Barbiturate administration, brain

Conventional treatment of raised ICP in this condition consists of artificial ventilation, osmotherapy, and barbiturate administration. The value and duration of these measures has come under scrutiny. Prolonged hyperventilation has been discouraged, as the potential decrease in cerebral arterial blood flow resulting from additional hypocarbia might exacerbate tissue ischemia (34). Early use of agents such as glycerol or mannitol, at least in theory, may actually hasten tissue shifts and therefore lead to an aggravation of brain edema (35). Barbiturate therapy has to date failed to prove to be of therapeutic benefit in the treatment of postischemic brain edema (36). 

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. 

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. 

Changes in plasma pH may also affect the distribution of toxic compounds by altering the proportion of the substance in the nonionized form, which will cause movement of the compound into or out of tissues. This may be of particular importance in the treatment of salicylate poisoning (see chap. 7) and barbiturate poisoning, for instance. Thus, the distribution of phenobarbital, a weak acid (pKa 7.2), shifts between the brain and other tissues and the plasma, with changes in plasma pH (Fig. 3.22). Consequently, the depth of anesthesia varies depending on the amount of phenobarbital in the brain. Alkalosis, which increases plasma pH, causes plasma phenobarbital to become more ionized, alters the equilibrium between plasma and brain, and causes phenobarbital to diffuse back into the plasma (Fig. 3.22). Acidosis will cause the opposite shift in distribution. Administration of bicarbonate is therefore used to treat overdoses of phenobarbital. This treatment will also cause alkaline diuresis and therefore facilitate excretion of phenobarbital into the urine (see below). 

Barbiturates such as phenobarbital are weak acids. The toxicity of the barbiturate is mainly the result of the effects on the central nervous system. Only the nonionized form of the drug will distribute into the central nervous system. The proportion ionized will depend on the pKa and the pH of the blood. By increasing the pH of the blood using sodium bicarbonate administration to the poisoned patient, ionization of the barbiturate will be increased and distribution to tissues such as the brain will be decreased. Urinary excretion of the barbiturate will also be increased because the urinary pH will be increased. 

Phenobarbital is utilized as a daytime sedative and anticonvulsant. It also induces several cytochrome P450 isozymes. Compared to other barbiturates, phenobarbital has a low oil/water partition coefficient, which results in slow distribution into the brain. It is available for oral, intravenous, or intramuscular administration. Doses for epileptic patients range from 60 to 200 mg per day. After a single oral dose of 30 mg, peak serum concentrations averaged 0.7 mg/L (n = 3). Repeated doses over a period of 7 days resulted in an average peak concentration of 8.1 mg/L.6 Chronic administration of 200 mg per day as anticonvulsant medication resulted in an average blood concentration of 29 mg/L (range = 16 to 48 mg/L).8... 

Thiopental Sodium, USP. Thiopental. sodium, sodium S-ethyl-S-(l-methylbutyl)-2-lhiobarbilurale (Pentothal Sodium). is the mo.st widely u.sed ultra-short-acting anc.sthctic barbiturate. Additionally, the compound is the prototype for the ultra-short-acting barbiturates. Most discussions of how structure influences duration of action in this group of agents relate specifically to it. The compound s onset of action is about equal to the time required for it to travel to the brain from the site of administration. Consciousness is regained within 30 minutes. 

I. Pharmacology. Phenobarbital Is a barbiturate commonly used as an anticonvulsant. Because of the delay In onset of the therapeutic effect of phenobarbital, diazepam (see p 415) Is usually the Initial agent for parenteral anticonvulsant therapy. After an oral dose of phenobarbital, peak brain concentrations are achieved within 10-15 hours. Onset of effect after intravenous administration is usually within 5 minutes, although peak effects may take up to 30 minutes. Therapeutic plasma levels are 15-35 mg/L. The dmg is eliminated by metabolism and renal excretion, and the elimination half-life is 48-100 hours. 

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