Jennifer A. Lowry

Significance of the imidazoline receptors in toxicology

Abstract Introduction. The alpha-2 adrenergic (AA-2) receptor agonists and imidazolines are common exposures in the American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS). Although the interaction between the AA-2 receptor and imidazoline receptors has been extensively studied, it largely remains unknown to health-care professionals. This review describes these interactions and mechanisms by which agonists affect physiologic responses binding to these receptors. Methods. Papers published in English from 1960 to 2013 were retrieved from PubMed. A total of 323 original articles were identified and 173 were included. Background. The toxicity associated with clonidine (e.g., bradycardia, miosis, and hypotension) is largely assumed to be secondary to the functional overlap of the AA-2 receptors and the mu receptors. However, the effects at the AA-2 receptor could not fully account for these symptoms. Subsequently, clonidine was found to produce its pharmacologic effect in the central nervous system (CNS) by interaction not only with the AA-2 receptor but also on selective imidazoline receptors. Imidazoline receptors. Since their discovery, three distinct classes of imidazoline receptors, also known as imidazoline binding sites or imidazoline/guanidinium receptive sites, have been characterized. Imidazoline-1 (I-1) receptors are involved in the hypotensive activity of clonidine and related compounds supporting the idea that the I-1 receptors are upstream from the AA-2 receptor and work in tandem for its effect on blood pressure. Additionally, stimulation of N-type Calcium-2 channels, G-protein inwardly rectifying potassium channel, adenosine receptors, phosphatidyl-choline-specific phospholipase C, and nicotinic receptors have been implicated to be involved. Previous studies have shown that I-1 receptors may also be involved in other physiologic responses beyond cardiac function. Imidazoline-2 (I-2) receptors interact with monoamine oxidase A and monoamine oxidase B leading to research that has focused on the effect of I-2 receptors and depression and the suggestion of a possible antidepressant action of the imidazolines. I-2 receptor ligands may have substantial antinociceptive activity and work synergistically with opioids in acute pain. Imidazoline-3 (I-3) receptors are located on the pancreatic β-cells and modulate glucose homeostasis. Imidazoline ligands. Four endogenous compounds have been found to bind and include clonidine-displacing substance, agmatine, harmane, and imidazole acetic acid. Significant interest in developing new agents with higher selectivity and affinity for I-1 receptors has resulted. Toxicology. Alpha-2 adrenoceptor and imidazoline receptor agonists such as clonidine and tetrahydrozoline are common ingestions reported to poison control centers. The most common toxic effects of clonidine are similar to those of the over-the-counter imidazolines and include CNS depression, bradycardia, hypotension, respiratory depression, miosis, hypothermia, and hypertension (early and transient). Based on their structure and subsequent studies, imidazoline receptors seem to be the primary binding site for these chemicals. Case reports typically illustrate rapid onset of action with serious side effects following ingestion of relatively small amounts. These agents have been reportedly used in drug-assisted sexual assaults. Conclusion. Much of the toxicity associated with drugs such as clonidine, guanfacine, and tetrahydrozoline are due to their binding to imidazoline receptors. Knowledge of the imidazoline receptors may lead to new therapeutic agents and inform management of patients with imidazoline overdose.

Cisapride: A potential model substrate to assess cytochrome P4503A4 activity in vivo

Cisapride was compared with midazolam in vivo to determine its potential applicability as a cytochrome P450 (CYP) 3A4 “probe.” As well, we evaluated whether cisapride was transported by P‐glycoprotein.

Serum concentrations in three children with unintentional tetrahydrozoline overdose

Background. Major symptoms can occur from tetrahydrozoline (THZ) overdoses in young children, requiring intensive care management. We report three cases that presented with CNS depression and cardiovascular effects where serum concentrations were performed. Case report. Case 1 ingested an unknown amount of eye drops containing THZ, resulting in altered mental status, bradycardia, hypothermia, and hypotension. Cases 2 and 3 ingested 7.5 mL of eye drops containing THZ. Case 2 presented to the emergency department (ED) without symptoms but became lethargic and bradycardic 90 min after ingestion. By contrast, Case 3 became lethargic 15 min after ingestion and required intubation on arrival to the ED. All children were admitted to ICU for observation and improved within 24 h of ingestion. Urine obtained for drug screening was positive for THZ. Blood was obtained to assess level using gas-chromatography mass-spectrometry (GC-MS). Case discussion. Case 1 had plasma levels of 51.4 and 23.6 ng/mL at 7 and 12 h, respectively, after ingestion, revealing a half-life of 4.4 h. Numerous case reports have been published documenting the dangers of ingesting these topical over-the-counter (OTC) products. However, human PK data are not available to help in our understanding of THZ toxicokinetics and disposition in humans after ingestion. Conclusion. We report three pediatric cases after ingestion of THZ where plasma concentrations were obtained with a calculated half-life of 4.4 h in one case.

