Jeanna M. Marraffa

The synthetic cannabinoid withdrawal syndrome.

Background:Little is known about the effects of synthetic cannabinoids. There has been only one previous report of a withdrawal syndrome from synthetic cannabinoids. We report two cases of a withdrawal syndrome from prolonged habitual use of synthetic cannabinoids. Discussion:Withdrawal from delta-9-THC has been described as a syndrome of anxiety, myalgias, chills, and anorexia. Synthetic cannabinoids are potent than delta-9-THC and thus the withdrawal syndrome is similar but more severe; however the symptoms do not seem to improve with delta-9-THC. The differences in presentation could be due to the fact that synthetic products may contain several heterogeneous compounds, including amphetamine-like substances. Conclusions:The acute withdrawal syndrome appears to be characterized mainly by anxiety and tachycardia in the absence of any neurological findings or electrolyte disturbances. We describe two patients with symptoms consistent with withdrawal presumably due to synthetic cannabinoid use. The most appropriate treatment for such patients remains unknown, however benzodiazepines are a reasonable first line approach and quetiapine may have some efficacy.

Cardiac conduction disturbance after loperamide abuse

Abstract Context. Prescription opioid abuse is a major public health concern and an ongoing epidemic in the United States. Loperamide is a widely available and inexpensive over-the-counter antidiarrheal with peripheral mu-opioid receptor activity. Online resources discuss the use of loperamide for the amelioration of withdrawal symptoms or recreational abuse. We describe the clinical course of 5 patients abusing loperamide, 3 of whom had life-threatening cardiac arrhythmias. Methods. In this observational case series, patients with cardiac arrhythmias or history of loperamide abuse with cardiac arrhythmias were identified; 5 patients were identified and 4 of the 5 patients were seen directly at the bedside. Clinical profile and outcome of patients is reported. Results. We report 5 patients with history of loperamide abuse; 3 of the 5 patients had life-threatening cardiac arrhythmias. One of the patients experienced a second life-threatening arrhythmia after he resumed loperamide abuse. Loperamide levels were obtained in 4 of the 5 patients and were at least one order of magnitude greater than therapeutic concentrations. Discontinuation of loperamide resulted in complete resolution of cardiac conduction disturbances. Conclusion. This case series describes several patients with cardiac conduction abnormalities and life-threatening ventricular arrhythmias temporally related to loperamide abuse. With the recent efforts to restrict the diversion of prescription opioids, increasing abuse of loperamide as an opioid substitute may be seen. Toxicologists should be aware of these risks and we urge all clinicians to report such cases to FDA Medwatch®.

The use of vasopressin in the setting of recalcitrant hypotension due to calcium channel blocker overdose

Treatment of hypotension caused by calcium channel blocker overdose (CCB) remains a challenge. We describe the successful use of vasopressin in two patients with massive CCB overdoses in whom hypotension was unresponsive to calcium, glucagon, insulin, and conventional vasopressor therapies. While various modes of treatments have been used to treat the hypotension of CCB overdose, this is the first report to our knowledge of the successful use of vasopressin in this clinical setting.

