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ANTHRAQUINONES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Anthraquinones are glycosides that have aglycones related to anthracene. They are contained in such natural products as cascara sagrada, frangula, aloe, rhubarb, senna, and chrysarobin (Tyler et al, 1988).

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) PLANTS CONTAINING ANTHRAQUINONES
    a) Rhamnus purshiana bark
    b) Rhamnus frangula bark
    c) Rhamnus catharticus fruits
    d) Aloes
    e) Rheum officiale (and other Rheum species)
    f) Cassia acutifolia leaves
    g) Cassia occidentalis
    h) Andira araroba wood
    i) Rubia tinctorum (madder root)
    2) SOME REPRESENTATIVE SYNTHETIC ANTHRAQUINONES
    a) Anthralin (a synthetic anthracenetriol)
    b) Danthron

Available Forms Sources

    A) FORMS
    1) TRADE NAMES IN OTHER COUNTRIES: Bekunis(R), Brevilax(R), Cascara evacuant(R), Celer-X(R), Colonorm(R), Depuran(R), Floripuran(R), Laxatan(R), Liquidepur(R), Palamkotta(R), and Peristaltine(R) are some of the trade names for the anthraquinone laxatives in other countries.
    B) SOURCES
    1) PLANTS CONTAINING ANTHRAQUINONES
    a) Rhamnus purshiana bark (Synonyms: Cascara sagrada)
    1) Contains the reduced forms of emodin-type glycosides. The product is generally stored for a year while the glycosides are converted to monomeric oxidized glycosides that have a milder cathartic action (Tyler et al, 1988).
    2) Two main types of anthracene compounds have been identified. One is normal O-glycosides (emodin-based), which represents 10 to 20 percent of the total; the other is aloin-like C-glycosides, making up the remainder.
    3) Some of the compounds in the later group include barbaloin, deoxybarbaloin (chrysaloin), and cascarosides A to D (Tyler et al, 1988).
    4) The bark must contain not less than 7% total hydroxyanthracene derivatives to be an "official" drug (Tyler et al, 1988).
    5) Casanthranol is a purified mixture of cascara sagrada anthranol glycosides (Tyler et al, 1988).
    b) Rhamnus frangula bark
    c) Rhamnus catharticus fruits
    d) Aloes
    1) The dried latex contains a number of anthraquinone glycosides. The primary glycoside is barbaloin (aloe-emodin anthrone C-10 glucoside) (Tyler et al, 1988).
    2) Although there is great variability from species to species, aloes generally contain 10 to 30% active ingredients (Tyler et al, 1988).
    3) Aloe anthraquinoles exert a more drastic catharsis than some other plants in this group, and are less likely to be advocated (Tyler et al, 1988).
    e) Rheum officiale and other Rheum species
    1) The dried rhizome and roots are used. The main constituents are rhein anthrones. The action of these anthrones is relatively drastic, therefore they are seldom used in medicine today (Tyler et al, 1988).
    f) Cassia acutifolia leaves (Synonyms: Senna)
    1) The main active ingredients are dimeric glycosides; their aglycones are composed of aloe-emodin and/or rhein. Sennosides is the name used for agents in highest concentration.
    g) Sennosides A & B (their aglycones are sennidin A & B) are found in the highest concentrations, with sennosides C and D being much less common (Tyler et al, 1988).
    h) Cassia occidentalis
    1) The roots and seeds of this plant contain approximately 1.9% free anthraquinones, and 4.5% total anthraquinones (Keeler & Tu, 1991).
    2) Anthraquinones identified in this plant include physcion, chrysophanol, rhein, and aloe-emodin (Keeler & Tu, 1991).
    i) Andira araroba wood
    1) Chrysarobin is a mixture of natural agents found in Goa powder. Goa powder is obtained from the wood of Andira anraroba.
    j) Chrysarobin contains a number of anthraquinones. An average composition might include chrysophenolanthrone or chrysophenolanthranol (30 to 40%), emodinanthrone-monomethyl ether (20%), and hydro-emodinanthrone-monomethyl ether (30%) (Tyler et al, 1988).
    1) Chrysarobin is very irritating to mucous membranes, so irritating that it has been used as a keratolytic. It is not used as much currently because of the varying concentration of the active ingredients and poor standardization (Tyler et al, 1988).
    k) Rubia tinctorum (madder root)
    1) An extract of this plant is used for preparation of the casings of ham and sausages in Japan. It contains lucidin, an agent that has exhibited mutagenic and DNA-damaging properties (Yasui & Takeda, 1983) Rizk, 1991).
    l) CASSIA OBTUSIFOLIA
