Case Files of the Medical Toxicology Fellowship at Drexel University

Case Presentation

A 28-year-old female was brought to the emergency department (ED) by her roommate after a suicide attempt, in which the patient took 29 capsules of an over-the-counter (OTC) sleep aid containing 50 mg of diphenhydramine (DPH) per capsule, for a total of 1450 mg, and consumed 100 ml of vodka. Her weight was 67 kg, yielding a dose of 22 mg/kg DPH. When a roommate arrived home from work several hours later, he noticed that the patient was walking aimlessly through the house and that “she was out of it.” The patient subsequently informed the roommate of her suicide attempt, at which point he brought her by car to our ED. According to the patient, the ingestion occurred 9 h prior to arrival.

In the ED, the patient complained of bilateral tingling and numbness in her legs and feet that had started within the last 4 h. She had a subjective sensation of inability to control the muscles in her legs and leg weakness. The patient denied any history of leg trauma, recent strenuous physical activity, or recent prolonged inactivity. Her medical history was significant for cervical dysplasia status post surgical excision and major depressive disorder. The patient denied taking any other prescribed or OTC medications, which her roommate corroborated.

Physical examination revealed a young, disheveled female with normal body habitus. Initial vital signs included a temperature of 36.4°C, heart rate 123 beats/min, respiratory rate 18 breaths/min, blood pressure 112/83 mm Hg, and pulse oximetry of 98% on room air. Pupils were 6 mm bilaterally and sluggishly reactive to light. Extraocular movements were intact. The mucous membranes of the oropharynx were dry. Cardiac examination was significant for a regular tachycardia, while the pulmonary examination was normal. Abdominal examination was significant for bowel sounds being present but decreased. The patient was alert and oriented to self and place, but not to time. She was able to answer simple questions, but was slow to respond. Strength, sensation, and deep tendon reflexes were normal. No ataxia or tremor was present. Extremity examination was significant for mottled skin color on the anterior legs bilaterally. Dorsalis pedis and posterior tibialis pulses were normal, as was sensation, strength, and capillary refill throughout the bilateral lower extremities.

What is the Pharmacology of DPH?

DPH is a first-generation H₁ antihistamine. It belongs to the ethanolamine subclass of antihistamines along with carbinoxamine, clemastine, dimenhydrinate, and doxylamine. Histamine receptors are categorized into four subtypes labeled H₁ through H₄, all of which are G protein-coupled receptors (GPCR). The H₁ receptor is coupled to G_q/11 and activation stimulates phospholipase C to hydrolyze phosphatidylinositol 4,5-bisphosphonate to diacyl glycerol and inositol 1,4,5-triphosphate [1]. Downstream effects include activation of protein kinase C, increased cytosolic Ca²⁺ ion, activation of phospholipase D, activation of phospholipase A₂, and activation of transcription factor NF-κB [1, 2]. H₁ receptor activity has been reported in numerous tissues and cell types, where these downstream intracellular changes are responsible for histaminergic effects such as bronchoconstriction, which occurs primarily due to increased cytosolic Ca²⁺ ion, and inflammatory cell accumulation, which occurs due to NF-κB promotion of cytokine and adhesion protein production [1, 2].

Although DPH is sometimes discussed as an H₁-receptor antagonist, that categorization is technically incorrect in that it actually acts as an inverse agonist. In the absence of stimulation, the G_q/11-coupled H₁ receptor exists in an equilibrium state of active and inactive conformations with a basal degree of activity. Ligands can, therefore, be characterized as full or partial agonists, full or partial inverse agonists, or neutral antagonists. Full or partial agonists bind to the GPCR, stabilizing the active confirmation and increasing receptor activity. Full or partial inverse agonists, conversely, stabilize the inactive confirmation, decreasing receptor activity below the basal level of activity. Neutral antagonists bind to the receptor and do not change the equilibrium state of active and inactive confirmations, but do prevent binding of other agonists or inverse agonists, thereby stabilizing the basal degree of activity (see Fig. 1). All H₁ antihistamines act as inverse agonists rather than as neutral antagonists, thereby decreasing the basal activity of the G_q/11-coupled H₁ receptor [2].

Fig. 1.

In the absence of stimulation, the G_q/11-coupled H₁ receptor exerts a basal level of activity. H₁-receptor ligands, therefore, may act as agonists, inverse agonists, or neutral antagonists. Full or partial agonists stabilize the active state resulting in increased receptor signaling, while full or partial inverse agonists stabilize the inactive state and decrease receptor signaling. Neutral antagonists bind the H₁ receptor without modifying the basal level of activity, but competitively inhibit the binding of other agonists or inverse agonists. (Adapted with permission from Leurs et al. [2])

DPH has a volume of distribution of 4.2 l/kg [3]. Bioavailability is approximately 60% due to a considerable first-pass effect. DPH undergoes CYP450 metabolism with the major metabolic pathways being N-demethylation and N-glucuronidation primarily via CYP2D6, with CYP1A2, CYP2C9, and CYP2C19 having minor roles [4, 5]. DPH is also a potent competitive inhibitor of CYP2D6, which may contribute to drug–drug interactions [6]. Less than 4% of DPH is excreted unchanged in the urine [7]. The terminal elimination half-life is approximately 9.2 h, but may vary significantly due to factors such as liver disease, CYP2D6 polymorphism, or coingestion of CYP inducers or inhibitors [3–5, 8, 9].

DPH exerts anti-inflammatory and anti-allergic activity via several mechanisms. Its main mechanism of action is to block the effects of mast cell and basophil-derived histamine on target tissues. However, at supratherapeutic concentrations it directly inhibits calcium ion channels on mast cells and basophils, thereby decreasing the release of other allergic mediators [2, 8]. The clinical relevance of this activity is unclear. Inverse agonism at the G_q/11-coupled H₁ receptor results in down-regulation of transcription factor NF-κB, thereby decreasing the transcription of cell adhesion molecules and inflammatory cytokines [2].

In addition to its therapeutic effects, DPH and other ethanolamine derivative H₁ antihistamines modulate the activity of other receptors and ion channels. DPH and the other ethanolamine antihistamines are potent competitive antagonists at muscarinic acetylcholine receptors [10]. DPH also acts as an antagonist at serotonin receptors, although the clinical relevance of this interaction is unclear [11].

DPH may also cause sodium channel blockade. The ability of DPH to interact with cardiac sodium channels may result in effects similar to the Class Ia antidysrhythmics [12]. Similar to local anesthetics, DPH has a greater affinity for inactivated sodium channels than for channels in the resting state [13]. The dissociation constant between diphenhydramine and the inactivated and resting sodium channels are approximately 10 μM and greater than 300 μM, respectively, while therapeutic plasma diphenhydramine concentrations are on the order of 0.1–1 μM [13]. Thus, the DPH concentrations necessary to achieve a significant sodium channel blockade exceed those encountered in therapeutic dosing. Such concentrations can, however, potentially be achieved in overdose scenarios.

DPH has also been reported to decrease outward current through human ether-a-go-go related gene (HERG1) potassium channels that are largely responsible for the rapid component of the delayed rectifier potassium current (I_Kr) [14]. This finding is consistent with reported DPH-induced inhibition of I_Kr in guinea pig ventricular myocytes and QTc prolongation in healthy volunteers given oral DPH [15]. The IC₅₀ for blockade of the delayed rectifier potassium current is 30 μM, approximately 40 times therapeutic diphenhydramine concentrations [15]. Again, the DPH concentrations necessary to produce this blockade are unlikely to be achieved with therapeutic dosing, but may be within the range of plasma concentrations achieved in the setting of overdose.

What Adverse Effects Might be Expected in a Patient Presenting After Acute DPH Overdose?

Understanding the pharmacology of DPH illuminates the adverse effects that are commonly encountered in the overdose setting. DPH is actively transported into the CNS by a saturable transport system [16]. Within the CNS, it acts as an inverse agonist at CNS histamine receptors, resulting in prominent drowsiness, impairment of cognitive function and psychomotor performance [8]. The central antihistaminic effects of DPH may be partly responsible for its intentional abuse [17].

Other CNS effects are modulated by its antimuscarinic activity. Delirium, confusion, and hallucinations are commonly reported. More severe central anticholinergic activity may result in seizures and status epilepticus [18, 19]. It has been suggested that the balance between CNS sedation and excitation may be age-dependent, with children and young adults manifesting primarily with CNS stimulation and older adults manifesting primarily with CNS depression [19]. Peripheral antimuscarinic activity may result in tachycardia, mydriasis, xerostomia, urinary retention, ileus, anhidrosis, and hyperthermia.

