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Home , Antazoline, Anticholinergic, Atropa belladonna, Biperiden, Brompheniramine, Brugmansia

Syndrome 23 William J. Boroughf

Contents The anticholinergic syndrome is common and Overview and Incidence ...... 521 may result from exposures to many or nat- ural substances (Table 1). Anticholinergic effects History ...... 521 are desired or intended effects for certain drugs Pathophysiology ...... 522 (i.e., , mydriatics, and belladonna Toxic Mechanism ...... 523 ) and are undesired or side-effects for Clinical Presentations and Life-Threatening other drugs (i.e., , , Complications ...... 525 , and antiparkinsonians). Both pre- Routes of Exposure ...... 526 Intention or Cause of Exposures ...... 526 scription and over-the-counter drugs may have Range of ...... 527 anticholinergic effects. Combined use of more Organ System Effects ...... 527 than one with anticholinergic effects Diagnosis ...... 529 increases the risk of anticholinergic toxicity. The Laboratory Tests ...... 529 anticholinergic syndrome, also called the anticho- Differential Diagnosis ...... 530 linergic , has peripheral and central Diagnostic Studies ...... 531 manifestations. The more serious adverse effects Treatment ...... 532 associated with large exposures to these agents are fi Speci c Treatment ...... 533 often a result of other physiologic properties of References ...... 534 these agents rather than the anticholinergic effects. Granacher and Baldessarini [3] and Hall and colleagues [4] were among the first to describe the central anticholinergic syndrome (CAS), a some- times dramatic form of anticholinergic toxicity in which (CNS) effects occur in the absence of peripheral anticholinergic man- ifestations. As with all anticholinergic syndromes, CAS may result from abuse, intentional or unintentional overdoses, or adverse drug reac- tions. A moderate stage of anticholinergism with and is the desired end * W.J. Boroughf ( ) point of certain forms of , but Emergency , University of Colorado School of Medicine, Denver, CO, USA achieving the desired stage of intoxication and e-mail: [email protected] avoiding toxicity is difficult.

# Springer International Publishing AG 2017 519 J. Brent et al. (eds.), Critical Care Toxicology, DOI 10.1007/978-3-319-17900-1_133 520 W.J. Boroughf

Table 1 Anticholinergic drugs and natural substancesa Table 1 (continued) Belladonna alkaloids sulfate Chlorpheniramine Belladonna extract Belladonna tincture Levo alkaloids of belladonna (Bellafoline) Clidinium (Quarzan) hydrobromide Hyoscine N-butylbromide sulfate Dimethindene Hyoscyamine hydrobromide Gastrointestinal antispasmodics Anisotropine methylbromide (Valpin) Butylscopolamine (Buscopan) (Librax) Dicyclomine hydrochloride (Bentyl) Glycopyrrolate (Robinul) methylsulfate (Tral) (Darbid) bromide (Cantil) bromide (Banthine) Atropine/ (Lomotil) Pyrilamine Methscopolamine bromide (Pamine) hydrochloride (Daricon) (Antrenyl) Antiulcer drugs (Pro-Banthine) Genitourinary antispasmodics hydrochloride (Urispas) Propantheline chloride (Ditropan) tartrate (Detrol) Antiparkinson drugs Cycloplegics Benztropine mesylate (Cogentin) (Cyclogyl) (Akineton) (Mydriacyl) hydrochloride Other drugs (Disipal) (Flexeril) Orphenadrine citrate (Norflex) Mefloquine (Kemadrin) Diphenidol (Vontrol) hydrochloride (Atrovent) (Artane) Antihistamines Neuroleptics [1] (Thorazine) Bromodiphenhydramine (Clozaril) Prochlorperazine (Zyprexa) Thiothixene (continued) (continued) 23 Anticholinergic Syndrome 521

Table 1 (continued) demonstrate a marked decrease in reported expo- antidepressants [2] sures and deaths from anticholinergic exposure in (Elavil) 2014 [5, 6]. Use of drugs with anticholinergic (Anafranil) activity is the most common cause of (Tofranil) pharmaceutical-induced [7]. Differences (Norpramin) in clinical effects result from not only the dose but (Sinequan) also variability in the degree of muscarinic recep- (Pamelor) tor blocking among agents [1, 2]. Large inten- (Vivactil) tional ingestions of sleeping pills, - (Surmontil) type sleeping pills, and tricyclic antidepressants (TCAs) are common causes of serious toxicity belladonna (deadly nightshade) within these groups. Antihistamine exposure is arborea (angel’s trumpet) the most common cause of unintentional anticho- (angel’s trumpet) linergic toxicity, whereas cyclic antidepressants Cestrum diurnum (day jessamine) and atypical antipsychotics are proportionally (night jessamine) Cestrum parqui (-leaved jessamine) larger origins of intentional exposures and toxicity metel (Hindu datura) [6]. Many anticholinergic-type adverse drug reac- (Jimson , thorn apple, tions and abuse are not reported to centers ) or adverse drug reaction programs, and their true Duboisra spp. incidence is unknown. In one study, 60% of niger (black henbane) elderly nursing home patients were taking at Lantana camara (yellow sage) least one anticholinergic agent, and 13% of Lycium halimifolium (matrimony vine) patients on anticholinergic drugs in one geriatric officinarum () unit had significant adverse effects [7]. Data from atropoides (crazy ) the American College of Medical Toxicology’s fl spp. (trumpet ower) Toxicology Investigators Consortium (ToxIC) dulcamara (woody nightshade) Case Registry reveal that of patients requiring (black nightshade) medical toxicologist-directed treatment, 6% of Mushrooms patients age 19–65 years and 4% of patients age Amanita cothurnata greater than 66 years had anticholinergic Amanita gemmata toxicity [8]. Amanita pantherina Amanita smithiana aBrand names given are examples of those in the United History States. Other countries may use similar or different brand names. Natural substances with anticholinergic proper- ties, such as nightshade plants, have long been used for their mind-altering properties by different Overview and Incidence cultures [9]. The alkaloids, primarily atropine and scopolamine, have been the active Data from the American Association of Poison ingredients of ancient witches’ brews and Control Centers National Poison Data System ointments (Pharmaka diabolics), love , indicate that anticholinergic exposures are com- intoxicants, , knockout agents, mon but usually not severe or fatal (Table 2)[5]. and . British soldiers were described as Of the more than 97,000 exposures reported in the “natural fools” for 11 days after consuming a United States in 2013, only one third of cases were salad containing of Datura stramonium treated in a healthcare facility (Table 3). These (Jimson weed) (see ▶ Chap. 111, “Anticholiner- data, compared to AAPCC data from 2002, gic Plants”)[10]. 522 W.J. Boroughf

