49: Antihistamines and Decongestants

Antihistamines and decongestants rank among the highest prescription and non prescription xenobiotics used in the United States. In 2011, antihistamines and cough and cold preparations ranked respectively 9th and 11th in substance categories most frequently involved in human exposures related calls to US Poison Control centers. Antihistamines ranked 11th place in categories associated with the largest number of fatalities in 2011 (Chap. 136).

Popular mythology suggests that expectorants or decongestants depress cough and relieve congestion, and antihistamines also promote sleep. In an effort to retain selected drugs on the nonprescription market, the US Food and Drug Administration (FDA) developed a nonprescription monograph rule allowing some medications in use before 1972 to remain on the market without new clinical trials. As such, many nonprescription decongestants, antihistamines, and expectorants remained available for children without adequate safety or efficacy data in younger age groups. Between the years 1998 and 2007, 8.7% of US parents surveyed reported to have used an antihistamine or decongestant containing remedy for their children younger than 12 years of age in the past week. The majority of these children were younger than 5 years of age. Pseudoephedrine, brompheniramine, and chlorpheniramine are the three most common ingredients used.¹⁷⁸

Unwanted effects associated with their use have posed significant public health problems particularly in children. Fatality studies associated with nonprescription cough and cold medicines reported that although uncommon, most deaths involved nontherapeutic dosages, administration for sedation purposes, and use in children primarily younger than 2 years of age.³⁴ However, the causality of death by cough and cold medicine is often debated. The data needed to prove this relationship are often incomplete because of such factors as the lack of postmortem drug quantification.¹³³ In 2007, a group of pediatricians and pharmacists petitioned the FDA requesting a change in labeling for children younger than 6 years of age on the basis that safety had never been demonstrated in this age group. This petition alerted the general public of the underestimated adverse effects of these xenobiotics.^143,166 In early 2008, the FDA Public Health Advisory announced that cough and cold products were not recommended for children younger than 2 years of age, and later that same year the Consumer Healthcare Products Association (CHPA), a trade group of generic drug manufacturers, announced that its members were voluntarily modifying product labels for cough and cold medicines to exclude children younger than 4 years of age.¹⁷¹

Despite their widespread use, many reviews of nonprescription medications for cough in adults and children found no evidence for the effectiveness of these xenobiotics.¹⁵⁴ Conclusions are similar regarding the use of antihistamines or decongestants in otitis media.²⁸ Moreover, many well-conducted studies of antihistamines in monotherapy or in combination with a decongestant for patients with upper respiratory illness reported a significant absence of overall symptom improvement.^154,176 It is also suggested that the majority of any perceived benefit of cough suppressants may be due to the sensory impact of sweetness and the placebo effect as well as the concerning intent of using the known adverse effect of sedation as a therapeutic goal.⁴⁵

A recent systematic review on the toxicity of common cough and cold remedies in children younger than 12 years of age concluded there is sufficient evidence of an unfavorable risk-to-benefit ratio to support measures aimed at restricting use of cough and cold medications in younger age groups.⁷³ As individuals seek to ameliorate the symptoms of an unpleasant illness, official restrictions in younger age groups have yielded concerns of increased off-label use of medicines intended for older age groups or substitution with other xenobiotics. Two recent analyses of both poison center data and emergency department (ED) visits reported significant decreases in annual rates of both therapeutic medication errors and overall ED visits related to cough and cold medicines. However, the rate of unintentional ingestions did not appear to have been modified after the marketing exposure changes in 2007, implying that further efforts to increase packaging safety and parental education are needed.^88,101,147

Despite many consumer-directed newsletter and media campaigns, it does not appear that overall use in the general population has decreased. This is indicated by the rising sales in the category “cough- and cold-related” nonprescription medications between 2008 and 2011, reaching $4.2 billion in 2011, higher than analgesics ($2.7 billion).²⁹ A survey done in 2010 for CHPA found that 93% of US adults prefer to treat their minor ailments with nonprescription products before seeking professional care, and 85% would do the same for their children.¹⁶⁰

Recreational use of antihistamines and decongestants as “legal highs” was reported as early as the 1970s.¹²⁴ The popular “T’s and blues,” referring to the combination of pentazocine (Talwin) and the antihistamine tripelennamine (blue-colored pills), were used intravenously as a substitute for heroin. In 1983, when naloxone was included in pentazocine (Talwin NX), abuse patterns decreased.¹⁰ Nonprescription sympathomimetics, such as pseudoephedrine, are also used as precursors in the synthesis of methamphetamine. Although the rates of potential adverse events are perceived as low, the issue takes on added significance when the magnitude of the exposure rates for these xenobiotics is considered. In a survey of 2528 participants distributed across the United States, 4.5% of adult participants in 2006 reported taking pseudoephedrine within the past week compared with 8.1% in 2002, and 3.8% reported the use of diphenhydramine compared with 4.4% in 2002.^82,153 Both poison center and clinical experience suggests that recreational use of antihistamines may be increasing. Dextromethorphan-containing products are widely used for recreational purposes (Chap. 38).

Regardless of intent, exposures to these xenobiotics are relatively frequent, as illustrated by the number of calls received to the American Association of Poison Control Centers (AAPCC). Compilation of the National Poison Data System (NPDS) reports for the years 2001 to 2010 shows that although the total number of exposure calls related to antihistamines has increased in the last 10 years, reaching 3% of calls, the percentage of exposure per population covered by AAPCC remains constant at 0.03%. In contrast, both pediatric and adult cough and cold preparation–related calls have decreased since 2007 (Chap. 136).

In combination with each other, analgesics or antipyretics, antihistamines, and decongestants are easily accessible to the public. This availability perpetuates the widespread public impression that nonprescription xenobiotics are “safe” and contributes to their frequent use, misuse, and abuse.

History and Epidemiology

History.

After the discovery of histamine, Daniel Bovet and other researchers at the Pasteur Institute attempted to synthesize antagonists to better understand its physiological role. In 1939, pyrilamine was found to be extremely effective in guinea pigs but not safe enough for humans. In 1941, phenbenzamine was the first antihistamine deemed suitable for clinical use.¹⁵⁶ Diphenhydramine was synthesized in 1943, and shortly after, in 1947, orphenadrine was derived. The more pronounced anticholinergic effects of the hydrochloride salt of orphenadrine explain its use in the treatment of Parkinson disease, and the citrate salt is used as muscle relaxant. In the same years, Searle and Company, in Chicago, modified diphenhydramine to reduce drowsiness. Dimenhydrinate, the resulting 8-chlorotheophylline salt, serendipitously cured a patient of her long-standing motion sickness. This benefit was proven in a clinical trial in 1949, in which 25% of the troops crossing the Atlantic from New York who received a placebo experienced seasickness compared with only 4% of those receiving dimenhydrinate.¹⁵⁶

Reports of adverse effects and toxicity were soon published. The first report of a death associated with diphenhydramine occurred in 1948.¹⁴ However, in this patient, several other factors could have been contributory to her demise. Deaths were also reported with methapyrilene, but given its frequent co-ingestion with propoxyphene or scopolamine and the variable postmortem serum concentrations reported, attribution of causality was difficult.¹³⁴ In the 1950s, more pediatric overdose cases were reported, and the resemblance to atropine poisoning was noted. At the time, treatment consisted of phenobarbital, “pressure respirations”, and cooling with tepid water sponges.¹³¹

In the following decade, more than 5000 compounds were synthesized by more than 500 chemists and tried for human use. Daniel Bovet was awarded the Nobel Prize in Physiology or Medicine in 1957 for his work related to the synthesis of compounds blocking the effects of bodily substances such as histamine.¹⁶

Cyclizine, a piperazine rather than a dimethylamine, was developed in the 1960s. It proved to be long acting and was used during the first manned flight to the moon by the National Aeronautic and Space Administration to control space sickness. It is no longer approved for use in the United States, although its derivative, hydroxyzine, remains in use.¹⁵⁶ In the 1970s, terfenadine was synthesized as a tranquilizer, but it lacked central nervous system (CNS) penetration. However, its peripheral antihistaminic effects proved useful. In 1989, more than 773 reactions to terfenadine were reported ranging from long QT interval to convulsions in supratherapeutic ingestions.³⁵ In 1992, the FDA issued a warning for the risk of torsade de pointes with terfenadine when administered with CYP3A4 inhibitors. Fexofenadine, its active metabolite, was marketed instead.¹⁵⁶

None of the initial xenobiotics could antagonize histamine-induced gastric acid secretion, leading to the determination of the existence of more than one type of histamine receptors. The histamine receptor subtypes were identified as H₁ and H₂. H₂ receptors were noted to be located in the stomach. Attempts to identify H₂ receptor antagonists identified guanylhistamine, a partial agonist, and initiated the understanding of the histamine receptors physiology.¹⁵⁵

Cimetidine was synthesized in 1972, but its binding to the heme moiety of the cytochrome P450 with resultant inhibition caused medication interactions as well as altered mental status.¹⁷³ Ranitidine, a less polar molecule, did not enter the CNS and did not interfere with the P450 cytochromes. It rapidly became one of the best-selling drugs and stayed so for many years.

