Tai C. Kwong

Organophosphate pesticides: biochemistry and clinical toxicology.

Organophosphate pesticides are used extensively worldwide, and poisoning by these agents, particularly in developing nations, is a serious public health problem. The toxicokinetics and toxicodynamics of organophosphate poisoning vary not only with the route and extent of exposure, but also the chemical structure of the agent. The mechanism of toxicity is the inhibition of acetylcholinesterase, resulting in an accumulation of the neurotransmitter acetylcholine and the continued stimulation of acetylcholine receptors. The standard treatment consists of reactivation of the inhibited acetylcholinesterase with an oxime antidote and reversal of the biochemical effects of acetylcholine with atropine. Patients who receive treatment promptly usually recover from acute toxicity but may suffer from neurologic sequelae.

Free drug measurements: methodology and clinical significance

Drug molecules circulate in blood in two forms: those in association with blood components such as proteins, red cells, or platelets and those which are unbound and are dissolved in plasma water [l-3]. The extent of drug binding to plasma proteins varies widely among different types of drugs. The protein-bound fraction ranges from less than 0.1 for caffeine and ethosuximide to greater than 0.99 for highly bound drugs such as warfarin and dicumerol[4]. The effects of changes in the extent of protein binding on free drug fraction and on drug metabolism are significant only for highly bound drug (greater than 80% bound), since even a relatively small change in the degree of binding has a dramatic effect on the free fraction. Albumin is quantitatively the most important drug binding protein for many drugs, particuIarly the neutral and anionic (acidic) drugs such as warfarin, phenytoin, and valproic acid [.5]. In recent years, cationic (basic) drugs such as propranolol quinidine, and the tricyclic antidepressants have been shown to bind not only to albumin, but also to other blood proteins such as &,-acid glycoprotein (AAG) and lipoproteins f6-8). In some cases, binding to AAG and lipoproteins exceeds that to albumin. Fluctuations in plasma levels of AAG and lipoprotein fractions such as low density lipoprotein are common and point to the importance of understanding the interactions of cationic drugs with these proteins f&9,10]. Table I lists those drugs which are commonly encountered in clinical chemistry laboratories. Protein binding has an important effect on the pharmacokinetics of drugs. The impact of alterations in protein binding on drug clearance depends on the clearance characteristics of the drug. Restrictively cleared drugs are those that are removed from plasma by glomerular filtration through the kidneys or by passive uptake by the liver. Only the free fractions of such drugs are cleared by these organs. Thus, clearance of highly protein bound and restrictively cleared drugs are sensitive to

Meconium analysis for improved identification of infants exposed to cocaine in utero

We screened anonymously all mothers and infants born during a 3 1/2-month period to determine the prevalence of intrapartum cocaine use, test the maternal characteristics that are specific predictors of intrauterine cocaine exposure (IUCE), and compare the sensitivity of infant urine versus meconium samples for identification of IUCE. Of 1237 live births during the study period, a sample was obtained from 1201 mother-infant pairs. The overall prevalence of documented intrapartum cocaine exposure was 66 (5.5%) of 1201 pairs. Previously developed drug screening guidelines had a sensitivity of 89% for detecting IUCE in infants. Direct comparisons of samples from the same mother-infant pair revealed that there were no cases in which cocaine was found in infant urine but not in meconium; however, infant urine testing missed 25% of the infants who had positive findings in meconium. We conclude that (1) meconium testing was more likely than urine testing to identify an infant with IUCE, detecting an additional 33%; (2) there was significant maternal cocaine use (5.5%) in a teaching hospital with a mixed patient population; (3) maternal characteristics known to identify infants at risk of having IUCE were useful in our population; and (4) IUCE of neonates admitted to the neonatal intensive care unit was more common than that of infants admitted to the regular newborn nursery.

