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CHAPTER 202: Anticholinergics 1309 achieved using four-factor prothrombin complex concentrate or threefactor prothrombin complex concentrate and fresh frozen plasma. For asymptomatic patients who have accidentally ingested a super warfarin, follow-up in 24 and 48 hours for coagulation studies should be arranged. Prevention measures should be emphasized. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Anticholinergics Frank LoVecchio INTRODUCTION Anticholinergic properties are present in over 600 compounds, including prescription drugs, over-the-counter medications, and plants (Table 202-1). Many of these substances possess anticholinergic activ ity as either a direct therapeutic effect or as an adverse effect in addition to their primary or predominant pharmacologic effect. Atropine (d,l -hyoscyamine), hyoscyamine, and scopolamine ( l -hyoscine) are natural alkaloids that represent prototypical anticholinergic compounds. Antihistamine (particularly diphenhydramine) overdose is the most common overdose that produces anticholinergic toxicity. 1 Toxicity in children may result from accidental ingestion of an anticholinergic medication, oral administration of hyoscyamine-containing agents to treat colic, topical use of diphenhydramine-containing salves, or therapeutic application of a transdermal hyoscine patch. 2-5 In the elderly, therapeutic doses of one or multiple medications with anticholinergic properties may produce anticholinergic symptoms, or they may simply cause ileus without other anticholinergic findings. 6,7 Ophthalmologic instillation of anticholinergic mydriatics can cause toxicity, especially in the elderly or young children; patients are therefore instructed to lie down and apply 5 minutes of gentle pressure on the nasolacrimal duct when instilling these agents. Atropine is the antidote for cholinergic syndromes produced from nerve agents or organophosphate insecticides.9 Administration of highdose atropine to someone without cholinesterase poisoning can result in anticholinergic toxicity. This occurred in Israel during the first Gulf War in 1991, when frightened civilians dosed themselves with atropine fearing an incoming Scud missile chemical weapon attack. Plant poisonings may result in an anticholinergic toxidrome. In Taiwan, the anticholinergic toxidrome is most commonly associated with plant exposures. 10 Belladonna alkaloid-containing plants have potent anti cholinergic effects and produce toxicity 1 to 4 hours after ingestion (sooner if smoked). Alkaloid plants are abused for their hallucinogenic effects. 11,12 Group poisonings with anticholinergic plants are common in adolescents seeking psychoactive hallucinogenic effects. 13,14 Inadvertent poisoning from the ingestion of belladonna-contaminated herbal teas and Chinese traditional medicines has been reported. 15,16 Ingestion of seeds and berries, sometimes due to mistaken identity, can produce anticholinergic toxicity. 17,18 Anticholinergics have been substituted for other abused psychoactive drugs and then sold to unwitting customers.19 Adulteration of commonly abused drugs (e.g., heroin, cocaine) with scopolamine or atropine has been observed. 20-22 PHARMACOLOGY Anticholinergic drug absorption can occur after ingestion, smoking, or ocular use. With oral ingestion, the onset of anticholinergic toxicity usually occurs within 1 to 2 hours.

