Tropane Alkaloid Poisoning

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Background

Alkaloids are plant metabolites that have a nitrogen-containing chemical ring structure, alkali-like chemical reactivity, and pharmacologic activity. The alkaloids represent a very diverse group of medically significant compounds that include well-known drugs like the opiates.

A subgroup of the alkaloids is the alkaloid amines. The 3 major pharmacologic groups of alkaloid amines are the hallucinogenic alkaloid amines, the stimulant alkaloid amines, and the highly anticholinergic tropane alkaloids (also called the belladonna alkaloids or bicyclic alkaloids).

Plants that contain the tropane alkaloids atropine, scopolamine, and hyoscyamine include the following:

All of these plants have long histories of hallucinogenic use and have been connected with sorcery, witchcraft, native medicine, and magico-religious rites dating back to 1500 BC and Homer's Odyssey. (Homer's use of the plant moly as an antidote to Circe's poisonous anticholinergic drugs may have been the first recorded use of an anticholinesterase to reverse central anticholinergic intoxication.)

Chinese herbal medicines containing tropane alkaloids have been used to treat asthma, chronic bronchitis, pain, and flu symptoms. In Mexico, Datura is taken by Yaqui women to lessen pain of childbirth. In Africa, a common use is to smoke leaves from Datura to relieve asthma and pulmonary problems. Many cultures worldwide add plants with tropane alkaloids (particularly Datura species) to alcoholic beverages to increase intoxication.

Recently, Datura has been used as a recreational hallucinogen in the US, resulting in sporadic cases of anticholinergic poisoning and death. Numerous cases of anticholinergic poisoning also have resulted from belladonna alkaloid contaminants in foods, including commercially purchased Paraguay tea (an herbal tea derived from Ilex paraguariensis), hamburger, honey,[4] stiff porridge made from contaminated millet, and homemade "moon flower" wine. Other accidental ingestions include misuse as an edible wild vegetable[5] and inclusion in homemade toothpaste,[6] as well as a large epidemic in New York and the eastern US that resulted from heroin contaminated with scopolamine[7] .

Although most tropane alkaloids cause an anticholinergic syndrome, a recent report indicates that the tropane alkaloid–containing medicinal herb Erycibe henri Prain ("Ting Kung Teng") contains a tropane alkaloid that may cause a cholinergic syndrome, as well as renal, hepatic, and erythrocyte toxicity.[8] This is considered atypical for the tropane alkaloids, which are predominantly strongly anticholinergic.

Pathophysiology

Toxicity from plants containing tropane alkaloids manifests as classic anticholinergic poisoning. Symptoms usually occur 30-60 minutes after ingestion and may continue for 24-48 hours because tropane alkaloids delay gastric emptying and absorption.

Scopolamine, acting as an antagonist at both peripheral and central muscarinic receptors, is thought to be the primary compound responsible for the toxic effects of these plants. Tropane alkaloids are found in all parts of the plants, with highest concentrations in roots and seeds.

Atropine is an artifact of purification, produced by racemization of l-hyoscyamine. The proportion of each alkaloid present varies among species, time of year, location, and part of plant. As little as one-half teaspoon of Datura seed, equivalent to 0.1 mg of atropine per seed, has caused death from cardiopulmonary arrest. The usual route of ingestion is as a tea, although ingesting seeds or other plant parts and smoking dried leaves also are common.

Epidemiology

Frequency

United States

Incidence is sporadic, with clusters of poisoning cases, mostly among adolescents using plants for their hallucinogenic effects.

According to the American Association of Poison Control Centers' National Poison Data System Annual Report 2007, 938 single exposures to anticholinergic plants were reported, and no deaths were documented.[9]

During 2005, 975 anticholinergic plant poisonings were reported to Poison Control Centers in the United States; 566 of these cases were treated in health care facilities.[10]

During 1998-2004, a total of 188 reported human exposures were identified by Texas Poison Control Centers.[11] Seventy-six percent of the exposures occurred in June-October, 82% of the cases occurred in males, and 72% of cases occurred in those aged 13-19 years.

Widespread access to information on hallucinogenic plants through the Internet may lead to a further increase in the incidence.

International

Worldwide incidence is unknown. However, cases have been reported in Germany, Italy, Greece, Saudi Arabia, Tanzania, Australia, Brazil, Hong Kong, Taiwan, Mexico, Chile, and Venezuela, attesting to broad geographic distribution of Datura species.

Mortality/Morbidity

Nonfatal cases are likely underreported.

Sex

Males are more frequently involved in cases of intentional exposure.

Age

No age predilection exists, although Datura use as a recreational drug is more common among adolescents. Accidental ingestion and resultant toxicity in children has been reported.