    1) Paste and extracts of sicklepod (C. obtusifolia) seeds have been used in the treatment of ringworm and other skin diseases, eye diseases, and as a cathartic (Acharya & Chatterjee, 1975; Kitanaka & Takido, 1981; Koo et al, 1976; pp 1343-1347; Shah & Shinde, 1967; Shibata et al, 1969).
    2) This plant is known to contain a number of different anthraquinone derivatives including emodin, rubrofusarin, chrysophanol, physcion, rhein, and sitosterol (Acharya & Chatterjee, 1975; pp 1343-1347; Raghunathan et al, 1974; Shah & Shinde, 1967).
    2) SOME REPRESENTATIVE SYNTHETIC ANTHRAQUINONES
    a) Anthralin (a synthetic anthracenetriol) is used as a keratolytic and has generally replaced chrysarobin (Tyler et al, 1988).
    b) Danthron
    1) Synonyms: 1,8-dihydroxyanthrone; 1,8-dihydroxy-9(10H)-anthracenone; anthralin (USAN); chrysazine; dioxyanthranol; CAS 1143-38-0.
    2) Danthron is a 1,8-dihydroxyanthraquinone prepared synthetically and used as a stimulant cathartic (Tyler et al, 1988).
    C) USES
    1) Natural and synthetic anthraquinones are widely used as colorants in foods, drugs, cosmetics, hair dyes, and textiles (Mori et al, 1986).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Anthraquinone laxatives are colonic-specific stimulant laxatives made from plant-derived compounds including aloe, cascara sagrada, frangula, rhubarb, chrysarobin, and senna. In addition, natural and synthetic anthraquinones are widely used as colorants in foods, drugs, cosmetics, hair dyes, and textiles.
    B) PHARMACOLOGY: Various anthraquinones (hypericin, emodin, rhein, emodin anthrone, emodin bianthone) have shown some antiviral activity. Plants that contain anthraquinones contain reduced glycosides of anthranols and anthrones, which are reduced derivatives of anthraquinones. These agents have more pronounced therapeutic action than the anthraquinones. Anthraquinone glycosides increase the tone of the smooth muscle in the large intestine wall. In laboratory experiments, some anthraquinone glycosides have antihepatotoxic properties. Aloe-emodin has some antileukemic properties. Dithranol, its 10-acetyl analogue and dimmers, completely inhibit cell growth and thymidine incorporation in human cultured cells and inhibit both DNA replication and repair synthesis. This interference is especially true for mitochondrial DNA. In vitro experiments showed that dithranol acted as an uncoupler of oxidative phosphorylation and could inhibit the adenosine triphosphate supply in epidermal cells, reducing the energy supply in keratinocytes and producing a therapeutic effect in psoriasis.
    C) TOXICOLOGY: These laxatives have a direct action on intestinal mucosa, increasing the rate of colonic motility, enhancing colonic transit, and inhibiting water and electrolyte secretion. They may also act on the intramural colon nerves and plexes. They also have stool softening properties. Sennosides are highly purified form of senna, which during the purification process eliminates components that may be responsible for cramping and griping.
    D) EPIDEMIOLOGY: Exposure to compounds containing anthraquinones is very common but serious adverse effects are extremely rare.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Following ingestion of an unknown amount of Cassia occidentalis beans, several children experienced vomiting, fever, irritability, agitation, elevated liver enzyme concentrations, seizures, altered sensorium, and coma. Blisters and skin sloughing of the buttocks and perineum have also been reported in young children following unintentional ingestion of senna-containing laxatives.
    2) MILD TO MODERATE TOXICITY: These agents have an irritant cathartic action. Most human cases are mild to moderate in severity, with nausea, vomiting, diarrhea, abdominal cramps, and palpitations as the primary symptoms. Dithranol is an irritant to the eyes and mucus membranes. In exposures, a red color is seen in alkaline urine and yellow-brown in acid urine. For commercial cascara sagrada preparations, there is a 6-hour delay in onset that is not seen in intoxications from fresh plant material due to other active ingredients in the plants. Vomiting is also more prevalent with fresh plant material. Finger clubbing has been reported with senna abuse, and is reversible upon discontinuation of the drug.
    3) SEVERE TOXICITY: Severe poisonings may produce kidney damage, including nephritis, gastrointestinal hemorrhage, muscular seizures, dyspnea, and fluid depletion.
    0.2.20) REPRODUCTIVE
    A) Casanthranol, danthron, senna, and cascara sagrada are in pregnancy category C.
    0.2.21) CARCINOGENICITY
    A) Various anthraquinones have been shown to have carcinogenic potential.