customers.19 Adulteration of commonly abused drugs (e.g., heroin, cocaine) with scopolamine or atropine has been observed. 20-22 PHARMACOLOGY Anticholinergic drug absorption can occur after ingestion, smoking, or ocular use. With oral ingestion, the onset of anticholinergic toxicity usually occurs within 1 to 2 hours. Because muscarinic blockade slows gastric emptying and decreases GI motility, absorption and peak clinical CHAPTER TABLE 202-1 Major Groups of Substances With Anticholinergic Activity Class and Subclass Prototypical Agent(s) Cyclic antidepressants Amitriptyline hydrochloride, imipramine hydrochloride, doxepin hydrochloride Antihistamines Ethanolamines Ethylenediamines Alkylamines Piperazines Phenothiazines Diphenhydramine, dimenhydrinate Tripelennamine Chlorpheniramine Loratadine, meclizine, cetirizine Prochlorperazine, promethazine Antiparkinson drugs Tropanes Piperidines Benztropine mesylate Trihexyphenidyl Antipsychotics Phenothiazines Nonphenothiazines Chlorpromazine, thioridazine, perphenazine Clozapine, olanzapine, molindone, loxapine, quetiapine Antispasmodics Cyclohexane carboxylic acids Quaternary ammonium Dicyclomine Methantheline bromide Belladonna alkaloids Tropanes Pyrrolidines Atropine, homatropine, scopolamine hydrobromide Glycopyrrolate Mydriatics Phenylacetates Pyridines Cyclopentolate hydrochloride Tropicamide Skeletal muscle relaxants Tricyclics Ethylamines Cyclobenzaprine hydrochloride Orphenadrine citrate Plants Datura species

theline bromide Belladonna alkaloids Tropanes Pyrrolidines Atropine, homatropine, scopolamine hydrobromide Glycopyrrolate Mydriatics Phenylacetates Pyridines Cyclopentolate hydrochloride Tropicamide Skeletal muscle relaxants Tricyclics Ethylamines Cyclobenzaprine hydrochloride Orphenadrine citrate Plants Datura species Mandragora species Brugmansia species Datura stramonium (Jimson weed), Datura candida (angel’s trumpet) Mandragora officinarum (mandrake) Brugmansia suaveolens (angel’s tear, maikoa, or white angel’s trumpet), Brugmansia versicolor (angel’s tear or angel’s trumpet) Mushrooms Amanita species Amanita muscaria, Amanita pantherina effects are often delayed. An example is diphenoxylate-atropine (e.g., Lomotil ® ), an antidiarrheal agent that may present with toxicity up to 12 hours after ingestion. Cholinergic receptors exist as two major subtypes: muscarinic recep tors and nicotinic receptors. Muscarinic receptors are found predomi nantly on autonomic effector cells that are innervated by postganglionic parasympathetic nerves, on some ganglia, and in the brain, particularly the hippocampus, cortex, and thalamus. Nicotinic receptors are found at peripheral autonomic ganglia, at neuromuscular junctions, and also in the brain. Acetylcholine is the neurotransmitter that modulates both receptor types. Genes encode for five muscarinic receptors through G-protein receptor activation; four seem to be physiologically active (Table 202-2). The structure of nicotinic receptors is complex, composed of several subunits that are encoded by multiple genes. The subunits are combined into four main families of nicotinic receptors: the muscle type, found at the neuromuscular junction; the ganglion type, found in autonomic ganglia; and two brain types found in the CNS. Anticholinergic drugs and plant toxins competitively inhibit or antagonize the binding of the neurotransmitter acetylcholine to mus carinic acetylcholine receptors. The term anticholinergic is technically Tintinalli_Sec15_p1187-1332.indd 1309 8/2/19 8:40 PM

nd in autonomic ganglia; and two brain types found in the CNS. Anticholinergic drugs and plant toxins competitively inhibit or antagonize the binding of the neurotransmitter acetylcholine to mus carinic acetylcholine receptors. The term anticholinergic is technically Tintinalli_Sec15_p1187-1332.indd 1309 8/2/19 8:40 PM 1310 SECTION 15: Toxicology a misnomer. A more accurate term is antimuscarinic agents, because anticholinergic agents do not antagonize effects at nicotinic acetylcho line receptors such as those at the neuromuscular junction. Clinical manifestations from these drugs are modulated through disturbances in the CNS (central effects) and the parasympathetic nervous system (peripheral effects) (Table 202-3). The signs and symptoms of anticholinergic toxicity are a result of both central and peripheral cholinergic blockade. The central anticholinergic syndrome refers to the clinical state when there is predomination of the TABLE 202-2 Muscarinic Receptors Receptor Target Organ Receptor Action When Stimulated M1 Autonomic ganglia Brain Salivary glands Stomach Decreases activity in autonomic ganglia Increases salivary and gastric acid secretion 2 Heart Decreases sinus node rate