Seeking to better understand the action of histamine in the CNS, animal studies in the early 1980s postulated the existence of another histamine receptor located presynaptically. The existence of a distinct H₃ receptor inhibiting the neuronal synthesis of histamine (autoreceptor) when stimulated was validated with the development of the selective agonist R-α-methylhistamine and antagonist thioperamide.⁶ A fourth histamine receptor has recently been identified. Its primary function seems to modulate inflammatory and immune responses as well as nociception.⁷⁰ The numerous functions of histamine and its receptors in the nervous system, immune system, and other organs are continually being appreciated. Trials are underway for the use of H₃ and H₄ histamine receptor antagonists in CNS cognitive disorder, obesity, and allergic rhinitis treatments.⁹⁸

Epidemiology.

Antihistamines are now available worldwide, and many do not require a prescription. These medications find widespread application in the treatment of conditions such as anaphylaxis, benign positional vertigo, dystonic reactions, hyperemesis gravidarum, gastroesophageal reflux disease, stress gastritis, and other histamine-mediated disorders. They are also used for their ability to act on other receptors in the treatment of serotonin toxicity. Additionally, they are used for symptomatic relief of allergy symptoms as in allergic rhinitis, conjunctivitis, or urticaria and are included in many combination cough and cold preparations as discussed previously. First-generation antihistamines are widely available without prescription and are also marketed as sleep aids. These two factors may contribute to their common ingestion in suicide attempts.¹²⁶ Second- and third-generation H₁ antihistamines are less frequently implicated in suicide attempts. Although reporting is not comprehensive, according to 2011 NPDS data, about one in five antihistamine-related exposures called to poison centers are intentional. A 10-year review of the NPDS statistics shows that although the total number of antihistamine exposures increased steadily from 2001 to 2010, with a peak of adult exposures in 2007. During this time, percentage of exposures per population served by the AAPCC has remained relatively constant. More than 35% of antihistamine exposures are related to diphenhydramine (Chap. 136).

H₂ antihistamines have a better safety profile in therapeutic and overdose situations.¹¹¹ Even though many references cite the possibility of bradydysrhythmias, hypotension, and cardiac arrest with massive ingestions or intravenous (IV) administration of H₂ antihistamines, these reports are rare. The incidence of adverse cardiovascular events with H₂ antihistamines is largely unknown. In the largest published review assessing 881 cases of lone cimetidine exposures, most were in children from 12 to 36 months of age, and 76% were unintentional in nature. No fatalities were observed.⁹¹ A review of NPDS reports from 2001 to 2010 did not identify any fatalities from single-product ingestion of cimetidine or other H₂ antihistamines. Only a few case reports of fatalities associated with acute exposures to H₂ antihistamines in adults can be found, mainly in forensic literature with little clinical information.⁷⁸

Children may be at increased risk for antihistamine toxicity. Most of the reported deaths in this age group are with diphenhydramine, but this may well be a reflection of its ubiquity.^104,114 Fatalities are also reported with other antihistamines, albeit often in combination with dextromethophan and pseudoephedrine, making it difficult to attribute the cause of death to the antihistamine alone.¹⁵ Liquid formulations attractive to children and topical preparations are available, resulting in unintentional ingestions when accessible. First-generation antihistamines are also administered for their sedative properties by parents and prescribed by pediatricians for various purposes, including promoting recovery of sick children or as a relief for working parents.^2,119 However, the result of a randomized trial of diphenhydramine for this indication showed it was no more effective than placebo for nighttime awakenings or parental happiness.¹⁰⁹

Pharmacology

Histamine Receptor Physiology.

H₁ receptors are located in the CNS, heart, vasculature, airways, sensory neurons, gastrointestinal (GI) smooth muscle, immune system, and adrenal medulla. Through H₁ receptors, histamine interacts with G proteins in the plasma membranes. Stimulation of H₁ receptors results in increased synthesis by phospholipases A₂and C, inositol-1,4,5-triphosphate, and several diacylglycerols (DAGs) from phospholipids located in cell membranes. Inositol-1,4,5-triphosphate causes release of calcium, which then activates calcium–calmodulin-dependent myosin light-chain kinase, resulting in enhanced cross-bridging and smooth muscle contraction. The active and inactive forms of this receptor subtype are in equilibrium at baseline, and histamine shifts the equilibrium to the active conformation.¹⁴⁹

H₁ receptors are most commonly associated with mediation of inflammation. The other functions of histamine and the H₁ receptor include control of the sleep–wake cycle, cognition, memory, and endocrine homeostasis. H₁ receptor stimulation also causes vasodilation, increases vascular permeability, and increases bronchoconstriction. Cardiac histamine H₁ receptor stimulation increases atrioventricular nodal conduction time.³⁶

H₂ receptors are located in cells of the gastric mucosa, heart, lung, CNS, uterus, and immune cells. H₂ receptor stimulation is mediated by ­adenyl cyclase activation of cyclic adenosine monophosphate (cAMP)–dependent protein kinase in smooth muscle and in parietal cells of the stomach and results in increased gastric acidity through stimulation of the H⁺-K⁺-ATPase pump, causing release of H⁺ into the gastric lumen. The action of histamine on the H₂ receptor increases sinus node automaticity, ventricular contraction force, and coronary flow as well as vascular permeability and mucus production in the airways.^70,149

H₃ receptors are found in neurons of the central and peripheral nervous systems, airways, and GI tract. The action of histamine on H₃ receptors of the CNS decreases further release of histamine, acetylcholine, dopamine, and serotonin. H₃ receptors partly act to prevent excessive bronchoconstriction and are implicated in control of neurogenic inflammation and proinflammatory activity.⁹⁸

H₄ receptors are located in leukocytes, bone marrow, spleen, lung, liver, colon, and hippocampus. The H₄ receptor plays a role in the differentiation of myeloblasts and promyelocytes and in eosinophil chemotaxis.⁹⁸

All four types of histamine receptors are heptahelical transmembrane molecules that transduce extracellular signals via G proteins to intracellular second-messenger systems.¹⁴⁹ Xenobiotics acting at each of the four histamine-­modulated receptor sites have been identified. To date, no H₃ or H₄ antihistamines are available for commercial clinical use (Fig. 49–1).

Histamine Receptors: Inverse Agonists versus Antagonists.

All known H₁ histamine antagonists function as inverse agonists and are not simply reversible competitive antagonists. Rather than preventing the binding of histamine to its receptor as in a classical competitive antagonist model, these xenobiotics stabilize the inactive form of the histamine receptor and shift the equilibrium to this inactive conformation¹⁴⁹ (Fig. 49–2).

However, for consistency with the medical literature and the current terminology for these xenobiotics, the terms antihistamine or histamine antagonist rather than inverse agonist are used.

H₁ Antihistamines.

Antiallergic and antiinflammatory activities of the H₁ antihistamines involve multiple mechanisms. Inhibition of the release of mediators from mast cells or basophils involves a direct inhibitory effect on calcium ion channels, thereby reducing the inward calcium current activated when intracellular stores of calcium are depleted. Inhibition of the expression of cell adhesion molecules and eosinophil chemotaxis involves downregulation of the H₁ receptor–activated nuclear factor (κB), which binds to promoter or enhancer regions of genes that regulate the synthesis of proinflammatory cytokines and adhesion proteins.¹⁴⁹

Another classification system of H₁ antihistamines stratifies them by sedating properties and ability to cross the blood–brain barrier and refers to them in terms of generations as they appeared into clinical use. Positron emission tomography (PET) is now the standard method used to assess H₁ receptor occupancy of antihistamines in the CNS.¹⁹⁰

First-generation H₁ antihistamines readily penetrate the blood–brain barrier and produce CNS effects, including sedation and performance impairment. Central effects of the first-generation H₁ antihistamines likely result from their high lipophilicity or lack of recognition by the P-glycoprotein efflux pump on the luminal surfaces of vascular endothelial cells in the CNS. First-generation H₁ antihistamines also bind to muscarinic, serotonin and to α-adrenergic receptors as well as ion cardiac channels. Their binding to the voltage sensitive Na⁺ channels produces use-dependent block because of their much higher affinity to the inactivated Na⁺ channels and their binding to the K⁺ channels (I K_r) alters repolarization (Chap. 16).^25,149

Six major classes of H₁ antihistamines are traditionally recognized based on molecular structure. The classes were initially populated by first-generation derivatives of ethylenediamine (mepyramine, tripelennamine), ethanolamine (diphenhydramine, doxylamine, orphenadrine, dimenhydrate), alkylamines (pheniramine, chlorpheniramine, brompheniramine), phenothiazines (promethazine), piperazines (hydroxyzine), and piperidines (azatadine). Many of the classic antihistamines are substituted ethylamine structures with a tertiary amino group linked by a two- or three-carbon chain with two aromatic groups. This structure differs from histamine by the absence of a primary amino group and the presence of a single aromatic moiety.