Table 2 Anticholinergic exposures and intent reported to US poison centers in 2014 (Extracted from Mowry et al. [6]) Agents Exposures Unintentional Intentional Other/adverse reaction Natural substances Mushrooma 37 12 21 4 Plantb 610 454 133 18 Anticholinergic 8,271 7,774 336 137 Antihistaminec 66,784 52,722 12,774 957 Gastrointestinal antispasmodicsb 1,325 1,022 221 68 Cyclic antidepressants 4,414 1,636 2,515 178 1,806 774 804 191 Atypical antipsychotics 15,907 5,822 9,103 753 Total 99,154 70,216 25,907 2,306 aIbotenic acid group bAnticholinergic type c Not including H2 antagonists

Table 3 Anticholinergic exposures and outcomes reported to US poison centers in 2014 (Extracted from Mowry et al. [6] Health care facility Outcome Agents presentation None Minor Moderate Major Death Natural substances Mushrooma 28 4 4 19 5 0 Plantb 191 164 71 80 8 0 Medications Anticholinergic 721 1,052 255 200 16 1 Antihistaminec 18,147 15,115 7,255 4,412 390 17 Gastrointestinal 456 387 193 110 4 0 antispasmodicsb Cyclic antidepressants 3,215 677 961 1,188 341 12 Phenothiazine 1,248 327 414 463 41 1 Atypical antipsychotics 11,816 2,850 4,481 3,639 399 15 Total 35,822 20,576 13,634 10,111 1,204 46 aIbotenic acid group bAnticholinergic type c Not including H2 receptor antagonists

Pathophysiology which leads to rapid cell membrane depolarization and cellular excitation. (ACh) is a key in Muscarinic receptors, however, are located in both the central and peripheral nervous system. the CNS (mainly brain (Fig. 2)), end-organ para- When released, ACh may activate either nicotinic sympathetic nerve endings, sympathetically inner- or muscarinic receptors (Fig. 1). Nicotinic recep- vated sweat glands and, to a lesser extent, tors (12 types: α2–α9 and β2–β5) are located in the autonomic ganglions and the adrenal medulla [11, CNS (mainly spinal cord), on postganglionic 12]. There are five types of cloned muscarinic autonomic (sympathetic and parasympa- receptors (M1 through M5), whose effects are thetic), and neuromuscular junctions. These mediated more slowly than nicotinic receptors receptors are ligand-gated ion channels for through guanosine triphosphate–binding proteins sodium (Na+) and calcium (Ca2+), activation of (G proteins). The primary intracellular messengers 23 Anticholinergic Syndrome 523 a b ACh AChEBChE

ACh

AChEBChE Nicotinic receptor Muscarinic Gi receptor CHT1 AcCoA ? Gq Muscarinic choline ACh receptor ACh ACh ChAT AcCoA Choline VAChT ACh VAChT ? Nicotinic ? ChAT & CHT1 receptor Choline Bronchial epithelial cell

Fig. 1 signaling in neurons and bronchial CHT1 does not appear necessary for choline transport for epithelial cells. (a) In neurons, choline for ACh synthesis ACh synthesis. In BEC, as for neurons, ChAT is utilized is transported by the choline high-affinity transporter for ACh synthesis; though there are multiple isoforms of (CHT1). ACh is then synthesized by the action of choline ChAT, different splicing products may be utilized in dif- acetyltransferase (ChAT) and packaged into synaptic ves- ferent cell types. Since CHT1 is not required and BEC do icles by the action of the vesicular acetylcholine transporter not have synaptic vesicles, the role of VAChTand CHT1 in (VAChT) and CHT1. ACh is then secreted by the complex ACh secretion is unknown, though both are expressed in processes that control synaptic release. Released ACh then BEC. ACh released by BEC is inactivated by the same interacts with postsynaptic nAChR and mAChR as well as as expressed in neurons. A key difference presynaptic receptors. Signaling is terminated by acetyl- is that released ACh is not limited just to synaptic commu- (AChE) and butyrylcholinesterase (BChE). nication but can also signal multiple neighboring cells as a Key signal transduction events lead to the generation of paracrine factor or more distal cells as a hormone (From action potentials, opening of membrane and internal ion Handbook of Experimental Vol 208. Fryer channels, muscle contraction and kinase activation. (b)In AD et al. eds, 2012, Springer, Munich, with permission) bronchial epithelial cells (BEC), though CHT1 is present, affected by muscarinic stimulation are Ca2+ and Toxic Mechanism cyclic monophosphate (cAMP).

