Several studies have supported Dr Gideon Koren’s 1993 landmark article, “Medications Which Can Kill a Toddler with One Tablet or Teaspoonful.” Although each study has its own merits, most focus solely on pediatric overdoses, and few provide an exhaustive reference list for real-time evaluation of ingestions in children and adults. The following xenobiotics warrant special attention because of their potential to cause serious outcomes, even after exposure to small volumes. This list does not imply that all pediatric exposures to these agents result in fatality, and the absence of a xenobiotic from this list does not indicate that it is necessarily safe. α1-Adrenergic agonists and imidazoline receptor agonists: Clonidine, guanfacine, naphazoline, oxymetazoline, tetrahydrozoline, xylazine (veterinary). Sulfonylureas: Chlorpropamide, glyburide, glipizide, glimepiride. Calcium channel blockers: Verapamil, diltiazem, nifedipine, amlodipine, nicardipine, nimodipine; β-Blockers: Metoprolol, labetalol, propranolol, sotalol. Tricyclic antidepressants: Imipramine, desipramine, amitriptyline, nortriptyline. Opioids: Codeine, hydrocodone, methadone, morphine, heroin. Antidiarrheals: Diphenoxylate plus atropine, loperamide. Salicylates and methyl salicylate: Oil of wintergreen, bismuth subsalicylate, mentholated balms, paramao or lawang root oil . Antipsychotics: Loxapine, thioridazine, chlorpromazine. Antimalarials: Chloroquine, hydroxychloroquine, quinine, primaquine. Antiarrhythmics: Quinidine, disopyramide, procainamide, flecainide, amiodarone. Camphor: A terpenoid used as an analgesic, antipruritic agent, and component of cooling gels, ointments, balms, mothballs, household fragrances, and essential oils. Oral camphor use occurs in some regions for religious ceremonies, traditional remedies, aphrodisiacs, or lactation suppression. Nonalkaloid toxic lignan: Podophyllin, podofilox. Unique plant toxins: Colchicine. Oral acetylcholinesterase inhibitors: Rivastigmine, donepezil, galantamine, carbamate pesticides. Methylxanthines: Theophylline, 1,3-dimethylxanthine, caffeine. Other opioids: Buprenorphine, fentanyl. Toxic alcohols: Methanol, ethylene glycol, diethylene glycol. Caustics and other household products: Acidic or alkaline household products, hydrofluoric acid, selenious acid, acetonitrile, methylene chloride. Accidental overdoses continue to occur regularly despite the implementation of various safety measures, including widespread public education, the use of childproof containers, and easy access to poison control centers. In the US, poison control centers receive more than 2.4 million calls annually, with more than 50% involving children younger than 6 years. Most pediatric accidental ingestions involve household cleaning products and analgesics, followed by cosmetics, foreign objects, and dietary supplements. Adult overdoses may be unintentional but often involve larger total doses or high-risk medications, including opioids and sedative-hypnotics. America's Poison Centers identify the 5 most common substance classes as analgesics, household cleaners, antidepressants, cosmetic or personal care items, and cardiovascular drugs. The number of ingestions involving cleaning products increased sharply during the COVID-19 pandemic but has since declined.

Terbinafine (TBNF), a lipophilic anti-fungal agent prescribed for onychomycosis distributes extensively into adipose, skin and peripheral tissues. TBNF and metabolite desmethyl terbinafine (DMT) are potent inhibitors of CYP2D6. A combination of prolonged half-life and CYP2D6 inhibition causes clinically significant interactions with drugs involving CYP2D6 metabolism that may persist for weeks after dosing cessation. A physiologically based pharmacokinetic (PBPK) model for TBNF and DMT incorporating in vitro and clinical information was developed and verified to predict their steady state pharmacokinetics. Experimentally determined Kiu,CYP2D6 for TBNF and DMT enabled to predict the interaction with CYP2D6 substrates Desipramine, Amitriptyline and Nortriptyline. The PBPK model predicted steady-state plasma concentration-time profiles of TBNF and DMT after daily administration of 250 mg and 125 mg TBNF were in agreement with the observed data, including sustained plasma concentrations after dosing cessation. This enabled prediction of drug interactions with the CYP2D6 substrates during and after termination of TBNF dosing. The distribution of TBNF into adipose and skin acts as a depot leading to its slow re-distribution back into plasma, followed by sequential metabolism to DMT and CYP2D6 inhibition. The model was validated against data from three independent drug interaction reports. This PBPK framework can be applied in different clinical pharmacology settings for drugs characterized by extensive distribution, formation rate limited metabolism and enzyme inhibition. The framework provides applicability in informing the rational design of clinical trials where sustained plasma drug levels warrant patient monitoring long after termination of dosing.

