Anticholinergic Syndrome 23 William J. Boroughf Contents The anticholinergic syndrome is common and Overview and Incidence ............................ 521 may result from exposures to many drugs or nat- ural substances (Table 1). Anticholinergic effects History ............................................... 521 are desired or intended effects for certain drugs Pathophysiology .................................... 522 (i.e., antispasmodics, mydriatics, and belladonna Toxic Mechanism .................................... 523 alkaloids) and are undesired or side-effects for Clinical Presentations and Life-Threatening other drugs (i.e., antihistamines, antidepressants, Complications ....................................... 525 antipsychotics, and antiparkinsonians). Both pre- Routes of Exposure .................................. 526 Intention or Cause of Exposures ..................... 526 scription and over-the-counter drugs may have Range of Toxicity .................................... 527 anticholinergic effects. Combined use of more Organ System Effects ................................ 527 than one drug 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 toxidrome, 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 central nervous system (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 euphoria and hallucinations is the desired end * W.J. Boroughf ( ) point of certain forms of substance abuse, but Emergency Medicine, 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 Chlorcyclizine Atropine sulfate Chlorpheniramine Belladonna extract Clemastine Belladonna tincture Cyclizine Levo alkaloids of belladonna (Bellafoline) Cyproheptadine Clidinium (Quarzan) Dexbrompheniramine Homatropine hydrobromide Dexchlorpheniramine Hyoscine N-butylbromide Dimenhydrinate Hyoscyamine sulfate Dimethindene Hyoscyamine Diphenhydramine Scopolamine hydrobromide Diphenylpyraline Gastrointestinal antispasmodics Doxylamine Anisotropine methylbromide (Valpin) Fexofenadine Butylscopolamine bromide (Buscopan) Hydroxyzine Clidinium bromide (Librax) Loratadine Dicyclomine hydrochloride (Bentyl) Meclizine Glycopyrrolate (Robinul) Methapyrilene Hexocyclium methylsulfate (Tral) Phenindamine Isopropamide iodide (Darbid) Pheniramine Mepenzolate bromide (Cantil) Phenyltoloxamine Methantheline bromide (Banthine) Promethazine Atropine/diphenoxylate (Lomotil) Pyrilamine Methscopolamine bromide (Pamine) Pyrrobutamine Oxyphencyclimine hydrochloride Tripelennamine (Daricon) Triprolidine Oxyphenonium bromide (Antrenyl) Antiulcer drugs Propantheline bromide (Pro-Banthine) Cimetidine Genitourinary antispasmodics Famotidine Flavoxate hydrochloride (Urispas) Propantheline Oxybutynin chloride (Ditropan) Ranitidine Tolterodine tartrate (Detrol) Antiparkinson drugs Cycloplegics Benztropine mesylate (Cogentin) Cyclopentolate (Cyclogyl) Biperiden (Akineton) Tropicamide (Mydriacyl) Orphenadrine hydrochloride Other drugs (Disipal) Cyclobenzaprine (Flexeril) Orphenadrine citrate (Norflex) Mefloquine Procyclidine (Kemadrin) Diphenidol (Vontrol) Trihexyphenidyl hydrochloride Ipratropium bromide (Atrovent) (Artane) Antihistamines Neuroleptics [1] Acrivastine Chlorpromazine (Thorazine) Antazoline Prochlorperazine Azatadine Fluphenazine Bromodiphenhydramine Clozapine (Clozaril) Brompheniramine Prochlorperazine Buclizine Olanzapine (Zyprexa) Carbinoxamine Thioridazine Cetirizine Thiothixene (continued) (continued) 23 Anticholinergic Syndrome 521 Table 1 (continued) demonstrate a marked decrease in reported expo- Tricyclic antidepressants [2] sures and deaths from anticholinergic exposure in Amitriptyline (Elavil) 2014 [5, 6]. Use of drugs with anticholinergic Clomipramine (Anafranil) activity is the most common cause of Imipramine (Tofranil) pharmaceutical-induced delirium [7]. Differences Desipramine (Norpramin) in clinical effects result from not only the dose but Doxepin (Sinequan) also variability in the degree of muscarinic recep- Nortriptyline (Pamelor) tor blocking among agents [1, 2]. Large inten- Protriptyline (Vivactil) tional ingestions of sleeping pills, antihistamine- Trimipramine (Surmontil) type sleeping pills, and tricyclic antidepressants Plants (TCAs) are common causes of serious toxicity Atropa belladonna (deadly nightshade) within these groups. Antihistamine exposure is Brugmansia arborea (angel’s trumpet) the most common cause of unintentional anticho- Brugmansia suaveolens (angel’s trumpet) linergic toxicity, whereas cyclic antidepressants Cestrum diurnum (day jessamine) and atypical antipsychotics are proportionally Cestrum nocturnum (night jessamine) Cestrum parqui (willow-leaved jessamine) larger origins of intentional exposures and toxicity Datura metel (Hindu datura) [6]. Many anticholinergic-type adverse drug reac- Datura stramonium (Jimson weed, thorn apple, tions and abuse are not reported to poison centers locoweed) or adverse drug reaction programs, and their true Duboisra spp. incidence is unknown. In one study, 60% of Hyoscyamus 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 Mandragora officinarum (mandrake) unit had significant adverse effects [7]. Data from Scopolia atropoides (crazy plant) the American College of Medical Toxicology’s fl Solandra spp. (trumpet ower) Toxicology Investigators Consortium (ToxIC) Solanum dulcamara (woody nightshade) Case Registry reveal that of patients requiring Solanum nigrum (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 Amanita muscaria 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 Solanaceae 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 potions, indicate that anticholinergic exposures are com- intoxicants, hallucinogens, knockout agents, mon but usually not severe or fatal (Table 2)[5]. and poisons. 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 leaves 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 Medications 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 Phenothiazine 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 receptor 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