Article

Post-mortem evidence of doxylamine in toxicological analyses

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Background: Doxylamine (DA) is widely available in pharmacies without prescription and can be used in suicidal intention because of its sedative and anticholinergic properties. Research of literature shows that only a few publications deal with post-mortem evidence of DA and its interpretation during toxicological examination. Material and methods: In this study, all cases with a positive detection of DA during toxicological analyses with high-performance liquid chromatography in the time period 2000 to 2010 at the Institute of Legal Medicine and Forensic Sciences in Berlin, Germany were retrospectively analysed and interpreted, taking into account police investigations, autopsy results and toxicological analyses. Results: In total, 22 cases with DA intoxications were discovered (♂ = 16/♀ = 6, age-at-death range 17 to 90 years). Maximum blood concentration was measured at 77.5 μg/mL. Cause of death was due to DA intoxication in eight suicide cases; seven of those were combined intoxications (DA and other substances, particularly diphenhydramine). During the evaluated time period no monointoxications with DA were discovered. Conclusion: Benchmarks published in past literature are meant as orientation during evaluation of post-mortem DA evidence. These should not be used as absolute values and need to be interpreted individually in each case. Post-mortem redistribution needs to be considered as a main factor in alteration of DA concentration measurement. Furthermore, proof of DA ingestion found in gastric content should only be interpreted quantitatively due to unreliable calculation of the ingested amount. In conclusion, a variety of factors, such as the time period between time of death and the time of the first toxicological analysis, the condition of the body and the findings at autopsy, must also be critically considered.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... 457 0 . 3 2 311 ; 1-2 5 (7-) 9-11 (-13) [4], [47], [87], [311], [827] Dronabinol (Delta-9-tetrahydrocannabinol, THC) 0.005-0.01 (-0.05) 137 50-100 [241], [ 471 3-11 [8], [47], [57,58], [87], [269] Epinephrine (Adrenaline) appr. ...
Article
Background and objectives: The toxicity of second-generation antihistamines after an overdose by a child is still unknown. The objective of this study is to use data from Poisons Centres in France to describe the toxicity profile of second-generation antihistamines for children and to compare the severity of poisoning observed from these with a first-generation antihistamine. Method: This was a retrospective, multi-centre and observational study focusing on human cases of single-substance exposure to a second-generation antihistamine and to mequitazine, reported between 1 January 2001 and 31 December 2016 in Poisons Centres in France. Results: From a total of 9403 children included, 5980 were exposed to a second-generation antihistamine and 3423 were exposed to mequitazine. The severity of exposure to second-generation antihistamines in children is low: among the children followed until a known outcome, 9% of children were symptomatic and in 97% of cases, the symptoms shown were of a minor-level severity (primarily drowsiness or restlessness). Depending on the substance, children who ingested doses 16 to 69 times the maximum recommended therapeutic dose remained asymptomatic. No deaths or severe symptoms were observed. No cases of lengthening of the QT interval or arrhythmias were identified. Mequitazine led to more symptoms than other substances (14.8% symptomatic children vs. 7.5%, Odd ratio (OR): 2.3 (2.0–2.6), p < 0.0001), more symptoms of moderate intensity (1.4 vs. 0.2%, OR: 8.3 (4.1–18.5), p < 0.0001) and more hospitalisation (19.1 vs. 8.7%, OR: 2.5, 95% CI: (2.2–2.8), p < 0.0001). Conclusion: The severity of poisoning from second-generation antihistamines appears to be low among children and considerably lower than poisoning caused by mequitazine.
