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:
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Baptisia species (false indigo)
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Cytisus species (scotch broom)
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Laburnum species (goldenchain, laburnum)
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Lupinus species (lupine, bluebonnet)
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Sophora species (mescal bean, frijolito)
Plants containing isoquinoline alkaloids with known toxicity include the following:
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Argemone species (prickly poppy)
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Chelidonium species (celandine poppy)
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Corydalis species (fitweed)
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Dicentra species (Dutchman’s breeches)
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Papaver species (poppy)
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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).
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:
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Use of medicinal herbs and/or preparations
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Recreational drug experimentation (most notably mescal bean and opium poppy)
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Drinking of milk from animals that ingest toxic plants (rare)
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Adulteration of mustard oil (international)
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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.
Based on case reports of lupin seed poisoning in children, the European Food Safety Authority (EFSA) concluded that children were more susceptible to the toxic effects of lupin alkaloids than adults and exposures above 10 mg/kg of body weight could be lethal. [11]