Odd-numbered receptors (M1,M3,M5)activatea Anticholinergic agents antagonize the effect of G protein that leads to the release of intracellular ACh by competitively blocking its binding to calcium, resulting in contraction either nicotinic or muscarinic ACh receptor sites. and gland secretion. Even-numbered receptors Clinically significant nicotinic ACh receptor

(M2,M4) activate a G protein that inhibits adenylyl blockade results in neuromuscular and cyclase, leading to reduced levels of cAMP. Thus, is most commonly encountered with the usage of the intracellular effects of muscarinic stimulation paralytic agents including depolarizing agents may lead to either stimulatory (depolarizing) or (e.g., succinylcholine) and nondepolarizing inhibitory (hyperpolarizing) effects on membrane -mimetic agents (e.g., pancuronium). potentials depending on the receptor types present Symptoms of nicotinic ACh antagonism may on any particular structure [13]. After release, ACh also arise from elapid envenomation due to the undergoes synaptic degradation via - effect of α- [14]. terase (AChE) into the inactive products choline Until recently, significant nicotinic ACh antag- and acetate. onism from ingestion was uncommon. 524 W.J. Boroughf

Fig. 2 Cholinergic cell groups (Ch1–8) and their brain Rtg rostral tegmental nucleus, DeC deep cerebellar nuclei, stem projections collapsed onto a schematic parasagittal LC locus coeruleus, Ve vestibular nuclei, PnC nucleus mouse brain section. Th thalamus, BG , Hy reticularis pontis caudalis, CN cranial nerves, RtSP5 spinal hypothalamus, O/H orexin/hypocretin neurons, SuC super- nucleus of the 5th nerve (From Handbook of Experimental ficial layers of superior colliculus, IntC intermediate layers Pharmacology Vol 208. Fryer AD et al. eds, 2012, of superior colliculus, ECIC external cortex of inferior Springer, Munich, with permission) colliculus, IP interpeduncular nucleus, Pn pontine nuclei,

However, between 2010 and 2016, there has been the so-called anticholinergic toxidrome may be rapid development and expanded use of electronic more appropriately characterized as an nicotine delivery systems (e.g., electronic ciga- antimuscarinic toxidrome. Effects of muscarinic rettes). These systems vaporize liquid nicotine ACh blockade may be divided into central and preparations from chambers that are often filled peripheral effects (Table 4). Generally, central by hand from a commercially available bottle of antimuscarinic activity results in changes in men- concentrated nicotine fluid. Appealing flavorings tation including agitation, picking movements, and colorful labeling conflict with poor regulation and hallucinations and peripheral antimuscarinic of packaging, likely contributing to a staggering activity results in anhidrosis, , tachycar- rise in liquid nicotine exposure reporting to the dia, and . These effects are often AAPCC, with more than half of the 3,073 expo- dose-dependent, with low level antagonism sures in 2015 occurring in children under 6 years resulting in decreases in sweating as well as bron- of age. These figures are compared to 2011 in chial and salivary secretion production. Moderate which there were only 271 total reported expo- antagonism may result in and mydri- sures [15]. Unfortunately, there has been similar asis with resultant loss in visual rise in published case reports of pediatric inges- [17]. Urinary retention and intestinal/gastric atony tions resulting in significant toxicity and death result from high degree peripheral muscarinic [15, 16]. ACh antagonism [12]. Muscarinic receptor antag- Muscarinic ACh receptor blockade is com- onists (e.g., atropine) are generally ineffective at monly encountered and makes up the bulk of blocking nicotinic sites. Tertiary agents more clinically significant exposures, so much so that readily cross the blood–brain barrier and are 23 Anticholinergic Syndrome 525

Table 4 of anticholinergic Table 5 Tertiary and quaternary anticholinergic (antimuscarinic) toxicity compounds Peripheral anticholinergic signs Tertiary amines Quaternary ammonium Dry , mouth, and axilla Naturally Occurring Alkaloids Atropine Urinary retention Belladonna Diminished bowel signs Hyoscyamine Mydriasis Scopolamine Loss of accommodation Semisynthetic derivatives Homatropine Homatropine Tachycardia methylbromide Methscopolamine Peripheral vasodilation Synthetic amine compounds Dysrhythmias Dicyclomine Clidinium Cardiogenic Oxybutynin Glycopyrrolate Central anticholinergic signs Ipratropium Agitation Tolterodine Mepenzolate Altered mental status Propantheline Cardiorespiratory arrest Clinical Presentations and Choreoathetosis Life-Threatening Complications Delirium The anticholinergic toxidrome is a constellation of Disorientation signs and symptoms potentially involving many Dysarthria different organ systems (see Table 4). Signs of Extrapyramidal reactions peripheral anticholinergic toxicity characteristi- Auditory and visual hallucinations cally, but not always, accompany central anticho- Incoherent speech linergic toxicity. The authors of a carefully Lethargy controlled clinical study meticulously described the onset and course of iatrogenic central anticho- linergic toxicity and its reversal by the cholinergic Stereotypy (i.e., repetitive gesturing or movements) agent [19]. They described three phases: induction, stupor, and delirium. In the induction phase, peripheral anticholinergic effects predominated. The stupor phase was characterized more likely to result in central anticholinergic by , restlessness, ataxia, hyperther- toxicity, whereas the converse is true of quater- mia, and hypertension. The third phase, delirium, nary agents (Table 5). Atropine typically causes was characterized by amnesia, , incoher- predominantly peripheral anticholinergic effects ent speech, and hallucinations. These phases rep- at low doses and additional central anticholinergic resent an overlapping continuum of toxicity rather effects at higher doses [17]. Still higher doses of than distinct transition points. Importantly, the atropine may result in shock, coma, and respira- delirium phase often outlasted the first two phases. tory failure [18]. Quaternary antimuscarinc com- These phases were described in the setting of pounds do not readily cross the blood–brain central anticholinergic toxicity from atropine, sco- barrier and are unlikely to result in central ACh polamine, and . They may differ somewhat nicotinic blockade. in the setting of other anticholinergic agents [19]. 526 W.J. Boroughf