Article
Doxylamine is a first-generation H1-antihistamine, which is mainly used for the treatment of insomnia. It is available without prescription and both accidental and intentional acute poisonings are frequent. The aims of this review of literature were to describe the natural history of doxylamine acute poisoning, to characterize the dose–effect relationship, and to identify the gaps of knowledge. Methods All papers with doxylamine in their title or abstract were identified in Pubmed and Toxline databases. After reading the abstracts, only those papers reporting acute poisoning cases or case series were retained for analysis. References cited in these articles (and not identified by the initial retrieval) were also included in the analysis. Results and discussion Finally, 36 pertinent publications were identified: 22 articles reporting on 24 poisoning cases and 14 papers presenting 14 case series (reporting on 2 to 442 cases). They show that CNS depression and anticholinergic effects are the earliest and most frequent manifestations of doxylamine acute poisoning. Severe complications are not rare: mostly inhalation pneumonia, seizures and rhabdomyolysis. The latter is the most frequent one. It generally appears within 10 hours after doxylamine ingestion and rises a peak within 4 days post-ingestion; it can be further complicated with acute renal failure. Available data do not allow the characterization of dose–effect relationship for most of the effects of doxylamine acute poisoning. The only exception is rhabdomyolysis: case series indicate that its probability is high when the ingested amount is more than 20 mg/kg, and that it is low under 13 mg/kg.
Article
Full-text available
Introduction In order to assess the significance of drug levels measured in intensive care medicine, clinical and forensic toxicology, as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. Therefore, it makes sense to offer a carefully referenced compilation of therapeutic and toxic plasma concentration ranges, as well as half-lives, of a large number of drugs and other xenobiotics for quick and comprehensive information. Methods Data have been abstracted from original papers and text books, as well as from previous compilations, and have been completed with data collected in our own forensic and clinical toxicology laboratory. The data presented in the table and corresponding annotations have been developed over the past 20 years and longer. A previous compilation has been completely revised and updated. In addition, more than 170 substances, especially drugs that have been introduced to the market since 2003 as well as illegal drugs, which became known to cause intoxications, were added. All data were carefully referenced and more than 200 new references were included. Moreover, the annotations providing details were completely revised and more than 100 annotations were added. Results For nearly 1,000 drugs and other xenobiotics, therapeutic ("normal") and, if data were available, toxic and comatose-fatal blood-plasma concentrations and elimination half-lives were compiled in a table. Conclusions In case of intoxications, the concentration of the ingested substances and/or metabolites in blood plasma better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications, and to support forensic and clinical expert opinions.
Article
Full-text available
Diphenhydramine (DPHM) overdose is a frequent cause of acute poisoning. Although its clinical features are well known, information about the dose-dependent toxicity of DPHM is still scarce. The objective of this study was to investigate the dose-dependent toxicity of DPHM in patients with acute DPHM poisoning. We have analyzed retrospectively all well-documented cases with DPHM monointoxications reported by physicians to the Swiss Toxicological Information Centre (STIC) between January 1984 and April 1996. In addition, a prospective study focusing on ingested DPHM doses and severity of symptoms was performed between May 1996 and December 1998. The retrospective and prospective studies included 232 and 50 patients with DPHM monointoxications, respectively. In both studies, mild symptoms (somnolence, anticholinergic signs, tachycardia, nausea/vomiting) occurred in 55-64%, moderate symptoms (isolated and spontaneously resolving agitation, confusion, hallucinations and ECG disturbances) in 22-27% and severe symptoms (delirium/psychosis, seizures, coma) in 14-18% of patients. Moderate symptoms occurred above ingested doses of 0.3 g DPHM. For severe symptoms the critical dose limit was 1.0 g DPHM. Although the frequency of delirium/psychosis remained constant or even decreased, coma and seizures were significantly (p<0.05) more frequent in the >1.5-g compared with the 1.0- to 1.5-g-dose group. These data demonstrate a clear dose-dependent acute toxicity of DPHM. They indicate that only patients with DPHM ingestions above 1.0 g are at risk for the development of severe symptoms and, therefore, should be hospitalized. Thus, the results contribute to the data basis required for a cost effective management of patients with DPHM overdose.
Article
Full-text available
Diphenhydramine is an antihistamine available in numerous over-the-counter preparations. Often used for its sedative effects in adults, it can cause paradoxical central nervous system stimulation in children, with effects ranging from excitation to seizures and death. Reports of fatal intoxications in young children are rare. We present five cases of fatal intoxication in infants 6, 8, 9, 12, and 12 weeks old. Postmortem blood diphenhydramine levels in the cases were 1.6, 1.5, 1.6, 1.1 and 1.1 mg/L, respectively. Anatomic findings in each case were normal. In one case the child's father admitted giving the infant diphenhydramine in an attempt to induce the infant to sleep; in another case, a daycare provider admitted putting diphenhydramine in a baby bottle. Two cases remain unsolved; one case remains under investigation. The postmortem drug levels in these cases are lower than seen in adult fatalities. We review the literature on diphenhydramine toxicity, particularly as it pertains to small children, and discuss the rationale for treating these cases as fatal intoxications.
