Barbiturates

Barbiturates refer to a class of general central nervous system depressants that are derived from barbituric acid, a chemical discovered in 1863 by the Nobel Prize winner in chemistry (1905) Adolf von Baeyer (1835-1917). Barbituric acid itself is devoid of central depressant activity; however, German scientists Emil Hermann Fischer and Joseph von Mering made some modifications to its structure and synthesized barbital, which was found to possess depressant properties. Scientists had been looking for a drug to treat anxiety and nervousness but without the dependence-producing effects of OPIATE drugs such as OPIUM, CODEINE, and MORPHINE. Other drugs such as bromide salts, CHLORAL HYDRATE, and paraldehyde were useful sedatives, but they all had problems such as toxicity or they left such a bad taste in patients' mouths that they preferred not to take them. Fischer and von Mering noted that barbital produced sleep in both humans and animals. It was introduced into chemical medicine in 1903 and was soon in widespread use.

By 1913, the second barbiturate, PHENOBARBI-TAL, was introduced into medical practice. Since that time, more than 2,000 similar chemicals have been synthesized but only about 50 of these have been marketed. Although the barbiturates were quickly used to treat a number of disorders effectively, their side effects were becoming apparent. The chief problem, an overdose, can result in respiratory depression, which can be fatal. By the mid-1950s, more than 70 percent of admissions to a poison-control center in Copenhagen, Denmark, involved barbiturates. Additionally, it became apparent that the barbiturates were subject to abuse, which could lead to dependence, and that a serious withdrawal syndrome could ensue when the drugs were abruptly discontinued. In the 1960s, the introduction of a safer class of hypnotic drugs, the BENZODIAZEPINES reduced the need for barbiturates.

Barbiturates are dispensed in distinctly colored capsules making them very easy to identify by the lay public. In fact, users within the drug culture often refer to the various barbiturates by names associated with their physical appearance. Examples of these names include blue birds, blue clouds, yellow jackets, red devils, sleepers, pink ladies, and Christmas trees. The term goofball is often used to describe barbiturates in general. All barbiturates are chemically similar to barbital, the structure of which is shown in Figure 1.

All barbiturates are general central nervous system depressants. This means that sedation, sleep, and even anesthesia will develop as the dose is increased. Some barbiturates also are useful in reducing seizure activity and so have been used to treat some forms of epilepsy. The various barbiturates differ primarily in their onset and duration of action, ability to enter the brain, and the rate at which they are metabolized. These differences are achieved principally by adding or subtracting atoms to the two branches on position #5 in Figure 1. The barbiturates are classified on the basis of their duration of action, which ranges from ultrashort-acting to long-acting. The onset of action of the ultrashort-acting barbiturates occurs in seconds and lasts a few minutes. The short-acting compounds take effect within a few minutes and can last four to eight hours, while the intermediate- and long-acting barbiturates can take almost an hour to take effect but last six to twelve hours. Table 1 lists the common barbiturates, their trade names, typical route of administration, and plasma half-life. The plasma half-life is a measure of how long the drug remains in the blood, but not how long the effects last, although it does provide a general indication of when to expect the effects to wane (a half-life of five hours means that one-half of the drug will be removed from the system in five hours; one-half of the remaining drug will be removed during the next five hours, etc.).

EFFECTS ON THE BODY AND THERAPEUTIC USES

Barbiturates affect all excitable tissues in the body. However, NEURONS are more sensitive to their effects than other tissues. The depth of central nervous system depression ranges from mild sedation to coma and depends on many factors including which drug is used, its dose, the route of administration, and the level of excitability present just before the barbiturate was taken. The most common uses for the barbiturates are still to promote sleep and to induce anesthesia. Barbiturate-induced sleep resembles normal sleep in many ways, but there are a few important differences. Barbiturates reduce the amount of time spent in rapid eye movement or REM sleep—a very important phase of sleep. Prolonged use of barbiturates causes restlessness during the late stages of sleep. Since the barbiturates remain in our bodies for some time after we awaken, there can be residual drowsiness that can impair judgment and distort moods for some time after the obvious sedative effects have disappeared. Curiously, some people are actually excited by barbiturates, and the individual may even appear inebriated. This paradoxical reaction often occurs in the elderly and is more common after taking phenobarbital.