Over-the-Counter Medications: Update on Cough and Cold Preparations

1. Jennifer A. Lowry, MD* 2. J. Steven Leeder, PharmD, PhD† 1. *Section of Clinical Toxicology, Division of Clinical Pharmacology, Toxicology and Therapeutic Innovations, Children’s Mercy Hospital, Department of Pediatrics, University of Missouri – School of Medicine, Kansas City, MO. 2. †Pediatric Clinical Pharmacology, Division of Clinical Pharmacology, Toxicology and Therapeutic Innovations, Children’s Mercy Hospital, Departments of Pediatrics and Pharmacology, University of Missouri-Kansas City, Kansas City, MO. Although there are benefits to the availability of over-the-counter products (eg, rapid access to effective medications, decreased utilization of the health care system, and patient autonomy), there also are risks to their use that clinicians should know and discuss with their patients and families. These include delay in seeking advice from a health care professional, increased drug-drug interactions, potential for misuse and abuse, and increased adverse effects when not used properly. After completing this article, readers should be able to: 1. Recognize that over-the-counter (OTC) cough and cold preparations have not been adequately studied in children younger than 6 years of age and that they are not recommended for treating the common cold. 2. Recognize the systemic effects of oral decongestants and antihistamines in infants and young children. 3. Recognize the signs and symptoms of acetaminophen and aspirin toxicity and know the management of overdose of these agents. 4. Be aware of potentially harmful additives in OTC medications. Over-the-counter (OTC) medications are widely marketed and frequently used to treat most health problems in adults and children. The use of symptomatic treatments, such as OTC medications for the common cold, is controversial. Children often receive analgesics, decongestants, antihistamines, expectorants, and cough suppressants during the course of their illnesses. However, these OTC products have not been proven to be safe and effective in young children. In addition, their common use puts children at risk for poisonings. Published data show no efficacy (no benefit) of OTC cough and cold preparations when compared to placebo for most ingredients in these products. After much review, the U.S. Food and Drug Administration (FDA) and the Consumer Healthcare Products Association issued …

2010 pediatric fatality review of the National Poison Center database: results and recommendations.

1New Jersey Poison and Information System, New Jersey Medical School Department of Preventive Medicine, 140 Bergen Street, Newark, US 2Morristown Medical Center, Department of Emergency Medicine, 100 Madison Avenue, Morristown, US, and Emergency Medical Associates, Livingston, US 3Children’s Mercy Hospitals and Clinics, Clinical Pharmacology and Medical Toxicology, 2401 Gillham Road, Kansas City, US, and The Department of Pediatrics, University of Missouri School of Medicine, Kansas City, US

Electronic cigarettes: Another pediatric toxic hazard in the home?

Electronic cigarettes (e-cigarettes) have recently gained attention in the media as an alternative to traditional smoking due to its increased use and lack of regulation. Originally marketed as a tobacco reduction or smoking cessation product, recreational use of e-cigarettes in adolescents and adults has doubled from 2010 to 2012. 1,2 Current use in Great Britain rose from 2.7% of adult smokers studied in 2010 to 6.7% in 2012. 2 Alternatively, adolescent data reveal that 9.3% of ever cigarette users had reported never smoking conventional cigarettes. 1 This trend in increased use has been associated with increased calls to the U.S. Poison Control Centers as evident in the article by Vakkalanka et al. in this issue. 3 In their study, unintentional exposures in children less than 6 years of age accounted for the most calls to poison control centers compared with other age groups. While the majority of patients followed had no more than minor effects reported, moderate, and major effects were found in this study. One fatality was reported, and, unfortunately, the clinical effects were not accounted for this age. Additionally, poison center data are unable to verify dose resulting in an incomplete account for the seriousness of these exposures. Parents and clinicians should be alarmed at these numbers and recognize the potential risk of harm to children and adolescents. It is known that children under the age of 6 years account for the majority of calls to poison control centers. Potential toxic exposures are relatively common in this age group due to their curious nature and frequent hand-to-mouth behaviors. Anticipatory guidance for poisoning prevention starts at the 9-month well-child visit and should continue for adolescents. However, unintentional poisonings in young children occur despite our best efforts often because caregivers do not recognize that harm can occur. Many chemicals are present in tobacco products that, used chronically, can result in harm. However, acute tobacco poisoning is largely due to the effects of nicotine. Nicotine binds to nicotinic acetylcholine receptors primarily in the autonomic nervous system. Early toxic signs and symptoms are refl ective of nicotinic cholinergic excess. Vomiting is the most common symptom. However, high doses of nicotine can result cardiac and neurologic adverse effects with tachycardia, agitation, and seizures occurring early; progressing to late manifestations of bradycardia, dysrhythmias, lethargy, and paralysis. While e-cigarettes are believed to be a safer form of “ smoking ” , this does not equate to safer forms of nicotine. Nicotine concentrations in e-cigarette solutions vary as there is no standard dose for manufacturers. E-cigarette solutions have mean nicotine concentrations of 8.5 – 22.2 mg/mL. 4