Article
Doxylamine succinate is an antihistamine of the ethanolamine class and commonly used as a nighttime sleep aid in the short-term management of insomnia. It is also used in combination with antitussive and decongestant agents for the temporary relief of common cold symptoms. There are few issues related with doxylamine succinate monointoxication in the literature and they are mostly associated with rhabdomyolysis. In this case report, we aim to overview a doxylamine succinate monointoxication case which seen rarely in the literature and make a review related with doxylamine succinate overdose.
Article
Histamine is an important neurotransmitter. Old (first-generation) H1- receptor antagonists such as chlorpheniramine, diphenhydramine, or triprolidine produce histamine blockade at H1-receptors in the central nervous system (CNS) and frequently cause somnolence or other CNS adverse effects. New (second generation) H1-antagonists such as cetirizine, fexofenadine, and loratadine represent an advance in therapeutics; in manufacturers' recommended doses, they enter the CNS in smaller amounts, produce relatively little somnolence or other CNS adverse effects, and do not exacerbate the adverse CNS effects of alcohol or other CNS-active chemicals. Two H1-antagonists, astemizole and terfenadine, have been found to prolong the QTc interval and, rarely, to cause cardiac dysrhythmias after overdose or under other specific conditions. This has led to withdrawal of regulatory approval for them. An H1-antagonist absolutely free from adverse effects under all circumstances is not yet available for use.
Article
During recent years we have witnessed the development of an increasing number of effective antihistaminic agents, whose role in the therapy of allergic disease has now become well established. Recently a great mass experiment has begun in the treatment of the common cold with these compounds, and striking claims have been made for the efficacy of their early administration. An avid public has been eagerly supplied by various manufacturers until at present the consumption of these agents is enormous. Reliable estimates are that the total sale of these drugs will reach $100,000,000 in 1950.1 Fortunately, the antihistaminic compounds have proved to be relatively nontoxic in the usual doses, though they do frequently give rise to bothersome side effects. There are, however, certain serious potentialities embodied in these agents, and a small number of deaths have occurred. It is our purpose in this report to call attention to the toxicity
Diphenhydramine (DPH), an H1-antihistamine, is identified during postmortem toxicological analyses on a relatively rare but still regular basis. This study examines suicidal intoxications with DPH by analyzing blood and gastric content concentration levels. Twenty cases of DPH intoxications within a 10-year period (2000-2010) were discovered by screening the autopsy records of the Institute of Legal Medicine and Forensic Sciences (ILMFS) in Berlin, Germany. In four cases, DPH levels were lower than 1 μg/mL and hence were not considered likely to be responsible for causing death. In 11 cases, DPH played a role in the fatal episode, and five of these cases were monointoxications. Considering that more than 8,000 autopsies were performed by the ILMFS within the time period under examination, there is only one monointoxication case every 2 years, which makes it a rare occurrence. In two of these intoxications, DPH was only measured in toxic but not "lethal" concentrations in blood, with a concentration of 5 μg/mL being generally used as the cut off between categories according to forensic literature. This raises the question as to whether a strict boundary for a "lethal" blood concentration, as suggested in some literature, can be set and applied in any of these cases. This study shows that an individual interpretation of each case is of utmost importance for correct classification. A thorough toxicological analysis of peripheral venous blood and gastric content, as well as a detailed work-up of the death circumstances, are the basis of an exact interpretation of intoxications with DPH.
Article
A fatal monointoxication with diphenhydramine in a male 28 year old is reported. The patient went into hyperpyrexia and tachycardia and died from sudden cardiac arrest. Hemorrhagic pulmonary edema and renal shock were the most prominent pathomorphological findings. At the time of death, the concentration of diphenhydramine was 5 mg/l plasma and was particularly high in the lungs (55 mg/kg) and kidneys (50mg/kg).
