Barbiturates in forensic toxicology

DEFINITION: Family of chemically related drugs belonging to the sedative-hypnotic class.

SIGNIFICANCE: The habit-forming drugs known as barbiturates have a variety of therapeutic applications and have been used as drugs of abuse. Barbiturates depress the central nervous system and can cause significant psychomotor performance impairment as well as fatal toxicity. The potential for toxic interactions with other drugs, including alcohol, is significant. Forensic toxicologists are often called upon to measure barbiturate concentrations in biological samples.

The barbiturates are a family of drugs with related chemical structures derived from barbituric acid. In the past, barbiturates were used extensively as sedative-hypnotics—that is, drugs that reduce anxiety and induce sleep. Barbiturates are also used as anticonvulsants and in anesthesia. Because of barbiturates’ significant potential for toxicity, their use has been largely replaced by the safer benzodiazepines, but selected barbiturates are still used in specific applications.

Effects

Barbiturates depress central nervous system (CNS) function in general rather than specific CNS functions. The severity of CNS depression increases with dose, potentially causing significant impairment of psychomotor skills (such as those required for safe driving) and, ultimately, fatal respiratory depression. Dose-dependent effects also extend to the peripheral nervous system, where they manifest primarily as reductions in blood pressure and heart rate. However, at appropriate sedative-hypnotic doses, these latter effects are not hazardous.

At subanesthetic doses, barbiturate effects may include euphoria, reduced anxiety and inhibitions, slurred speech, loss of coordination, and dizziness. CNS depression intensifies with increasing dose; sedation becomes more pronounced, and significant stupor, drowsiness, and loss of coordination may ensue. Anesthetic doses produce coma as well as depressed respiration and blood pressure. Uncontrolled overdose can result in fatal respiratory depression. These effects are intensified in combination with other CNS depressants (such as alcohol or benzodiazepines), and significant impairment or death may occur at lower barbiturate doses (or blood concentrations) when such drugs are coadministered.

Chronic barbiturate use results in the development of tolerance—that is, progressively larger doses are required to achieve a given effect. Repeated administration of and tolerance to the effects of one barbiturate confers tolerance to the effects of the others as well as to other depressant compounds with similar mechanisms of action (for example, alcohol and benzodiazepines). Chronic use can lead to physical dependence and corresponding upon cessation of use. Symptoms of barbiturate withdrawal range from minor symptoms—nausea, vomiting, agitation, and confusion—to more severe symptoms including seizures, hallucinations, delirium tremens, very high fevers (hyperpyrexia), and death.

Other Chemical and Pharmacological Properties

Barbiturates are weakly acidic and are often prepared as the sodium salts. Their weakly acidic nature becomes important in the design of analytical methods requiring extraction of the drug from a complex forensic sample (for example, blood or tissue). Alteration of the chemical structure results in variation in drug potency (the magnitude of effect at a given dose) and time course of action.

Even in cases where the drug effects last a short time, barbiturates have a relatively long time course within the body. One indicator of this is the half-life of the drug, or the time required for the reduction of drug concentration to 50 percent of its original value. Half-life values for the various barbiturates range from approximately 3 hours to 80 hours. Any drug with a long half-life poses the risk of accumulation in the blood if dosing regimens are not carefully monitored, creating the potential for toxicity. Half-life is also related to the duration of drug action: Typically, a drug with a shorter half-life has a shorter duration of action. This is relevant to forensic investigation, as the half-life is indicative of the time window over which a drug may be detected in the blood; generally, a drug is essentially completely eliminated from the blood within five elimination half-lives.

Duration of action and half-life are important considerations in the choice of a barbiturate for a particular therapeutic action. For example, thiopental is an ultrafast-acting barbiturate, typically used in induction of anesthesia. Due to its high lipid solubility, it is rapidly and extensively distributed into the central nervous system, wherein it exerts its anesthetic effect through depression of various functions. The elimination half-life for thiopental is 8 to 10 hours, although its ability to diffuse into and out of the CNS results in anesthetic action lasting only minutes following a single intravenous dose. Conversely, phenobarbital, a barbiturate used as an anticonvulsant and as a sedative-hypnotic, is significantly longer acting, with a half-life of 80 to 120 hours.