The characteristic general appearance of the adverse drug reaction, but few data have been anticholinergic syndrome is a restless, delirious published to support this. Anticholinergic adverse patient who is picking at the bed sheets, cloth- drug reactions occur most frequently as a result of ing, and imaginary objects in the air. Speech is increased sensitivity to a therapeutic dose or as a characteristically rapid, mumbling, and incom- result of combinations of anticholinergic agents. prehensible [20]. Hallucinations are usually Very young and very old individuals and patients visual but sometimes may be auditory. Dilated with underlying organic brain syndromes are said and tachycardia are often present, but to be more susceptible to CAS [4, 27, 28]. For neither is essential to the diagnosis. Public unknown reasons, some patients have developed disrobing is a common feature (particularly in the anticholinergic syndrome from exposures to plant-based toxicity), possibly due to the deliri- anticholinergic skin patches that most patients ous uninhibited patient’ssensationofflushing tolerate without problems. [29] and hot skin [20]. Unintentional Overdose Toddlers and mentally infirm people are common Routes of Exposure victims of unintentional or accidental overdose. Use of combinations of prescribed or over-the- The anticholinergic syndrome may result from counter anticholinergic agents is a common oral, pulmonary (smoking), ocular, dermal, buc- cause of unintentional overdose. cal, rectal, or vaginal routes of exposure to anti- cholinergic agents. Oral exposures are most Intentional or Suicidal Overdose common in reported cases and include intentional Suicidal ingestions of over-the-counter sleeping ingestion of pills, , or teas. Pulmonary or pills usually involve anticholinergic antihista- inhalational exposures usually are associated minic agents. Although these exposures are com- with substance abuse, although nebulized atro- mon and usually mild to moderate in severity, pine treatment of is an exception [21, severe outcomes or death occasionally results 22]. Ocular and dermal exposures more com- [30, 31]. monly are unintentional exposures and are diffi- cult to recognize. Witches’ ointments were Recreational Abuse applied intentionally to the whole body, including Self-administration of anticholinergic agents to the axillae, rectum, and vagina [9]. Horse traders induce the desired euphoria, stupor, and halluci- rolled Datura leaves together and inserted them nations through induction of anticholinergism is into the rectums of old nags to make them appear well described [32, 33]. Abuse of anticholinergic to be as fiery as thoroughbreds [9]. Exposure to drugs or natural substances is a particular problem ophthalmologic drops has resulted in the anticho- of adolescents who are too young to buy alcoholic linergic syndrome as an of thera- beverages legally [34–36]. In the fourteenth and peutic use and has been an agent of drug- fifteenth centuries, henbane often was added to facilitated assault or robbery. Dermal exposures beer for its hallucinogenic and mind-altering to topical diphenhydramine and scopolamine properties [9]. Anticholinergic agents prescribed patches are well-known causes of systemic anti- to prevent or treat extrapyramidal or dystonic cholinergic effects [23–26]. reaction due to neuroleptics have been abused by schizophrenics and individuals without psychiat- ric illnesses. In one study of schizophrenic Intention or Cause of Exposures patients, careful scrutiny revealed that 6.5% of 214 consecutively admitted schizophrenic Adverse Drug Reactions patients abused trihexyphenidyl [36]. Emergency Many authors have stated empirically that anti- department physicians in the 1980s often gave a cholinergic syndrome occurs frequently as an placebo injection to patients with suspected 23 Anticholinergic Syndrome 527 dystonic reactions in hopes of discovering indi- with some features that resemble the anticholiner- viduals with feigned who were seeking gic syndrome. However, and ibotenic intravenous anticholinergic drugs [37–39]. The acid are actually pharmacologic modulators of the delayed absorption associated with these agents gamma amino butyric acid – glutamic acid neuro- plus the biologic variability in natural substances transmitter system. Intentional (recreational) and makes it particularly difficult for users to titrate unintentional (toddler ingestions) exposures to the dose of these agents to reach the desired end these types of mushrooms only rarely produce point of hallucinations while avoiding more severe anticholinergic-like syndrome [49]. severe toxicity.