Article
Die Selbsttötung ist eine wichtige Erscheinungsform des nichtnatürlichen Todes und muss von anderen gewaltsamen Todesarten, aber auch von unerwarteten Todesfällen aus natürlicher Ursache abgegrenzt werden. Die Unterscheidung gründet sich einerseits auf die Erhebung und Interpretation der postmortal erhobenen (rechts)medizinischen Befunde, andererseits auf die ganzheitliche Berücksichtigung der Vorgeschichte und der kriminalistischen Umstände am Fundort der Leiche. Voraussetzung für eine Beurteilung durch den Leichenschauarzt und/oder den Rechtsmediziner ist die Kenntnis der Methoden der Suizidbegehung und ihrer pathomorphologischen Korrelate. Dazu gehören neben suizidtypischen Befundkonstellationen und Verletzungsbildern auch ungewöhnliche Manifestationsformen. Einen hohen Auffälligkeitswert haben kombinierte Suizide, bei denen verschiedene Selbsttötungsmethoden gleichzeitig oder nacheinander angewandt werden, sowie gemeinschaftliche und erweiterte Suizide. Auch manche Ereignisorte verdienen besondere Aufmerksamkeit. Mit der Möglichkeit der Simulation und der Dissimulation einer Selbsttötung muss in der forensischen Praxis gerechnet werden.
Postmortem redistribution (PMR) is an accepted toxicological phenomenon that may affect the interpretation of postmortem blood concentrations. The extent of PMR is not well understood for some drugs. This report describes the PMR of selected substances resulting from the analysis of 149 cases comparing blood specimens taken at admission of the deceased to the mortuary and then at autopsy. Blood was collected in preserved tubes containing 1 % sodium fluoride/potassium oxalate. All cases were subject to a full autopsy and blood extracts were analyzed using a targeted screen by LC-MS/MS. 30 drug or drug metabolites that were detected with an incidence of 6 or more were included in this study. The pre-autopsy interval ranged from 0.5 to 164 h (6.4 days) with an average of 64 h for the cases analyzed. The increase in drug concentration from mortuary admission to autopsy ranged from 30 % for drugs such as citalopram, mirtazapine, and sertraline to 300 % for doxylamine. Only 7 drugs of the 30 studied showed increases of greater than 20 % when comparing autopsy to mortuary admission blood irrespective of the length of the postmortem interval. Drugs including methadone, EDDP, fluoxetine, mirtazapine, and sertraline all showed statistically significant increases during the pre-autopsy interval (p < 0.05) while 6-acetylmorphine, 9-hydroxy-risperidone, and caffeine showed significant decreases (p < 0.05) from mortuary admission to autopsy. While femoral blood is thought to reduce PMR, this data shows that for some drugs significant redistribution can occur even when taking peripheral specimens irrespective of the delay in the postmortem interval.
Article
The present report highlights the possible adverse effects of doxylamine, a common over the counter sleep aid. Doxylamine is an antihistamine that at toxic doses can cause anticholinergic effects, including seizures, rhabdomyolysis and death. The following case describes a patient with doxylamine toxicity who presented with seizure and confusion. Our patient was managed symptomatically, and remained otherwise stable throughout his hospitalisation. This case is atypical in terms of a delayed rhabdomyolysis and a false positive urine drug screen test for methadone. There is evidence that doxylamine at toxic levels can lead to false positives for methadone and phencyclidine testing using immunoassay-based urine drug screen kits. Urine drug screen testing on patients who are hospitalised is typically performed using immunoassays. However, in certain cases confirmatory secondary testing may be required. Doxylamine is prone to abuse and knowledge of the clinical presentation of its toxicity and the management of acute overdose can be life-saving.