The association of some H₁-receptor antagonists with serious cardiac dysrhythmias has been well established and has resulted in the withdrawal of astemizole and terfenadine from the market [14]. DPH overdose has been reported to result in QTc prolongation, dimorphic or flattened T waves, polymorphic ventricular tachycardia, Brugada syndrome-like electrocardiograph findings, and wide complex tachycardia [20–24]. These dysrhythmias may be related to DPH modulation of I_Kr and HERG1 potassium channels, DPH-induced sodium channel blockade, or some combination of the two.

Case Continuation

Initial laboratory studies were consistent with rhabdomyolysis with a creatine kinase of 10,605 U/l and an initial creatinine of 1.1 mg/dl (97 mmol/l). Acetaminophen and salicylate levels were below detection limits, a serum ethanol level was 42.4 mg/dl (9.20 mmol/l), and a urine drugs of abuse immunoassay screen was negative for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, and phencyclidine. A chemistry panel was within normal limits with the exception of an elevated serum phosphorus concentration of 7.2 mg/dl (normal range 1.5 – 4.5 mg/dl); the serum potassium concentration was 4.4 mmol/l.

What are the Possible Etiologies for Rhabdomyolysis in this Patient?

Rhabdomyolysis has been previously reported in the setting of DPH and other ethanolamine-derivative antihistamine overdose [25, 26]. It has also been previously reported specifically in the setting of ethanol and DPH overdose [27]. There are two broad categories of rhabdomyolysis that may be responsible for this patient’s presentation: primary drug-induced rhabdomyolysis and secondary rhabdomyolysis. Rhabdomyolysis has been reported following DPH overdose in the absence of secondary or traumatic etiologies, suggesting that it may cause primary drug-induced rhabdomyolysis [28, 29]. The mechanism by which DPH causes direct myotoxicity is unclear, however, and no consistent dose–response relationship has been established. Doxylamine, another ethanolamine-derivative antihistamine associated with rhabdomyolysis, has been reported to be more likely to cause rhabdomyolysis following ingestions of greater than 20 mg/kg [30]. Dimenhydrinate, a chlorotheophylline salt of DPH marketed for motion sickness, is similarly associated with rhabdomyolysis.

Secondary rhabdomyolysis may occur due to muscle compression during a period of unresponsiveness, muscular hyperactivity (e.g., seizure, hypothermia with shivering) with energy depletion, hypokalemia or impaired production of adenosine triphosphate (e.g., uncoupling oxidative phosphorylation) [31]. With this patient, there was an unknown period of time after the alcohol and DPH ingestion when the patient was not directly observed. Although not suggested by history, during this time she may have had a period of several hours of unconsciousness with resulting compression of various muscle compartments or unwitnessed seizures.

Similarly, ethanol has been associated with primary drug-induced and secondary rhabdomyolysis. Ethanol may cause both an acute myopathy with rhabdomyolysis as well as chronic skeletal muscle damage [32]. Ethanol may increase the susceptibility of skeletal muscle to other myotoxic substances by induction of CYP450 on skeletal muscle sarcoplasmic reticulum; this could account for the sporadic nature of alcohol-induced rhabdomyolysis [33]. Convincing evidence of this hypothesis, however, is lacking, and the reported amount of ethanol consumed in this case would be insufficient to have reasonably caused rhabdomyolysis.

What Other Xenobiotics Cause Rhabdomyolysis?

Numerous other xenobiotics are associated with rhabdomyolysis, although the mechanism of muscle injury varies. For some xenobiotics, the mechanism of injury is limited to secondary rhabdomyolysis, while in other cases, direct myotoxicity is responsible. Comprehensive lists of xenobiotics associated with rhabdomyolysis have been compiled elsewhere and are beyond the scope of this discussion [31]. However, some xenobiotics deserve special mention either because of the mechanism by which or frequency with which they cause rhabdomyolysis.