Parsonage-Turner syndrome (PTS) is a rare neuromuscular disorder. Parvovirus B19 infection commonly causes a childhood exanthematous illness. Most previous case reports have documented unilateral parvovirus B19-associated PTS along with the systemic manifestations of parvovirus infection. This report highlights parvovirus B19-associated bilateral PTS without systemic manifestations. A 20-year-old gentleman was asymptomatic one and a half months ago when he developed an acute onset of excruciating right shoulder pain. After 7-10 days, he developed weakness and wasting in the right shoulder girdle. One month into the illness, he developed similar complaints in the left shoulder. At presentation, there was marked wasting of the bilateral deltoids, biceps, triceps, and the periscapular muscles. The motor power was Medical Research Council (MRC) grade 0/5 at the right shoulder, elbow, and wrist joints and grades 1/5 and 4/5 at the left shoulder and elbow joints, respectively. Bilateral hand grip was weak. The deep tendon reflexes were absent in both upper limbs. Touch, pain, and temperature sensation were lost by 50-60% over the right upper limb and by 30-40% over the left upper limb. Nerve conduction studies and electromyography (NCS-EMG) were suggestive of a bilateral pan-brachial plexopathy. The brachial plexus MRI showed short-tau inversion recovery (STIR) hyperintensity involving all the roots, divisions, and cords of the bilateral brachial plexus. Cerebrospinal fluid (CSF) revealed five cells and mildly elevated protein levels. Parvovirus B19 DNA was detected in both the CSF and serum. Serum parvovirus B19 IgG antibodies were positive, while IgM antibodies were negative. Thus, a diagnosis of parvovirus B19-associated bilateral PTS was made. He was given analgesics, gabapentin, nortriptyline, and duloxetine for pain. He received intravenous methylprednisolone (1000 mg) followed by oral steroids (1 mg/kg) along with intravenous immunoglobulin (IVIG) and physiotherapy. Clinicians must consider parvovirus B19-associated PTS as a possibility, especially when evaluating rapidly progressive bilateral brachial plexitis, even in the absence of typical viral prodromal symptoms such as fever, rash, and arthralgia.

Many drugs that block voltage-gated K+ channels encoded by the human ether-à-go-go-related gene (hERG) can cause long QT syndrome and life-threatening cardiac arrhythmias, yet the molecular mechanisms that determine this risk remain unclear. A process that may counteract arrhythmogenic hERG block, termed facilitation, is common to many clinically approved hERG blockers, including nifekalant, amiodarone, promethazine, imipramine, nortriptyline, haloperidol, verapamil, carvedilol, metoprolol, propranolol, quinidine, fluoxetine, and chlorpheniramine. Facilitation is an increase in hERG current, under certain conditions, due to these blockers. Here, we propose that an agonism-while-blocking mechanism underpins facilitation. We focus on nifekalant, a class III antiarrhythmic drug and exemplar hERG blocker that induces facilitation. We tested the hypothesis that nifekalant opens hERG channel gates while blocking, and that unblocking of these open-yet-blocked channels results in supranormal hERG current. We developed rate-theory kinetic models to identify features of agonism-while-blocking that produce facilitation. We generated atomistic models that predict that nifekalant blocks the hERG conduction path while modulating the intracellular conduction gate. Voltage-clamp measurements revealed that agonism-while-blocking can result in nifekalant block and facilitation. We speculate that this agonism-while-blocking mechanism contributes to the relative safety of hERG blockers that induce facilitation.

Tricyclic antidepressant (TCA) overdose is a potentially life-threatening condition characterized by anticholinergic, cardiotoxic, and neurotoxic effects. Amitriptyline is a highly lipophilic TCA metabolized by cytochrome (CYP)2C19, CYP3A4, and CYP2D6 and may be associated with altered metabolism with concurrent use of cannabinoids, mutations of the CYP enzymes, and elevated body mass index (BMI). With higher levels of adipose tissue, elevated BMI can lead to a larger volume of distribution for lipophilic drugs. Deviations from expected drug clearance may prolong toxicity and complicate management. We describe a 15-year-old female with obesity (BMI of 36 kg/m[2]) and a complex psychiatric history who presented after an intentional overdose of approximately 750 mg of amitriptyline. On arrival, she was unresponsive with a Glasgow Coma Scale (GCS) score of 3, tachycardia, respiratory distress, and electrocardiographic evidence of TCA cardiotoxicity, including a wide complex tachycardia and QRS prolongation. She required emergent intubation, sodium bicarbonate therapy, seizure prophylaxis, serial electrocardiograms, laboratory monitoring, and intensive care monitoring. Despite appropriate supportive management and based on typical half-life estimates under therapeutic conditions, QRS prolongation persisted, and serum amitriptyline/nortriptyline levels remained markedly elevated on day seven (combined level 612 ng/mL) and detectable on day ten (combined level 131 ng/mL). The prolonged elimination observed in this case was likely multifactorial, with cannabinoid use potentially contributing to prolonged toxicity through interactions with CYP enzymes. Additional contributing factors may have included elevated BMI or CYP enzyme polymorphisms. Although CYP testing was not performed in this case, consideration of testing in similar presentations in the future may aid in clinical management if a mutation is identified. The contribution of elevated BMI in this case remains speculative, as current evidence regarding its effects on the pharmacokinetics of lipophilic drugs is inconsistent, highlighting the importance of further studies on this topic. This case illustrates the impact of cannabinoid use and other factors on the pharmacokinetics of amitriptyline and underscores the need for prolonged monitoring, serial electrocardiograms, and consideration of extended drug clearance in cases of pediatric patients with TCA overdose. Clinicians should be aware that standard half-life estimates may underestimate the duration of toxicity in populations that have factors influencing metabolism.