Article
The aim of this study was to investigate the associative factors of rhabdomyolysis in patients with doxylamine overdose who had normal creatine phosphokinase levels at admission. This study included 169 patients who visited the emergency department of a tertiary teaching hospital after doxylamine overdose between January 1, 1998, and March 31, 2009. Demographic information, clinical variables, and laboratory data were investigated for the associative factors of rhabdomyolysis. Thirty-five (21%) of the 169 patients developed rhabdomyolysis. Patients who developed rhabdomyolysis differed from those who did not in the amount of doxylamine ingested, sex, heart rate, initial value of serum creatinine, and alanine aminotransferase. In the multivariate regression analysis, the only reliable predictors of rhabdomyolysis were the amount of doxylamine ingested (P = .004) and heart rate (P < .001). Observation and laboratory follow-up are required for patients with large reported ingestions or tachycardia on admission, even if their creatine phosphokinase levels were normal.
Results from toxicological analyses in death investigations are used to determine whether foreign substances were a cause of death, whether they contributed to death, or whether they caused impairment. Drug concentrations are likely to change during pre-terminal stages due to altered pharmacokinetics, to treatment during resuscitation or in the intensive care unit, to concomitant illness or to the presence of drug tolerance. The potential for postmortem changes must be considered in all but a few drugs. Formation of new entities as well as degradation of drugs may occur, especially in putrefied corpses; in addition, body fluids and tissues may be severely affected by autolysis and putrefaction. Specimens should be selected based on individual case history and on their availability. Analytical procedures should be performed in accordance with a proper quality assurance program for toxicological investigations. Problems are most likely to occur during the isolation and identification of a drug. Interpretation of analytical results is often limited by the inadequate information provided in a particular case.
Article
First-generation H(1)-antihistamines obtained without prescription are the most frequent form of self-medication for allergic diseases, coughs and colds and insomnia even though they have potentially dangerous unwanted effects which are not recognized by the general public. To increase consumer protection by bringing to the attention of regulatory authorities, physicians and the general public the potential dangers of the indiscriminate use first-generation H(1)-antihistamines purchased over-the counter in the absence of appropriate medical supervision. A GA(2)LEN (Global Allergy and Asthma European Network) task force assessed the unwanted side-effects and potential dangers of first-generation H1-antihistamines by reviewing the literature (Medline and Embase) and performing a media audit of US coverage from 1996 to 2008 of accidents and fatal adverse events in which these drugs were implicated. First-generation H(1)-antihistamines, all of which are sedating, are generally regarded as safe by laypersons and healthcare professionals because of their long-standing use. However, they reduce rapid eye movement (REM)-sleep, impair learning and reduce work efficiency. They are implicated in civil aviation, motor vehicle and boating accidents, deaths as a result of accidental or intentional overdosing in infants and young children and suicide in teenagers and adults. Some exhibit cardiotoxicity in overdose. This review raises the issue of better consumer protection by recommending that older first-generation H(1)-antihistamines should no longer be available over-the-counter as prescription- free drugs for self-medication of allergic and other diseases now that newer second- generation nonsedating H(1)-antihistamines with superior risk/benefit ratios are widely available at competitive prices.
Article
A three-year old male ingested approximately 100 tablets of Bendectin. He developed tonic-clonic seizures followed by cardiac arrest. Toxicologic analysis yielded high levels of doxylamine, dicyclomine, and pyridoxine in blood, peritoneal fluid, and tissue homogenates. The antihistamine, doxylamine succinate appears to be the toxic constituent. Analytical methods used to document the case are herein described.
Article
One hundred and nine cases of monointoxication with doxylamine were evaluated with respect to age distribution, amount ingested, plasma level, and clinical symptomatology. The age of 60% of the patients ranged between 16 and 30 years. In about 60% of the cases 10 to 40 times a single therapeutic dose (25 mg) was ingested. Doxylamine plasma concentrations exceeded the maximum plasma level after a therapeutic dose by a factor of 10 to 40 in two-thirds of cases. The most frequent symptoms included impaired consciousness, seizures, tachycardia, mydriasis and a 'psychosis' similar to that in catatonic stupor. A serious complication may be rhabdomyolysis with subsequent impairment of renal function and acute renal failure. No symptoms were observed in 39% of the patients. No correlation was found between the amount ingested or doxylamine plasma level and the clinical symptomatology. Primary detoxication included gastric lavage, administration of activated charcoal and sodium sulfate. Regarding the high frequency of doxylamine overdose and its possible complications the question arises as to whether doxylamine-containing preparations should be subjected to prescription.