Laboratory Monitoring

    A) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor renal function and liver enzymes in symptomatic patients.
    C) Monitor vital signs and mental status.
    D) A red color is seen in alkaline urine, which turns a yellow-brown in acid urine. The red urine should be differentiated from hematuria.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION PROCEDURE
    1) There is no evidence for the use of dialysis, hemoperfusion, urinary alkalinization, or multiple dose charcoal for toxic exposures. Dialysis or hemoperfusion are extremely unlikely to be helpful in toxic patients.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with minimal symptoms from therapeutic or accidental use of anthraquinones may be managed at home.
    2) OBSERVATION CRITERIA: Patients with self-harm exposures or worsening symptoms should be sent to a healthcare facility for observation for 4 to 6 hours. Patients may be discharged home if they are asymptomatic or clearly improving.
    3) ADMISSION CRITERIA: Patients with worsening symptoms that do not improve with initial treatments should be admitted to the hospital for further evaluation. Depending on the severity of their symptoms (eg, seizures, altered mental status), they may require intensive care admission. Patients may only be discharged from the hospital when they are asymptomatic or clearly improving.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Depending on the type and severity of symptoms, different consultants may be needed (eg, intensivists for patients requiring intensive care unit, nephrologists for patients with severe fluid and electrolyte abnormalities and nephritis, etc.).
    H) PITFALLS
    1) Unfamiliarity with anthraquinones and the different symptoms that different anthraquinones can cause.
    I) PHARMACOKINETICS
    1) Following oral administration, the anthraquinone glycosides are poorly absorbed. Following hydrolysis by colonic bacteria, moderate absorption of senna and cascara occurs. Orally administered senna and cascara laxatives usually produce a bowel movement within 6 to 12 hours and 6 to 8 hours, respectively. However, the effects may not be seen for 24 hours. With rectal suppositories, colonic evacuation usually occurs in 30 minutes to 2 hours. Following oral administration and hydrolysis by colonic bacteria, anthraquinones are partially eliminated renally, in feces, and in bile.
    J) PREDISPOSING CONDITIONS
    1) Extremes of age may be predisposed to toxicity. Deaths have been reported in small children related to anthraquinone-containing natural substances.
    K) DIFFERENTIAL DIAGNOSIS
    1) Other causes of gastrointestinal upset (eg, viral illnesses, bacteria, irritable bowel syndrome, etc.) may mimic symptoms of anthraquinone toxicity.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION
    1) Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature normal saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persists afterwards, an ophthalmologic examination should be performed.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION
    a) Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. If pain and irritation persists, evaluation at a healthcare facility may be needed.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. CHILDREN: Deaths were reported in a 3-year-old and a 20-month-old following ingestion of an unknown number of Rhamnus berries. Diarrhea followed by superficial partial thickness burns occurred in a 3-year-old child following ingestion of 10 to 15 tablets of a senna-based laxative. Blisters and skin sloughing of the buttocks occurred in several children with a mean age of 2.4 years following ingestion of a senna-based laxative at doses ranging from 15 mg to 375 mg (mean 105 mg).
    B) THERAPEUTIC DOSE: SENNA: ADULTS: Initially, 17.2 mg sennosides (2 tablets) orally once daily; MAX, 34.4 mg sennosides (4 tablets) twice daily. CHILDREN: 12 YEARS OR OLDER: Initially, 17.2 mg sennosides (2 tablets) orally once daily; MAX, 34.4 mg sennosides (4 tablets) twice daily. 6 TO 11 YEARS: Initially, 8.6 mg sennosides (1 tablet) orally once daily; MAX, 17.2 mg sennosides (2 tablets) twice daily. 2 TO 5 YEARS: Initially, 4.3 mg sennosides (one-half tablet) orally once daily; MAX, 8.6 mg sennosides (1 tablet) twice daily. LESS THAN 2 YEARS OF AGE: Dosing is not provided.

Clinical Effects

Summary Of Exposure

    A) USES: Anthraquinone laxatives are colonic-specific stimulant laxatives made from plant-derived compounds including aloe, cascara sagrada, frangula, rhubarb, chrysarobin, and senna. In addition, natural and synthetic anthraquinones are widely used as colorants in foods, drugs, cosmetics, hair dyes, and textiles.
    B) PHARMACOLOGY: Various anthraquinones (hypericin, emodin, rhein, emodin anthrone, emodin bianthone) have shown some antiviral activity. Plants that contain anthraquinones contain reduced glycosides of anthranols and anthrones, which are reduced derivatives of anthraquinones. These agents have more pronounced therapeutic action than the anthraquinones. Anthraquinone glycosides increase the tone of the smooth muscle in the large intestine wall. In laboratory experiments, some anthraquinone glycosides have antihepatotoxic properties. Aloe-emodin has some antileukemic properties. Dithranol, its 10-acetyl analogue and dimmers, completely inhibit cell growth and thymidine incorporation in human cultured cells and inhibit both DNA replication and repair synthesis. This interference is especially true for mitochondrial DNA. In vitro experiments showed that dithranol acted as an uncoupler of oxidative phosphorylation and could inhibit the adenosine triphosphate supply in epidermal cells, reducing the energy supply in keratinocytes and producing a therapeutic effect in psoriasis.
    C) TOXICOLOGY: These laxatives have a direct action on intestinal mucosa, increasing the rate of colonic motility, enhancing colonic transit, and inhibiting water and electrolyte secretion. They may also act on the intramural colon nerves and plexes. They also have stool softening properties. Sennosides are highly purified form of senna, which during the purification process eliminates components that may be responsible for cramping and griping.
    D) EPIDEMIOLOGY: Exposure to compounds containing anthraquinones is very common but serious adverse effects are extremely rare.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Following ingestion of an unknown amount of Cassia occidentalis beans, several children experienced vomiting, fever, irritability, agitation, elevated liver enzyme concentrations, seizures, altered sensorium, and coma. Blisters and skin sloughing of the buttocks and perineum have also been reported in young children following unintentional ingestion of senna-containing laxatives.
    2) MILD TO MODERATE TOXICITY: These agents have an irritant cathartic action. Most human cases are mild to moderate in severity, with nausea, vomiting, diarrhea, abdominal cramps, and palpitations as the primary symptoms. Dithranol is an irritant to the eyes and mucus membranes. In exposures, a red color is seen in alkaline urine and yellow-brown in acid urine. For commercial cascara sagrada preparations, there is a 6-hour delay in onset that is not seen in intoxications from fresh plant material due to other active ingredients in the plants. Vomiting is also more prevalent with fresh plant material. Finger clubbing has been reported with senna abuse, and is reversible upon discontinuation of the drug.
    3) SEVERE TOXICITY: Severe poisonings may produce kidney damage, including nephritis, gastrointestinal hemorrhage, muscular seizures, dyspnea, and fluid depletion.

