Original Author: Paul Perry, Ph.D, BCPP
Latest Revisers: Paul Perry, Ph.D, BCPP, Brian C. Lund,
Pharm.D.
Creation Date: 1996
Peer Review Status: Internally Peer Reviewed
Anticholinergic neuropsychiatric effects may occur secondary to standard or excessive doses of these compounds. This handout will discuss the presentation and management of these reactions as the result of intentional (e.g., abuse) or nonintentional ingestion.
RESPONSIBLE AGENTS
Anticholinergic psychosis, toxic delirium, anticholinergic syndrome, and atropine psychosis describe the acute organic brain syndrome that may result from the ingestion or administration of over 600 different licit and illicit plants, chemicals, and pharmaceutical agents having anticholinergic properties (Shader and Greenblatt 1972, Greenblatt and Shader 1973, Tune 1980).
Agents possessing these pharmacologic actions include the tricyclic antidepressants, antipsychotics, antihistamines, cycloplegics, antispasmodics, antiparkinsonian agents, proprietary sleeping medications, belladonna alkaloids, and some toxic plants. Poisonings from these agents have been reported in all parts of the world.
More recently, the H2 blockers (i.e., cimetidine, ranitidine) have been reported to produce a syndrome indistinguishable from anticholinergic psychosis. This is a dose-related condition primarily reported with cimetidine. Also, ranitidine has been implicated (Tune et al 1992, Mach et al 1995). Patient at a significant risk of neuropsychiatric reactions with cimetidine are receiving doses >300 mg/d and have hepatic and/or renal impairment.
ABUSE POTENTIAL
The first report of abuse of an anticholinergic was reported in 1960 (Hidalgo and Mowers 1990, Land et al 1991). Over 100 cases have been reported in the literature of excessive use of benztropine, trihexyphenidyl, or procyclidine. Case reports and small studies indicate that patients experience a buzz (e.g., euphoria) and/or are more relaxed, energetic, and sociable while ingesting these compounds. Patients noted to abuse anticholinergics are more likely to have a history of polysubstance abuse and an Axis II diagnosis of antisocial personality disorder (Hidalgo and Mowers 1990). Though one report indicates that trihexyphenidyl might have a higher abuse than other anticholinergics (Hidalgo and Mowers 1990), this conclusion was not shared by other authors (Land et al 1991). Tolerance to the euphorigenic effects can occur as trihexyphenidyl doses from 15 to 2000 mg/d of have been reported (Hidalgo and Mowers 1990). It is important to note that some patients with schizophrenia increase the dose of their anticholinergic to reduce their extrapyramidal side effects (Hidalgo and Mowers 1990). If a patient with an extrapyramidal side effect is abusing anticholinergics, then an alternative treatment such as beta-blockers or amantadine might be considered (see Treatment of Extrapyramidal Side Effects handout).
PRESENTATION
Anticholinergic psychosis is characterized by various neuropsychiatric signs, including disorientation, confusion, recent memory loss, agitation, dysarthria, incoherent speech, push of speech, hallucinations, delusions, ataxia, periods of hyperactivity alternating with periods of somnolence, paranoia, anxiety, and coma (Adcock 1971, Ananth 1973, Anath et al 1970, Bernstein and Leff 1967, Duvoisin and Katz 1968, Gowdy 1972, Granacher and Baldessarini 1975, Granacher and Baldessarini 1976, Greenblatt and Shader 1973, Heiser and Gillin 1971, Johnson 1967, Mikolich et al 1975, Rumack 1973, Shafer and Greenblatt 1972, Shafer and Allen 1971, Ullman and Groh 1970). Hallucinations associated with anticholinergic psychosis are usually visual but may also be auditory or tactile or all three (Shader and Greenblatt 1972, Shafer and Allen 1971, Ullman and Groh 1972). The visual hallucinations are characterized by picking, plucking or grasping at, or gathering of imaginary objects seen on clothing or suspended in space. The vivid imageries encountered with stramonium intoxication appear to be of simple objects such as flowers, small people, animals, or colors (Gowdy 1972, Johnson 1967). Tactile hallucinations of crawling insects are occasionally noted (Gowdy 1972).
Physical signs resulting from postganglionic, parasympathetic blockade (antimuscarinic action) include widely dilated, poorly reactive pupils; warm, dry skin; facial flushing; decreased secretions of the mouth, pharynx, nose, and bronchi; foul-smelling breath; fever; tachycardia; elevated blood pressure; decreased bowel activity; hyperreflexia; and urinary retention (Shader and Greenblatt 1972, Shafer and Allen 1971, Ullman and Groh 1972). The central and peripheral signs of anticholinergic intoxication can be summarized by the colloquialism, "Hot as a hare, red as a beet, dry as a bone, blind as a bat, and mad as a wet hen" (Adcock 1971).
Although rare, deaths have resulted directly or indirectly from anticholinergic intoxications (Johnson 1967, Shader and Greenblatt 1972, Slovis et al 1971). Fever and delirium in serious anticholinergic overdosage may progress to coma and, finally, to cardiac and respiratory depression (Granacher and Baldessarini 1976). Heiser (1971) suggests that deaths may occur, especially in children, possibly as a result of hyperpyrexia or brain stem depression. Gowdy (1972) reported five deaths resulting indirectly from stramonium intoxication in which the delirious individuals died from exposure or drowning. Thus, the intoxicated patient must be hospitalized for his own safety until his sensorium has cleared.
MANAGEMENT
Persons experiencing anticholinergic psychosis resulting from therapeutic doses of anticholinergic agents can be managed with offending agent(s) discontinuation. Pharmacologic management is not necessary in the majority of cases.
