8/7/2018 Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e > Chapter 202: Anticholinergics Dan Quan; Frank Lovecchio INTRODUCTION Approximately 620 compounds have anticholinergic properties, including prescription drugs, over-the- counter medications, and plants (Table 202-1). Many of these substances possess anticholinergic activity as either a direct therapeutic eect or an adverse eect, in addition to their primary or predominant pharmacologic eect. Atropine (d,l-hyoscyamine), hyoscyamine, and scopolamine (l-hyoscine) are natural alkaloids that represent prototypical anticholinergic compounds. 1/16 8/7/2018 TABLE 202-1 Major Groups of Substances with Anticholinergic Activity Class and Subclass Prototypical Agent(s) Cyclic Amitriptyline hydrochloride, imipramine hydrochloride, doxepin hydrochloride antidepressants Antihistamines Ethanolamines Diphenhydramine, dimenhydrinate Ethylenediamines Tripelennamine Alkylamines Chlorpheniramine Piperazines Loratadine, meclizine, cetirizine Phenothiazines Prochlorperazine, promethazine Antiparkinson drugs Tropanes Benztropine mesylate Piperidines Trihexyphenidyl Antipsychotics Phenothiazines Chlorpromazine, thioridazine, perphenazine Clozapine, olanzapine, molindone, loxapine, quetiapine Nonphenothiazines Antispasmodics Cyclohexane Dicyclomine carboxylic acids Methantheline bromide Quaternary ammonium Belladonna alkaloids Tropanes Atropine, homatropine, scopolamine hydrobromide Pyrrolidines Glycopyrrolate Mydriatics 2/16 8/7/2018 Class and Subclass Prototypical Agent(s) Phenylacetates Cyclopentolate hydrochloride Pyridines Tropicamide Skeletal muscle relaxants Tricyclics Cyclobenzaprine hydrochloride Ethylamines Orphenadrine citrate Plants Datura species Datura stramonium (Jimson weed), Datura candida (angel's trumpet) Mandragora species Mandragora oicinarum (mandrake) Brugmansia species Brugmansia suaveolens (angel's tear, maikoa, or white angel's trumpet), Brugmansiaversicolor (angel's tear or angel's trumpet) Mushrooms Amanita species Amanita muscaria, Amanita pantherina 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, administration of hyoscyamine-containing agents to treat colic, the topical use of diphenhydramine-containing salves, and therapeutic application of a transdermal hyoscine patch.2,3,4,5 In the elderly, therapeutic doses of one or multiple medications with anticholinergic properties may produce anticholinergic symptoms or ileus without all the signs of the anticholinergic toxidrome.6,7 Ophthalmologic instillation of anticholinergic mydriatic agents can cause toxicity, especially in the elderly or young children; thus patients are instructed to lie down and apply 5 minutes of gentle pressure on the nasolacrimal duct when instilling these agents.8 Atropine is the antidote for a cholinergic syndrome produced from a nerve agent or an organophosphate insecticide.9 Use of high-dose atropine by someone without cholinesterase poisoning may result in anticholinergic toxicity within 1 hour. 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 anticholinergic eects producing toxicity 1 to 4 hours aer ingestion or sooner if smoked. Alkaloid plants are 3/16 8/7/2018 abused for their hallucinogenic eects.11,12 Group anticholinergic plant poisonings are common in adolescents seeking these psychoactive hallucinogenic eects.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, such as heroin or cocaine, with scopolamine or atropine has been observed.20,21,22 PHARMACOLOGY Anticholinergic drug absorption can occur aer 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 eects are oen delayed. An example is diphenoxylate-atropine (e.g., Lomotil®), an antidiarrheal agent that may present with toxicity up to 12 hours aer ingestion. Cholinergic receptors exist as two major subtypes: muscarinic receptors and nicotinic receptors. Muscarinic receptors are found predominantly on autonomic eector 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, neuromuscular junctions, and also the brain. Acetylcholine is the neurotransmitter that modulates both receptor types. Five genes encode for muscarinic receptors through G protein receptor activation; four seem to be physiologically active (Table 202- 2). 4/16 8/7/2018 TABLE 202-2 Muscarinic Receptors Receptor Target Organ Receptor Action When Stimulated M1 Autonomic ganglia Decreases activity in autonomic ganglia Brain Increases salivary and gastric acid secretion Salivary glands Stomach M2 Heart Decreases sinus node rate and slows conduction through the atrioventricular node Decreases the force of atrial contraction and possibly ventricular contraction M3 Smooth muscle Bronchospasm Endocrine/exocrine Mild vasodilation glands Increases saliva and gastric acid production Iris Constricts the pupil M4 CNS Multiple actions M5 Has not been elucidated 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 muscarinic acetylcholine receptors. The term anticholinergic is technically a misnomer; a more accurate term is antimuscarinic agents, because anticholinergic agents do not antagonize the eects at nicotinic acetylcholine receptors, such as at the neuromuscular junction. Clinical manifestations from these drugs are modulated through disturbances in the CNS (central eects) and the parasympathetic nervous system (peripheral eects) (Table 202-3). 5/16 8/7/2018 TABLE 202-3 Muscarinic and Antimuscarinic Eects Organ Stimulation or Muscarinic Eect Antagonism or Antimuscarinic Eect Brain Complex interactions Complex interactions Possible improvement in memory Impairs memory Produces agitation, delirium, and hallucinations Fever Eye ↓ pupil size (miosis) ↑ pupil size (mydriasis) ↓ intraocular pressure ↑ intraocular pressure ↑ tear production Loss of accommodation (blurred vision) Mouth ↑ saliva production ↓ saliva production Dry mucous membranes Lungs Bronchospasm Bronchodilation ↑ bronchial secretions Heart ↓ heart rate ↑ heart rate Slows atrioventricular conduction Enhances atrioventricular conduction Peripheral Vasodilation (modest) Vasoconstriction (very modest) vasculature GI ↑ motility ↓ motility ↑ gastric acid production ↓ gastric acid production Produces emesis Urinary Stimulates bladder contraction and ↓ bladder activity expulsion of urine Promotes urinary retention Skin ↑ sweat production ↓ sweat production (dry skin) Cutaneous vasodilation (flushed appearance) 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 the central eects of 6/16 8/7/2018 muscarinic receptor antagonism predominate, with fever, agitation, delirium, and coma. The peripheral anticholinergic syndrome refers to the syndrome seen with peripheral muscarinic antagonism, such as tachycardia, flushed dry skin, dry mouth, ileus, and urinary retention. The full range of clinical manifestations associated with anticholinergic overdose may only be partly explained by muscarinic receptor blockade. Many of these anticholinergic agents possess activity at other cell membrane receptors, and toxicity aer overdose can be a mixture of multiple pharmacologic mechanisms. For example, the clinical findings associated with cyclic antidepressant overdose are only partly characterized by the anticholinergic eects that vary considerably among dierent cyclic antidepressants. The most life-threatening complications of cyclic antidepressant overdose are a result of the sodium-channel blocking eects on the heart, producing wide-complex tachydysrhythmias, not the anticholinergic eects. Intravenous injection of antihistamines, particularly those aecting the H1 histamine receptor antagonists (diphenhydramine), seems to cause euphoria in some patients. This eect may be attributed to the drug increasing dopamine levels in the nucleus accumbens area of the brain that stimulates the reward and motivation system.23 CLINICAL FEATURES The classic features of the anticholinergic toxidrome can be stated as: