Quinolizidine and Isoquinoline Poisoning 

Updated: Mar 26, 2018
Author: David Vearrier, MD, MPH; Chief Editor: Asim Tarabar, MD 

Overview

Practice Essentials

Quinolizidine and isoquinoline are a widely distributed, heterogeneous group of alkaloids with members of each group having known toxicity to humans and domestic animals. Plants containing quinolizidine alkaloids with known toxicity include the following:

  • Baptisia species (false indigo)

  • Cytisus species (scotch broom)

  • Laburnum species (goldenchain, laburnum)

  • Lupinus species (lupine, bluebonnet)

  • Sophora species (mescal bean, frijolito)

Plants containing isoquinoline alkaloids with known toxicity include the following:

  • Argemone species (prickly poppy)

  • Chelidonium species (celandine poppy)

  • Corydalis species (fitweed)

  • Dicentra species (Dutchman’s breeches)

  • Papaver species (poppy)

  • Sanguinaria species (bloodroot)

Cytisine, a tricyclic quinolizidine alkaloid found in Baptisia, Cytisus, Laburnum, and Sophora species, has nicotinelike effects on the gastrointestinal (GI) tract and the central nervous system (CNS). These plants may be smoked recreationally for their stimulant effects and mild hallucinogenic properties.

Mescal bean may have been used by Native American peoples for ceremonial and medicinal purposes. Sophora root is used in traditional Chinese medicine where it is known as "Ku Shen" and is used to treat dysentery, scabies, itchy rashes such as with eczema, skin lesions, jaundice, edema, urinary dysfunction, and vaginal discharge.

Lupinus species contain sparteine, a tetracyclic quinolizidine alkaloid, and lupinine, a bicyclical quinolizidine alkaloid. Lupinus species are broadly divided into bitter lupins, which contain high levels of alkaloids in their seeds, and sweet lupins, which contain lower levels of alkaloids and are cultivated for human consumption. Sweet lupins do contain sparteine and lupinine and must be soaked in water to prevent toxicity following ingestion. These two alkaloids are also found in other genera.

The toxic isoquinoline alkaloids include papaverine, sanguinarine, dihydrosanguinarine, protoverine, berberine, coptisine, protopine, and chelidonine. They act as GI tract irritants and CNS stimulants. Their neurologic effects range from relaxation and euphoria to seizures; for example, prickly poppy is smoked as a euphoriant. Papaverine, found in prickly poppy and bloodroot, has been used medically as a smooth muscle relaxant.[1]

These alkaloids are also vasodilatory. Prickly poppy extracts act as capillary dilators and have been implicated in epidemic glaucoma in India.

Sanguinaria species (bloodroot) extract was US Food and Drug Administration (FDA) approved and used commercially as a dental plaque inhibitor; however, it is no longer added to commercially available toothpaste and mouthwash due to concerns that long-term use may cause oral leukoplakia. Sanguinaria extract may still be purchased over the Internet, where it is marketed as a mouthwash for dental decay, as an escharotic for skin lesions including cancer, and as a tea for a variety of indications. It is not FDA approved for these uses.

Celandine extracts have been used in the herbal treatment of GI disorders, including dyspepsia, gallstone disease, and irritable bowel syndrome. Celandine extracts have been shown to increase the flow of bile acids and decrease right upper quadrant pain due to biliary dyskinesia. Celandine extract also has stimulatory effects on smooth muscle contraction in the stomach and spasmolytic effects in the small intestine, which may explain its historical use in dyspepsia and irritable bowel syndrome. However, herbal preparations of celandine have been implicated in numerous cases of hepatotoxicity.

Argemone oil poisoning is relatively common in India, where it is known as epidemic dropsy and is a result of argemone oil being added as an adulterant to mustard oil. In 1998, an epidemic of argemone oil poisoning in New Delhi involved 3000 victims and 60 deaths.[2]  Argemone oil poisoning has also been reported after transcutaneous absorption from adulterated mustard oil used in massages.

Depending on the plant ingested, patients may present with a nicotinoid, anticholinergic, or opioid toxidrome (see Presentation). Assays for isoquinoline or quinolizidine alkaloids are not routinely available. Instead, the workup is devoted principally to excluding other possible causes of the patient’s symptoms (see Workup). The cornerstone of treatment is GI decontamination with activated charcoal. Supportive care generally is all that is required postdecontamination (see Treatment and Medication).