Typically sensorium and psychosis will clear within 36 to 48 hours in these patients. Patients should be observed in a closed ward setting until signs and symptoms abate.
Patients experiencing an acute psychotic episode precipitated by a significant overdose anticholinergic drug may require constant supervision for several hours or days to prevent accidental injury, aspiration of vomitus, and excessive fatigue from increased motor activity and to control hyperthermia (especially when treating children). Serious anticholinergic intoxication can be managed by using physostigmine salicylate (Antilirium) (Crowell and Ketchum 1967, Duvoisin and Katz 1968, Granacher and Baldessarini 1975, Granacher and Baldessarini 1976, Heiser and Gillin 1971, Rumack 1973, Slovis et al 1971, Ullman et al 1970).
Physostigmine, a cholinesterase inhibitor, is a tertiary amine able to cross the blood-brain barrier. The drug has both central and peripheral cholinomimetic actions (Granacher and Baldessarini 1975). Neostigmine bromide and methylsulfate, pyridostigmine bromide and edrophonium chloride, also cholinesterase inhibitors, are quaternary amines incapable of crossing the blood-brain barrier and, therefore, are able only to reverse peripheral anticholinergic effects (Crowell and Ketchum 1967, Granacher and Baldessarini 1975, Granacher and Baldessarini 1976, Rumack 1973). Physostigmine salicylate has been used successfully to treat severe poisonings caused by many different anticholinergic agents. In doses of 1 to 4 mg, physostigmine salicylate is able to reverse the delirium and coma produced by 200 mg or more of atropine sulfate (Duvoisin and Katz 1968, Granacher and Baldessarini 1975).
Specific indications for physostigmine are seizures, severe hallucinations, hypertension, and supraventricular arrhythmias causing cardiac compromise. Reversal of these symptoms occurs within minutes after administration of a test dose if the diagnosis is correct. The pediatric test dose is 0.5 mg slow IV over two minutes while the adult test dose is 2.0 mg slow IV over two minutes. IV push administration can precipitate seizures. The dose may be repeated after 30 to 60 minutes if the symptoms reappear, not exceeding an individual dose of 1 to 2 mg in adults.
It may be necessary to give additional doses of the drug every 30 minutes to 2 hours because physostigmine's duration of action is short compared to that of the anticholinergics. It is important to remember that relapse intervals tend to lengthen as the anticholinergic agent is excreted and that fixed physostigmine dosing intervals should be lengthened. The medical staff should chart the vital signs, mental status, bowel activity, and urinary output of the patient. This will assist in determining the need for additional doses of physostigmine (Granacher and Baldessarini 1975, Heiser and Gillin 1971, Granacher and Baldessarini 1976). The patient's mental status should be observed closely for 8 to 12 hours after the last dose of physostigmine. In addition, it should be remembered that the pupillary dilatation produced by atropine may persist for hours or days, even following injection of physostigmine salicylate (Shader and Greenblatt 1972, Granacher and Baldessarini 1975).
If physostigmine dosage becomes excessive, resulting in cholinergic (parasympathetic) stimulation, an anticholinergic agent may be indicated. Symptoms of parasympathetic stimulation include excessive salivation, rhinorrhea, increased bronchial secretions, dyspnea, miosis, hyperhidrosis, vomiting, diarrhea, abdominal and biliary colic, frequency of urination, and bradycardia. Atropine sulfate can be used to reverse these effects but, because it produces CNS effects, it may contribute to delirium. Glycopyrrolate (Robinul) and methscopolamine bromide (Pamine) are the drugs of choice for reversing physostigmine's peripheral toxicity, especially gastrointestinal symptoms, because both agents are quaternary amines which do not cross the blood-brain barrier. Each 1 mg of physostigmine salicylate may be counteracted with IM injection of either 0.4 mg of glycopyrrolate, 0.5 mg of methscopolamine bromide, or 0.5 mg of atropine sulfate (Granacher and Baldessarini 1976).
The relative contraindications to use of physostigmine, because of the drug's cholinergic properties, include diabetes, gangrene, coronary artery disease, heart block, peptic ulcer disease, hypothyroidism, asthma, or other respiratory disease, ulcerative colitis, bowel or bladder obstruction, glaucoma, pregnancy, myotonia congenita, and myotonia atrophica (Granacher and Baldessarini 1975, Granacher and Baldessarini 1976). Extreme caution should be exercised before vigorous physostigmine treatment is instituted in patients with these conditions. The decision to treat any patient with physostigmine should be based on the presence of severe signs and symptoms of anticholinergic intoxication not merely on a history of anticholinergic ingestion.
Management of an overdose victim should also include the usual modes of treatment. Gastric lavage, emetics, activated charcoal, cathartics, etc., should be used when indicated. When delirium is a major concern in the treatment of a patient, it is important that an agent with anticholinergic properties not be used. Phenothiazines possess sedative properties but are also strongly anticholinergic, especially those with piperidine-containing side- chains such as thioridazine (Granacher and Baldessarini 1975, Granacher and Baldessarini 1976, Snyder and Yamamura 1977). If pharmacologic sedation is required to control the behavior of delirium, agitation, or violence, a benzodiazepine such as diazepam or chlordiazepoxide, rather than other neuroleptics, should be given orally or, for rapid onset of action, by IV injection (Shader and Greenblatt 1977).
TREATMENT RECOMMENDATIONS - SUMMARY
Therapeutic Dose Intoxication
Overdose Treatment
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