and slows conduction through the atrioventricular node Decreases the force of atrial contraction and possibly ventricular contraction 3 Smooth muscle Endocrine/exocrine glands Iris Bronchospasm Mild vasodilation Increases saliva and gastric acid production Constricts the pupil 4 CNS Multiple actions M5 Has not been elucidated TABLE 202-3 Muscarinic and Antimuscarinic Effects Organ Stimulation or Muscarinic Effect Antagonism or Antimuscarinic Effect Brain Complex interactions Possible improvement in memory Complex interactions Impairs memory Produces agitation, delirium, and hallucinations Fever Eye ↓ Pupil size (miosis) ↓ Intraocular pressure ↑ Tear production ↑ Pupil size (mydriasis) ↑ Intraocular pressure Loss of accommodation (blurred vision) Mouth ↑ Saliva production ↓ Saliva production Dry mucous membranes Lungs Bronchospasm ↑ Bronchial secretions Bronchodilation Heart ↓ Heart rate Slows atrioventricular conduction ↑ Heart rate Enhances atrioventricular conduction Peripheral vasculature Vasodilation (modest) Vasoconstriction (very modest) GI ↑ Motility ↑ Gastric acid production Produces emesis ↓ Motility ↓ Gastric acid production Urinary Stimulates bladder contraction and expulsion of urine ↓ Bladder activity Promotes urinary retention Skin ↑ Sweat production ↓ Sweat production (dry skin) Cutaneous vasodilation (flushed appearance) central effects (fever, agitation, delirium, coma) of muscarinic receptor antagonism. The peripheral anticholinergic syndrome refers to peripheral muscarinic antagonism’s constellation of findings: tachycardia, flushed dry skin, dry mouth, ileus, and urinary retention. The full range of clinical manifestations associated with anticholin ergic overdose may be only partly explained by muscarinic receptor blockade. Many of these anticholinergic agents possess activity at other cell membrane receptors, and toxicity after overdose can be a mixture of pharmacologic mechanisms. For example, the clinical findings associ ated with cyclic antidepressant overdose are only partly characterized by anticholinergic effects that vary considerably among different cyclic antidepressants. The most life-threatening complications of cyclic anti depressant overdose do not result from anticholinergic effects, but are rather a result of myocardial sodium channel–blocking effects and widecomplex tachydysrhythmias. IV injection of antihistamines, particularly of those (e.g., diphen hydramine) affecting H 1 histamine receptor antagonists, seems to cause euphoria in some patients; this translates to abuse potential.

gic effects, but are rather a result of myocardial sodium channel–blocking effects and widecomplex tachydysrhythmias. IV injection of antihistamines, particularly of those (e.g., diphen hydramine) affecting H 1 histamine receptor antagonists, seems to cause euphoria in some patients; this translates to abuse potential. The effect may be attributed to the drug’s increasing dopamine levels in the brain’s nucleus accumbens area (which stimulates the reward and motivation system). CLINICAL FEATURES The classic features of the anticholinergic toxidrome can be stated as: • Dry as a bone • Red as a beet • Hot as a hare • Blind as a bat • Mad as a hatter • Stuffed as a pipe Dry skin (especially dry axillae) and dry mucous membranes (e.g., dry mouth) are the typical peripheral clinical manifestations, the result of impaired sweat gland and salivary gland secretions, respectively. The skin may be warm and flushed (red) from cutaneous vasodilatation. Other typical peripheral features of muscarinic blockade include hypo active or absent bowel sounds secondary to decreased peristalsis and GI motility. A palpable bladder or enlargement on bedside US secondary to urinary retention may be seen. Sinus tachycardia is usually present. More malignant dysrhythmias are less common. Ingestions of large amounts of diphenhydramine have been associated with wide-complex tachydysrhythmias from a sodium channel–blocking effect (not from an anticholinergic effect). 24,25 Diphenhydramine overdose has been reported to cause QT-interval prolongation. 