Drugs of abuse are commonly implicated in rhabdomyolysis [34]. Opiates and sedative-hypnotics are associated with rhabdomyolysis secondary to muscle compression during periods of unresponsiveness. Sympathomimetics such as cocaine, amphetamines, methamphetamine, MDMA, and phencyclidine are associated with rhabdomyolysis secondary to muscle overuse. Additionally, cocaine appears to have direct myotoxic effects and catecholamine excess also is implicated in direct myotoxicity [35, 36].

Hypokalemia is a proximate cause of rhabdomyolysis for a number of xenobiotics associated with total body potassium depletion. While the mechanism by which hypokalemia induces rhabdomyolysis remains unproven, evidence suggests that hypokalemia may reduce the ability of metabolically active muscles to induce local vasodilation and impair muscle glycogen production [37, 38]. Rhabdomyolysis, which may be subclinical in severity, has been reported to occur in up to 28% of hypokalemic patients admitted to the hospital [39]. Xenobiotics that have been reported to induce hypokalemic rhabdomyolysis include diuretics, mineralocorticoids, amphotericin B, and toluene [31, 40, 41]. Glycyrrhizin, a component of licorice used for its sweetness and distinctive flavor, has mineralocorticoid activity and has been implicated in rhabdomyolysis following its consumption in herbal medications, candies and beverages sweetened with the compound [42–46]. Glycyrrhizin is approved as a sweetener in the European Union and in Japan, while in the United States it may be used for flavoring but not as a sweetener. Of note, most licorice candy sold in the United States is artificially flavored and does not contain glycyrrhizin.

Malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome are all associated with rhabdomyolysis [47]. Therefore xenobiotics associated with each of these syndromes have the potential to induce rhabdomyolysis. Baclofen withdrawal syndrome may mimic malignant hyperthermia or neuroleptic malignant syndrome and similarly is associated with rhabdomyolysis [48].

Venoms are another important cause of rhabdomyolysis. A number of snake venoms are associated with rhabdomyolysis, including pit vipers (Subfamily Crotalinae), true vipers (Subfamily Viperinae), sea snakes (Family Hydrophiidae), and Australasian elapids (Family Elapidae) [49]. Rhabdomyolysis has been reported following envenomation by insects of the Order Hymenoptera, including hornets, wasps, honey bees, and fire ants with clinically significant rhabdomyolysis being reported only following multiple stings [50–54]. Rhabdomyolysis has been rarely reported with spider envenomation including that of the genera Latrodectus and Loxosceles [55–57]. Other envenomations that may rarely involve rhabdomyolysis include the scorpions of genus Centruroides and the centipede Scolopendra heros [58, 59].

What Treatments Should be Undertaken in a Patient with Rhabdomyolysis?

The goal of treatment for rhabdomyolysis is to prevent myoglobinuric renal injury. Renal injury in the setting of rhabdomyolysis is due to renal vasoconstriction and myoglobin precipitation resulting in renal tubule obstruction and injury. Intravascular volume depletion is common in rhabdomyolysis due to sequestration of fluid in damaged myocytes. Renal vasoconstriction occurs due to activation of the renin–angiotensin axis, increased sympathetic tone, and oxidant-injury induced local release of vascular mediators (e.g., thromboxane A2) [60]. Aggressive intravenous hydration to correct the intravascular depletion and renal vasoconstriction is the cornerstone of rhabdomyolysis treatment.

Urine alkalinization offers theoretical benefits in that tubular precipitation of myoglobin is increased in acidic urine and alkalinization inhibits redox cycling of myoglobin thereby reducing oxidant injury to renal tubules [60]. Despite these theoretical benefits, the use of sodium bicarbonate does not appear to prevent renal failure, the need for dialysis, or mortality in patients with rhabdomyolysis [61]. Similarly, the use of mannitol or loop diuretics to increase urinary flow offers the theoretical benefit of decreasing the concentration of myoglobin in the renal tubules, however, clinical studies have failed to show benefit from their administration [60, 61].

Case Continuation

Treatment in the ED consisted of a 3-l bolus of normal saline followed by a normal saline infusion at one and one-half times the calculated maintenance rate. Oxycodone/acetaminophen tablets were given for pain and the patient was admitted to a telemetry level of care.