Chronic amitriptyline overdose in a child

Abstract Amitriptyline, a tricyclic antidepressant, has a well-described toxicity profile, and acute ingestions are common in the pediatric toxicology world.12 However, little can be found in the literature regarding chronic overdose. We describe a case of a 6-year-old girl who was prescribed amitriptyline 30 mg nightly for sleep problems, but was mistakenly given 300 mg (15 mg/kg) nightly for over a month. She was noted to have mental status changes and difficulty reading several days after starting the medication. She presented to the local childrens hospital in status epilepticus with significant cardiac conduction abnormalities on ECG. Her total amitriptyline/nortriptyline level was found to be 1676 ng/mL (normal therapeutic level 50–300 ng/mL). She was treated for several days with sodium bicarbonate. Within 24 h, her neurologic status improved and had returned to baseline within several days. Her ECG normalized, and she was discharged home, without apparent sequelae. A brief discussion of possible protective mechanisms (including pharmacogenomic) is presented.

The Interplay between Pharmacokinetics and Pharmacodynamics

1. Tracy L. Sandritter, PharmD, BCPPS*,† 2. Matthew McLaughlin, MD, MS† 3. Michael Artman, MD‡ 4. Jennifer Lowry, MD† 1. *University of Missouri–Kansas City School of Pharmacy, Kansas City, MO 2. †Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation and 3. ‡Department of Pediatrics, Children’s Mercy Hospital, Kansas City, MO * Abbreviations: ADHD: : attention-deficit/hyperactivity disorder ADME: : absorption, distribution, metabolism, and elimination ADR: : adverse drug reaction CYP: : cytochrome P450 ED50: : pharmacologic effect in 50% of patients FDA: : Food and Drug Administration GFR: : glomerular filtration rate HLA: : human leukocyte antigen NSAID: : nonsteroidal anti-inflammatory drug OTC: : over the counter OTFC: : oral transmucosal fentanyl citrate P-gp: : P-glycoprotein SSRI: : selective serotonin reuptake inhibitor TD50: : toxic effect in 50% of patients TI: : therapeutic index Drug efficacy and safety depend on all aspects of pharmacokinetics and pharmacodynamics for optimal treatment. Assessment of efficacy, drug-drug interactions, and adverse drug reactions is essential for optimal outcomes. Pediatricians should fully consider these aspects of drug therapy every time a medication is prescribed. 1. Recognize that drug efficacy depends on multiple factors, including pharmacokinetics (absorption, distribution, metabolism, and elimination) and pharmacodynamics (the effect of the drug at the end organ). 2. Identify situations where dose adjustments are necessary to maintain the serum concentration within the normal therapeutic range and prevent toxicities. 3. Understand important intrinsic and extrinsic factors affecting drug response. 4. Review synergistic and detrimental drug-drug interactions that lead to altered pharmacodynamic responses due to the presence of another drug, a food, or herbal treatment. 5. Discuss predictable and idiosyncratic adverse drug reactions and identify federal adverse drug reporting systems. Pharmacokinetics and pharmacodynamics determine the clinical effects of drug therapy. Pharmacokinetics (what the body does to the drug) is defined as the quantitative study of drug absorption, distribution, metabolism, and elimination (ADME). Pharmacodynamics is clinically more elusive and difficult to precisely quantify. Pharmacodynamics is the study of the biochemical and physiological effects of drugs in the body. Thus, pharmacodynamics can be thought of as “what the drug does to the body.” Despite being 2 distinct entities, there is substantial interplay between pharmacokinetics and the resultant pharmacodynamics. Understanding this can be challenging. The correlation between the dose administered and the resulting drug concentration at the site of action ultimately contributes to the pharmacodynamic response. Thus, pharmacodynamics describes the relationship between drug concentration and the desirable clinical effects of a medication as well …