26,27 Dilated pupils are often a delayed clinical finding (12 to 24 hours) that may not be observed despite the presence of other anticholinergic signs. The delirium of the central anticholinergic syndrome is characterized by restlessness, irritability, disorientation, confusion, agitation, auditory and visual hallucinations, and incoherent speech. The anticholinergic toxic patient has great difficulty interacting appropriately with envi ronmental stimuli. Lilliputian (“little people”) hallucinations have been described in this setting. Repetitive picking at the bed clothes or imaginary objects is also characteristic. A characteristic feature of anticho linergic delirium is dysarthria, manifested by a staccato speech pattern and difficult-to-comprehend speech. This may be exacerbated by severe dysphasia from decreased mucous secretion. High-pitched cries may sometimes be heard. Patients may also exhibit jerking movements of the extremities and seizures. Although this delirium is usually accompanied by the peripheral manifestations discussed earlier, clinical presentations vary. Tachycardia without delirium or delirium without tachycardia may occur. “ Agitated depression” can occur from both central excitation and depression. Depression is usually associated with higher doses; features include lethargy, somnolence, and coma. Overdose with olanzapine, an atypi cal antipsychotic with significant anticholinergic properties, produces unpredictable mental status fluctuations that can range from somnolence to agitation lasting for hours. Tintinalli_Sec15_p1187-1332.indd 1310 8/2/19 8:40 PM

doses; features include lethargy, somnolence, and coma. Overdose with olanzapine, an atypi cal antipsychotic with significant anticholinergic properties, produces unpredictable mental status fluctuations that can range from somnolence to agitation lasting for hours. Tintinalli_Sec15_p1187-1332.indd 1310 8/2/19 8:40 PM CHAPTER 202: Anticholinergics 1311 Agitation-induced hyperthermia is a worrisome complication of anticholinergic toxicity, and its development may be significantly potentiated by decreased sweating, movement, and the inability to dissipate heat. A markedly elevated body temperature may lead to multisystem organ dysfunction and rhabdomyolysis, resulting in coagulopathy as well as liver, kidney, and brain injury. Fatalities associated with anti cholinergic overdose are characterized by severe agitation, status epi lepticus, hyperthermia, wide-complex tachydysrhythmias (usually from sodium channel–blocker effect), and cardiovascular collapse. The risk of toxicity for most anticholinergic agents is typically dose related. For example, severity of diphenhydramine overdose correlates with the amount ingested, with moderate symptoms occurring after ingestion of 300 milligrams 30 and 7.5 milligrams/kg in children, 31 and severe symptoms seen only after ingestions of 1000 milligrams or more in adults. DIAGNOSIS  DRUG SCREENING In patients with altered mental status, obtain routine laboratory evaluation, including measurement of electrolytes, glucose, creatine kinase, and pulse oximetry. In most cases of isolated anticholinergic toxicity, these tests should be normal. Limited urine drugs-of-abuse screening generally does not detect anticholinergic agents, although some rapid screens may produce positive results for cyclic antidepressants due to the structural similarities of some anticholinergic compounds, particularly diphenhydramine and hydroxyzine. Comprehensive urine drug screens, usually performed by thin layer chromatography or mass spectrometry, may detect most antihistamines and phenothiazines, although such testing does not usually detect plant alkaloids, scopolamine, or atropine and, in general, is cost prohibitive and insufficiently timely to assist in care. A positive drug screen for an anticholinergic agent only indicates exposure, such as a therapeutic dose, and does not necessarily imply an overdose or supratherapeutic ingestion.  DIFFERENTIAL DIAGNOSIS The differential diagnosis of anticholinergic toxicity includes lifethreatening presentations such as viral encephalitis, Reye’s syndrome, head trauma, alcohol and sedative-hypnotic withdrawal, postictal state, other intoxications, neuroleptic malignant syndrome, and acute psychotic disorders. The difference between anticholinergic toxicity and sympathomimetic toxicity (e.g., cocaine toxicity, delirium tremens) can be subtle, because patients with either may develop tachycardia, mydriasis, and delirium. The presence of red dry skin and the absence of bowel sounds suggest anticholinergic poisoning. 32 At times, patients presenting with acute psychotic disorders may have an abnormal mental status, suggesting anticholinergic toxicity, but true delirium and attention deficits are much more characteristic of the latter condition. Other CNS disorders, such as viral encephalitis, may also affect cholinergic outflow and produce similar anticholinergic clinical signs not related to a toxic exposure. TREATMENT Treatment of anticholinergic toxicity primarily includes observation, monitoring, and supportive care ( Table 202-4). Temperature monitoring and treatment of hyperthermia are essential. GI decontamination with activated charcoal may be warranted to decrease absorption if the ingestion occurred within 1 hour of presentation.