Loperamide toxicokinetics: serum concentrations in the overdose setting

A web-based study published in 2013 suggested that loperamide was being abused to attenuate the symptoms of opioid withdrawal.1 Marraffa et al recently reported a case series of patients who presented with cardiac conduction disturbances after loperamide abuse.2 This case series outlined the clinical course of 5 patients, 3 of whom experienced life-threatening arrhythmias. Isolated serum levels were reported in four of these patients. We report a subsequent hospitalization and pharmacokinetic profile of one of the patients in the case series.2 A 30-year-old male presented to an outlying facility for a syncopal episode. The initial electrocardiogram (ECG) revealed a heart rate of 60 beats per minute, a QRS measurement of 192 ms, and a QT of 704 ms. He left against medical advice, only to be found pulseless and apneic by a family member hours later. He was brought back to the outlying facility and demonstrated multiple ventricular arrhythmias, including one episode of polymorphic ventricular tachycardia. He was transferred to our facility after being defibrillated multiple times. The patient reported that he had resumed his abuse of loperamide and had been taking two hundred 2-mg tablets daily for the last seven days. He has had at least four prior hospitalizations with a similar presentation associated with loperamide abuse. The patient’s cardiac conduction disturbance was managed with a continuous infusion of isoproterenol. The conduction disturbance slowly resolved with a QRS of 96 ms and QTc of 489 ms on hospital day 9. He was discharged to an inpatient psychiatric facility on hospital day 13 with a QRS of 94 ms and a QT/QTc of 406/483 ms. Due to his prolonged toxicity we obtained serum loperamide concentrations at multiple time points to better understand his pharmacokinetic profile. The reported pharmacokinetic half-life of loperamide is approximately 9–13 h, although longer half lives up to about 40.9 h have been reported with doses of 16 mg in healthy volunteer studies.3–4 The toxicokinetics of loperamide have not been previously reported. The patient presented to our facility 20 h after his last reported 400-mg dose. On presentation his loperamide level was 120 ng/mL. His loperamide serum levels 32, 44, 57, and 70.5 h post-ingestion were 47 ng/mL, 30 ng/mL, 30 ng/mL, and 20 ng/mL, respectively (Figure 1). Published peak loperamide concentrations after doses of 2–16 mg were reported to be between 0.24 and 3.1 ng/mL and occurred 4–5.9 h after administration.5–6 His first two serum concentrations demonstrated an initial decline consistent with the reported half-life based on population kinetics (8.9 h). However, subsequent serum concentrations demonstrated a half-life of approximately 34.8 h. Interpretation of this kinetic data is complicated by the patient’s history of Crohn’s disease, multiple small bowel resections, and ileostomy. Additionally, the patient did receive a single dose of buprenorphine 12 mg sublingually and amiodarone 150 mg intravenously 35 and 38 h after his reported ingestion, respectively. No other cytochrome P450 inhibitors or inducers were given during the time frame when serum concentrations were drawn. A comprehensive drug panel including synthetic cannabinoids and designer drugs conducted on urine by NMS Labs was negative. Our patient’s ECG changes are consistent with previously published case reports.2,7 The elimination half-life observed in our patient is not consistent with the reported half-life. Loperamide is a m-receptor agonist, which may reduce gastrointestinal motility and result in delayed absorption of drug.8 Delayed absorption in the overdose setting may result in prolonged toxicity. Loperamide has also been reported to antagonize calcium channels, which may result in reduced gastrointestinal motility.9 The elimination kinetics of loperamide are not known in the overdose setting and a multicompartment pharmacokinetic model cannot be excluded. Our patient also received medications that inhibit both cytochrome P450 3A4 and 2D6 enzymatic metabolism. These enzyme families are reported to play a role in the hepatic conversion of loperamide to the N-demethyl metabolite, and inhibition might have further slowed the elimination of parent drug.10 Genetic alterations in these enzymatic pathways could also alter the kinetics of loperamide, which may explain the wide range in half-lives reported in one pharmacokinetic study.3 It is unclear what, if any, impact the patient’s altered gastrointestinal tract may have had on the kinetics of loperamide. Further kinetic studies are needed to assess the toxicokinetics of loperamide.

Quantitative Measurement of Acetyl Fentanyl and Acetyl Norfentanyl in Human Urine by LC-MS/MS