Background

Quinolizidine and isoquinoline are a widely distributed, heterogeneous group of alkaloids with members of each group having known toxicity to humans and domestic animals. Plants containing quinolizidine alkaloids with known toxicity include the following:

  • Baptisia species (false indigo)

  • Cytisus species (scotch broom)

  • Laburnum species (goldenchain, laburnum)

  • Lupinus species (lupine, bluebonnet)

  • Sophora species (mescal bean, frijolito)

Plants containing isoquinoline alkaloids with known toxicity include the following:

  • Argemone species (prickly poppy)

  • Chelidonium species (celandine poppy)

  • Corydalis species (fitweed)

  • Dicentra species (Dutchman’s breeches)

  • Papaver species (poppy)

  • Sanguinaria species (bloodroot)

Cytisine, a tricyclic quinolizidine alkaloid found in Baptisia, Cytisus, Laburnum, and Sophora species, has nicotinelike effects on the gastrointestinal (GI) tract and the central nervous system (CNS). These plants may be smoked recreationally for their stimulant effects and mild hallucinogenic properties.

Mescal bean may have been used by Native American peoples for ceremonial and medicinal purposes. Sophora root is used in traditional Chinese medicine where it is known as "Ku Shen" and is used to treat dysentery, scabies, itchy rashes such as with eczema, skin lesions, jaundice, edema, urinary dysfunction, and vaginal discharge.

Lupinus species contain sparteine, a tetracyclic quinolizidine alkaloid, and lupinine, a bicyclical quinolizidine alkaloid. Lupinus species are broadly divided into bitter lupins, which contain high levels of alkaloids in their seeds, and sweet lupins, which contain lower levels of alkaloids and are cultivated for human consumption. Sweet lupins do contain sparteine and lupinine and must be soaked in water to prevent toxicity following ingestion. These two alkaloids are also found in other genera.

The toxic isoquinoline alkaloids include papaverine, sanguinarine, dihydrosanguinarine, protoverine, berberine, coptisine, protopine, and chelidonine. They act as GI tract irritants and CNS stimulants. Their neurologic effects range from relaxation and euphoria to seizures; for example, prickly poppy is smoked as a euphoriant. Papaverine, found in prickly poppy and bloodroot, has been used medically as a smooth muscle relaxant.

These alkaloids are also vasodilatory. Prickly poppy extracts act as capillary dilators and have been implicated in epidemic glaucoma in India.

Sanguinaria species (bloodroot) extract was US Food and Drug Administration (FDA) approved and used commercially as a dental plaque inhibitor; however, it is no longer added to commercially available toothpaste and mouthwash due to concerns that long-term use may cause oral leukoplakia. Sanguinaria extract may still be purchased over the Internet, where it is marketed as a mouthwash for dental decay, as an escharotic for skin lesions including cancer, and as a tea for a variety of indications. It is not FDA approved for these uses.

Celandine extracts have been used in the herbal treatment of GI disorders, including dyspepsia, gallstone disease, and irritable bowel syndrome. Celandine extracts have been shown to increase the flow of bile acids and decrease right upper quadrant pain due to biliary dyskinesia. Celandine extract also has stimulatory effects on smooth muscle contraction in the stomach and spasmolytic effects in the small intestine, which may explain its historical use in dyspepsia and irritable bowel syndrome. However, herbal preparations of celandine have been implicated in numerous cases of hepatotoxicity.

Argemone oil poisoning is relatively common in India, where it is known as epidemic dropsy and is a result of argemone oil being added as an adulterant to mustard oil. In 1998, an epidemic of argemone oil poisoning in New Delhi involved 3000 victims and 60 deaths.[2] Argemone oil poisoning has also been reported after transcutaneous absorption from adulterated mustard oil used in massages.

Depending on the plant ingested, patients may present with a nicotinoid, anticholinergic, or opioid toxidrome (see Presentation). Assays for isoquinoline or quinolizidine alkaloids are not routinely available. Instead, the workup is devoted principally to excluding other possible causes of the patient’s symptoms (see Workup). The cornerstone of treatment is GI decontamination with activated charcoal. Supportive care generally is all that is required postdecontamination (see Treatment and Medication).

Pathophysiology

Quinolizidine and isoquinoline are alkaloids, which are alkali-like compounds that form salts with acids and contain nitrogen, generally in heterocyclic and/or ring structures. Found in a wide variety of plants, animals, and fungi, many alkaloids have medicinal and toxic properties.

Cytisine is similar in action to nicotine. GI irritation is common, and toxic ingestions almost invariably result in emesis. Onset of symptoms is rapid. GI upset and vomiting start 45 minutes to 4 hours after ingestion. CNS effects include drowsiness, weakness, loss of coordination, muscle fasciculations, seizures, coma, and mydriasis. Some anticholinergic effects, such as urinary retention, may manifest. Respiratory failure, as in nicotine poisoning, is observed in patients with severe cases.