Malicious Use Range of Toxicity The addition of anticholinergic agents such as scopolamine to other substances of abuse may Toxicity varies greatly among the various sub- lead to unusual or serious toxicity. Substitution stances with anticholinergic properties. Toxicity of scopolamine for [40] and addition of is greatest for the TCAs primarily because of their scopolamine to [41] have been reported. α- receptor–blocking and sodium Surreptitious addition of scopolamine to bever- channel–blocking effects rather than their anti- ages is a well-known method of drug-facilitated cholinergic properties. In a pediatric series of sexual assault or crime [42–44]. The German term auto-injector atropine exposures, lower injected Altsitzerkraut, meaning “old sitter herb,” refers to doses resulted mainly in mild peripheral effects, the use of henbane to induce a lethal form of whereas higher doses resulted in hyperthermia anticholinergic toxicity to an inactive old and central effects [50]. In adults, atropine doses person [9]. Because there is no history of exposure of 0.032 mg/kg caused peripheral effects and in these cases and the usual simple toxicologic doses of 0.13–0.17 mg/kg caused central effects screens are negative, misdiagnosis is common. [19]. These studies suggest that peripheral effects occur at lower doses than do central effects. As Toxic Causes or Sources little as 4–5 eye drops (probably less in children) Many types of prescription and over-the-counter containing 4% atropine or 0.25% scopolamine has medications and natural substances have anticho- been reported to cause the anticholinergic syn- linergic properties (see Table 1). The anticholin- drome [51, 52]. ergic syndrome may result from intentional or unintentional exposure to toxic amounts of these individual agents or in combinations. Many mem- Organ System Effects bers of the plant family Solanaceae contain or belladonna alkaloids. Plants that can Seizures cause the anticholinergic syndrome contain vari- Anticholinergic poisoning is a common cause of able amounts of the following toxic alkaloids: drug-induced seizures, the risk of which may be solanine, atropine, and scopolamine. Anticholin- agent-dependent. Seizures were not observed in a ergic plant toxicity is discussed in detail in the series of 20 cases of severe atropinization second- chapter devoted to that topic. Scopolamine is the ary to mostly unintentional auto-injector dis- primary tropane in Jimson weed. concen- charge during the Persian Gulf War [50]. In TCA trations of specific types of plants and mushrooms overdose, the prevalence of seizures has been are well known to vary with location, climate, and reported to be 3–30% [53–55]. However, the path- season. Natural brews, such as teas or wines made ophysiology of TCA-induced seizures is poorly from these plants, are notorious for their intoxi- understood and may not be entirely due to their cating abilities [45–48]. Mushrooms containing anticholinergic effects. In nine children hospital- muscimol/ are often described as ized after ingesting Amanita pantherina or Ama- capable of causing hallucinations and a syndrome nita muscaria mushrooms, seizures or myoclonic 528 W.J. Boroughf

Fig. 3 Muscarinic signaling pathways in supraventricular synthesis by directly activating all isoforms of adenylyl (sinoatrial, atrial, and atrioventricular) myocytes. Acetyl- cyclase (AC) via the α subunit (αs) of the stimulatory G choline (ACh) acts through M2 receptors to regulate protein Gs. Changes in cAMP affect targets of protein ACh-activated Kþ channels via a membrane-delimited kinase A (PKA)-dependent phosphorylation such as mechanism involving direct activation by the ϐΥ subunits tropinin I (TnI), phospholamban (PLN), and the L-type 2+ of the inhibitory G protein Gi. ACh also acts through M2 Ca channel. Changes in cAMP also directly regulate receptors to inhibit adenylyl cyclase (AC) activity via the α pacemaker channels, which are permeable to both Na+ + subunit (αi)ofGi, resulting in a decrease in cAMP produc- and K (From Handbook of Experimental Pharmacology tion. This may occur in the absence or presence of Vol 208. Fryer AD et al. eds, 2012, Springer, Munich, with that stimulate cAMP production. (NEPi) permission) acts through b1-adrenergic receptors to stimulate cAMP twitching occurred in 44% [49]. Understanding antagonism of the ACh-induced peripheral vaso- the true incidence of seizures may be clouded by dilation (Fig. 4). However, anticholinergic agents abnormal muscle activity (e.g., jerks, twitches, that possess or α-adrenergic rigidity) secondary to anticholinergic toxicity antagonistic properties may result in that may be confused with seizures by laypersons due to direct vasodilation. Cardiotoxicity may and less experienced health care providers. further complicate hemodynamic instability due Because seizures have been considered by some to development of advanced heart block or ven- to be a relative contraindication to physostigmine tricular dysrhythmia. Together, these effects may use, the reported observation of seizures by less lead to cardiovascular collapse and refractory experienced or trained personnel must be evalu- shock. Of note, moderate anticholinergic expo- ated carefully. sure in a susceptible host may also lead to severe toxicity [56]. Cardiovascular Effects Mild to moderately severe anticholinergic syn- Gastrointestinal Effects drome is associated with sinus tachycardia and Anticholinergic agents may decrease intestinal hypertension. The tachycardia may result primar- peristalsis and delay gastric emptying [57]. For ily from blocking of the M2-receptors on the sino- drugs, this is a desired effect and atrial node.(Fig. 3). Hypertension results from leads to decreased intestinal . When 23 Anticholinergic Syndrome 529

Fig. 4 Muscarinic signaling pathways in the vasculature. oxide (NO), which can diffuse into adjacent vascular In endothelial cells, acetylcholine (ACh) acting through M3 smooth muscle cells, where it stimulates soluble guanylyl or M5 receptors stimulates phospholipase C (PLC) activity cyclase (sGC) to produce cGMP. Protein kinase G (PKG) through the G protein Gq. Subsequent production of activated by cGMP promotes relaxation. In vascular smooth inositoltriphosphate (IP3) acts on the IP3 receptor (IP3R) muscle cells, ACh acting through M1 or M3 receptors 2+ in the endoplasmic reticulum to release Ca . The resulting stimulates PLC-dependent production of IP3 and the subse- rise in cytosolic Ca2+ activates endothelial nitric oxide quent release of Ca2+ from the ER. This results in Ca2+ and synthase (eNOS) via a calmodulin (CM)-dependent mech- CM-dependent kinase (CamKII) activation of myosin light anism. Activation of eNOS leads to the production of nitric chain kinase (MLCK), which promotes contraction

undesired or excessive, these effects may lead to Urinary Tract Effects or drug-induced . This effect Anticholinergic agents reduce bladder tone and also may lead to delayed peak absorption and may lead to urinary retention. This is especially prolonged toxicity of anticholinergic agents as a problem for an elderly man with prostatic hyper- well as other co-ingestants. trophy and increases the risk of urinary tract infec- tions. In many patients with anticholinergic Effects toxicity, urinary retention may necessitate the Severe forms of the anticholinergic syndrome use of bladder catheterization. If not addressed may be associated with rhabdomyolysis resulting early, significant urinary retention may further in release of myoglobin into the blood and neph- contribute to agitation. rotoxicity [58–62]. Rhabdomyolysis in this set- ting may be a result of hyperthermia, excess motor activity or muscle tone, or dependent-type Diagnosis pressure injury secondary to deep coma. Laboratory Tests Temperature Effects Anticholinergic agents inhibit sweating, which In the United States, many toxicologic screens are reduces one’s ability to dissipate excess body immunoassays designed to detect common drugs heat. Excess motor activity or muscle tone of abuse at levels above the US Substance Abuse increases body heat. Hyperthermia can result and Mental Health Services Administration from increased heat generation and impaired thresholds. This type of drug of abuse screen cooling secondary to sweating inhibition. This is does not detect any of the anticholinergic agents especially true in environments with high ambient listed in Table 1. Some immunoassay screens also temperatures. provide qualitative or semiquantitative detection 530 W.J. Boroughf of TCAs or other analytes, such as methylene- Table 6 Differential diagnoses of anticholinergic dioxymethamphetamine (“ecstacy”). Gas chro- syndromes matography combined with mass spectroscopy is Intoxications a commonly employed technique in comprehen- sive drug and substance screening that can detect many but not all of these agents [63, 64]. Although quantitative assays are available for most anticho- Lithium linergic agents, they are usually unnecessary in Lysergic acid diethylamide (LSD) the clinical management of patients with anticho- Monoamine oxidase inhibitors (MAOI) linergic syndrome and rarely can be done in a (PCP) Salicylates clinically useful time frame. In certain cases Selective serotonin inhibitors (e.g., in fatalities or atypical presentations), other – Sympathomimetics (e.g., cocaine, , laboratory techniques (e.g., gas liquid chroma- ) tography, high-pressure liquid chromatography, or high-pressure thin-layer chromatography) Withdrawal syndromes may be required to identify the anticholinergic Ethanol agent. - Differential Diagnosis Malignant hyperthermia Neuroleptic malignant syndrome The differential diagnosis includes many condi- tions that resemble the anticholinergic syndrome Metabolic (Table 6). Many of these diagnoses can be elimi- Disulfiram (Antabuse) reactions nated by a careful history and physical examina- Hepatic failure tion combined with routine laboratory tests. A Hypercapnia history of anticholinergic exposure, typical mani- Hyperthyroidism festations of peripheral and central anticholinergic Hypoglycemia toxicity, and a typical time course for resolution of Hyponatremia clinical effects are adequate for most clinical diag- Hypoxia noses of anticholinergic syndrome. In some cases, Pheochromocytoma Uremia little to no peripheral anticholinergic findings are Wernicke’s syndrome noted [4]. Although several physical findings, such as dry skin and decreased bowel sounds, Encephalitis are said to be useful in distinguishing anticholin- Meningitis ergic syndrome from other causes of agitated Sepsis fi delirium, the sensitivity and speci city of these Psychiatric illnesses findings are not well documented. Hall and col- Schizophrenia leagues [4] stated that hyperthermia was seen in only 20% of adults and 25% of children and that Other causes fewer than 10% of patients with central anticho- Cerebral vasculitis linergic toxicity manifest constipation, ileus, uri- Cerebrovascular accident nary retention, and convulsions. These Cerebral contusion percentages appear to be estimates, and the num- Postictal state ber of cases on which they were based was not Postconcussive syndrome provided. This report also stated that the most Partial complex seizures reliable signs of the anticholinergic syndrome Anti-NMDA-receptor encephalitis 23 Anticholinergic Syndrome 531 were dilated and sluggishly reactive pupils, con- urine osmolarity, blood nitrogen, and creati- fusion, disorientation, incoherence, memory nine may occur as a result of prerenal azotemia impairment, facial flushing, dry mucous mem- secondary to poor fluid intake and increased branes, tachycardia, agitation, picking or grasping insensible losses associated with agitation and movements, ataxia, motor incoordination, and hyperthermia. Increased creatinine also may visual and auditory hallucinations [4]. In eight occur with rhabdomyolysis-induced acute renal victims of surreptitious scopolamine use, dry failure. Hyperthermia and agitation may lead to mouth and skin were noted in 100% and rhabdomyolysis, which is associated with decreased bowel sounds were noted in 25% increased amounts of myoglobin in the serum [42]. Published reviews of Datura stramonium and the urine. Urine with excess myoglobin (Jimson weed) intoxication signs report wide appears brown or pink and tests positive on a ranges of clinical antimuscarinic features with urine orthotolidine test for blood, but no red dry mucous membranes and dry skin present in blood cells are seen in the microscopic urinalysis. 