History

As in any patient presenting with an acute change in mental status or suspected poisoning, attempt to obtain the following information:

Initial signs and symptoms may include the following:

Initial signs and symptoms may be followed by hyperthermia, confusion, agitation, combativeness, seizures, coma, and death.

Amnesia regarding events following ingestion of tropane alkaloids is common.

Identification of ingested plants can be diagnostic of tropane alkaloid poisoning.

Datura species, the most commonly encountered plants containing tropane alkaloids, are 3-5 foot annuals with coarse-toothed leaves.

Trumpet-shaped flowers are 3-5 inches in length, with white-pale-violet colored petals (see the images below).


View Image

Datura stramonium (jimson weed). Note 4-5 inch long white flowers.© 2000 Richard Wagner


View Image

Datura stramonium flower. Note the trumpetlike shape.© 2000 Richard Wagner

Most important for taxonomic identification are spiny, round, chambered seed pods (see the image below).


View Image

Datura stramonium (close-up of unripe seed pods). Note spiny appearance of pods.© 2000 Richard Wagner

Physical

The mnemonic "red as a beet, dry as a bone, blind as a bat, mad as a hatter, and hot as a hare" is useful to remember the anticholinergic toxidrome.

Vital signs

Head, ears, eyes, nose, and throat

Abdomen

Neurologic

Laboratory Studies

Imaging Studies

Other Tests

Procedures

Prehospital Care

Transport patient to nearest emergency facility with capabilities for advanced life support (ALS), at minimum. Primary assessment should focus on airway and respiratory, circulatory, and neurologic systems.

Emergency Department Care

As in all cases of suspected poisoning, follow the ABCDEs of emergency medicine (airway, breathing, circulation, disability, exposure), then the ABCDEs of toxicology (antidotes, basics, change absorption, change distribution, change elimination).

Provide oxygen and intubate if significant CNS or respiratory depression exists and no gag reflex is present. Assess circulation and initiate cardiac and pulse oximetry monitoring. Obtain a 12-lead ECG and evaluate for QRS prolongation, ischemia, and evidence of arrhythmia.

Sinus tachycardia is common and does not require treatment for a stable patient. Obtain blood for laboratory analysis and bedside glucose measurement while obtaining IV access. Inspection after full-body exposure should be performed to assess signs of trauma or seizure.

Agitated or hallucinating patients often respond to reassurance and a darkened room. If chemical restraint is required, benzodiazepines are the drugs of choice. Early consultation with a poison control center is frequently helpful.

Consider GI decontamination foremost. Ipecac is contraindicated because of the potential for seizures. Gastric lavage is controversial; while it is commonly performed, no reliable data on outcomes exist to support its use, and the risk of aspiration and other complications is increased. Administer activated charcoal (1-2 g/kg) orally or per nasogastric or orogastric tube. One or 2 additional doses may be given at 1- or 2-hour intervals to ensure adequate gut decontamination.

An ileus without distension is not a contraindication to a single dose of charcoal, and charcoal given alone may be as effective or more effective than emesis and lavage procedures. Use of cathartics to hasten elimination from GI tract remains controversial. Sorbitol may be used with first dose of charcoal; further use may cause serious fluid shifts to the intestine, diarrhea, dehydration, and hypernatremia.

Tropane alkaloids are lipophilic and cross the blood-brain barrier; hemodialysis and hemoperfusion are generally ineffective. No effective methods of changing distribution or elimination of tropane alkaloids exist.

Specific antidote for tropane alkaloid toxicity is physostigmine salicylate, a reversible acetylcholinesterase inhibitor capable of directly antagonizing CNS manifestations of anticholinergic toxicity.

Physostigmine (at doses lower than those producing peripheral side effects of salivation, lacrimation, urination, defecation, emesis) can reverse central effects of the following conditions:

However, unless relative certainty can be established that the toxicity present is due to tropane alkaloid poisoning and not to co-ingestants or other substances, confirmatory peripheral manifestations of anticholinergic toxicity should coexist prior to administration of physostigmine.

Physostigmine has been used as a diagnostic tool for tropane alkaloid poisoning, but this use is controversial.

Physostigmine can induce a life-threatening cholinergic crisis (eg, seizures, respiratory depression, asystole). Since most patients can be safely treated without this antidote, physostigmine preferably should be used in consultation with a poison control center and generally should be used only for patients in the following states:

Physostigmine is contraindicated in patients receiving tricyclic antidepressants, disopyramide, quinidine, procainamide, cocaine, or other agents producing cardiac conduction abnormalities. Relative contraindications include reactive airway disease, intestinal obstruction, and administration of depolarizing paralytic agents.