Article
A 25-year-old female died from a suicidal overdose of imipramine, acetaminophen, codeine, diphenhydramine, and ethanol. Blood samples from ten segregated arterial and venous sites, twenty-four tissue samples, cerebrospinal fluid, vitreous humor, and bile were analyzed. Imipramine and desipramine, which were highly concentrated in the liver and lungs, each showed marked site dependent differences in blood concentrations. The highest concentrations were in pulmonary venous blood and the lowest in peripheral venous blood. Imipramine concentrations in the ten blood samples differed by as much as 760% (range 2.1 to 16.0 mg/L). Blood desipramine concentrations ranged from 1.4 to 10.6 mg/L. In contrast, blood concentrations of acetaminophen differed by less than 20% (55 to 65 mg/L) and blood ethanol concentrations ranged from 151 to 175 mg/100 mL. Blood concentrations of diphenhydramine ranged from 0.34 to 2.07 mg/L and codeine from 0.33 to 0.89 mg/L. The data illustrates that a marked site dependent variability in postmortem blood concentrations exists for some drugs but not others.
Article
A rapid and sensitive high-performance liquid chromatographic (HPLC) assay for the quantitative determination of doxylamine in plasma is described. The drug levels of doxylamine in plasma were monitored after the oral administration of a single 25-mg tablet of doxylamine succinate to each of 20 male volunteers. The compound was extracted from the plasma samples, concentrated under a nitrogen stream, and analyzed by HPLC using normal-phase chromatography with detection at 254 nm. The detection limit is approximately 5 ng/ml.
Article
A fatal monointoxication with diphenhydramine in a male 28 year old is reported. The patient went into hyperpyrexia and tachycardia and died from sudden cardiac arrest. Hemorrhagic pulmonary edema and renal shock were the most prominent pathomorphological findings. At the time of death, the concentration of diphenhydramine was 5 mg/l plasma and was particularly high in the lungs (55 mg/kg) and kidneys (50 mg/kg).
Article
To answer the question, "Is this death due to a drug overdose?" requires at least that the drug be unequivocally identified and a blood concentration reliably determined. The approach taken in this case as standard addition technique and use of three different chromatographic techniques-high performance liquid chromatography (HPLC), high performance thin-layer chromatography (HP-TLC) and gas chromatography/mass spectrometry (GC/MS). Each of the chromatographies was carried out on the same extract by splitting the residue three ways. HPLC provided a quantitative result which was 1.2 mg/L in blood and HP-TLC and GC/MS confirmed this result with additional quantitative data, information about two metabolites (nordoxylamine and dinordoxylamine) and conclusive identification. Blood nordoxylamine was 0.52 mg/L and doxylamine plus metabolites in urine was 25 mg/L.
Article
Histamine is an important neurotransmitter. Old (first-generation) H1-receptor antagonists such as chlorpheniramine, diphenhydramine, or triprolidine produce histamine blockade at H1-receptors in the central nervous system (CNS) and frequently cause somnolence or other CNS adverse effects. New (second generation) H1-antagonists such as cetirizine, fexofenadine, and loratadine represent an advance in therapeutics; in manufacturers' recommended doses, they enter the CNS in smaller amounts, produce relatively little somnolence or other CNS adverse effects, and do not exacerbate the adverse CNS effects of alcohol or other CNS-active chemicals. Two H1-antagonists, astemizole and terfenadine, have been found to prolong the QTc interval and, rarely, to cause cardiac dysrhythmias after overdose or under other specific conditions. This has led to withdrawal of regulatory approval for them. An H1-antagonist absolutely free from adverse effects under all circumstances is not yet available for use.
Article
Doxylamine is an antihistamine of the ethanolamine class. It is used primarily as a sleep-inducing agent. Only a few reports can be found in the literature about lethal intoxications with doxylamine, but many with combined intoxications. Doxylamine is, aside from diphenhydramine, the only chemically defined active ingredient in some sleeping medications which is available without a prescription in the Federal Republic of Germany. Two cases of doxylamine poisoning are presented, in which high doxylamine concentrations were found in the blood and organs.