ment of anticholinergic toxicity primarily includes observation, monitoring, and supportive care ( Table 202-4). Temperature monitoring and treatment of hyperthermia are essential. GI decontamination with activated charcoal may be warranted to decrease absorption if the ingestion occurred within 1 hour of presentation. Although the ben efit of activated charcoal is equivocal after 1 hour from ingestion, the decreased gut motility associated with anticholinergic ingestions may warrant charcoal administration beyond this 1-hour window. 34-36 Multidose activated charcoal is not recommended in patients with impaired GI motility, such as occurs with anticholinergic toxicity. 37 Ipecac syrup, which has no indication in any overdose patient, is contraindicated in anticholinergic toxicity. 31,38 A rare case of pharmacobezoar has been reported with diphenhydramine overdose; this should be a consider ation if the toxidrome continues longer than expected.39 The major therapeutic challenge in the treatment of moderate to severe anticholinergic poisoning involves obtaining adequate control of the agitated individual . Inadequate sedation may lead to worsening or prolonged hyperthermia, rhabdomyolysis, and traumatic injury. Although physical restraints may be required to gain initial control, pharmacologic sedation is strongly recommended, because prolonged use of physical restraints in the struggling and agitated patient may lead to further complications. Pharmacologic sedation should begin with IV administration of a benzodiazepine, such as lorazepam or diazepam. Benzodiazepines are not a specific antidote, and some patients may be refractory to large doses. Phenothiazines should be avoided because of their own anticho linergic effects. In severe cases of agitation when adequate sedation cannot be achieved without impairing respiration, mechanical ventilation and deep sedation may be necessary. IV sodium bicarbonate should be used to treat wide-complex tachydysrhythmias. 24,25 Class IA antiarrhythmic agents should be avoided because of their own sodium channel blockade properties. Physostigmine is a reversible acetylcholinesterase inhibitor (mecha nistically related to the carbamate insecticides) that crosses the blood– brain barrier due to its lipophilic tertiary ammonium properties. Acetylcholinesterase inhibition results in acetylcholine accumulation that reverses both central and peripheral anticholinergic effects. Using physostigmine to reverse anticholinergic toxicity is controversial. 40,41 The major adverse effects of physostigmine—profound bradycardia and seizures—were historically touted as common, but evidence for this belief is lacking. 42 Importantly, the risk of these adverse effects appears greater in patients without anticholinergic toxicity, so accurate diagnosis of anticholinergic toxicity is important before administering physostigmine. 41,42 Evidence for benefits of physostigmine in anticholinergic toxicity is mixed. Retrospective analysis of 52 patients43 and case reports44-46 found that physostigmine was significantly better in controlling agitation and reversing delirium compared with benzodiazepines and was associated with fewer complications and a shorter recovery time. There was no difference in adverse effects between the two groups. Conversely, a dif ferent case series did not find that physostigmine use reduced complications or shortened length of stay in 17 patients with severe agitation and delirium after Jimson weed ingestion. 47 However, no adverse effects or complications were observed from physostigmine use. Physostigmine can be used in cases of severe agitation and delirium from pure anticholinergic toxicity, especially in cases necessitating physical restraints and manifesting resistance to benzodiazepines.

after Jimson weed ingestion. 47 However, no adverse effects or complications were observed from physostigmine use. Physostigmine can be used in cases of severe agitation and delirium from pure anticholinergic toxicity, especially in cases necessitating physical restraints and manifesting resistance to benzodiazepines. The adult dose of physostigmine is 0.5 to 2 milligrams (pediatric dose is 0.02 milligram/kg with a maximum dose of 2 milligrams) by slow IV administration over 5 minutes. When physostigmine is effective, a sig nificant decrease in agitation should be apparent within 15 to 20 minutes. Provide continuous cardiac monitoring before and during adminis tration of physostigmine to assess for potential bradycardia. Monitor the patient for signs of cholinergic excess, such as diarrhea, urination, miosis, bradycardia, bronchospasm, bronchorrhea, emesis, lacrimation, and salivation. In cases of uncertain anticholinergic poisoning, a diagnostic challenge with physostigmine is not recommended because TABLE 202-4 Treatment of Anticholinergic Toxicity Action Agent Comments GI decontamination Activated charcoal May be more effective due to the decreased GI motility Sedation Benzodiazepines Decreases the risk of hyperthermia, rhabdomyolysis, and traumatic injuries Wide-complex tachyarrhythmias Sodium bicarbonate Arrhythmia due to sodium channel blockade; avoid class IA antiarrhythmics (procainamide) Cholinesterase inhibition Physostigmine Use for cases of severe agitation or delirium; avoid when cardiac conduction abnormalities are present (see “Treatment” section) Tintinalli_Sec15_p1187-1332.indd 1311 8/2/19 8:40 PM