Pediatric Cardiovascular Toxicity: Special Considerations

Pediatric exposures to xenobiotics are more frequent than in any other age group. In 2011, U.S. poison control centers dealt with 2,333,004 human exposures with major occurrences in children 19 years of age and under (62%). Children are more likely to be poisoned by substances that are readily available. While the majority are of low toxicity and result in no symptoms, there are toxins that can result in significant morbidity and mortality of children. A number of dramatic pharmacokinetic, pharmacodynamic, and psychosocial changes occur as preterm infants mature toward term, as infants mature through the first few years of life, and as children reach puberty and adolescence. Understanding normal cardiac development is essential prior to discussing the adverse effects that toxins can have on the developing heart. Embryology is important to pediatric cardiology because it helps to clarify the etiology and pathogenesis of cardiac malformations. Respiratory rate, heart rate, and blood pressure have age-specific normal values. Additionally, differences occur when comparing electrocardiogram waveforms between adults and children. Toxicology should be in the differential of every pediatric patient or a dangerous condition may be missed.Pediatric exposures to xenobiotics are more frequent than in any other age group. In 2011, U.S. poison control centers dealt with 2,333,004 human exposures with major occurrences in children 19 years of age and under (62%). Children are more likely to be poisoned by substances that are readily available. While the majority are of low toxicity and result in no symptoms, there are toxins that can result in significant morbidity and mortality of children. A number of dramatic pharmacokinetic, pharmacodynamic, and psychosocial changes occur as preterm infants mature toward term, as infants mature through the first few years of life, and as children reach puberty and adolescence. Understanding normal cardiac development is essential prior to discussing the adverse effects that toxins can have on the developing heart. Embryology is important to pediatric cardiology because it helps to clarify the etiology and pathogenesis of cardiac malformations. Respiratory rate, heart rate, and blood pressure have age-specific normal values. Additionally, differences occur when comparing electrocardiogram waveforms between adults and children. Toxicology should be in the differential of every pediatric patient or a dangerous condition may be missed.

Principles of Pharmacogenetics and Pharmacogenomics: Application of Pharmacogenetics and Pharmacogenomics in Pediatrics: What Makes Children Different?

Historically, submissions to the Food and Drug Administration (FDA) have been based on safety and efficacy data obtained from clinical trials conducted in adults with limited or no data from children. As a result, pediatricians and other health care professionals have relied on empiric therapeutic strategies, largely the consequence of treatment on a trial-and-error basis. In essence, the absence of information in the product label forces pediatricians to choose between avoiding the use of a medication that may be beneficial and using a medication “off-label” in the absence of evidence-based safety and efficacy data with the accompanying potential for ineffective and harmful outcomes. During the past fifteen years, new federal laws and regulations have increased the level of scientific and clinical rigor of investigations aimed at ensuring that the use of medications by children is, indeed, safe and effective. Interested readers are referred to a detailed chronology of events occurring between 1994 and 2002 (1), and a contemporary discussion of the issues surrounding more recent legislative activities, such as the Pediatric Research Equity Act (PREA) of January 2003 (2). In general, it is recognized that growth and development are accompanied by changes in the physiological and biochemical processes determining drug disposition and response, for example, drug absorption, distribution, metabolism, excretion, and targets of drug response (3). However, the acquisition of information that can inform safe and efficacious use of medications in children of different ages or developmental stages has been a relatively recent development, increasing dramatically in recent years as a consequence of the various legislative initiatives. It is now apparent that extrapolation of adult data to pediatric populations is quite inappropriate because drug clearance may be greater than or, in some cases, less than that observed in adults (4). Thus, even though weight-based dosing strategies are becoming more sophisticated and have improved abilities to use adult data to infer drug clearance in children (5), they are unlikely to provide consistent dosing guidelines across all pediatric age groups or chemical classes. This is largely due to the variability in the developmental patterns of expression of the various drug-metabolizing enzymes and transporters involved in the disposition of individual compounds. Furthermore, evidence that the response to some medications may be different in children relative to adults despite comparable drug exposure is beginning to accrue (e.g., buspirone [4]), implying that age-related differences in drug targets and downstream signal transduction pathways may also be present.