Opioid abuse involving emerging opioid compounds is a growing public health problem, which was highlighted recently by cases of human morbidity and mortality linked to acetyl fentanyl abuse. Unfortunately, the lack of information available on the toxicology and metabolism of acetyl fentanyl precludes its detection in human samples. The following study was conducted to test a new analytical procedure for the simultaneous quantification of acetyl fentanyl and its predicted metabolite, acetyl norfentanyl, in human urine. Metabolic reference standards and deuterium-labeled internal standards were synthesized for use in an assay that coupled solid-phase extraction (SPE) with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The accuracy (% Relative Error <5%) and inter- and intrarun precision (%CV <20%) of this new method resulted in low levels of quantification (∼1 ng/mL). Similar results were obtained using liquid chromatography columns manufactured with phenyl-hexyl and biphenyl stationary phases (r(2) > 0.98). Preliminary human liver microsomal and in vivo rodent studies demonstrated that acetyl fentanyl is metabolized by cytochrome P450s to acetyl norfentanyl. Urine samples from rats treated with a toxic dose of acetyl fentanyl contained high concentrations of acetyl fentanyl and acetyl norfentanyl. Further toxicokinetic studies are required to fully elucidate the metabolic pathways responsible for acetyl fentanyl detoxification and excretion.

Oral administration of fomepizole produces similar blood levels as identical intravenous dose.

Introduction. Fomepizole is available intravenously (IV) for the treatment of methanol and ethylene glycol poisoning. Few studies demonstrate that fomepizole achieves effective serum concentrations after IV or oral (PO) use. The objective was to describe the comparative pharmacokinetics of fomepizole after a single PO and IV dose. Methods. This was a prospective, randomized, crossover trial in 10 healthy volunteers. Each received 15 mg/kg fomepizole, PO and by 30 minute IV infusion. Serum was collected at 0, 0.25, 0.5, 1, 2, 4, 7, 12, 24, 36, and 48 hours (h) and stored at −70°C. Candidate models were fit to the IV and PO data, simultaneously, using iterative 2-stage analysis weighted by the estimated inverse observation variance. Time above the MEC (T>MEC) was determined by numeric integration of the fitted functions using 10 μmoles/L as the minimum effective concentration (MEC). Results. Seven females and 3 males were enrolled. Sole complaints included headache and dizziness in 3 subjects and 10/10 reported an unpleasant taste. The final PK model was 2-compartment with 0-order IV and 1st-order PO input (following a fitted TLag) and Michaelis-Menten elimination. PO fomepizole was rapidly absorbed with a bioavailability of ∼100%. The Km was 0.935 ± 0.98 μmoles/L and the Vmax was 18.57 ± 9.58 μmoles/L/h. T>MEC was 32 h with agreement between PO and IV dosing. Conclusions. This is the first study that effectively determines a human Vmax and Km for PO and IV fomepizole. PO and IV administration of fomepizole result in similar pharmacokinetic parameters.

Profound metabolic acidosis and oxoprolinuria in an adult

IntroductionProfound metabolic acidosis in critically ill adults sometimes remains unexplained despite extensive evaluation.Case ReportA 58-year-old female presented in a confused state to the emergency department; she had been confused for several days. Laboratory evaluation revealed a high anion gap metabolic acidosis and modestly elevated acetaminophen level. Lactic acid was only modestly elevated. There was no evidence of ketoacids, salicylate, methanol, or ethylene glycol. A urine sample submitted on day 1 of hospitalization revealed a markedly elevated level of 5-oxoproline.DiscussionOriginally described in children with an inherited defect of glutathione synthetase, 5-Oxoproline is an unusual cause of metabolic acidosis. More recently this disturbance has been recognized in critically ill adults without a recognized inherited metabolic disorder. In most of these cases there has been the concomitant use of acetaminophen. Any causal relationship between acetaminophen and this disturbance is speculative.ConclusionIn critically ill adults with unexplained metabolic acidosis, 5-Oxoproline should be considered in the differential.