Following GI decontamination, most patients rarely require more than physiologic monitoring and psychologic support.

Patients experiencing agitation and hallucinations usually respond to reassurance and benzodiazepines.

Most phenothiazines are contraindicated because of their anticholinergic properties.

If signs or symptoms of urinary retention exist, Foley catheterization should be performed for bladder decompression.

Consultations

Medication Summary

Activated charcoal is indicated for all tropane alkaloid poisonings, within an hour of ingestion, with the possible exception of poisoning from smoking leaves. Benzodiazepines are first-line agents for agitation and seizures. Physostigmine should be used only for life-threatening complications.

Activated charcoal (Liqui-Char)

Clinical Context:  Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. An extremely important component of tropane alkaloid poisoning. May decrease severity and duration of poisoning. Does not dissolve in water.

For maximum effect, administer within 30 min after ingesting poison.

Class Summary

Activated charcoal is used after a drug or plant ingestion to limit adsorption of toxins. Traditionally given after the stomach has been emptied by emesis or lavage, recent evidence indicates that it may be used alone, without lavage.

Lorazepam (Ativan)

Clinical Context:  Sedative hypnotic with short onset of effects and relatively long half-life. DOC if IV access is available.

Increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Monitoring patient's blood pressure after administering dose is important. Adjust prn.

Midazolam (Versed)

Clinical Context:  Used as alternative in termination of refractory status epilepticus. Because midazolam is water soluble, it takes approximately 3 times longer than diazepam to peak EEG effects. Thus clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Published reports of IM and anecdotal reports of nasal use exist (when IV access is not possible).

Diazepam (Valium)

Clinical Context:  Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Frequently used in prehospital systems since refrigeration is not required.

Class Summary

First-line agents for treatment of tropane-alkaloid-induced seizures. Lorazepam is thought to be most effective and has a longer seizure half-life than diazepam.

Physostigmine (Antilirium)

Clinical Context:  Reversible anticholinesterase inhibitor that increases the concentration of acetylcholine at cholinergic synapses. The only reversible anticholinesterase inhibitor that readily crosses the blood-brain barrier to produce the desired CNS effects. Some recommend repeated slow IV pushes of 0.1-0.3 mg q3min to a maximum of 2 mg to decrease potential for life-threatening cardiovascular adverse effects.

Class Summary

Physostigmine is indicated only for reversal of life-threatening complications of tropane alkaloid poisoning (eg, tachydysrhythmias with hemodynamic compromise, seizures refractory to other therapeutic interventions, and severe agitation or hallucinations unresponsive to other therapy). The decision to use physostigmine ideally should be made in consultation with a toxicologist or poison control center.

Further Inpatient Care

Base admission decisions on patient's signs and symptoms.

Asymptomatic patients without signs of anticholinergic toxicity or altered mental status may be discharged after 6 hours of observation.

Admit symptomatic patients to an ICU setting for monitoring and treatment. They may be discharged after a symptom-free period of 6 hours without use of supportive therapy or antidotes and after appropriate consultations and follow-up have been arranged.

Author

Richard A Wagner, MD, PhD, FACEP, FAAEM, Staff Physician, William Beaumont Army Medical Center, El Paso, TX

Disclosure: Nothing to disclose.

Coauthor(s)

Samuel M Keim, MD, Associate Professor, Department of Emergency Medicine, University of Arizona College of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Michael S Beeson, MD, MBA, FACEP, Professor of Emergency Medicine, Northeastern Ohio Universities College of Medicine and Pharmacy; Attending Faculty, Akron General Medical Center

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

Disclosure: Nothing to disclose.

Michael Hodgman, MD, Assistant Clinical Professor of Medicine, Department of Emergency Medicine, Bassett Healthcare

Disclosure: Nothing to disclose.

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

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Datura stramonium (jimson weed). Note 4-5 inch long white flowers.© 2000 Richard Wagner

Datura stramonium flower. Note the trumpetlike shape.© 2000 Richard Wagner

Datura stramonium (close-up of unripe seed pods). Note spiny appearance of pods.© 2000 Richard Wagner

Datura stramonium (jimson weed). Note 4-5 inch long white flowers.© 2000 Richard Wagner

Datura stramonium flower. Note the trumpetlike shape.© 2000 Richard Wagner

Datura stramonium (close-up of unripe seed pods). Note spiny appearance of pods.© 2000 Richard Wagner

Datura stramonium is the plant shown. © 2000 Richard Wagner

The plant shown is foxglove (Digitalis purpura), which contains cardiac glycosides, not tropane alkaloids. © 2000 Richard Wagner