Some H₁ antihistamines have relatively unique properties that have led to special uses or marketing. Although dimenhydrinate, chlorpheniramine, cyproheptadine, promethazine, and pyrilamine have been studied for their local anesthetic properties mediated by sodium channel binding, diphenhydramine is the most used antihistamine for this purpose in dentistry since the 1960s.⁹² Concerns arose with tissue irritation and skin necrosis when diphenhydramine hydrochloride 5% was used. Even though the 1% solution produces erythema without necrosis, its use should be reserved for patients truly allergic to conventional local anesthetics.¹⁵² Diphenhydramine and doxylamine find frequent application in nonprescription sleeping medications because of their sedative effects. Diphenhydramine and dimenhydrinate have relatively strong antimuscarinic activity and are used for the management of motion sickness. Oxatomide, a sedating H₁ antihistamine, may possess mast cell stabilizing properties possibly mediated via calcium-channel blockade and is associated with dyskinesia. Cyproheptadine has 5-HT₂ antagonist properties and is used in the treatment of serotonin toxicity.

Second-generation H₁ antihistamines are peripherally selective and have a higher therapeutic index. Second-generation H₁ antihistamines do not penetrate the CNS well because of their hydrophilicity, their relatively high molecular weight, and recognition by the P-glycoprotein efflux pump on the luminal surfaces of vascular endothelial cells in the CNS.²⁵ Second-generation H₁ antihistamines include astemizole, azelastine, cetirizine, ebastine, ketotifen, levocabastine, loratadine, mizolastine, olopatadine, and terfenadine. They have lower binding affinities for the cholinergic, α-adrenergic, and β-adrenergic receptor sites than do the first-generation antihistamines. Many are prodrugs that need to be converted in the liver to hydrosoluble metabolites.

Although not officially accepted terminology, metabolites or active enantiomers of second-generation H₁ antihistamines such as desloratadine, levocetirizine, and fexofenadine are sometimes referred to as third-generation antihistamines. They have fewer adverse drug reactions, but no study has confirmed their therapeutic advantages over the parent compounds. ­Fexofenadine, however, does not have the cardiac toxicity of its parent drug terfenadine. In a test of wheal suppression, which correlates better to receptor occupancy than plasma concentrations, fexofenadine had the earliest onset of action, and levocetirizine showed maximal inhibition at 3 and 6 hours.^37,58

Cautious prescribing practice may lead to a preference for second-­generation H₁ antihistamines in patients whose activities are safety critical and may be affected by any psychomotor impairment (eg, those who ­operate motor vehicles).^63,103 In a randomized placebo-controlled driving simulator trial, 60 mg of fexofenadine did not interfere with driving performance. However, 50 mg of diphenhydramine produced poorer driving performance than ethanol (100 mg/dL). Of note, subjective feelings of drowsiness were not predictors of impairment.¹⁸³ Despite these findings, care must be exercised in the selection and use of second-generation H₁ antihistamines because some subjective or objective sedation may still result from their use, especially if higher-than-recommended dosages are taken, particularly with cetirizine.^38,137 Furthermore, a meta-analysis suggested that the differentiation between sedating and nonsedating H₁ antihistamines may be blurry, with some studies lacking the methodology to correctly distinguish between medication adverse effects and the signs and symptoms of the condition being treated.^12,163 Overall, it appears that the relative incidence of anticholinergic and CNS adverse effects caused by second-generation H₁ antihistamines may be similar to that produced by placebo.³⁸ Using recommended doses of antihistamines, PET scanning shows that first-generation antihistamines occupy more than 70% of the H₁ receptors in the frontal cortex, temporal cortex, hippocampus, and pons. In contrast, the second-generation antihistamines occupy less than 20% to 30% of the available CNS H₁ receptors.^162,163

H₂ Antihistamines.

These structural analogs of histamine are highly selective inhibitors of the H₂ receptor site. Cimetidine is the original antihistamine in this class; it includes the imidazole ring of histamine (Fig. 49–3). Although ranitidine and famotidine have a furan (ranitidine) or thiazole (famotidine) group instead, they retain significant structural similarity to histamine.

The effectiveness of H₂ antihistamines in the treatment of diseases caused by excessive gastric acid secretion is improved further by their concomitant alteration in the response of parietal cells to acetylcholine and gastrin, two other stimulants for gastric acid secretion (Fig. 49–4). Of note, H₂ antihistamines have little pharmacologic effect elsewhere in the body, and they have weak CNS penetration secondary to their hydrophilic properties.

H₃ Antihistamines.

These xenobiotics are the focus of much research; however, none are currently commercially available.¹⁹² Some prototypical drugs include ciproxifan, clobenpropit, pitolisant, and thioperamide. This category is further divided into the imidazole-based and non–imidazole-based series.¹⁷² Because of nootropic (cognitive enhancement) and stimulant effects, it has been suggested that H₃ antihistamines might play a future role in the treatment of attention deficit and hyperactivity disorder, narcolepsy, depression, or dementia. Pitolisant has been granted orphan drug status in the European Union and United States. Its benefit in the treatment of narcolepsy is contested, and it is currently in clinical trials for Parkinson disease and schizophrenia.¹⁴² Conessine, a herbal used in Ayurvedic medicine for dysentery, is also a selective H₃ antihistamine.^55,138

H₄ Antihistamines.

No commercially available xenobiotics of this class are currently available. Because of their association with mast cells and eosinophils, H₄ antagonists clinical trials are studying their potential therapeutic benefit in the treatment of allergic rhinitis, asthma, and autoimmune disorders.¹⁴⁹

Atypical Antihistamines

Other xenobiotics have been named atypical antihistamines because of their inhibitory effect on the enzyme histidine decarboxylase, which catalyzes the transformation of histidine to histamine as opposed to action on the H₁ receptor. Tritoqualine has been commercially available in Europe since the 1960s and is used for persistent allergic rhinitis.¹²⁵ To date, no case report of overdose with atypical antihistamines has been published.

Pharmacokinetics and Toxicokinetics

H₁ Antihistamines

Absorption.

H₁ antihistamines are generally well absorbed after oral administration, and most achieve peak plasma concentrations within 2 to 3 hours. Although less well studied, dermal absorption appears to be consequential, especially with extensive or prolonged application to abnormal skin.¹⁶⁷ The maximum antihistaminic effect occurs several hours after peak serum concentrations. In supratherapeutic or overdose circumstances, absorption can be prolonged by the antimuscarinic effect on the GI tract.

Although ingestion is the usual route of exposure, rare cases of topical preparations containing diphenhydramine and promethazine cause agitation attributed to anticholinergic toxicity in children. Blood concentrations in these patients may be above the peak therapeutic concentration of 0.06 mg/L.^{50,72,141,146,188} Many cases were with concomitant varicella infection, blurring the causality of the clinical findings attributed to topical diphenhydramine alone. Lumbar punctures were not done to exclude encephalitis, but symptoms improved with cessation of diphenhydramine. Several cases occurred after a bath, calling into question the role of peripheral vasodilation in increasing dermal absorption. Some patients had concomitant oral diphenhydramine therapy but none exceeding the recommended dose of 5 mg/kg/day. One death solely after exposure to topical diphenhydramine is reported in a child with eczema.¹⁶⁷ All cases of topical antihistamine-induced toxicity involved administration over significant body surface area on abnormal skin.

Distribution.

Antihistamines are typically lipid soluble with variable octanol/water partition coefficients. They are also highly bound to plasma protein in therapeutic concentrations. The saturability of protein binding in toxic concentrations is largely unknown. The average volume of distribution is between 0.5 and 12 L/kg but can extend to 30 L/kg with desloratadine.

Metabolism.