46–94% of patients [65, 66]. In unknown cases, Quantitative serum concentrations of skeletal comprehensive laboratory testing can be used to muscle , particularly creatinine phospho- detect some of the more commonly used drugs kinase, and urinary myoglobin levels can confirm and abused substances. the diagnosis of rhabdomyolysis. Rhabdomyoly- sis also may increase the serum potassium and phosphate concentrations and decrease the serum Diagnostic Studies calcium levels. Marked agitation may be associ- ated with an increased anion gap metabolic acido- Toxicologic Analyses sis, increased serum lactate, and decreased serum Most of the common causes of the anticholinergic bicarbonate. Sustained or severe hyperthermia syndrome are not detected on routine toxicologic may result in disseminated intravascular coagula- screens, which usually consist of immunoassays tion, characterized by increased coagulation to detect drugs of abuse. An exception is the times, increased D-dimer and fibrin split products, qualitative immunoassay for TCAs, which also and decreased platelets and fibrinogen levels. can yield false-positive results in the presence of other anticholinergic drugs, such as diphenhydra- Differential Features mine and certain and anticonvul- The anticholinergic syndrome may be character- sants such as . Although ized by the mnemonic “mad as a hatter, red as a quantitative levels of most of the drugs and anti- beet, dry as a bone, blind as a bat, hot as a hare cholinergic alkaloids in Table 1 are available from and tachy as a leisure suit.” The syndrome is reference laboratories, they are rarely necessary. usually, but not always, a combination of periph- Because of variable susceptibility to these agents, eral and central anticholinergic toxicity (see quantitative levels for diagnostic confirmation Table 4). When it occurs without signs of periph- may not be reliable [67]. Quantitative levels of eral anticholinergic toxicity, the anticholinergic other agents may be useful in ruling out the anti- syndrome may be misdiagnosed as a primary psy- cholinergic syndrome. chiatric , especially without a history of excess anticholinergic exposure and with a nega- Abnormal Routine Laboratory Test tive toxicologic screen [68]. Misdiagnoses are Findings more common in very young and very old patients Many standard laboratory tests may be abnormal [23, 69, 70]. Anti- N-methyl-D-aspartic acid in patients with the anticholinergic syndrome. receptor encephalitis is an important recently Patients who are agitated or delirious may have a described syndrome occurring primarily in mild increase in white blood cell counts secondary young females that may closely mimic features to demargination. Increases in serum sodium, of both central and peripheral anticholinergic 532 W.J. Boroughf toxicity as a result of paraneoplastic effects (most (Grade III recommendation). However, activated commonly ovarian teratoma) [71, 72]. Many other charcoal has not been shown to affect the outcome and medical problems may also resem- of these patients. The administration of activated ble the anticholinergic syndrome and may be dif- charcoal should be done cautiously, if at all, in ficult to distinguish clinically (see Table 6). patients with altered mentation or risk of seizures, Although it is said that dry skin and absent unless their airways are mechanically protected. bowel sounds distinguish anticholinergic syn- Patients with severe toxicity and patients who are drome from poisoning, there are few unable to protect their airway should undergo published data to evaluate the sensitivity or spec- rapid-sequence intubation. ificity of these findings. Ophthalmologic prepara- Patients who are significantly agitated must be tions are particularly problematic because many protected from hurting themselves or others. Sig- patients do not include them when listing their nificant agitation associated with the anticholiner- current medications [28]. In a suspected case of gic syndrome should be treated by reversal with anticholinergic syndrome, a diagnostic challenge either an anticholinesterase (i.e., physostigmine) with physostigmine doses may be attempted as or a sedating agent (chemical restraint) (Grade I long as contraindications (see ▶ Chap. 161, “Phy- recommendation). The use of physical restraints sostigmine”) are not present [73]. alone may result in significant rhabdomyolysis if the patient fights vigorously or persistently against them. Physical restraint should be used Treatment only as an adjunct to chemical restraints, in case the latter wear off unexpectedly. Large amounts of Most cases of the anticholinergic syndrome are may be required to achieve adequate not life-threatening and require little more than chemical restraint or sedation in anticholinergic observation and general supportive care. Because syndrome cases. In a comparative study of phy- these patients are at risk of hurting themselves or sostigmine versus for the anti- others and of sudden deterioration due to seizures cholinergic syndrome, the mean total or respiratory distress, they should be observed doses were , 53.1 mg; carefully until major signs of toxicity have dissi- , 35.5 mg; and , 31.7 mg pated. Less commonly encountered severe cases [79]. Watkins et al. demonstrated the use of phy- may require complicated and expert supportive sostigmine alone resulted in significantly lower care [74, 75]. More severe cases of the anticho- rates of intubation compared to benzodiazepines linergic syndrome usually are seen with agents alone or a combination with other sedating agents that have other important, potentially toxic prop- [80]. can be used to calm delirious erties, such as sodium channel or α-adrenergic patients, but concerns about QTc interval prolon- receptor blockade (e.g., TCAs, neuroleptics, gation and proarrhythmias warrant QTc monitor- diphenhydramine). Delayed gastric emptying ing during its use [81, 82]. Because haloperidol and drug absorption are major concerns. In a has some mild anticholinergic properties, many reported case of severe benztropine toxicity, medical toxicologists believe it should be avoided severe anticholinergic poisoning persisted for in patients with the anticholinergic syndrome. 9 days after a large single ingestion [76]. Anecdot- However, published systematic reviews have not ally, one author reported recovery of Jimson weed demonstrated any significance difference in out- seeds 23 h after ingestion [77]. A review of comes or adverse effects between typical and 15 cases of anticholinergic plant poisoning atypical antipsychotics in the setting of all-cause reported a mean latency to onset of symptoms of delirium [83, 84]. As there exist no published 2.7 h [78]. Based on these reports, gastrointestinal clinical studies with respect to typical or atypical decontamination with activated charcoal may be use in the specific setting of acute useful for a longer time after ingestion of these anticholinergic-induced delirium, the above con- agents than for the usual types of acute overdose cerns remain theoretical. 23 Anticholinergic Syndrome 533