Article
Doxylamine succinate, an over-the-counter antihistamine, is commonly used as a nighttime sleep aid in the short-term management of insomnia. It is also used in combination with antitussive and decongestant agents for the temporary relief of common cold symptoms. Doxylamine is frequently involved in accidental and intentional overdoses. Rhabdomyolysis and secondary acute renal failure are rare but potentially serious complications, making early recognition and treatment essential. With the large number of nonprescription antihistamines and sleep aids available to the general public, it is important to keep in mind that overdose is a potential problem. The complications associated with overdose of these medications are just as life threatening as those associated with prescription drugs. A high index of suspicion and evaluation of rhabdomyolysis is warranted in antihistamine toxicity. We report an observation of severe rhabdomyolysis associated with doxylamine overdose.
Article
Histamine has an important role as a chemical messenger in physiologic responses, neurotransmission, allergic inflammation, and immunomodulation by way of the H1-receptor. Most H1-antihistamines, which are useful in treating these effects, possess similar efficacy in allergic rhinoconjunctivitis and chronic urticaria. However, there are clinically relevant differences among them in their pharmacology and safety profiles.
Article
The antihistaminic drug diphenhydramine (DPH) is mainly used as a sedative, hypnotic and antiemetic. In many countries it is over-the-counter available, very common, and generally regarded as a harmless drug. Sixty-eight non-fatal and 55 fatal poisonings with DPH alone or in combination with other drugs were investigated in the Institute of Legal Medicine of the University Hospital Charité between 1992 and 2004. The analytical investigations were performed by HPLC with photodiode array detector (HPLC-DAD). The DPH concentrations ranged from 0.5 to 8.9 microg/mL in the non-fatal cases and from 0.3 to 119 microg/mL in fatal cases. The intoxication symptoms stated during emergency admission were inconsistent, with somnolence, sedation and retardation on one hand and tachycardia, anticholinergic syndrome, agitation, hallucinations, confusion, tremor, convulsions, delirium and coma on the other. In three cases rhabdomyolysis occurred. A concentration above 5 microg/mL can be regarded as potentially lethal. In many of the survivors the time course of the concentrations of DPH and the metabolites desmethyldiphenhydramine (DM-DPH) and diphenylmethoxyacetic acid (DPMA) were investigated. Whereas DM-DPH is present in blood from the very beginning because of the high first pass metabolism, DPMA is slowly formed over several metabolic steps. For this reason, the concentration ratio DPMA/DPH can be used for an approximate estimation of the time between drug intake and sampling in clinical cases or of the survival time after drug ingestion in death cases. In some of the deaths the concentrations in heart blood were much higher than in venous blood. This is explained mainly by agonal aspiration of the vomited gastric content. Besides the majority of suicidal cases also a case of child maltreatment and a case, in which the drug was forcibly administrated in a drug facilitated crime, were investigated. From the results it follows that diphenhydramine is not less poisonous than other prescribed hypnotics. However, despite the hallucinogenic effects, an abuse for recreational purposes was not observed until now.
Disposition of Toxic Drugs and Chemicals in Man
  • Doxylamine
Doxylamine, in: R.C. Baselt (Ed.), Disposition of Toxic Drugs and Chemicals in Man, Biomed. Publ., Foster City, California, 2002, pp. 367-368.
  • F E R Simons
F.E.R. Simons, Advances in H1-antihistamines, N. Engl. J. Med. 351 (21) (2004) 2203-2217.
Clarke's Analysis of Drugs and Poisons
  • Doxylamine
Doxylamine, in: A.C. Moffat, M.D. Osselton, B. Widdop (Eds.), Clarke's Analysis of Drugs and Poisons, 3rd ed., Pharmaceutical Press, Philadelphia, Pennsylvania, 2004, pp. 962-963.
Report of a case with analytical follow-up
  • E Hausmann
  • H Wewer
  • H H Wellhöner
E. Hausmann, H. Wewer, H.H. Wellhöner, et al., Lethal intoxication with diphenhydramine. Report of a case with analytical follow-up, Arch. Toxicol. 53 (1) (1983) 33-39.