Cutaneous exposure to celandine and bloodroot extracts may cause a contact dermatitis, and ingestion of celandine extract is known to be hepatotoxic,[3] with numerous cases of acute cholestatic hepatitis reported in the literature. Rarely, necrotizing hepatitis has been reported. Celandine extract has also been implicated in a case of hemolytic anemia.[4]

Corydalis species (fitweed) ingestion has demonstrated delayed hepatotoxicity.

Argemone oil has been reported to cause oxidative stress by reducing levels of glutathione reductase and glucose-6-phosphate reductase in erythrocytes and glutathione, alpha-tocopherol, and glutathione-S-transferase in erythrocytes and liver.[5] Sanguinarine and related isoquinoline alkaloids are the active toxins in argemone oil responsible for its adverse effects. Others postulate that sanguinarine toxicity is additionally mediated by inhibition of Na+ K+ ATPase, inhibition of DNA polymerase, inhibition of the cytochrome P-450 system, and accumulation of pyruvate due to increased rates of glycogenolysis.

Bloodroot extract, which contains the alkaloid sanguinarine, is a strong escharotic that causes cell cycle blockade and apoptosis, especially in cancerous cells.

Both argemone oil and isolated sanguinarine alkaloid have also been reported to be genotoxic in humans,[6] and argemone oil consumption is linked with an elevated incidence of gallbladder carcinoma in India.

Sparteine has been reported to have cardiac, ganglioplegic, and oxytocic effects, while lupinine is anticholinergic. Both have been reported to cause sedation.

Ingestion of poppies may result in narcotic effects from opiate alkaloids and papaverine, as well as hypotension and cardiovascular collapse.

Etiology

Risk factors for quinolizidine and/or isoquinoline plant toxicity include the following:

  • Use of medicinal herbs and/or preparations

  • Recreational drug experimentation (most notably mescal bean and opium poppy)

  • Drinking of milk from animals that ingest toxic plants (rare)

  • Adulteration of mustard oil (international)

  • Childhood ingestion of ornamental plants (most notably Laburnum)

Epidemiology

United States statistics

Most of the isoquinolines are noxious in smell and taste, which discourages ingestion; thus, human toxicity is rare. Interestingly, some domesticated species tolerate ingestion of isoquinoline and other alkaloids, and humans can ingest toxic alkaloids from the milk of a poisoned animal and then manifest symptoms.

Isolated American and European case reports exist of toxicity following ingestion of improperly washed lupini beans. The incidence of alkaloid poisoning is low and probably underreported. Laburnum, mescal bean, and lupine have pealike or brightly colored seeds that may attract children; toxic alkaloids are concentrated in these seeds, and consumption may result in serious morbidity and mortality.

International statistics

As mentioned above, outbreaks of argemone oil poisoning are relatively common in India, where it has been used to adulterate more expensive mustard oil. Outbreaks have also been reported in Mauritius, Fiji, Madagascar, and South Africa.

Laburnum poisoning is reported widely in Great Britain and Europe; 50 cases were documented in 1979. One group in Germany, recorded 892 exposures between 1998 and 2004, and, of these, 45 demonstrated moderate or major effects.[7] Concern regarding the toxicity of this plant may greatly exceed actual clinical effects in many cases.[8, 9]

Numerous cases of celandine-induced hepatotoxicity have been reported in Europe. Many of these patients were prescribed celandine preparations for gastric and biliary disorders.[10]

Prognosis

Most patients recover fully, requiring only GI decontamination and supportive care, and can be discharged from the emergency department after a period of observation. Patients with systemic symptoms require admission and close observation to prevent morbidity or mortality. Rarely, seizure, cardiovascular collapse, and aspiration secondary to emesis may complicate care.

Celandine has been reported to have significant hepatotoxicity. However, prognosis is good with resolution of hepatotoxicity after cessation of celandine exposure. No fatal cases or cases requiring liver transplantation have been reported in the peer-reviewed medical literature.

Mortality is rare. A single adult case of death from Laburnum poisoning was reported in a man with schizophrenia. Sporadic case reports of fatality have been documented with mescal bean and other quinolizidine and isoquinoline alkaloids. Epidemic outbreaks of argemone oil poisoning have led to numerous deaths.