Hepatic metabolism is the primary route of metabolism for antihistamines.¹²¹ Cetirizine, fexofenadine, and levocetirizine are exceptions. A poor metabolizer phenotype of desloratadine has been identified in children and adults. In these individuals, the apparent half-life of desloratadine is 50 hours or more compared with the average population whose half-life is around 26 hours.¹²⁸ This variability has not been shown to impact the safety profile of desloratadine. Many Asian patients can acetylate therapeutic concentrations of diphenhydramine to a nontoxic metabolite twice as rapidly as white patients, making Asians much less sensitive to both the psychomotor and sedative effects.¹⁵⁸ Results of a study of 100 patients in a sample of 2074 antihistamine users reporting excessive daytime sleepiness after use of H₁ antihistamines (predominantly chlorpheniramine) suggest that the presence of the CYP2D6*10 allele is a risk factor for development of H₁ antihistamine–induced adverse drug reactions.¹³⁹

Excretion.

Unchanged antihistamines and metabolites are renally excre­ted. Chlorpheniramine urinary excretion is increased in acidic urine. Elderly adults (mean age, 69 years) had similar time to peak concentrations but longer elimination half-lives of diphenhydramine compared with young adults.¹⁵¹

Elimination half-life is quite varied for all H₁ antihistamines with chlorpheniramine, hydroxyzine, azelastine, and levocabastine exhibiting the longest termination half-lives up to 24 hours.¹⁴⁹

The duration of action ranges from 3 hours to 24 hours, which is much longer than predicted from the serum elimination half-lives of the antihistamines. One study addressing the pharmacokinetics of diphenhydramine found that children (mean age, 8.9 years) reached peak plasma concentrations faster and had a shorter mean elimination half-life than young adults for the same dosage per kilogram.¹⁴⁹ Similar findings were observed with hydroxyzine.¹⁵⁰ In another volunteer study, desloratadine doses of 1 and 1.25 mg in children between the ages of 6 months and 2 years were found to provide a single dose target exposure (area under the plasma concentration–­time curve) comparable with that experienced by adults receiving the recommended 5-mg dose.⁵⁷

Modifications in therapeutic doses may be required for patients with hepatic or renal dysfunction, young people, and elderly adults. Such modifications often must be made empirically because formal studies and recommendations for many xenobiotics are lacking. Patients with renal dysfunction might be more susceptible to developing toxicity from acute ingestion of a second-generation antihistamine, and dose adjustment is recommended for cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine.³³

Drug interactions.

Recognized pharmacokinetic drug interactions involving the H₁ antihistamines are generally caused by modulation of CYP450 metabolism (most often CYP2D6 or CYP3A4) or via interference with active transport mechanisms such as P-glycoprotein or organic anion transporter polypeptide (OATP). The currently available second-generation H₁ antihistamines undergo fewer clinically relevant pharmacokinetic interactions than the first-generation H₁ antihistamines.^9,40

H₂ Antihistamines

Absorption.

Cimetidine is rapidly and completely absorbed after oral administration, but only 40% to 50% of ranitidine and famotidine are bioavailable with a peak concentration within 3 hours. All have reduced absorption when administered concomitantly with food.

Distribution.

Cimetidine has a volume of distribution of approximately 2 L/kg. Famotidine and ranitidine have a variable volume of distribution in different age groups ranging from 1 to 4 L/kg. All have protein binding in the range of 15% to 25%.

Metabolism.

Cimetidine has some hepatic metabolism (15%), but ranitidine and famotidine do not (<5%).

Excretion.

Up to 70% of ranitidine is eliminated unchanged in the urine, and 10% is eliminated unchanged in the stool. Famotidine and cimetidine are also primarily renally excreted. Renal excretion is lower for oral than for IV administration.

Elimination half-life.

The elimination half-life in patients with normal renal function is approximately 2 hours, but the half-life is substantially prolonged with impaired renal function (up to 10 hours) and in elderly adults (4 hours).

Interactions.

Cimetidine is responsible for numerous drug–drug interactions because it can inhibit cytochrome P450 activity, thereby impairing hepatic drug metabolism. It can reduce hepatic blood flow, resulting in decreased clearance of drugs that are highly extracted by the liver. None of the other currently available H₂ antihistamines inhibit the cytochrome P450 oxidase system.¹⁰⁵ Additionally, by altering gastric pH, cimetidine and all of the other H₂ antagonists may alter the absorption of acid-labile ­xenobiotics. Finally, cimetidine and ranitidine are associated with myelosuppression, particularly when administered with xenobiotics capable of causing bone marrow suppression.⁷

Cimetidine is an inhibitor of ethanol-oxidizing activity of gastric alcohol dehydrogenase (ADH) in human isoenzymes, but inhibition by nizatidine and famotidine is negligible. It is likely a result of the thiazole group of these H₂ antihistamines preventing binding to the enzymatic substrate site.¹⁵⁹ In vitro data regarding ranitidine inhibition of gastric ADH yielded conflicting results. However, a human study comparing oral versus IV ethanol kinetics with ranitidine showed a significant reduction in first-pass metabolism.^19,64 The first-pass metabolism of ethanol is influenced by the gastric mucosa, but it is unclear by which mechanisms ranitidine might influence increases in blood ethanol concentrations.¹¹⁷ The literature on the clinical relevance of these effects is conflicting.¹⁸ A meta-analysis of the effect of H₂ antihistamines on serum ethanol concentrations reported small elevations with cimetidine and ranitidine when administered concurrently, but the overall effect seemed unlikely to be clinically significant related to the accepted legal definitions of intoxication.¹⁸⁴ However, a later study reported raised ethanol concentrations in the range known to impair driving skills when ranitidine was taken regularly for 7 days before drinking.⁵ Asians are known to have increased gastric ADH as well as decreased ALDH-2.¹¹⁸ Combined therapy with H₁ and H₂ antihistamines were tried as a treatment for the “Asian flush” reaction with encouraging results. However, only H₂ antihistamines blocked the flushing reaction¹¹⁰ (Table 49–1).

Pathophysiology

The pathophysiology of acute H₁ antihistamine overdose is largely an extension of the expected therapeutic and adverse effects. These effects can be classified in broad categories according to the type of receptors involved. Acute H₂ antihistamine toxicity can be explained by a loss of selectivity for the gastric H₂ receptor and inhibition of the cardiac H₂ receptors responsible for positive chronotropy and inotropy.^84,187

The pathophysiology of H₁ antihistamine abuse is thought to be multifactorial. Humans are reported to abuse dimenhydrinate and diphenhydramine for their euphoric and hallucinogenic effects as well as for their reported anxiolytic and anticholinergic properties.⁶⁰ Recreational ingestion up to 5 g is reported, although most common recreational doses used to experience euphoria and hallucinations average 1 g.⁵⁹ Promethazine often combined with codeine, is widely abused in certain demographic groups.

However, animal studies of self-administration and conditioned place preferences suggest that antihistamines also have a rewarding potential independent of its euphoric effects, which increases with use. ­Dimenhydrinate abuse is linked to the stimulant effect of the 8-chlorotheophylline component but alone does not produce rewarding effects. However, diphenhydramine antagonizes muscarinic receptors, modulates serotonin function, enhances dopamine concentrations, and potentiate opioid receptors. It is now thought that the combination of diphenhydramine and the methylxanthine 8-chlorotheophylline as in dimenhydrinate has synergistic effect on the rewarding potential.⁵⁹ The dose–response for this to occur in humans remains to be studied. Older antihistamines such as chlorpheniramine are also selective serotonin receptor inhibitors, which might explain their nonmedical use⁶² (Table 49–2).

Clinical Manifestations

H₁ Antihistamines.

The toxic doses for each antihistamine are not well defined. The oft-cited threshold of toxicity of three to five times the therapeutic dose for first-generation antihistamines as well as cetirizine, loratadine, and fexofenadine originating from algorithms in various articles has never been validated.¹⁶⁴ Extrapolating plasma concentrations to an ingested dose is not accurate in predicting clinical effects for diphenhydramine and doxylamine.^89,90 A dose-dependent relationship for diphenhydramine toxicity was published indicating a high risk of seizures with ingestions above 1.5 g in adults.¹²⁹

Neurologic.

Acute overdose of first-generation H₁ antihistamine usually results in the onset of toxicity within 2 hours. Dose–response effect accounts for the wide spectrum of altered mental status observed. Drowsiness seen in milder poisoning can rapidly progress to obtundation and seizures with larger ingestions. Compared with adults, children may more commonly present with excitation, irritability, or ataxia as well as being more prone to having hallucinations or seizures.⁸ Patients typically exhibit an anticholinergic syndrome, including mydriasis, tachycardia, hyperthermia, dry mucous membranes, urinary retention, diminished bowel sounds, and altered mental status such as disorientation and hallucinations. The skin may appear flushed, warm, and dry. Hyperthermia occurs in severe cases and correlates with the extent of agitation, ambient temperature and humidity, and length of time during which the patient cannot dissipate heat because of anticholinergic-mediated reduction in sweating (Chap. 30).