Seizures may be seen in severe cases of anti- administration of intravenous fluids (Grade I rec- cholinergic toxicity. Although apparent successful ommendation), though the benefit of adding man- terminations of anticholinergic-associated sei- nitol or sodium bicarbonate is less clear. zures with physostigmine have been reported Myoglobin is less likely to precipitate in the [85, 86], seizures believed to be secondary to renal tubules and cause nephrotoxicity when the physostigmine use also have been reported urine is dilute and alkaline [100, 101]. [87–89]. Animal studies suggest that physostig- mine has limited efficacy against seizures second- ary to anticholinergic toxicity [90–93]. Because of Specific Treatment concerns over limited efficacy and even enhanc- ing propensity to seizures, physostigmine is not Some physicians prefer to treat the anticholiner- indicated as an therapy. Benzodi- gic syndrome primarily with supportive care, azepines are the primary for carefully titrated sedation, and intubation and anticholinergic-induced seizures. Seizures refrac- artificial ventilation if necessary [102]. Other tory to benzodiazepines may be treated with bar- physicians prefer to use physostigmine for cases biturates or as a second line agents of severe anticholinergic poisoning presenting (Grade III recommendation). Patients not respon- without significant cardiovascular toxicity, in sive to those agents may be treated as described in hopes of avoiding the need for excess sedation, ▶ Chap. 20, “Toxicant-Induced Seizures.” intubation, and artificial ventilation [70]. This is Severe hyperthermia (temperature >40 C) further supported by Watkins et al. who found may result in direct tissue injury and rapid cardio- that, in patients with severe anticholinergic- vascular collapse and therefore should be treated induced agitation, the use of physostigmine aggressively. In addition to liberal doses of ben- alone resulted in significantly lower rates of intu- zodiazepines to decrease adrenergic tone, rapid bation compared to benzodiazepines (1.8 cooling is mandatory (Grade II-2 recommenda- . 8.4%, respectively) [80]. Physostigmine is a tion). Ice water immersion provides the most short-acting, nonselective cholinesterase inhibi- rapid reduction in core body temperature, albeit tor that is a tertiary amine capable of crossing the potentially limited by logistical constraints blood–brain barrier. It has been reported to be [94]. Other methods of cooling include effective in reversing anticholinergic toxicity ice-cooled saline infusion, evaporative methods from drugs [79, 103–105] and natural substances. (wet sheets and fans), and ice packs to the axilla (The clinical pharmacology of this agent is and groin. Novel cooling devices developed for discussed in detail in ▶ Chap. 161, “Physostig- post-cardiac arrest target temperature manage- mine.”)[106, 107] Although physostigmine was ment have received limited study but appear to popular in the 1970s and early 1980s, its use dimin- be inadequate [94]. sodium occasion- ished after reports of serious adverse effects in TCA ally appears as a recommended adjunctive agent overdoses [108–110]. Currently the use of physo- for toxicant-induced hyperthermia. While there stigmine to reverse central anticholinergic toxicity appears to be some evidence in its use for neuro- remains somewhat controversial among some leptic malignant syndrome, there is no published emergency medicine physicians.112 Many of these data supporting its use in anticholinergic-induced perceived risks seem to be unfounded in the eyes of hyperthermia [95–99]. Instead, severe muscular the medical toxicology community.112 Doses of rigidity that does not respond to benzodiazepines 2 mg (or 0.02 mg/kg) of physostigmine over should be met with neuromuscular paralysis to 2 min will reliably reverse anticholinergic syn- eliminate continued thermogenesis [94]. dromes. The pharmacokinetic half-life of physo- Rhabdomyolysis may occur secondary to stigmine is approximately 20 min, although the marked agitation, increased muscle tone, or severe pharmacodynamic effect lasts longer. Neverthe- hyperthermia. In the absence of renal failure, less, it is not uncommon for the clinical effect of rhabdomyolysis treatment includes early liberal physostigmine to wear off before the 534 W.J. Boroughf anticholinergic delirium resolves. In these cases, 12. Brown JH, Taylor P. Muscarinic receptors: agonists physostigmine can be readministered. Because of and antagonists. In: Hardman JG, Limberd LE, Molinoff PB, et al., editors. 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