 

Presentation

History

For all ingestions, obtain as complete a history as possible, including the following:

  • Medications

  • Allergies

  • Suspected ingestion

  • Time of ingestion

  • Possible co-ingestions

Identify the plant ingested if possible. An on-site plant reference text and an established relationship with an emergency plant taxonomy consultant are useful resources.

Patients with celandine-induced hepatotoxicity may report nausea, vomiting, night sweats, pruritis, rash, fatigue, jaundice, and dark brown urine. In patients taking celandine preparations, these symptoms may occur in a tight time relationship to preparation usage.

Patients with cytisine ingestion (ie, Baptisia, Cytisus, Laburnum, and Sophora species) may complain of the following:

  • Vomiting

  • Diarrhea

  • GI cramping

  • Palpitations

  • Confusion

  • Tremor

  • Weakness

Patients who have ingested Sophora root may complain of the following:

  • Excessive salivation

  • Abnormal gait

  • Shortness of breath

  • Muscle spasm

  • Dizziness

  • Palpitations

  • Nausea

  • Vomiting

  • Constipation

Reduced libido and impotence have been reported with Sophora root ingestion, though those cases involved the use of formulations containing other herbs. Three case reports of adverse effects after ingestion of 60 g of Sophora root extract suggest that significant toxicity may occur at that dose.[11]

Following argemone oil poisoning, patients may complain of the following:

  • Whole-body swelling

  • Headache

  • Vomiting

  • Diarrhea

  • Shortness of breath

Following ingestion of Lupinus alkaloids, patients may complain of anticholinergic symptoms such as the following:

  • Blurry vision

  • Dry mouth

  • Confusion

  • Palpitations

  • Flushing

  • Fever

Following ingestion of poppy seed tea, patients may complain of drowsiness and weakness. Occasionally, these symptoms can progress to respiratory arrest and death.[12]

Physical Examination

Celandine ingestion may result in cholestatic hepatitis with jaundice and bilirubinuria.

Cytisine ingestion causes a nicotinic toxidrome with the following manifestations:

  • Hyperactive bowel sounds

  • Vomiting

  • Diarrhea

  • Fasciculations

  • Weakness

  • Diaphoresis

  • Mydriasis

  • Seizures

  • Coma

Sophora root ingestion may be associated with the following:

  • Vomiting

  • CNS agitation or depression

  • Ataxia

  • Diaphoresis

  • Seizures

  • Respiratory depression

Physical examination following argemone oil ingestion may reveal the following:

  • Pitting edema of the extremities

  • Rales or rhonchi consistent with pulmonary edema

  • Flushing of the skin

  • Hypotension

  • Vomiting

  • Diarrhea

Exposure to morphine and papaverine from poppy seeds can produce the typical signs of opioid toxidrome, as follows[12] :

  • Depressed mental status

  • Miosis

  • Mild hypotension and bradycardia

  • Respiratory failure

 

DDx

Diagnostic Considerations

As with any ingestion, consider co-ingestions, especially those that are potentially serious and treatable (eg, tricyclic antidepressants, acetaminophen). Consider all possible causes for altered mental status, including infectious diseases such as meningitis and encephalitis.

Differential Diagnoses

 

Workup

Approach Considerations

Assays for isoquinoline or quinolizidine alkaloids are not routinely available. Instead, the workup is devoted principally to excluding other possible causes of the patient’s symptoms. Consulting a medical toxicologist or poison control center may prove helpful in developing differential diagnoses and identifying toxic ingestion.

In patients with celandine exposure, liver function tests may demonstrate markedly elevated serum aminotransferases and direct and total bilirubin. Urinalysis may demonstrate bilirubinuria. If performed, liver biopsy may demonstrate hepatocellular injury with periportal and intralobular necrosis. Septal fibrosis has also been reported.[10]

A toxicology screen may be helpful in excluding amphetamine ingestion, but false-positive results may occur. Blood chemistries may be useful in assessing for other potential intoxicating ingestions. Perform a fingerstick glucose test for altered mental status, to rule out hypoglycemia. Perform a complete blood count (CBC), urinalysis, and blood and urine cultures in febrile patients with altered mental status. Perform lumbar puncture on any febrile patient with altered mental status if meningitis is considered as a potential diagnosis.

Always consider acetaminophen and salicylate levels in any potential toxic ingestion. Always obtain serum or urine human chorionic gonadotropin (HCG) levels in women of childbearing age.

Obtain an electrocardiogram in all patients with possible toxic ingestions to evaluate for sodium or potassium channel blockade resulting in prolonged QRS complex or QT intervals. Consider a computed tomography scan of the head in any patient whose altered mental status is not clearly due to toxicity of the ingested substance.