Heent

    3.4.3) EYES
    A) DITHRANOL is an irritant to the eyes and mucous membranes (S Sweetman , 2001).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PALPITATIONS
    1) Palpitations were seen in one case report of 6 women who became toxic after ingesting an anthraquinone-containing herbal tea (MMWR, 1978).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PALPITATION
    a) FROGS: 200 mg of emodin increased the rate and force of contraction of an isolated frog heart after an initial depression. Repeated injections showed decreasing effectiveness. The effect was not seen in propranolol pretreated hearts (Dwivedi et al, 1988).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) Dyspnea is mentioned as a sign of severe poisoning (Cooper & Johnson, 1984; Corvevin, 1887).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) Ten children, who ingested an unknown amount of Cassia occidentalis beans, experienced vomiting, fever, abnormal body movements, and extreme irritability and agitation, that progressed to altered sensorium and coma within 24 hours after onset of symptoms. Three of the children also developed generalized seizures. Nine children died within 3 days of hospitalization. One child recovered following supportive care and was subsequently discharged 3 days post-admission (Vashishtha et al, 2007).
    b) CASE-CONTROL STUDY: A case-control study was conducted, involving children with acute hepatomyoencephalopathy (n=18), a term coined by the investigators and characterized by vomiting, agitation, abnormal movements, rapid progression to coma, and elevated serum aminotransferases, creatine phosphokinase, and lactic dehydrogenase. The study also included 3 age-matched neighborhood controls (n=54), living in similar conditions, for each case. Investigation of the area surrounding the houses of both cases and controls revealed that Cassia occidentalis appeared to grow in abundance in each instance. Interviews with the parents revealed that 8 children (44.4%) in the study group recently ate Cassia beans prior to onset of symptoms, as compared with 3 (5.6%) in the control group (p <0.001; 95% CI 2.56 to 88.77; OR=12.89) (Vashishtha et al, 2007a).
    c) CASE REPORT: A 3-year-old girl presented with fever, vomiting, self-inflicted bite marks on her forearms and a 2 day history of excessive crying after ingesting some beans 3 days prior to presentation that were later identified as Cassia occidentalis. At admission, the patient was lethargic with a Glasgow coma score of 9. Physical examination indicated an enlarged liver and laboratory data revealed elevated liver enzymes, an INR of 2.87, a PT of 33.6 sec (control 11.7 sec), a PTT greater than 180 sec (control 27 sec), and creatine phosphokinase (CPK), CPK-MB, and lactate dehydrogenase concentrations of 1226 units/L, 837 units/L, and 1413 units/L, respectively. Signs and symptoms, in addition to the laboratory data, were indicative of a diagnosis of hepatomyoencephalopathy. With supportive therapy, the patient gradually improved and was discharged on hospital day 8 without neurological sequelae. Further interview of the family members indicated that an elder sibling had also ingested the beans, developing similar symptoms, but died before receiving medical treatment (Nirupam et al, 2013).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Muscular seizures are a rare sign of severe intoxication (Cooper & Johnson, 1984).
    b) Generalized seizures were reported in 3 children who ingested an unknown amount of Cassia occidentalis beans (Vashishtha et al, 2007).
    C) DIZZINESS
    1) Dizziness is occasionally seen in severe intoxications (Lampe & Fagerstrom, 1968).
    D) FEELING AGITATED
    1) WITH POISONING/EXPOSURE
    a) Extreme irritability and agitation were reported in several children following ingestion of an unknown amount of Cassia occidentalis beans (Nirupam et al, 2013; Vashishtha et al, 2007; Vashishtha et al, 2007a).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS DEPRESSION
    a) CNS depression was seen in animals tested with injections of emodin. Analgesia was also noted with injection. These effects have not been noted in human overdose (Dwivedi et al, 1988).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) The primary toxic manifestation is a watery diarrhea (van der Graaff, 1932), often associated with abdominal cramping (MMWR, 1978; Keeler & Tu, 1983). The action of these agents is to stimulate the wall of the lower intestine.
    2) There may be hemorrhage and bloody diarrhea in some cases (Cooper & Johnson, 1984; Lampe & Fagerstrom, 1968).
    3) Increased stimulant activity was seen when emodin was injected into animals. The effects were blocked by atropine pretreatment (Dwivedi et al, 1988).
    B) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may also be present in overdose (Lampe & McCann, 1985).
    b) Vomiting was reported in several children who ingested an unknown number of Cassia occidentalis beans (Nirupam et al, 2013; Vashishtha et al, 2007; Vashishtha et al, 2007a).
    C) MELANOSIS
    1) A benign condition of the colonic mucosa (MELANOSIS COLI) may occur with prolonged use of the anthraquinones. This is generally reversible within 4 to 12 months after drug discontinuation (Curry & Tatum-Butler, 1990; Gilman et al, 1990).
    D) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) Poor colonic function (CATHARTIC COLON) may result from chronic use of anthraquinone laxatives (Riley, 1991).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) ALOE VERA
    1) CASE REPORT: A 24-year-old man, with no previous history of liver disease or alcohol consumption, had been taking 500 mg/day of aloe vera (1 capsule/day) for 3 weeks and subsequently developed jaundice, pruritus, nausea and vomiting, abdominal pain, and fatigue. Laboratory studies revealed elevated liver enzyme levels and a liver biopsy showed portal and acinar infiltrates, primarily consisting of lymphocytes, monocytes, and eosinophils, as well as necrosis, all of which is indicative of acute hepatitis. The patient completely recovered, with a normalization of his liver enzyme levels, within 6 weeks after discontinuing the aloe vera (Kanat et al, 2006).
    b) CASCARA SAGRADA
    1) CASE REPORT: A 48-year-old man developed jaundice, abdominal pain, nausea, anorexia, and elevated liver enzyme levels 3 days after ingesting cascara sagrada, 1 capsule three times daily for 3 days. One week later, the patient was also noted to have ascites with a paracentesis documenting a serum ascites-albumin gradient of 1.3. A liver biopsy showed severe portal inflammation with intracanalicular bile stasis and mild steatosis. The patient gradually recovered following discontinuation of the cascara sagrada (Nadir et al, 2000).
