbital serves as its own base (so the yield is limited to 50%) and reacts readily with... 

Lehane, D.P. et al. 1976. Therapeutic drug monitoring Measurements of antiepileptic and barbiturate drug levels in blood by gas chromatography with nitrogen-selective detector. Ann Clin Lab Sci. 6 404. 

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... 

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. 

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. 

Since GABA-ergic synapses are confined to neural tissues, specific inhibition of central nervous functions can be achieved for instance, there is little change in blood pressure, heart rate, and body temperature. The therapeutic index of benzodiazepines, calculated with reference to the toxic dose producing respiratory depression, is greater than 100 and thus exceeds that of barbiturates and other sedative-hypnotics by more than tenfold. Benzodiazepine intoxication can be treated with a specific antidote (see below). 

Toxic symptoms may be dose-dependent and merely an exaggeration of the therapeutically desirable response, e.g., the coma of barbiturate overdosage and persistence of muscular paralysis after succinylcholine administration, or an unpredictable effect of the drug upon an organ or tissue remote from that upon which the therapeutic effect is manifested. 

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. 

Thiopental is an extremely short-lasting barbiturate that makes anesthesia pleasant and smooth for the patient. When using the usual therapeutic doses, coming back into consciousness happens 15 min after administration. Thiopental has a straightforward dose-requiring oppressive effect on the myocardium, central nervous system, and to a lesser effect acts on the smooth muscle of blood vessels. It is used for narcosis in brief surgical operations. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

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