Toxicology and Therapeutic Drug Monitoring
Amanda J. Jenkins
INTRODUCTIONToxicology is the study of the adverse effects of chemicals on living organisms. Clinical toxicology is a subspecialty with emphasis on management of a poisoned patient. The application is focused on human beings but may be equally relevant to veterinary medicine. The principles of clinical toxicology are applied to four main areas—emergency toxicology, therapeutic drug monitoring (TDM), addiction medicine, and pain management.
EMERGENCY TOXICOLOGY□ Purpose
The majority of poisoned patients enter the health care system in the emergency department. The clinical effects of a potential toxin depend upon the dose, route and length of exposure, and general health of the patient. Treatment is often based on exposure history and signs and symptoms of poisoning based on physical examination. Laboratory testing may be performed to confirm the physician’s diagnosis or to identify a toxin in the absence of a differential diagnosis.
Knowledge of toxidromes is important as a starting point for patient evaluation (Table 16-1). These consist of a collection of signs and symptoms that are typically produced by specific toxins. Specific toxidromes may have overlapping symptoms that are affected by individual variability, comorbidities, and coingestants. Further, not all agents in a class of poisons will produce all the signs and symptoms consistent with a particular toxidrome. Treatment is generally supportive. Providers should be fully conversant with effective decontamination and accepted enhancement of clearance measures, and also antidotes used for specific agents.
TABLE 16-1. Signs and Symptoms of Common Toxidromes | ||||||||||||||||||
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□ Application
The analytical capabilities of clinical toxicology laboratories vary but typically consist of screening and confirmation.
□ Screening Methods and Limitations
Screening tests are usually conducted on urine and provide presumptive results. These require little or no sample preparation and are frequently immunoassay based. These tests have high sensitivity; however, they have limitations due to moderate specificity. They provide an indication or preliminary evidence of the presence of drugs/metabolites in a specimen. Many commercially available tests cross-react with multiple drugs within a class due to the choice of target drug. They may also be sensitive to adulterants, which may produce invalid results. Clinicians must be aware of the commercial tests utilized in their laboratory, as cross-reactivities differ between manufacturers and within manufacturers over time.
These tests are typically performed on automated chemistry analyzers and have rapid throughput. Although individual drug-drug classes are available, many hospital laboratories offer these tests as panels and are available on a STAT basis.
Immunoassay testing may be based on
Radioimmunoassay (RIA)
Enzyme multiplied immunoassay technique (EMIT)
Enzyme-linked immunosorbent assay (ELISA)
Fluorescence polarization immunoassay (FPIA)
Kinetic interaction of microparticles in solution (KIMS)
Cloned enzyme donor immunoassay (CEDIA)
Immunoassays are typically qualitative assays, although semiquantitative results are possible with some kits. For qualitative testing, the instrument is calibrated at one concentration, called the cutoff concentration. For example, when utilizing EMIT, all specimens that have absorbance values equivalent to this
cutoff calibrator or greater will be reported as positive. Manufacturers provide this calibrator, so the laboratory has no choice but to use this concentration unless the kit provided is modified (e.g., by dilution, to obtain alternate/userdefined cutoffs). Any modification of the test must be validated appropriately by the laboratory to assure the modified assay is fit for use. Laboratories may also preprepare urine specimens by hydrolyzing samples to break the glucuronide bond, thereby increasing the detectability of drugs that are highly conjugated.
cutoff calibrator or greater will be reported as positive. Manufacturers provide this calibrator, so the laboratory has no choice but to use this concentration unless the kit provided is modified (e.g., by dilution, to obtain alternate/userdefined cutoffs). Any modification of the test must be validated appropriately by the laboratory to assure the modified assay is fit for use. Laboratories may also preprepare urine specimens by hydrolyzing samples to break the glucuronide bond, thereby increasing the detectability of drugs that are highly conjugated.