The route of administration of the drug is also dependent on the desired therapeutic action. Barbiturates used as sedative-hypnotics or anticonvulsants may be administered orally and have a slower onset of action than those given by parenteral (for example, intravenous) administration, where the onset of drug action is very rapid. Accordingly, parenteral administration is typically used in the treatment of status epilepticus (a condition in which the brain is in a state of persistent seizure) and for general anesthesia. The route of administration is ultimately related to the maximum blood drug concentration achieved, and therefore the magnitude of drug effect, at a given dose. Consequently, knowledge of the route of administration is valuable to toxicological interpretation. It should be noted, however, that some drugs intended for oral administration—in tablet form—are illicitly administered by parenteral routes, potentially leading to greater toxic effects.

The metabolism of most barbiturates occurs primarily in the liver, where the drugs undergo various biotransformation reactions (such as oxidation) that reduce or eliminate pharmacological activity. In a few cases (for example, aprobarbital, phenobarbital), renal elimination of unchanged drug into the urine also occurs to a significant extent. Consequently, barbiturate metabolism may be affected by processes that affect hepatic metabolism (for example, liver disease or drug interactions). Inhibited barbiturate metabolism may result in the development of significant toxicity.

Forensic Analysis and Interpretation of Evidence

Law-enforcement personnel may encounter barbiturates in the form of suspicious materials (for example, tablets) requiring identification or quantitative analysis. Forensic scientists may analyze biological samples (such as blood, tissues, urine, or stomach contents) to establish exposure to barbiturates. Correlation of toxic symptoms with measured barbiturate concentration is done in both clinical and forensic settings and in attempts to establish a toxicological cause of death.

Methods used for forensic barbiturate analysis include immunoassay, spectrophotometry, gas or liquid chromatography, and mass spectrometry. Usually, the analysis of biological samples for barbiturates requires preparatory steps to extract the drug from the complex matrix and minimize or eliminate other compounds (such as lipids or proteins) that may be present in those samples that may interfere with analysis, leading to spurious results. The exact nature of the sample preparation steps taken is determined by the nature of the sample being analyzed. Solid samples typically require dissolution or digestion as a first step.

Extraction of drugs from complex samples may be accomplished through the manipulation of chemical conditions (such as pH adjustment) and subsequent partition into a suitable organic solvent system or into a solid phase with subsequent recovery. Following extraction, analysis is typically done using gas or liquid chromatography to separate extracted constituents for accurate quantitative analysis.

The interpretation of measurements requires consideration of the nature of the sample analyzed as well as the measured drug concentration. Drug concentrations in blood may allow estimation of toxic effect, with consideration given to the potential for tolerance to drug action. Conversely, detection of a barbiturate in hair under properly controlled conditions is indicative of drug exposure only, but it may be useful in establishing an approximate time line of drug exposure.

The forensic detection of a particular barbiturate must be considered in the context of the case under investigation. The tolerance of the individual must be considered in the interpretation of measured barbiturate concentrations as well. For example, in toxicological analysis of blood samples from a known epileptic, the detection of phenobarbital may be consistent with a therapeutic regimen, and some degree of tolerance may often be assumed. In routine forensic practice, tolerance is difficult or impossible to quantify, so interpretation is difficult. Correlation of a measured blood concentration with toxicity or fatality requires comparison of the result to other similar cases that have been previously reported, giving due consideration to the history of use of barbiturates and other drugs by the subject, the detection of other relevant drugs in the sample (such as CNS depressants), and any observed symptoms (such as shallow breathing, impaired coordination, or slurred speech).

Bibliography

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