Thomas Persoon, M.S.*
Upon completion of this section the reader will be able to:
1) Define therapeutic drug monitoring and outline circumstances where it is useful.
2) Discuss the role of sample timing in obtaining accurate therapeutic drug monitoring results.
3) List the drugs commonly seen in the office practice setting which require therapeutic monitoring, and discuss important aspects of their pharmacology as it relates to therapeutic drug monitoring.
4) Discuss urine drug screening in the office practice environment.
5) Recognize some factors which may affect the accuracy of urine drug screen results.
6) Outline some factors which are useful in evaluating a reference laboratory for drug screening.
Within the scope of office practice, it is sometimes important to measure the serum concentration of drugs which have been prescribed for the patient, to insure that the drug's serum concentration is within the therapeutic range. Therapeutic Drug Monitoring, often abbreviated TDM, is the term used to describe this process. TDM is useful for those drugs where:
Patients who are likely candidates for therapeutic drug monitoring are those taking anticonvulsant drugs, tricyclic antidepressants, digoxin, theophylline, or lithium. Other drugs such as gentamicin must also be monitored, but use of these drugs is usually limited to hospitalized patients.
A heightened awareness of the negative effects of illicit drugs, combined with development of technologies which allow on-site detection of these drugs in body fluids, has led to the introduction of screening for drugs of abuse into the office laboratory practice.
Immunoassay is the technology most often used for measuring both therapeutic and illicit drugs in body fluids. Like other laboratory tests, drug tests are subject to quality controland proficiency testing requirements. Under CLIA-88, drug tests are considered either moderately or highly complex, depending upon the drug measured and the device used for the measurement.
Thomas Persoon, M.S.
Samples for TDM must be obtained at the proper elapsed time after a dose for valid interpretation of results. Drawing the blood sample at an incorrect time is the most frequent source of error when therapeutic drug monitoring results do not agree with clinical impressions. Therapeutic ranges are established based on steady state concentrations of the drug. Steady state is generally achieved about five half-lives after oral dosing has begun. Drawing a sample before steady state has been achieved will result in a drug concentration which does not correctly reflect the dose - serum concentration relationship. In some instances, it may be useful to draw peak and trough levels. Peak levels are achieved at the point of maximum drug absorption. Trough levels are achieved just before the next dose.
The type of sample used for TDM is also important. For most drugs, therapeutic ranges are reported for serum concentrations. Some TDM test methods may be certified for use with both serum and plasma. The test kit manufacturer's instruction sheet will specify which samples are acceptable. There are some reports in the literature that serum or plasma from evacuated blood collection tubes containing separator gels can give erroneous TDM results. If possible, tubes with separator gels should be avoided.
a. Anticonvulsant Drugs
Common anticonvulsant drugs which require therapeutic monitoring
include phenytoin
(Dilantin®), carbamazepine
(Tegretol®), valproic
acid (Depakene®), primidone
(Mysoline®), and phenobarbital.
Since primidone is metabolized to phenobarbital, both drugs must be
measured when the patient is taking primidone.
Anticonvulsant drugs are usually measured by immunoassay. Immunoassays are generally free from interferences and require very small sample volumes.
b. Digoxin
The cardioactive drug digoxin is a good candidate for therapeutic
monitoring. The bioavailability of different oral digoxin
preparations is highly variable. Digoxin pharmacokinetics follow a
two-compartment model, with the kidneys being the major route of
elimination. The elimination half life in a patient with normal renal
function is about 36 hours. Patients with renal disease or changing
renal function should especially be monitored, since their
elimination half life will change. The therapeutic range for digoxin
is based on blood samples obtained 8 hours after the last dose in
patients with normal renal function. To compare a patient's digoxin
level with the published normal ranges, the patient should have been
on their current dose for three to five days (so they have attained
steady state) and the sample should be drawn around 8 hours after
their last oral dose. Digoxin levels obtained earlier than these
recommended times may be falsely elevated. Digoxin measurements are
almost always made using an immunoassay. Some immunoassays currently
available have cross-reactivity with a hormone-like substance know as
digoxin-like immunoreactive factor, or DLIF. Care must be taken to
distinguish between digoxin and digitoxin, another cardiac glycoside.
Digoxin assays generally have a low cross-reactivity with digitoxin,
but digitoxin serum therapeutic levels may be 10 times those of
digoxin. The manufacturer's insert for the laboratory test kit will
list significant interferences or cross-reactivities for the test.
Digoxin results obtained using reagent kits from different
manufacturers may not always agree with each other due to
differential reaction of metabolites. Some measure of the differences
between manufacturer's reagent kits can be obtained by reviewing
proficiency sample means, which are usually grouped by kit
manufacturer.
c. Theophylline
Theophylline is a bronchodilator with highly variable inter-individual
pharmacokinetics. Serum levels must be monitored after achievement of
steady-state concentrations to insure maximum therapeutic efficacy
and prevent toxicity. Trough levels are usually measured. Immunoassay
is the most common method used for monitoring this drug.
d. Lithium
Lithium compounds are used to treat bipolar depressive disorders. Serum
lithium concentrations are measured by ion selective electrode
technology. An ion selective electrode has a membrane which allows
passage of the ion of interest but not other ions. A pH meter is an
example of an ion selective electrode which responds to hydrogen ion
concentrations. The electrode response to the ion of interest is
measured as a change in electrical potential (millivolts) versus a
reference electrode. A lithium electrode will respond to lithium
concentrations but not to other small cations such as potassium.