Cutoff concentrations for these kits have historically been decided with reference to the U.S. Department of Health and Human Services federally mandated cutoffs for federal workplace drug testing, which include phencyclidine, opioids, cannabinoids (marijuana), cocaine metabolite, and amphetamines. These cutoff concentrations are not generally appropriate for clinical use, since the cutoff values for several drug/drug classes such as opioids are high (see Table 16-2). This decreases the likelihood of false-positive results. The detection of drug abuse rather than legitimate drug use is targeted in this application (see Forensic Toxicology). However, immunoassay drug testing kits utilizing lower cutoff concentrations are available from some manufacturers.
Practitioners should be aware of what drugs are detected by the tests ordered. For example, immunoassays for opiates target morphine and typically do not produce positive results with samples containing synthetic and semisynthetic opioids such as oxycodone, fentanyl, and tramadol.
Table 16-3 lists approximate detection times of several drugs in urine. This is dependent on several factors including dose, frequency and route of administration, formulation, and patient-related factors such as disease, coingested drugs, and genetic polymorphisms.
□ Confirmation Methods and Limitations
Confirmation or definitive tests are typically performed following a positive screening result. Screening by immunoassay provides presumptive results only. Confirmatory tests are ordered if it is necessary to identify a specific drug,
obtain a quantitative result, or make a determination for legal purposes. For example, a positive opiate immunoassay result will not establish the identity of the opiate. A more specific test is required. These are typically chromatography and mass spectrometry (MS) based and are not performed on a “STAT” basis. Turnaround times may limit the usefulness of testing in an acute setting.
obtain a quantitative result, or make a determination for legal purposes. For example, a positive opiate immunoassay result will not establish the identity of the opiate. A more specific test is required. These are typically chromatography and mass spectrometry (MS) based and are not performed on a “STAT” basis. Turnaround times may limit the usefulness of testing in an acute setting.
TABLE 16-2. U.S. DHHS Cutoff Concentrations for Urine | ||||||||||||||||||||||||||||||
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TABLE 16-3. Approximate Detection Times of Drugs in Urine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Chromatography is a separation process based on the differential distribution of sample constituents between a moving mobile and a stationary phase. Chromatography is a separation technique, not identification. MS provides identification, since it provides mass and charge information unique to individual drugs. Identification may not be necessary in TDM. For definitive testing sample, pretreatment, extraction, and complex instrumental analysis may be required. Common methods used for confirmation tests are
□ Interpretation of Quantitative Results in Urine
Drug concentrations in urine are not reflective of the dose of drug administered or a specific dosing regimen. Semiquantitative results provided by immunoassays
may reflect contributions from more than one drug. For example, a presumptive positive immunoassay screen for opiates may be due to the presence of morphine, heroin, 6-acetylmorphine, and codeine in the specimen. Confirmation testing should provide identification of each drug present and may also provide quantitative results for each specific drug. In these instances, the laboratory may report total or free drug levels, that is, drug present that may be conjugated or unconjugated.
may reflect contributions from more than one drug. For example, a presumptive positive immunoassay screen for opiates may be due to the presence of morphine, heroin, 6-acetylmorphine, and codeine in the specimen. Confirmation testing should provide identification of each drug present and may also provide quantitative results for each specific drug. In these instances, the laboratory may report total or free drug levels, that is, drug present that may be conjugated or unconjugated.
The concentration of drug present in a random urine specimen is the result of the drug delivery system, acute or chronic drug administration, the time of specimen collection, the hydration status of the individual, renal and hepatic function, urine pH, the presence of other drugs resulting in drug interactions, individual pharmacokinetics, and pharmacogenetic polymorphisms. Urine drug/creatinine ratios may be calculated in order to minimize effects on drug concentrations due to changes in the fluid intake of the patient. Monitoring over time may assist in the determination between abstinence and renewed drug use.
□ Specimen Validity and Drug Testing Background
Specimen validity is an important aspect of laboratory testing. Validity refers to the correct specimen identity (i.e., a urine sample is human urine). The collectors of samples in physician offices and other sites have the responsibility of ensuring that adequate specimens are collected from patients. The validity of a specimen may be questioned if the sample is substituted or adulterated.
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