The general use of barbiturates as hypnotics (SLEEPING PILLS) has decreased significantly, since they have been replaced by the safer benzodiazepines. Phenobarbital and butabarbital are still available, however, as sedatives in a number of combination medications used to treat a variety of inflammatory disorders. These two drugs also are used occasionally to antagonize the unwanted overstimulation produced by ephedrine, AMPHETAMINE, and theophylline.

Since epilepsy is a condition of abnormally increased neuronal excitation, any of the barbiturates can be used to treat convulsions when given in anesthetic doses; however, phenobarbital has a selective anticonvulsant effect that makes it particularly useful in treating grand mal seizures. This selective effect is shared with mephobarbital and metharbital. Thus, phenobarbital is often used in hospital emergency rooms to treat convulsions such as those that develop during tetanus, eclampsia, status epilepticus, cerebral hemorrhage, and poisoning by convulsant drugs. The benzodiazepines are, however, gradually replacing the barbiturates in this setting as well.

It is not completely understood how barbiturates work but, in general, they act to enhance the activity of GABA on GABA-sensitive neurons by acting at the same receptor on which GABA exerts its effects (see Figure 2). GABA is a NEUROTRANSMIT-TER that normally acts to reduce the electrical activity of the brain; its action is like a brake. Thus, barbiturates enhance the braking effects of GABA to promote sedation. There is an area in the brain called the reticular activating system, which is responsible for maintaining wakefulness. Since this area has many interconnecting or polysynaptic neurons, it is the first to succumb to the barbiturates, and that is why an individual becomes tired and falls asleep after taking a barbiturate.

PHARMACOKINETICS AND DISTRIBUTION

The ultrashort-acting barbiturates differ from the other members of this class mainly by the means by which they are inactivated. Methohexital and its relatives are very soluble in lipids (i.e., fatty tissue). The brain is composed of a great deal of lipid; when the ultrashort-acting barbiturates are given intravenously, they proceed directly to the brain to produce anesthesia and unconsciousness. After only a few minutes, however, these drugs are redistributed to the fats in the rest of the body so their concentration is reduced in the brain. Thus, recovery from IV barbiturate anesthesia can be very fast. For this reason, drugs such as methohexital and thiopental are used primarily as intravenous anesthetic agents and not as sedatives.

The other longer-acting barbiturates must be metabolized by the liver into inactive compounds before the effects wane. Since these metabolites are more soluble in water, they are excreted through the kidneys and into the urine. As is the case with most drugs, metabolism and excretion is much quicker in young adults than in the elderly and infants. Plasma half-lives are also increased in pregnant women because the blood volume is expanded due to the development of the placenta and fetus.

TOLERANCE, DEPENDENCE, AND ABUSE

Repeated administration of any number of drugs results in eventual compensatory changes in the body. These changes are usually in the opposite direction of those initially produced by the drug such that more and more drug is needed to achieve the initial desired effect. This process is called TOLERANCE. There are two basic mechanisms for tolerance development: tissue tolerance and metabolic or pharmacokinetic tolerance. Tissue tolerance refers to the changes that occur on the tissue or cell that is affected by the drug. Metabolic tolerance refers to the increase in the processes that metabolize or break down the drug. This process generally occurs in the liver. Barbiturates are subject to both types of tolerance development.

Tolerance does not develop equally in all effects produced by barbiturates. Barbiturate-induced respiratory depression is one example. Barbiturates reduce the drive to breathe and the processes necessary for maintaining a normal breathing rhythm. Thus, while tolerance is quickly developing to the desired sedative effects, the toxic doses change to a lesser extent. As a result, when the dose is increased to achieve the desired effects (e.g., sleep), the margin of safety actually decreases as the dose comes closer to producing toxicity. A complete cessation of breathing is often the cause of death in barbiturate poisoning (Rall, 1990).

If tolerance develops and the amount of drug taken continues to increase, then PHYSICAL DEPENDENCE can develop. This means that if the drug is suddenly stopped, the tissues' compensatory effects become unbalanced and withdrawal signs appear. In the case of barbiturates, mild signs of withdrawal include apprehension, insomnia, excitability, mild tremors, and loss of appetite. If the dose was very high, more severe signs of withdrawal can occur, such as weakness, vomiting, decrease in blood pressure regulatory mechanisms (so that pressure drops when a person rises from a lying position, called orthostatic hypotension), increased pulse and respiratory rates, and grand mal (epileptic) seizures or convulsions. DELIRIUM with fever, disorientation, and HALLUCINATIONS may also occur. Unlike withdrawal from the opioids, withdrawal from central nervous system depressants such as barbiturates can be life threatening. The proper treatment of a barbiturate-dependent individual always includes a slow reduction in the dose to avoid the dangers of rapid detoxification.