Some patients with high therapeutic dosing or after overdose develop a central anticholinergic syndrome in which CNS anticholinergic effects, such as hallucinations, outlast peripheral anticholinergic effects. At a later stage of ingestion the lack of tachycardia, skin changes, or other peripheral anticholinergic manifestations complicates establishment of the correct diagnosis for antihistamine poisoned patients unless there is a clear exposure history.^56,182 Ingestion of second-generation H₁ and H₂ antihistamines usually does not result in significant CNS depression or anticholinergic effects except perhaps in pediatric patients or in adults with altered pharmacokinetic parameters. Although dry mouth and mydriasis are common adverse therapeutic effects, sedation is of the greatest concern.

Seizures can occur at any point in time in the course of the poisoning but typically begin in the first few hours and represent severe toxicity. Chlorpheniramine is both a serotonin reuptake inhibitor and a postsynaptic 5-HT_1A and 5-HT_2A receptor agonist.⁷⁹ Agonism of 5-HT receptors is associated with seizures. All first-generation H₁ antihistamines can produce seizures, although pheniramine seems to be more proconvulsant than others.²¹ Up to 22% of drug-induced seizures in children have been related to an antihistamine exposure, and diphenhydramine is a common cause of recreational drug-induced seizures.^1,52,165

Mydriasis develops at both therapeutic and toxic doses, with most patients describing blurred vision or diplopia. Both vertical and horizontal nystagmus may occur in patients with diphenhydramine overdose.⁴⁸

In a review of 136 patients with diphenhydramine overdose, somnolence, lethargy, or coma occurred in approximately 55% of patients, and 15% experienced a catatonic stupor.⁸⁹ Several reports suggest that young children experience more respiratory complications, CNS stimulation, anticholinergic effects, and seizures than do adults.¹¹⁴ In a placebo-controlled study comparing the CNS effects of the first- and second-generation H₁ antihistamines, the second-generation antihistamines caused less cognitive dysfunction and somnolence.^38,69 This finding was corroborated in the simulated driving model in which loratadine produced significantly less impairment than diphenhydramine.⁶³ Use of diphenhydramine compared with loratadine in a work setting results in significantly higher injury rates.⁵¹ Observational postmarketing cohort studies conducted in England on large numbers of patients reported rates of sedation or drowsiness of fewer than 1% for desloratadine and levocetirizine.^95,96

Cardiovascular.

Sinus tachycardia is a consistent finding after overdose with an H₁ antihistamine with anticholinergic effects and can persist after other toxic manifestations and delirium have resolved. Both hypotension and hypertension may occur.¹⁰⁰ These findings probably relate more to the patient’s age, volume status, and vascular tone than to a specific class of antihistamines. Binding to inactivated channels results in prolongation of both the QRS complexes and QT intervals may occur with any first-­generation H₁ antihistamine at doses that are supratherapeutic.^27,92 Brugada-pattern electrocardiographic (ECG) changes are also reported.^99,191

Cardiotoxicity observed with terfenadine and astemizole may result from accumulation of the parent drug in cardiac tissue after inhibition of drug elimination (eg, terfenadine–ketoconazole interaction) and may be exacerbated by electrolyte (eg, Ca²⁺) imbalances or concomitant use of another ion channel blocker.^13,68 They are no longer approved for use in the United States and many other countries. Second-generation H₁ antihistamines currently available are less dysrhythmogenic.^65,127 Rare cases of QT interval prolongation have been reported in therapeutic situations, but the incidence of dysrhythmias with second-generation in overdose is unknown.³ One study reported six cases of patients taking amiodarone with loratadine who presented with episodes of torsade de pointes and syncope. Amiodarone accumulation has not been reported with co-treatment with loratadine, and all patients made a full recovery after loratadine was stopped. Loratadine accumulation via P450 CYP3A4 inhibition by amiodarone is the mechanism suspected to explain this occurrence.⁴ QT interval prolongation is reported with cetirizine (mainly with kidney failure or large ingestions), but none has been published with desloratadine or levocetirizine.³

Other.

Rhabdomyolysis can occur in patients with extreme agitation or seizures after an H₁ antihistamine overdose.⁵³ Rhabdomyolysis is commonly noted in patients who overdose with doxylamine even in the absence of trauma or other common etiologies such as seizures, shock, or crush injuries. The mechanism remains undefined. A prospective study found that 87% of patients who ingested more than 20 mg/kg of doxylamine developed rhabdomyolysis, and this dose was the best predictor of this complication.⁷⁵ Another retrospective review found a dose of more than 13 mg/kg to be the only predictive factor of doxylamine-induced rhabdomyolysis.⁸⁶ Rhabdomyolysis is reported as a rare adverse event after diphenhydramine overdose.⁴⁷ One case of compartment syndrome with diphenhydramine alone was published.¹⁷⁷ This complication more commonly occurs in association with other factors such as ethanol intoxication or immobilization. Creatine kinase concentrations are reported as high as 262,000 UI/L without seizure activity.^42,47,85

Unless complications such as aspiration or kidney failure develop, most patients are symptomatic for 24 to 48 hours with resolution of cardiac symptoms occurring before neurologic recovery. Anticholinergic delirium and residual sinus tachycardia can last a few days, but generally neither needs cardiac monitoring in intensive care settings. Other adverse effects mostly seen in therapeutic use include pancytopenia and cholestatic jaundice (cetirizine) fixed-drug rash, urticaria, photosensitivity, hyperthermia, transaminitis, or agranulocytosis. Hypersensitivity reaction to antihistamines is exceptionally rare but has been reported.³⁹ Postmortem findings are generally limited to pulmonary and visceral congestion, suggesting cardiogenic causes of death.⁸⁰

Special populations.

Elderly patients are more susceptible to adverse events because kidney and liver dysfunction delay antihistamine metabolism.⁶⁹ All H₁ antihistamines cross the placenta, and some are teratogenic in animals. First- and second-generation agents fall into FDA categories B and C and should be individually addressed, avoiding or minimizing exposure when possible (Chap. 31). Because of their antimuscarinic effects, the first-generation antihistamines are generally contraindicated in patients with glaucoma or benign prostatic hypertrophy.

H₂ Antihistamines.

These xenobiotics are well tolerated in overdose even after large ingestions. Patients may develop tachycardia, dilated and sluggishly reactive pupils, slurred speech, and confusion.^157,173 In a retrospective study of acute cimetidine overdoses, 8.9% of patients had symptoms related to the ingestion, and those with reported moderate medical outcomes had ingested cimetidine with suicidal intent. Severe dysrhythmias, including ventricular fibrillation and bradycardia leading to fatal ­cardiac arrest in rapid IV infusion of cimetidine, are reported.¹⁴⁵ Deaths are reported in rare instances in large ingestion of cimetidine.⁸⁷

Famotidine and ranitidine produce even fewer dose-related toxicities in overdose. In addition, they are less likely than cimetidine to induce or inhibit the cytochrome P450 enzyme system, thereby producing fewer drug–drug interactions.⁷¹

Diagnostic Testing

The bedside diagnosis of antihistamine toxicity is a clinical one. Antihista­mines cause false-positive results on several rapid urine drug screens by immunoassay to amphetamines (ranitidine), methadone (diphenhydramine, doxylamine), and phencyclidine (diphenhydramine, doxylamine). Cyproheptadine, diphenhydramine, and hydroxyzine have given false-positive results to tricyclic antidepressants (TCAs) in serum immunoassays only.¹⁶¹ Such results have caused concerns, particularly in children, and should always be confirmed if malicious intent is suspected.¹³⁵

Comprehensive blood or urine analysis screening with liquid chromatography/mass spectroscopy (LC/MS) or gas chromatography/mass spectroscopy (GC/MS) can provide antihistamine concentrations, but these are more useful in medicolegal or forensic situations. The turnaround time usually needed is unlikely to provide results at the time of initial assessment. Moreover, treatment is based on alleviation or correction of toxic signs or symptoms and should not depend on a concentration result that has not been shown to correlate with toxicity.^85,89,90 Measurement of antihistamine concentrations in body fluids is not readily available and is generally unnecessary for clinical assessment and management.

Several publications have estimated the toxic diphenhydramine concentration in children to be around 5 mg/L. Fatal antihistamine concentrations are reported with great variability. However, as occurs in adults, toxic effects and fatalities are reported with lower concentrations. Considering diphenhydramine is subject to postmortem redistribution, it would be prudent to obtain blood samples as soon as possible to aid in determining the cause of death in fatalities involving these xenobiotics.⁸

Management

General Management.

The initial management of a given exposure can begin by a consultation with a poison control center. Guidelines are published and validated with regards to the evidence-based out-of-hospital management of diphenhydramine and dimenhydrinate exposure allowing for home observation for any ingestion under 7.5 mg/kg in children younger than 6 years of age or under 300 mg or 7.5 mg/kg for adults and older children.^11,140 Other criteria for medical evaluation for other antihistamines vary according to local practices, but in general, ingestions of less than five times the maximal therapeutic dose is rarely toxic.