    c) SENNA
    1) CASE REPORT: A 77-year-old man developed abdominal pain, jaundice, fatigue and elevated liver enzymes (AST 481 IU/L, ALT 657 IU/L, conjugated bilirubin 2.75 mg/dL, unconjugated bilirubin 2.16 mg/dL, ALP 160 IU/L, GGT 237 IU/L) following the daily use of an herbal laxative containing sennoside (15 to 30 mg/day) for over 3 months. The patient was taking no other medications and serological testing was found to be within normal limits. A liver biopsy revealed enlarged portal tracts with a predominantly lymphocytic inflammatory infiltrate compatible with cholestatic hepatitis. Liver enzymes gradually improved and were within normal limits one month after sennoside was discontinued (Sonmez & Yilmaz, 2005).
    B) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Elevated liver enzyme concentrations were reported in 10 children who ingested an unknown amount of Cassia occidentalis beans (Vashishtha et al, 2007).
    b) CASE-CONTROL STUDY: A case-control study was conducted, involving children with acute hepatomyoencephalopathy (n=18), a term coined by the investigators and characterized by vomiting, agitation, abnormal movements, rapid progression to coma, and elevated serum aminotransferases, creatine phosphokinase, and lactic dehydrogenase. The study also included 3 age-matched neighborhood controls (n=54), living in similar conditions, for each case. Investigation of the area surrounding the houses of both cases and controls revealed that Cassia occidentalis appeared to grow in abundance in each instance. Interviews with the parents revealed that 8 children (44.4%) in the study group recently ate Cassia beans prior to onset of symptoms, as compared with 3 (5.6%) in the control group (p <0.001; 95% CI 2.56 to 88.77; OR=12.89) (Vashishtha et al, 2007a).
    c) CASE REPORT: A 3-year-old girl presented with fever, vomiting, self-inflicted bite marks on her forearms and a 2 day history of excessive crying after ingesting some beans 3 days prior to presentation that were later identified as Cassia occidentalis. At admission, the patient was lethargic with a Glasgow coma score of 9. Physical examination indicated an enlarged liver and laboratory data revealed elevated liver enzymes, an INR of 2.87, a PT of 33.6 sec (control 11.7 sec), a PTT greater than 180 sec (control 27 sec), and creatine phosphokinase (CPK), CPK-MB, and lactate dehydrogenase concentrations of 1226 units/L, 837 units/L, and 1413 units/L, respectively. Signs and symptoms, in addition to the laboratory data, were indicative of a diagnosis of hepatomyoencephalopathy. With supportive therapy, the patient gradually improved and was discharged on hospital day 8 without neurological sequelae. Further interview of the family members indicated that an elder sibling had also ingested the beans, developing similar symptoms, but died before receiving medical treatment (Nirupam et al, 2013).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) OLIGURIA
    1) Oliguria and proteinuria may be seen in severe cases (Lampe & Fagerstrom, 1968).
    B) ABNORMAL URINE
    1) A red color is seen in alkaline urine, which turns a yellow-brown in acid urine. This is called the borntrager's reaction and is diagnostic for anthraquinones. The red urine should be differentiated from hematuria (Lampe & Fagerstrom, 1968).
    C) NEPHRITIS
    1) Large doses of anthraquinones may cause nephritis (Hardman et al, 1996).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An INR of 2.87, a PT of 33.6 sec (control 11.7 sec), and a PTT greater than 180 sec (control 27 sec) were reported in a 3-year-old girl who ingested an unknown amount of Cassia occidentalis beans (Nirupam et al, 2013).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LEUKOCYTOSIS
    a) RATS given Cassia obtusifolia seeds containing anthraquinones developed myeloid hyperplasia with peripheral leukocytosis, thrombocytosis, and mild anemia when diets contained greater than 0.5 percent seeds (Voss & Brennecke, 1991).
    2) PLATELETS ABNORMAL
    a) In vitro experiments have shown that anthraquinones found in Cassia obtusifolia have anti-platelet aggregation properties (Yun-Choi & Kim, 1990).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) Some anthraquinones have been shown to be sensitizers.
    2) Jadassohn (1926) reported a case of allergic dermatitis to aloe where emodin was the sensitizer. Others have also considered the anthraquinones in aloe and Rhamnus to be sensitizers that may produce dermatitis (Cronin, 1968; Mitchell & Rook, 1979).
    B) NAIL FINDING
    1) Finger clubbing has been reported with abuse of senna. The condition is reversible with discontinuation of the drug (JEF Reynolds , 1991; Levine et al, 1981; Silk et al, 1975) Malmquist, 1980; (FitzGerald & Redmond, 1983).
    C) SKIN IRRITATION
    1) Dithranol may cause a burning sensation especially on perilesional skin (S Sweetman , 2001).
    D) BURN
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: During a prospective study involving over-the-counter (OTC) laxative ingestions, 88 cases of unintentional OTC senna-containing laxative ingestions in young children were reported, with the subsequent development of diarrhea. The mean and median ages of the children were 2.4 and 2 years, respectively, and the doses of senna ingested ranged from 15 to 375 mg (mean 105 mg; median 75 mg). Of the 88 children, 50 (57%) were in diapers continuously, 10 (11%) were in diapers overnight only, and 28 (32%) were fully potty-trained. Ten children (11%) experienced blisters and skin sloughing in the buttocks and perineum, with the mean time to onset of blisters occurring 14.5 +/- 6.8 hours post ingestion (range 6 to 24 hours) and the mean duration of skin sloughing occurring 56.8 +/- 18.4 hours post ingestion (range 36 to 96 hours). All 10 children were in diapers continuously (Spiller et al, 2003).
    b) CASE REPORT: After the inadvertent ingestion of 10 to 15 Ex-lax (senna based laxative) chocolate tablets, a 3-year-old child developed superficial partial thickness burns in the perianal area and buttocks within 10 minutes of experiencing diarrhea. Following supportive care and treatment with topical silver sulfadiazine, the child recovered completely a week later (Durani et al, 2006).