Following admission, the patient continued to have worsening pain in her lower extremities. Reexamination of the patient 18 h after arrival revealed absence of bilateral posterior tibialis and left dorsalis pedis pulses. General surgery was consulted for concern for compartment syndrome. Tense compartments were noted in the bilateral legs and the left thigh. The patient was unable to actively move the left foot, and was unable to actively dorsiflex the right foot. The patient was clinically diagnosed with compartment syndrome and taken to the operating suite where she underwent a left thigh lateral-incision two-compartment fasciotomy and bilateral leg two-incision four-compartment fasciotomies. During fasciotomy, the muscle appeared to be viable, although increased interstitial fluid was noted. No debridement was deemed necessary.

What is the Mechanism by which Xenobiotics Cause Compartment Syndrome?

Compartment syndrome can occur in any condition in which there is significant skeletal muscle damage in a fascial compartment. Release of osmotically active particles from damaged skeletal muscle raises the intracompartmental osmotic pressure. As fluid shifts into the compartment, hydrostatic pressures may increase to the degree that perfusion within the compartment is impaired. Muscle ischemia then worsens the rhabdomyolysis, further sustaining or exacerbating compartment pressure elevation.

Xenobiotics implicated in rhabdomyolysis may be similarly implicated in compartment syndrome. Drugs of abuse, for example, associated with rhabdomyolysis due to compression, overuse, or direct myotoxicity, may also cause compartment syndrome [62, 63]. Similarly, patients with crotaline venom-induced rhabdomyolysis may go on to develop compartment syndrome. The incidence of compartment syndrome after crotaline envenomation has been reported in several case series and varies from less than 2% to greater than 10% [64–66].

Creatine supplementation increases compartment pressures in the absence of muscle necrosis due to increased osmotic pressures from myocyte creatine uptake. These increases appear to be greatest immediately post-exercise when compartment pressures in the anterior compartment of the leg may be 40 mm Hg greater in subjects using creatine than in control subjects [67]. However, it is not clear that the increased compartment pressures associated with creatine supplementation are sufficient to increase the risk of compartment syndrome [68]. While compartment syndrome has been reported in bodybuilders following strenuous exercise in the setting of high dose creatine supplementation, it is not known whether the creatine intake played a significant role in the development of the compartment syndrome [69, 70].

What Treatments Should be Undertaken for Patients with Xenobiotic-Induced Compartment Syndrome?

In most cases, xenobiotic-induced compartment syndrome should be treated with standard measures/therapies. If compartment syndrome is suspected, intracompartmental pressures and surgical consultation should be rapidly obtained. Patients with clinical compartment syndrome or with compartment pressures above 30 mm Hg should undergo fasciotomy to relieve the elevated compartment pressures and prevent myonecrosis.

While most xenobiotic-induced compartment syndromes should be treated using the standard measures cited above, some authors have suggested that fasciotomy should not be undertaken as an initial therapy for rattlesnake venom-induced compartment syndrome [71]. Rattlesnake venom directly induces myonecrosis independently of elevated compartment pressures and relief of elevated compartment pressures in that setting may have limited effect on the degree of myonecrosis [72]. Conversely, tissue swelling and intracompartmental hemorrhage due to crotaline envenomation may mimic compartment syndrome, despite normal intracompartmental pressures, resulting in unnecessary fasciotomy.

Some animal studies suggest that fasciotomy may worsen myonecrosis and outcome in the setting of snakebite-induced compartment syndrome, although others have questioned the methodology in these studies [73–75]. Administration of antivenom and mannitol may reverse compartment syndrome without surgical intervention [76]. At this time, controversy exists over the most effective approach to crotaline-induced compartment syndrome and further research, with emphasis on long-term functional outcomes, is needed [71].

Case Continuation

Following the fasciotomies, the patient had palpable bilateral dorsalis pedis and posterior tibialis pulses and normal dorsiflexion and plantar flexion bilaterally. She continued to have decreased sensation in the left foot that gradually resolved over the remainder of her hospitalization. On postoperative day #11, the patient underwent delayed primary closure of the three fasciotomies.

The patient’s serum creatine kinase concentration peaked at 233,900 U/l and she also developed moderate, transient myoglobinuric renal failure with a peak creatinine of 3.4 mg/dl (301 mmol/l), for which hemodialysis was not required. Over a 2-week period, her blood urea nitrogen and creatinine concentrations returned to their baseline values. She was transferred to an inpatient psychiatric facility for further management of her major depressive disorder 15 days after admission.