The opioid abuse and misuse epidemic: Implications for pharmacists in hospitals and health systems

PURPOSE The current epidemic of prescription opioid abuse and misuse in the United States is discussed, with an emphasis on the pharmacists role in ensuring safe and effective opioid use. SUMMARY U.S. sales of prescription opioids increased fourfold from 1999 to 2010, with an alarming rise in deaths and emergency department visits associated with the use of fentanyl, hydrocodone, oxycodone, and other opioid medications. Signs and symptoms of opioid toxicity may include altered mental status, hypoventilation, decreased bowel motility, central nervous system and respiratory depression, peripheral vasodilation, pulmonary edema, hypotension, bradycardia, and seizures. In patients receiving long-term opioid therapy for chronic pain, urine drug testing is an important tool for monitoring and assessment of therapy; knowledge of opioid metabolic pathways and assay limitations is essential for appropriate use and interpretation of screening and confirmatory tests. In recent years, there has been an increase in federal enforcement actions against pharmacies and prescription drug wholesalers involved in improper opioid distribution, as well as increased reliance on state-level prescription drug monitoring programs to track patterns of opioid use and improper sales. Pharmacies are urged to implement or promote appropriate guidelines on opioid therapy, including the use of pain management agreement plans; policies to ensure adequate oversight of opioid prescribing, dispensing, and waste disposal; and educational initiatives targeting patients as well as hospital and pharmacy staff. CONCLUSION Pharmacists in hospitals and health systems can play a key role in recognizing the various forms of opioid toxicity and in preventing inappropriate prescribing and diversion of opioids.

How many creatine kinase “isoenzymes” are there and what is their clinical significance?

Recently, there has been a growing awareness of creatine kinase (CK) electrophoretic bands which exhibit mobilities different from those of CK-MM, MB and BB. These electrophoretic bands have been designated as “variant”, “atypical”, or “macro-CK” isoenzymes, and their mobilities can be cathodic or anodic [l-5]. Anodic variants have been found between the origin and CK-MM and also between CK-MM and CK-MB bands. Their formation has been variously attributed to polymeric aggregation of CK monomers, or to complexing of CK isoenzymes with immunoglobulins, lipids, lipoproteins, or unknown serum components. Cathodic variant bands, on the other hand, have generally been assumed to be of mitochondrial origin [6,7]. These variant isoenzymes are of both practical and clinical interest to laboratory scientists and physicians. A number of reports have already appeared dealing with their origin and possible clinical significance. In this brief review, we propose to examine critically the generally adopted procedures for characterization of variant CK isoenzymes and some of the assumptions underlying their clinical interpretation. Variant CK isoenzymes are commonly detected by electrophoresis and initially defined as such by their unusual electrophoretic mobilities compared to those of CK-MM, MB and BB isoenzymes. Immunochemical techniques have been used to characterize further the components of the variant bandsimmunoinhibition assays using anti-CK-M and anti-CK-B antisera to determine if the variant isoenzymes have CK-M or CK-B immunoreactivity [2,3,5] and immunoprecipitation techniques with antisera of different specificities (e.g., antiserum against IgG) to identify the unknown complexing substance [2,3,8]. In addition, tests based on physical properties, e.g., stability to heat treatment and urea dissociation, molecular size by gel permeation chromatography, are frequently used. Although more sophisticated techniques, e.g., ion exchange chromatography [ 1,9], isoelectric focusing [ 10,111, and gel filtration chromatography [ 12,131 can also detect variant isoenzymes, those techniques are not used routinely in clinical laboratories, and have not been responsible for the initial detection of most of the reported cases of variant CK isoenzymes. For this reason, we chose to restrict our discussion to the

DETECTION OF DRUG USE DURING PREGNANCY

Several methods of drug testing are efficacious in identifying and monitoring drug use during pregnancy. Urine screening remains the most commonly used method despite the limited period during which drugs can be detected. Hair has been recognized as a possible alternate test specimen, but wider acceptance of hair testing must await better understanding of drug disposition in hair, answers to the issues relating to interpretation, and the development of less demanding laboratory techniques. Regardless of the matrix used, proper interpretation of the results of drug testing requires familiarity with the sensitivity, specificity, and limitations of the laboratory methodologies employed. Moreover, unconfirmed positive results may actually be false-positives and must be interpreted with caution, particularly if they are the basis for major clinical decisions.

Urine Drug Testing for Pain Management

An epidemic of prescription drug abuse in the United States has increased the burden on clinical toxicology testing laboratories. Urine drug testing provides objective evidence for compliance and aberrant drug behavior in patients on chronic (non-cancer) pain management. This article describes the testing menu, drug testing assays including tandem mass spectrometry and their limitations, interpretation of opiate results and clinical considerations.