Reproductive

    3.20.1) SUMMARY
    A) Casanthranol, danthron, senna, and cascara sagrada are in pregnancy category C.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    CASANTHRANOLC
    DANTHRONC
    SENNAC
    CASCARA SAGRADAC
    Reference: Briggs et al, 1998

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Various anthraquinones have been shown to have carcinogenic potential.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) CHRYSAZIN has been shown to be carcinogenic in rats and mutagenic in Salmonella typhimurium (Mori et al, 1985; Mori et al, 1986; Brown & Brown, 1976; Tikkanen et al, 1983).
    2) All laxatives containing danthron were discontinued due to reports of intestinal and liver tumors with chronic high doses in animals (Hardman et al, 1996; Curry & Tatum-Butler, 1990). Although not specifically demonstrated, danthron is potentially a human carcinogen.

Genotoxicity

    A) Various anthraquinones have been shown to have mutagenic potential. Many are frameshift mutagens.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor renal function and liver enzymes in symptomatic patients.
    C) Monitor vital signs and mental status.
    D) A red color is seen in alkaline urine, which turns a yellow-brown in acid urine. The red urine should be differentiated from hematuria.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) In cases where diarrhea and vomiting have been excessive, fluid and electrolyte abnormalities might be seen. In such cases, monitor for electrolyte loss and/or dehydration.
    2) Monitor renal function and liver enzymes in symptomatic patients.
    4.1.3) URINE
    A) SPECIFIC AGENT
    1) A red color is seen in alkaline urine, which turns a yellow-brown in acid urine. This is called the borntrager's reaction and is diagnostic for anthraquinones. The red urine should be differentiated from hematuria (Lampe & Fagerstrom, 1968).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs and mental status.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with worsening symptoms that do not improve with initial treatments should be admitted to the hospital for further evaluation. Depending on the severity of their symptoms (eg, seizures, altered mental status), they may require intensive care admission. Patients may only be discharged from the hospital when they are asymptomatic or clearly improving.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with minimal symptoms from therapeutic or accidental use of anthraquinones may be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Depending on the type and severity of symptoms, different consultants may be needed (eg, intensivists for patients requiring intensive care unit, nephrologists for patients with severe fluid and electrolyte abnormalities and nephritis, etc.).
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with self-harm exposures or worsening symptoms should be sent to a healthcare facility for observation for 4 to 6 hours. Patients may be discharged home if they are asymptomatic or clearly improving.