A Rare Ingestion of the Black Locust Tree

Background: The Black Locust (Robinia Pseudoacacia) tree contain toxalbumins, robin and phasin, that exert their toxic effects by inhibition of protein synthesis. Despite the potential dangers of Black Locust intoxication, reports of human toxicity after ingestion are rare. We report the first human intoxication of Black Locust bark in North America in over one hundred years. Case Report: An eight‐year‐old male was brought to the emergency department 6 hours after chewing and expelling the Black Locust bark. He presented with emesis, which began approximately 2.5 hours after exposure. His vital signs were as follows: oral temperature, 97.5° F; blood pressure, 128/75 mmHg; heart rate, 114 beats per minute; respiratory rate, 15 breaths per minute. Initial treatment included 4 mg IV ondansetron, which resolved the vomiting, one dose of activated charcoal, and intravenous fluids. He was then admitted to the intensive care unit (ICU) for observation of signs of toxicity. Laboratory findings were unremarkable except for a white blood cell of 18.4 K/uL and an elevated alkaline phosphatase of 183 U/L. The patient remained asymptomatic throughout his stay in the ICU and was discharged on the fifth day of admission with a normal white blood cell of 4.1 K/uL and an alkaline phosphatase of 251 U/L. Conclusion: Patients with clinical toxicity following the ingestion of Black Locust are expected to do well with supportive care and observation.

Compounded ointment results in severe toxicity in a pediatric patient.

Background Dermal drug delivery is becoming more common, as evidenced by the increased numbers of compounding pharmacies preparing topical products for chronic pain management. Consumers may not appreciate the potency or dangers associated with some of the drugs in these preparations. Pediatric patients are especially at risk for significant toxicity with accidental exposures. We report a case of severe toxicity in an 18-month-old boy from exposure to his father’s compounded pain ointment. Case An 18-month-old previously healthy child had an ointment applied topically to a diaper rash by his mother, consisting of a single pump of a prescription ointment that her husband received from a compounding pharmacy for neck pain. Approximately 20 minutes later, when the child had been put down for a nap, he had gasping respiration but was otherwise unresponsive. Emergency medical services was called, and the child was unresponsive. In the ED, vital signs were pulse of 57 beats/min, blood pressure 74/35 mm Hg, respiratory rate 21 breaths/min, and O2 saturation 98% on a nonrebreather. Fingerstick glucose was 105 mg/dL. In the ED, physical examination was significant for unresponsiveness, pinpoint pupils, and hyporeflexia. The patient’s mental status continued to deteriorate with depressed respirations, and he was intubated. Laboratory results were noncontributory. Electrocardiogram revealed only sinus bradycardia. The patient was transported to a pediatric intensive care unit. He did well over the next several hours with supportive care and had return to normal vital signs over the following 12 hours. He was extubated the following morning without problems. Blood taken at the time of ED presentation had a serum clonidine level of 9.2 ng/mL (reference range, 0.5–4.5 ng/mL) and a norketamine level of 41 ng/mL (reporting limit, >20 ng/mL). Conclusions Dermal absorption of drugs leading to significant toxicity in children is well known. Our patient had toxicity from a topical pain medication compounded with several potent drugs known to cause central nervous system depression. There has been an increase in the use of this drug delivery system for management of chronic painful conditions. The popularity and attractiveness of such preparations may be the perception that they are somehow safer and more natural than taking pills. This perception and the fact that these are not dispensed in child-proof containers and are often mailed to the patients without pharmacist counseling can lead to increased inadvertent exposures in the pediatric population.

Profound metoprolol-induced bradycardia precipitated by acetaminophen-propoxyphene.

Pharmacokinetic studies demonstrate that propoxyphene is a potent inhibitor of cytochrome P450 (CYP) 2D6. Clinically significant sequelae have not been previously reported. We report a case of this inhibition manifested by life‐threatening bradycardia in a patient receiving a CYP2D6 substrate, metoprolol. A 48‐year‐old man came to the emergency department complaining of dizziness 3 hours after ingesting metoprolol, at his usual dose, and 2 tablets of propoxyphene, newly begun postoperatively. Four hours after ingestion of both drugs, the patient was noted to have a ventricular rate of about 30 beats/min with underlying atrial fibrillation. The patients ventricular response returned to normal within 11 hours of ingestion. We have demonstrated the clinical importance of the interaction between propoxyphene and metoprolol likely resulting from inhibition of hepatic clearance of metoprolol by propoxyphene. Underscoring the clinical relevance of CYP2D6 inhibition by an analgesic of questionable efficacy should proscribe its use.