Patients presenting to hospitals after exposure of any antihistamine must be triaged and medically assessed quickly, generally within 30 minutes of arrival, because those who will develop severe complications may be initially indistinguishable from those who will have a benign course, and the window for GI decontamination may soon elapse.

The individual should be attached to a cardiac monitor and observed for signs of sodium channel antagonism (increased QRS complex duration), potassium channel blockade (prolonged QT interval), and related dysrhythmias, as well as for seizures. IV access should be established and airway protection ensured.

Gastrointestinal decontamination can be undertaken with care to avoid aspiration in patients with large ingestions of first-generation H₁ antihistamines or early presentations but is generally not needed for H₂ antihistamines. The use of oral activated charcoal (AC), although more effective if administered early with regards to time of ingestion, can be considered even after a delay for ingestion of large amounts that might reduce absorption time. Multiple dose AC or whole-bowel irrigation (WBI) is usually not indicated. Neostigmine administration was used with success in drug-induced ileus, thus facilitating gut decontamination.²⁴

Enhanced elimination techniques do not benefit the toxicity of these xenobiotics because of their large volumes of distribution, extensive protein binding, and absence of enterobiliary circulation. However, exceptional case reports have been published using hemoperfusion and hemodialysis with resolution of the dysrhythmias previously unresponsive to treatment. These patients had ingested 20 mg/kg (adult) and 50 mg/kg (child) of diphenhydramine. All cases reported diphenhydramine concentrations in the fatal range. The mechanism proposed to explain these recoveries is that removal of diphenhydramine from the toxic compartment during extracorporeal treatment might have been enough to improve the distributive shock suspected to be from α-adrenergic blockade.^106,113,179 Unfortunately, no clearance data, only blood concentrations before and after dialysis, have been reported, thus making conclusions on the efficacy of enhanced removal debatable and not recommended.

Assessment of the serum acetaminophen concentration is important because of its inclusion in many cough and cold products. Other laboratory studies should be obtained as indicated by history or physical signs and symptoms. Kidney function and creatine kinase should be obtained on all patients, particularly in patients with seizures or doxylamine overdose. Serum pregnancy tests should be obtained in women of childbearing age. An ECG should be obtained on all patients during the initial assessment and repeated at regular intervals, particularly if physostigmine use is considered.

The patient’s vital signs and mental status must be monitored. Serial assessments of the patient’s vital signs, particularly temperature, and mental status should be made. The potential for clinical deterioration necessitates management of symptomatic patients in a monitored environment.

Specific Treatments.

Sedation can increase the risk for aspiration. Intubation to secure the airway is recommended when excessive sedation compromises ventilation.

Seizures should be treated with an IV benzodiazepine such as 2 to 4 mg (0.05–0.1 mg/kg in children) of lorazepam or 10 mg (0.2–0.5 mg/kg in children) of diazepam with repeated dosing as necessary.^49,74 Hypertonic saline (3%) has also been shown to be effective in diphenhydramine-induced seizures in an animal model.⁶⁷ Recurrent seizures refractory to benzodiazepines or sodium bicarbonate should be treated with propofol or general anesthesia. Phenytoin use is discouraged as in most toxicologic-induced seizures.

Hypotension generally responds to isotonic fluids (0.9% sodium chloride solution or lactated Ringer solution). If the desired increase in blood pressure is not attained, sodium bicarbonate therapy or vasopressors can be titrated to achieve an acceptable blood pressure. In one instance, cardiogenic shock and myocardial depression resulting from a 10 g ingestion of pyrilamine could only be reversed with an intraaortic balloon counterpulsation device.⁵⁴ This approach should rarely be needed.

The sodium channel blocking (type IA antidysrhythmic) properties of diphenhydramine and other antihistamines may lead to wide-complex dysrhythmias that resemble those that occur after TCA overdose (Chap. 71).Hypertonic sodium bicarbonate reverses diphenhydramine or other antihistamine-associated conduction abnormalities^27,49,74,144 (Antidotes in Depth: A5).

Type IA (quinidine, procainamide, disopyramide), IC (flecainide), and III (amiodarone, sotalol) antidysrhythmics are contraindicated because of their capacity to prolong the QRS and QT intervals. The use of IV lipid emulsion is reported with an ingestion of 1250 to 2500 mg of diphenhydramine. The common mechanism of action on sodium channels with TCAs and local anesthetics likely explains its success in restoring cardiac activity within minutes of administration after 60 minutes of unsuccessful resuscitation with 50 mEq of sodium bicarbonate, 2 mg of epinephrine, IV glucose, and 1 mg of atropine.⁷⁷

Rhabdomyolysis associated nephrotoxicity should be prevented by early use of IV fluid, NaCl 0.9%, to produce a urine output of 1 to 3 mL/kg/h. Once established, antihistamine-induced rhabdomyolysis is treated with IV fluids.¹²⁰ Although urinary alkalinization may be helpful to prevent myoglobin-induced nephrotoxicity, its usefulness is controversial and might be best reserved when urinary pH is lower than 6.5.²⁶ Serum potassium and ECGs should be obtained to exclude significant hyperkalemia from muscle injury or acute kidney injury. Initial hypocalcemia caused by precipitation of phosphate from muscle breakdown should not be replaced unless dangerously low because calcium redistributes into the circulation in later phases.¹²⁰

Cooling via evaporative methods (tepid mist or cooling blanket or fan) is generally sufficient, but patients with severe hyperthermia should receive more rapid cooling using an ice bath. Hyperthermic patients should be monitored for the development of disseminated intravascular coagulation and other complications. The goal is to return the patient to a normothermic state. There is insufficient evidence to recommend therapeutic hypothermia in poisoned patients with antihistamines.

Agitation or psychosis generally responds readily to titration of a ben­zodiazepine. Although most commonly a direct central effect, other frequent causes of agitation such as urinary retention or bright lights shone into dilated eyes unable to accommodate should not be forgotten. Physostigmine may effectively reverse the peripheral or central anticholinergic syndrome and can be used as a benzodiazepine-sparing strategy, but should only be considered after the initial cardiovascular toxicity, if present, has resolved or is no longer a possibility. It should be used with caution in an attempt to reverse coma or sedation caused by anticholinergic toxicity.

In a retrospective comparison of physostigmine and benzodiazepines, physostigmine was found to be safer and more effective for treating anticholinergic agitation and delirium.²² Contraindications to physostigmine use include wide QRS complex or bradycardia noted by ECG, asthma, and pulmonary disease. The primary benefits of physostigmine use in patients with antihistamine overdose include restoration of GI motility, elimination of agitation, and possible obviation of the need for computed tomography (CT) scan or lumbar puncture if the patient regains a normal mental status and can provide a clear history. The anticipated benefits of physostigmine must outweigh the potential risks before its use.

Before physostigmine is administered, the patient should be attached to a cardiac monitor, and secure IV access should be established. Physostigmine (1–2 mg in adults; 0.5 mg in children) should be administered by IV bolus over 5 to 10 minutes with continuous monitoring of vital signs, ECG, breath sounds, and oxygen saturation by pulse oximetry. The initial dose of physostigmine can be repeated at 5- to 10-minute intervals if anticholinergic symptoms are not reversed and cholinergic symptoms such as salivation, diaphoresis, bradycardia, lacrimation, urination, or defecation do not develop. When improvement occurs as a result of physostigmine, repeated doses of physostigmine at 30- to 60-minute intervals may be necessary, taking into account the fact metabolism of the offending xenobiotic is occurring and that subsequent doses might need to be lowered to avoid cholinergic symptoms. Another alternative for confirmed central anticholinergic symptoms expected to last many hours could be the administration of oral anticholinesterases such as donepezil, tacrine, or rivastigmine.^37,116 They are noncompetitive reversible anticholinesterases, crossing the blood–brain barrier, with a longer duration of action than physostigmine. Continuous infusion of physostigmine has also been used successfully.¹²³ Benzodiazepines can be used, but excessive sedation with repetitive dosing can present undesirable effects. A dose of IV atropine should be available at the patient’s bedside to treat cholinergic toxicity if it occurs (Antidotes in Depth: A9).

History and Epidemiology

History.