Monitoring

    A) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor renal function and liver enzymes in symptomatic patients.
    C) Monitor vital signs and mental status.
    D) A red color is seen in alkaline urine, which turns a yellow-brown in acid urine. The red urine should be differentiated from hematuria.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/ NOT RECOMMENDED
    1) Emesis is not required. Due to the cathartic action of this agent, vomiting and diarrhea may be seen with overdose.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    2) Monitor renal function and liver enzymes in symptomatic patients.
    3) Monitor vital signs and mental status.
    4) A red color is seen in alkaline urine, which turns a yellow-brown in acid urine. The red urine should be differentiated from hematuria.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) PSYCHOMOTOR AGITATION
    1) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    2) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    3) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    4) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) ENHANCED ELIMINATION
    1) There is no evidence for the use of dialysis, hemoperfusion, urinary alkalinization, or multiple dose charcoal for toxic exposures. Dialysis or hemoperfusion are extremely unlikely to be helpful in toxic patients.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. CHILDREN: Deaths were reported in a 3-year-old and a 20-month-old following ingestion of an unknown number of Rhamnus berries. Diarrhea followed by superficial partial thickness burns occurred in a 3-year-old child following ingestion of 10 to 15 tablets of a senna-based laxative. Blisters and skin sloughing of the buttocks occurred in several children with a mean age of 2.4 years following ingestion of a senna-based laxative at doses ranging from 15 mg to 375 mg (mean 105 mg).
    B) THERAPEUTIC DOSE: SENNA: ADULTS: Initially, 17.2 mg sennosides (2 tablets) orally once daily; MAX, 34.4 mg sennosides (4 tablets) twice daily. CHILDREN: 12 YEARS OR OLDER: Initially, 17.2 mg sennosides (2 tablets) orally once daily; MAX, 34.4 mg sennosides (4 tablets) twice daily. 6 TO 11 YEARS: Initially, 8.6 mg sennosides (1 tablet) orally once daily; MAX, 17.2 mg sennosides (2 tablets) twice daily. 2 TO 5 YEARS: Initially, 4.3 mg sennosides (one-half tablet) orally once daily; MAX, 8.6 mg sennosides (1 tablet) twice daily. LESS THAN 2 YEARS OF AGE: Dosing is not provided.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) ALOE
    a) The use of aloe as a laxative has been superseded by other less toxic agents; aloe has more drastic and irritating effects. Aloe may be found in some combination products (S Sweetman , 2001).
    2) CASCARA SAGRADA
    a) Bitter Cascara (the fluid extract) - l mL (Tyler et al, 1988).
    b) Aromatic Cascara sagrada - 5 mL
    c) Cascara sagrada extract - The usual recommended oral dose for Cascara sagrada to relieve constipation is 325 mg (1 tablet) at bedtime (Riley, 2000).
    3) ALOE/CASCARA SAGRADA
    a) The usual recommended adult dose for combination products containing aloe and cascara is 200 mg and 300 mg (2 tablets), respectively, with a full glass of water (Prod Info Nature's Remedy(R), 1991).
    4) DANTHRON
    a) 75 to 150 mg (Tyler et al, 1988).
    5) SENNA
    a) Initially, 17.2 mg sennosides (2 tablets) orally once daily; MAX, 34.4 mg sennosides (4 tablets) twice daily (OTC Product Information, as posted to the DailyMed site 02/2013)
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) ALOE
    a) The use of aloe as a laxative has been superseded by other less toxic agents; aloe has more drastic and irritating effects. Aloe may be found in some combination products (S Sweetman , 2001).
    2) ALOE/CASCARA SAGRADA
    a) The usual recommended dose for children 8 to 15 years of age using combination products containing aloe and cascara is 100 mg and 150 mg (1 tablet), respectively, with a full glass of water (Prod Info Nature's Remedy(R), 1991).
    3) SENNA
    a) 12 YEARS OR OLDER: Initially, 17.2 mg sennosides (2 tablets) orally once daily; MAX, 34.4 mg sennosides (4 tablets) twice daily (OTC Product Information, as posted to the DailyMed site 02/2013)