Bonded-phase extraction of plasma tricyclic antidepressant drugs for gas chromatographic analysis

The tricyclic antidepressants (TADS) are the most effective and, generally, the most popular antidepressants in clinical use [I]. Evidence to date suggests that in patients with endogenous depression, clinical response is correlated with an effective range of plasma concentrations [2-41. The gradual onset of action and the wide inter-individual variation in steady-state TAD concentrations in patients receiving the same dose provide a rationale for drug level monitoring in non-responding or poorly responding patients. Drug level monitoring can aid in dosage adjustments to attain more efficient and safe treatment [2,5,6]. Therapeutic concentrations are low, in the pg/l range (e.g. 50-150 pg/l for nortriptyline), and require analytical techniques of high sensitivity. Such techniques include gas chromatography equipped with either a nitrogen-sensitive or an electron capture detector, high performance liquid chromatography and mass spectrometry. Critical reviews appraising these methods have been published [7,8]. In most of these procedures, sample preparation involves multiple solvent extractions in basic and acidic media, accompanied by obligatory centrifugal separation steps. As such, they are cumbersome and time-consuming and would be undesirable for clinical laboratories which are burdened with increasingly higher demands for therapeutic drug monitoring of TADS. We describe a simple procedure for the analysis of plasma TAD levels. It includes an uncomplicated and efficient sample preparation step, which does not require solvent extraction, and rapid analysis by gas chromatography using a nitrogen-sensitive detector.

Utilization management in toxicology.

Recent upward trends in the prevalence of abuse of prescription drugs and illicit substances have resulted in increased demands for toxicology testing to support the emergency department and drug treatment in pain management programs. This review will discuss the challenges faced by clinical laboratories to manage the utilization of toxicology tests, particularly those ordered in managing poisoned patients in the emergency department and chronic pain patients on opioid therapy. Optimal utilization of toxicology tests to support the emergency department relies on selecting the appropriate tests for the patient, and the availability of the results in a timely fashion. Two tiers of toxicology testing systems with different requirements for turnaround time will be discussed. In patients with chronic pain urine drug testing, including screening and confirmation testing are used extensively in pain management to monitor patient compliance. A thorough understanding of the performance characteristics of the test methodologies and drug metabolism is a key to making a proper analytical and clinical interpretation of the test results and will contribute to effective utilization of these tests. In addition, the reimbursement system is an important factor in the decision making process for test selection utilization as significant costs can be incurred by both payers and patients. Collaboration, trust, and effective communication among clinicians, patients, and clinical laboratory professionals are essential for effective utilization of toxicology testing.

Interpretation of Urine Drug Testing Results in Patients Using Transdermal Buprenorphine Preparations for the Treatment of Chronic Noncancer Pain

OBJECTIVE To determine whether the prevailing liquid chromatography and tandem mass spectroscopy assay (LC-MS/MS) assay designed to monitor buprenorphine compliance of the sublingual formulation used in the substance abuse treatment setting can be extrapolated to the transdermal formulation used in the chronic pain treatment setting, which is 1000-fold less concentrated. DESIGN Retrospective chart review. SUBJECTS Self-reported compliant patients using the transdermal or sublingual formulations of buprenorhphine. Transdermal patch application was also visually confirmed during clinic visits. METHODS Urine drug test results from a LC-MS/MS were compared between samples from transdermal and sublingual patients. RESULTS While all sublingual patients tested positive for at least one metabolite of buprenorphine, only 69% of the transdermal patients did so. In addition, the most abundant metabolite in the transdermal patients was buprenorphine-glucuronide, as compared with norbuprenorphine-glucuronide in sublingual patients. CONCLUSIONS These data suggest that currently available urine drug tests for buprenorphine, including the more expensive LC-MS/MS based assays, may not be sufficiently sensitive to detect the metabolites from transdermal buprenorphine patients. This study highlights the need to evaluate the value and sensitivity of urine drug tests given the wide range of buprenorphine dosing in clinical practice. These results underscore the need for additional cost benefit analyses comparing different confirmatory drug testing techniques including many commercially available drug testing options.