Decongestants are xenobiotics acting on α-adrenergic receptors, producing vasoconstriction, decreasing edema of mucous membranes, and improving bronchiolar air movement. Ma Huang, the horsetail plant of the Red Emperor, was used in China for at least 2000 years before it was introduced into Western medicine in the late 19th century by Japanese researchers, who isolated the active ingredient from Ephedra plants. Ephedrine, the first xenobiotic of the sympathomimetic amine class to be used pharmaceutically, was first approved in 1926 by the Council of Pharmacy and Chemistry of the American Medical Association and was very popular in the treatment of asthma. Amphetamines were later synthesized to palliate to a shortage of Ephedra plant availability. Pseudoephedrine is a natural stereoisomer of ephedrine, and phenylephrine was introduced into clinical medicine in the 1930s and in 1949 replaced amphetamines in several compounds. Amphetamine was marketed as nasal decongestant (Benzedrine Inhaler), which was eventually withdrawn in the 1960s because of widespread abuse.

Imidazoline decongestants, on the other hand, were derived from piperazine compounds while investigating their use as uric acid remedies to combat gout. As more imidazolines were synthesized for gout treatment, one of the compound, tolazoline, was found to have weak adrenergic blocking activity but its naphthyl analogue produced the reverse effect. Naphazoline was introduced in the 1940s as a decongestant. In the decades that followed, many imidazoline decongestants have been developed and tried for clinical use.¹⁵⁵

Epidemiology.

Despite many years of widespread decongestant use in the United States and sporadic case reports of adverse effects, the magnitude and public health significance of adverse effects of this class of medications has only recently been appreciated. From 1991 to 2000, the FDA received 22 spontaneous reports of hemorrhagic stroke associated with phenylpropanolamine (PPA) use, and more than 30 other cases were reported in the literature since 1979. Statistical analysis published in 2000 confirmed that PPA is an independent risk factor for hemorrhagic stroke in women.^23,83 The FDA recommended removal of PPA from the market in 2000 because of its association with intracranial hemorrhages. Many manufacturers took steps to remove or reformulate PPA-containing products well before the FDA rule-making process could be completed.

Fatality rates with decongestants suffer from the selection bias of case reporting as well as which xenobiotics are examined. One study addressing the cause of death in children did not include imidazoline derivatives in their search strategy but these xenobiotics might have been included in part of the cases assessed.³⁴ Despite these biases, studies report a positive association between fatalities in children under 2 years of age and pseudoephedrine containing cough and cold medications resulting in high pseudoephedrine concentrations. Additional nonfatal adverse events also occurred in the children during that study period.³⁰

The majority of exposures are unintentional. NDPS data from 2011 report that only one in five cough and cold preparation exposures are ­intentional. In another study, postmortem analysis of unexpected infant fatalities yielded 10 deaths (ages 17 days–10 months) associated with the use of cough and cold medicines.¹³³ In response to new information and concerns, the FDA required labeling changes on medications aimed toward young children. In January 2012, the US Consumer Product Safety Commission proposed a new rule requiring child-resistant packaging for any nonprescription drug product containing the equivalent of 0.08 mg or more of an imidazoline in a single package.¹⁷⁰

Recreational use of ephedrine-containing stimulants is common, and combinations of these xenobiotics with caffeine or other herbs may be marketed as “herbal ecstasy” (Chap. 45). The sale of dietary supplements containing Ephedra, Ma Huang, Sida cordifolia, and pinellia (ephedrine alkaloids) was banned by the FDA in 2004 because of concerns over their cardiovascular effects, including hypertension, seizures, stroke, and dysrhythmias.⁵⁸ Companies challenged this rule in court, but it was finally upheld in 2006. Xenobiotics that contain chemically synthesized ephedrine, traditional Chinese herbal remedies, and herbal teas are not covered by the rule. Specific guidelines as to what constitutes a traditional remedy are still unclear and are currently under the FDA dietary supplement category.¹⁶⁹ Since then, many manufacturers have substituted ephedra by Citrus aurantium, whose principal ingredient is p-synephrine, and are marketing products as being “ephedra free.”¹³² The FDA ban on sales of ephedra had a significant reduction on the number of calls to poison centers and in the number of deaths.¹⁹³

Imidazoline abuse is also associated with strokes, although population incidences are not reported.⁹⁷ Of all the decongestants, only ephedrine and pseudoephedrine are on the list of xenobiotics monitored in competitive sports.¹⁸⁹ Phenylephrine and synephrine concentrations in urine are no longer monitored.

The Combat Methamphetamine Act signed into law in March 2006 limited methamphetamine precursor availability and additional precautions in pharmacies such as dispensing limits for nonprescription quantities, requesting personal identification, and storage of the medications behind pharmacy counters. This aimed to reduce potential harm associated with these xenobiotics by closing loopholes contained in the previous 2000 regulations.¹⁶⁸ The success of such stricter measures has yet to be quantified.^107,115,135 Travel and Internet purchases being more common, it can also be expected that individuals might present with toxicity from xenobiotics not otherwise available in their countries of residence.

Pharmacology

Decongestants can be divided into two categories, sympathomimetic amines and imidazolines.

Sympathomimetics.

The decongestants phenylephrine, pseudoephedrine, ephedrine, and PPA reduce nasal congestion by stimulating the α-adrenergic receptor sites on vascular smooth muscle⁷⁶ (Fig. 49–5). Both α₁ and α₂ receptor subtypes are linked to a Gq protein activating smooth muscle contraction via the IP₃ signal transduction pathway (Fig. 49–6). This process constricts dilated arterioles and reduces blood flow to engorged nasal vascular beds. The α-adrenergic mediated decrease in volume ultimately lowers resistance to airflow. Prolonged topical administration may produce rebound congestion upon discontinuation; possible mechanisms include desensitization of receptors and mucosal damage. This damage is caused by α₂-adrenergic mediated arteriolar constriction resulting in decreased blood supply to the mucosa.

Phenylephrine is a direct α₁-adrenergic receptor agonist with very little β-adrenergic agonist activity at therapeutic doses. Pseudoephedrine and ephedrine are mixed-acting direct and indirect nonspecific α_1,2-adrenergic and β_1,2-adrenergic receptor agonists. Pseudoephedrine is the d-isomer of ephedrine and has only up to 25% of the adrenergic receptor activity of ephedrine.⁴³ PPA is an α_1,2-adrenergic receptor stimulant devoid of β-adrenergic receptor activity. PPA can directly stimulate α_1,2-adrenergic receptors and can indirectly stimulate these receptors by causing norepinephrine release.

Imidazolines.

The decongestant effects of the imidazoline class of xenobiotics results from their vasoconstrictive action as α-adrenergic agonists, with binding to α₂-adrenergic receptors on blood vessels. In addition, these medications show high affinity for imidazoline receptors, which are located in the ventrolateral medulla and some peripheral tissues. Three classes of imidazoline receptors are recognized. I₁ receptors mediate the inhibitory actions of imidazolines xenobiotics to lower blood pressure. I₂ receptor is an important binding site for monoamine oxidase, and I₃ receptor regulates insulin secretion from pancreatic cells.⁶¹ The imidazoline receptor field is in expansion as more physiological roles are found for these receptors, namely cell proliferation, regulation of body fat, inflammation, pain and opioid addiction, appetite, epilepsy, and neuroprotection. Table 49–3 summarizes the pharmacologic and toxic effect of available decongestants.

The imidazoline (I) category of direct sympathomimetic receptor agonists is generally reserved for topical application. The agonists in this class are used for their local effects in the nasal passages and the eyes. The more common medications include oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, and naphazoline hydrochloride (Fig. 49–7). The α₁-adrenergic mediated vasoconstriction is complemented by an additive effect of preferential binding to α₂-adrenergic receptors located on resistance vessels regulating blood flow. The imidazoline decongestants such as oxymetazoline and naphazoline are pure central and peripheral α₂-adrenergic receptor agonists; tetrahydrozoline stimulates α₂-adrenergic receptors and H₂ receptors. These medications are primarily used as nasal decongestants. Tetrahydrozoline is available without a prescription as an ophthalmic preparation to decrease conjunctival injection.

Selective α₂-adrenergic receptor agonists acting on nasal veins for decongestant effect are being developed to minimize toxicity and adverse effects associated with current nonselective decongestants affecting nasal veins and arteries.³¹

Pharmacokinetics and Toxicokinetics

Sympathomimetics.

Phenylephrine and other decongestants of this class are pharmacologically active after topical or oral administration. Absorption from the GI tract is rapid, with peak blood concentrations occurring within 2 to 4 hours of ingestion. They have variable hepatic metabolism via monoamine oxidase and mainly renal excretion. Children have shorter elimination half-lives of pseudoephedrine than adults at doses under 60 mg. Urinary elimination of pseudoephedrine is pH dependent.¹⁴⁸ Pseudoephedrine is excreted in breast milk, but use during lactation is considered acceptable.