 

Treatment

Approach Considerations

Exploratory ingestions in young children may not result in any toxicity. Therefore, asymptomatic patients with minimal ingestions may be managed expectantly. Patients with substantial ingestions may benefit from gastrointestinal (GI) decontamination with activated charcoal (1 g/kg). Supportive care generally is all that is required postdecontamination. Continuous cardiac monitoring and frequent vital sign determinations are warranted.

Most patients recover fully and can be discharged from the emergency department after a period of observation. Patients with systemic symptoms require admission and close observation to prevent morbidity or mortality.

Prehospital Care

Transport the patient to the nearest emergency facility with advanced life support (ALS) capabilities. Focus the assessment and treatment on airway, breathing, and circulation (the ABCs). Interventions include the following:

  • Check the serum glucose level and treat if hypoglycemic

  • Consider naloxone if the patient has symptoms suggestive of opioid toxidrome

  • Obtain intravenous access and provide oxygen and cardiac monitoring

  • Use benzodiazepines to treat seizures

Emergency Department Care

Emergency care is primarily supportive, focusing on airway, breathing, circulation, disability, and exposure (ABCDEs). Provide supplemental oxygen. If central nervous system or respiratory depression is present, intubate and provide ventilatory support.

Check the serum glucose level and treat if the patient has hypoglycemia. Consider intravenous naloxone for any patient with altered mental status and an opiate toxidrome.

Consider decontamination with activated charcoal in any patient who presents within 4 hours after the ingestion. Ideally, activated charcoal should be administered within 30 minutes of the ingestion. A single dose usually is adequate.

Induction of emesis with ipecac syrup provides little benefit and is associated with increased risk of aspiration if the patient's mental status declines and is therefore not recommended. Similarly, gastric lavage, while useful in poisonings with risk of substantial morbidity or mortality, is not recommended for isoquinoline or quinolizidine alkaloid exposure as risks of the procedure outweigh potential benefits.

The use of diuretics has been suggested for diffuse edema from argemone oil poisoning, but evidence of efficacy has not yet been established. Similarly, antioxidant therapy has been suggested though evidence of efficacy has not yet been established.

Patients with no signs of neurologic or cardiovascular involvement may be discharged from the hospital after 6 hours of observation. Admit any patient with altered mental status, seizure activity, or cardiovascular instability to an intensive care unit (ICU) setting for observation and further treatment as needed.

Long-Term Monitoring

Instruct a responsible individual to return the patient to the emergency department immediately if altered mental status, seizure, vomiting, or any other concerns arise. Ensure close follow-up care with a pediatrician or internist. Refer patients who may have ingested Chelidonium majus (greater celandine) for follow-up repeat liver function testing and complete blood cell count.

Caution against further ingestion of herbal medications. Family members of intoxicated children should be instructed to remove offending plants from their landscaping.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce toxicity, reduce morbidity, and prevent complications. Activated charcoal is the treatment of choice for all quinoline and/or isoquinoline plant ingestions. It is the most effective substance known for adsorbing most poisons. Ipecac syrup administered as a precursor to charcoal is no longer recommended.

Benzodiazepines can be used for patients who experience seizures. Opiate antagonists can be used to reverse opiate toxidrome.

Antidotes, Other

Class Summary

Gastrointestinal (GI) decontamination with oral activated charcoal is selectively used in the emergency treatment of poisoning caused by some drugs and chemicals. The network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Consider decontamination with activated charcoal in symptomatic patients or patients with substantial ingestions who present within 1 hour after the ingestion.

Activated charcoal (Actidose-Aqua, EZ-Char, Kerr Insta-Char)

Activated charcoal prevents absorption of toxic alkaloids by adsorbing them in the intestine. Activated charcoal does not dissolve in water. For maximum effect, administer this agent within 30 minutes after ingestion.

Anticonvulsants, Other

Class Summary

Benzodiazepines are agents of choice for cytisine-induced or other alkaloid-induced seizures.

Lorazepam (Ativan)

Lorazepam is beneficial for its sedative and anticonvulsant effects.

Diazepam (Valium, Diastat, Diastat AcuDial, Diastat Pediatric)

Diazepam is beneficial for its sedative and anticonvulsant effects. This agent has a relatively long half-life. It may be given intramuscularly if intravenous access is not available.

Opioid Reversal Agents

Class Summary

These agents are used in patients with altered mental status and opiate toxidrome, which can result from ingestion of poppy seeds.

Naloxone

Naloxone prevents or reverses opioid effects (eg, hypotension, respiratory depression, sedation), possibly by displacing opiates from their receptors.