Several small analyzers which measure lithium using ion selective
electrode technology are available. Earlier methods that measured
lithium by flame photometry are obsolete.
e. Tricyclic Antidepressants
The tricyclic antidepressant drugs include imipramine and its
pharmacologically active metabolite desipramine; amitriptyline and
its metabolite nortriptyline; and doxepin and its metabolite
nordoxepin. Both the parent drugs and the metabolites are available
as pharmaceuticals. These drugs are primarily used to treat bipolar
depressive disorders. Imipramine may also be used to treat enuresis in children, and severe Attention
Deficit Hyperactivity Disorder that is refractory to methylphenidate.
Potential cardiotoxicity is the major reason to measure these drugs.
Immunoassay methods are available for measuring imipramine and the
other tricyclics, but high performance liquid chromatography (HPLC)
methods are considered the gold standard. HPLC is beyond the scope of
most physician office laboratories. When measuring tricyclic
antidepressants which have pharmacologically active metabolites, it
is important to measure both the parent drug and the metabolite.
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Urine screening tests for drugs of abuse detect general classes of compounds, such as amphetamines, barbiturates, benzodiazepines, or opiates. Drug screening also includes testing for cocaine, marijuana, and phencyclidine (PCP). The screening test for cocaine detects benzoyl ecgonine, the major metabolite of cocaine.The marijuana test detects D-9-tetrahydrocannabinol, a principle product of marijuana smoke. The screening tests themselves cannot distinguish between illicit drugs and prescription compounds of the same class. A patient taking codeine and another taking heroin would both have a positive screening test for opiates. Some over-the-counter medications can cause a positive drug screen in a person who has not taken any illegal or prescription drugs. For instance, over-the-counter sympathomimetic amines such as pseudoephedrine and phenylpropanolamine may cause a false-positive screen for amphetamines.Substances which give a false positive screening test for cocaine are rare. Being present in a room where marijuana is being smoked, and inhaling secondary smoke, is generally not enough to cause a positive screening test for marijuana. Because D-9-tetrahydrocannabinol, the major marijuana metabolite, is highly fat-soluble, it remains in the body for long periods of time and can be detected in the urine for weeks after marijuana has been smoked.
Eating food containing poppyseeds may result in a positive urine screening test for opiates, since poppyseeds contain naturally-occurring opiates. However, confirmation testing will distinguish between positive opiate tests resulting from poppyseed ingestion and those resulting from heroin or other opiates, because different metabolic breakdown products are present.
b. Sample collection
In an attempt to avoid detection of illicit drug use, some people who are asked to give a urine sample for drug screening will attempt to substitute the urine of another person or adulterate their urine specimens, using either commercially available adulterants or home-brew recipes. In settings where the urine drug screen result may be used for employment or legal actions, procedures to minimize the chance that an adulterated sample is being submitted may be required. These include measuring the temperature or pH of the urine immediately following voiding and using tamper-proof containers. The United States Substance Abuse and Mental Health Services Administration (SAMHSA) provides guidelines for collection of urine specimens for those persons covered under federal drug screening regulations.
c. Test methods The most commonly used test method for screening urine for drugs of abuse is immunoassay. In larger laboratories, the tests are often performed on the highly automated analyzers which also perform other urine and blood chemistries. Methods are also available for several smaller batch-type chemistry analyzers. Radioimmunoassays can be used for large batches of samples.
A number of single use devices incorporating immunoassays and designed to be used outside of the traditional laboratory are also available. These devices require FDA approval to be sold in the United States, and their use in non-medical environments such as workplaces and halfway houses for criminals may be regulated by state laws. They are generally acceptable for use in the office practice environment. Some home use drug testing kits are also being sold. These generally are not testing devices themselves, but are specimen containers which are to be filled and sent to a central laboratory, where the actual testing is done. The price of the kit includes the testing.
A more recent development is the use of hair as a sample for drug screening. Hair gives a history of chronic drug use rather than documenting recent usage.
All positive urine screening tests for drugs should be confirmed, especially if any medical, legal, or employment consequences can result from the positive test. The accepted confirmatory test for all drugs is gas chromatography-mass spectrometry, often abbreviated GC-MS. GC-MS can identify the specific substance ingested by recognizing not only the molecular structure of the original compound but also its pattern of metabolites. In the confirmatory test, the drugs in the urine sample are isolated on a small chromatographic column, eluted with an organic solvent, and injected into the gas chromatograph-mass spectrometer. The gas chromatograph separates the substances present, and then each substance is broken into molecular fragments by the mass spectrometer. The molecular fragmentation pattern for each substance is unique, allowing for identification of the substance by comparison with a computer library of known fragmentation patterns. GC-MS technology is beyond the scope of most hospital laboratories, so samples requiring confirmation will need to be sent to a reference laboratory.