Toxic effects can occur at therapeutic dosage in population with altered pharmacokinetics such as end-stage kidney disease. A meta-analysis found a dose–response relationship between blood pressure and pseudoephedrine in therapeutic situations.¹³⁶ Toxic symptoms are an extension of the adverse effects and follow a similar dose–response curve.

Imidazolines.

The imidazolines are rapidly absorbed from the GI tract and mucous membranes. Despite their use for many decades, their metabolism has been poorly studied.¹⁰² Their elimination half-lives are from 2 to 4 hours. All imidazoline preparations have a relatively rapid onset of action, with 60% of maximum effectiveness occurring after only 20 minutes. Oxymetazoline is the only medication with duration of action more than 8 hours. The other preparations have an average duration of action of approximately 4 hours.

The toxicity of these medications follows a dose–response curve and accentuates the action on receptors. There is no information regarding modification of pharmacokinetics parameters in supratherapeutic conditions.

Pathophysiology

Sympathomimetic. Sympathomimetic decongestants cause their toxic effects via excessive stimulation of the adrenergic system and in effect produce signs and symptoms associated with the sympathomimetic toxidrome. Excessive vasoconstriction can result in end-organ damage to the brain, retina, heart, and kidneys.

Imidazolines. Imidazolines stimulate imidazoline receptors and produce a sympatholytic effect that in supratherapeutic conditions results in marked bradycardia and hypotension as well as a sympathomimetic ­syndrome.

Clinical Manifestations

Sympathomimetics.

Ingestions of less than 1 mg/kg of pseudoephedrine in children have been reported to produce almost no toxicity and are generally managed conservatively without the need for hospital evaluation. A study of acute ingestions in children age 6 months to 5 years reported an absence of symptoms at doses lower than 120 mg and lethargy with doses above 360 mg.¹⁸⁶ After a decongestant overdose of this class, most patients present with a sympathomimetic syndrome with CNS stimulation, hypertension, tachycardia, or reflex bradycardia in response to pure α₁-adrenergic agonist induced hypertension (Chap. 76). Approximately four to five times the recommended dose of pseudoephedrine may be required to cause hypertension.^43,46 An increase in sinus dysrhythmias is reported in adults with ingestion of 120 mg of pseudoephedrine and moderate exercise.¹⁷ Headache was the most common initial symptom (39%) reported by patients who later developed severe toxicity from PPA. In 45 patients who developed hypertensive encephalopathy from PPA ingestion, 24 patients developed intracranial hemorrhages, 15 developed seizures, and six died.⁹³ Seizures, myocardial infarction, bradycardia, atrial and ventricular dysrhythmias, ischemic bowel infarction, and cerebral hemorrhages are reported, even with therapeutic dosing.^23,180 In a review of 500 reports of adverse reactions from patients who had ingested ephedrine and associated stimulants as dietary supplements, eight fatalities from myocardial infarction and cerebral hemorrhage were reported.¹²² Psychosis, agitation, and manic behavior have been reported with acute ingestion.

Imidazolines.

When ingested, the imidazoline decongestants naphazoline, oxymetazoline, tetrahydrozoline, and xylometazoline are potent central and peripheral α₂-adrenergic and imidazoline receptor agonists. In overdose, they can cause CNS depression, and initial brief hypertension followed by hypotension, bradycardia, and respiratory depression similar to clonidine (Chap. 63).⁶⁶ Children are particularly sensitive to the effects of the imidazoline decongestants. Cases of acute stroke have been reported in adults with naphazoline abuse.³²

Rare cases of cardiomyopathy with apical ballooning (Takotsubo) after large ingestion or chronic use of pseudoephedrine or oxymetazoline are reported.^181,194 Acute respiratory distress syndrome from vasoconstriction of pulmonary vessels can also occur with both classes of decongestants. ­Reversible encephalopathy with bilateral posterior hemispheric edema on neuroimaging was reported after nonprescription use of pseudoephedrine albeit in a patient with an autoimmune disorder that might have been a predisposing factor.⁴⁴ Toxic effects usually resolve within 8 to 16 hours. ­However, they may persist for more than 24 hours if a sustained-release product is ingested.

Diagnostic Testing

The bedside diagnostic of decongestant toxicity is a clinical one. Sympathomimetic decongestants can cause false-positive results on several rapid urine drug screens by immunoassay to amphetamines.¹¹² Comprehensive blood or urine analysis screening test by LC/MS or GC/MS can be obtained for research purposes, in child abuse, or in forensic studies to determine the cause of death. They have no role in the immediate clinical management of poisoned patients.

Management

Patients presenting after an exposure to decongestants should be triaged promptly and brought to a monitored environment. A cardiac monitor should be attached to the patient and observed for dysrhythmias. IV access should be established and airway protection ensured. GI decontamination with AC should be done in large ingestions of pseudoephedrine if no contraindications are present. A retrospective study of xylometazoline ingestion in children reported toxicity above nasal or oral exposure exceeding 0.4 mg/kg body weight. Ingestions of more than 0.1 mg/kg of naphazoline or tetrazoline produced severe toxicity in children. The decision to give AC in these instances should be made individually because liquid formulations are rapidly absorbed and might not be amenable to AC adsorption by the time of presentation.¹⁷⁴ AC administration may be beneficial several hours after ingestion of sustained-release decongestant preparations. More than one dose of AC may be considered to complete GI decontamination in massive ingestion of oral preparations, but multidose AC for enhanced elimination purposes has no role. WBI and renal-enhanced elimination techniques are not indicated.

Specific Treatment

Neurologic toxicity.

Patients with extreme agitation, seizures, and psychosis should initially be treated with administration of oxygen and IV benzodiazepines, titrated upward to effect. A patient with a persisting headache, focal neurologic deficits, or abnormal neuropsychiatric examination findings after decongestant ingestion should be evaluated for cerebral hemorrhage by noncontrast head CT. If the timing of the imaging is delayed, reducing the sensitivity of this modality, subsequent lumbar puncture to exclude subarachnoid hemorrhage might be required.

Respiratory toxicity.

Children presenting with respiratory depression from imidazoline decongestants have responded to naloxone. These case reports are too few to establish the efficacy of this therapy. Nevertheless, the use of naloxone in imidazoline toxicity seems to pose low risk in non–opioid-dependent patients. Many poison centers do recommend it.^20,81

Cardiovascular toxicity.

Tachycardia, palpitations, and hypertension can occur in mild poisoning and usually respond to benzodiazepines. A patient who remains hypertensive or is believed to have chest pain of ischemic origin should be treated with phentolamine, an α-adrenergic antagonist, or nicardipine. Labetalol has been proposed and used in some reported cases; however, because of its different affinity for α- and β-adrenergic receptors depending on the route of administration, its use is not recommended when coronary vasospasm is suspected.¹⁷⁵ Labetalol is a more potent β- than α-adrenergic receptor blocker when given intravenously.^94,108β-Adrenergic antagonists should be avoided because of concern for unopposed α-adrenergic effects. An ECG is required, and any elevation of the ST segment warrants immediate consultation with a cardiologist.

Patients with ventricular dysrhythmias from sympathomimetic decongestants should be treated with standard doses of lidocaine or sodium bicarbonate. The evidence for efficacy of amiodarone in this setting is still lacking.^41,130 PPA may cause hypertension with a reflex bradycardia and atrioventricular block that is responsive to standard doses of atropine. Atropine must be used with caution because it can cause a dangerous increase in blood pressure as the reflex bradycardia reverses. Therefore, a vasodilator such as phentolamine is preferred because the stimulus for the bradycardia is corrected with reversal of the hypertension.

Imidazoline-induced hypertension rarely requires therapy, but in the setting of symptomatic hypertension, a short-acting α-adrenergic antagonist such as phentolamine may be administered.¹⁸⁵ However, the hypertension is generally transient and followed by hypotension. Initial antihypertensive therapy could exacerbate toxicity and should only be reserved for cases in which severe hypertension represents a true urgency for end-organ damage.

• Anticholinergic toxicity is expected with H₁ antihistamines within a few hours of ingestion.

• Cardiotoxicity via sodium channel antagonism can be fatal and is treated with sodium bicarbonate.

• Physostigmine or other anticholinesterases can be used to reverse anticholinergic effects of H₁ antihistamines.

• H₂ antihistamines rarely result in symptoms or signs of toxicity.

• Decongestants used for recreational purposes can be ingested in doses producing toxic effects. The management is mainly supportive.

• Patients with abnormal mental status or seizures should be investigated to exclude intracranial hemorrhages

• Topical imidazoline decongestants can produce toxicity.

• Sympathomimetic decongestants follow the same treatment guidelines as amphetamines and other agents of the sympathomimetic class.

Acknowledgment

Anthony J. Tomassoni, MD, and Richard S. Weisman, PharmD, contributed to this chapter in previous editions.

References