Few, if any, illegal laboratories manufacture barbiturates. Diversion of licit production from pharmaceutical companies is the primary source for the illicit market. Almost all barbiturate users take it by mouth. Some try to dissolve the capsules and inject the liquid under their skin (called skin-popping) but the toxic effects of the alcohols used to dissolve the drug and the strong alkaline nature of the solutions can cause lesions of the skin. Intravenous administration is a rare practice among barbiturate abusers.

Many barbiturate users become dependent to some degree during the course of treatment for insomnia. This type of problem is called iatrogenic, because it is initiated by a physician. In some instances the problem will be limited to continued use at gradually increasing doses at night, to prevent insomnia that is in turn due to withdrawal. However, some individuals who are susceptible to the euphoric effects of barbiturates may develop a pattern of taking increasingly larger doses to become intoxicated, rather than for the intended therapeutic effects (for example, to promote sleepiness). To achieve these aims, the person may obtain prescriptions from a number of physicians and take them to a number of pharmacists—or secure their needs from illicit distributors (dealers). If the supply is sufficient, the barbiturate abuser can rapidly increase the dose within a matter of weeks. The upper daily limit is about 1,500 to 3,000 milligrams; however, many can titrate their daily dose to the 800 to 1,000 milligram range such that the degree of impairment is not obvious to others. The pattern of abuse resembles that of ethyl (drinking) ALCOHOL, in that it can be daily or during binges that last from a day to many weeks at a time. This pattern of using barbiturates for intoxification is more typically seen in those who, from the beginning, obtain barbiturates from illicit sources rather than those who began by seeking help for insomnia.

Barbiturates are sometimes used along with other drugs. Often, the barbiturate is used to potentiate, or boost, the effects of another drug upon which a person is physically dependent. Alcohol and HEROIN are commonly taken together in this way. Since barbiturates are "downers," they also are used to counteract the unwanted overstimulation associated with stimulant-induced intoxication. It is not uncommon for stimulant abusers (on COCAINE or amphetamines) to use barbiturates to combat the continued "high" and the associated motor disturbances associated with heavy and continued cocaine use. Also, barbiturates are used to ward off the early signs of withdrawal from alcohol.

Treatment for barbiturate dependence is often conducted under carefully controlled conditions, because of the potential for severe developments, such as seizures. Under all conditions, a program of supervised withdrawal is needed. Many years ago, pentobarbital was used for this purpose and the dose was gradually decreased until no drug was given. More recently, phenobarbital or the benzodiazepines—CHLORDIAZEPOXIDE and diazepam—have been used for their greater margin of safety. The reason that the benzodiazepines sometimes work is because the general central nervous system depressants—barbiturates, alcohol, and benzodiazepines—develop cross-dependence to one another. Thus a patient's barbiturate or alcohol withdrawal signs are reduced or even eliminated by diazepam.

(SEE ALSO: Addiction: Concepts and Definitions; Withdrawal)

BIBLIOGRAPHY

CSÁKY, T. Z. (1979). Cutting's handbook of pharmacology: The actions and uses of drugs, 6th ed. New York: Appleton-Century Crofts.

HENNINGFIELD, J. E., & ATOR, N. A. (1986). Barbiturates: Sleeping potion or intoxicant? In The encyclopedia of psychoactive drugs. New York: Chelsea House.

MENDELSON, J. H., & MELLO, N. K. (1992). Medical diagnosis and treatment of alcoholism. New York: McGraw-Hill.

RALL, T. W. (1990). Hypnotics and sedatives: Ethanol. In A. G. Gilman et al. (Eds.), Goodman and Gilman's the pharmacological basis of therapeutics, 8th ed. New York: Pergamon.

WINGER, G., HOFFMAN, F.G., & WOODS, J. H. (1992). A handbook of drugs and alcohol abuse: the biomedical aspects, 3rd ed. New York: Oxford University Press.

SCOTT E. LUKAS