    b) 6 TO 11 YEARS: Initially, 8.6 mg sennosides (1 tablet) orally once daily; MAX, 17.2 mg sennosides (2 tablets) twice daily (OTC Product Information, as posted to the DailyMed site 02/2013)
    c) 2 TO 5 YEARS: Initially, 4.3 mg sennosides (one-half tablet) orally once daily; MAX, 8.6 mg sennosides (1 tablet) twice daily (OTC Product Information, as posted to the DailyMed site 02/2013)
    d) LESS THAN 2 YEARS OF AGE: Dosing is not provided (OTC Product Information, as posted to the DailyMed site 02/2013).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) RHAMNACEAE: Banach (1980) reported the deaths of a 3-year-old and a 20-month-old after ingestion of an unknown number of Rhamnus berries (Banach, 1980).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) RHAMNUS FRUITS: In reports to Toxicology Centers throughout Europe, there are exposures reported, but none has resulted in serious symptoms (Frohne & Pfander, 1984).
    2) RHEUM SPECIES: Determination of a toxic dose is very difficult when dealing with the plant material. Various species have different concentrations (Fairbairn & Lou, 1951).
    a) Chinese rhubarb contains 0.53% to 0.76% of rhein-like compounds that produce catharsis .
    b) English rhapontic rhubarb had a concentration of 0.21% to 0.41% of the same compounds.
    c) French rhapontic and Austrian rhapontic rhubarb contained only traces of these agents.
    d) Maurin (1923) tested several rhubarbs and found the average total hydroxymethylanthraquinone concentration ranged from 2.45% to 4.35%. The highest concentration was in Shensi flat rhubarb (Maurin, 1923)
    B) PEDIATRIC
    1) CASE SERIES: During a prospective study involving over-the-counter (OTC) laxative ingestions, 88 cases of OTC senna-containing laxative ingestions in young children were reported, with the subsequent development of diarrhea. The mean and median ages of the children were 2.4 and 2 years, respectively, and the doses of senna ingested ranged from 15 to 375 mg (mean 105 mg; median 75 mg). Ten children (11%) experienced blisters and skin sloughing in the buttocks and perineum, with the mean time to onset of blisters occurring 14.5 +/- 6.8 hours post ingestion (range 6 to 24 hours) and the mean duration of skin sloughing occurring 56.8 +/- 18.4 hours post ingestion (range 36 to 96 hours). All 10 children were in diapers continuously (Spiller et al, 2003).
    2) CASE REPORT: After the inadvertent ingestion of 10 to 15 Ex-lax (senna based laxative) chocolate tablets, a 3-year-old child developed superficial partial thickness burns in the perianal area and buttocks within 10 minutes of experiencing diarrhea. Following supportive care and treatment with topical silver sulfadiazine, the child recovered completely a week later (Durani et al, 2006).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Various anthraquinones have been tested for antiviral activity. Hypericin (an emodin dimer), emodin, rhein, emodin anthrone, and emodin bianthrone have all shown some activity (Wood et al, 1990).
    B) These glycosides will hydrolyze to yield di-, tri-, or tetrahydroxyanthraquinones or derivatives of these compounds (Tyler et al, 1988).
    C) The plants which contain anthraquinones usually also contain glycosides of anthranols and anthrones, which are reduced derivatives of anthraquinones. These agents have an even more pronounced therapeutic action than the anthraquinones (Tyler et al, 1988).
    D) Once hydrolysis is accomplished, and the aglycones of the anthraquinones are free, there is little therapeutic activity. The sugar portion of the glycoside facilitates absorption and translocation of the aglycone to the site of action (Tyler et al, 1988).
    E) Anthraquinone glycosides exhibit their effect by increasing the tone of the smooth muscle in the wall of the large intestine (Tyler et al, 1988).
    F) Some anthraquinone glycosides have shown antihepatotoxic properties in laboratory experiments (Wong et al, 1989).
    G) Aloe-emodin has been shown to possess anti-leukemic properties (Kupchan & Karim, 1976).

Toxicologic Mechanism

    A) ANTHRAQUINONE LAXATIVES are colonic-specific stimulant laxatives made from plant-derived compounds including aloe, cascara sagrada, frangula, and senna. Danthron, a synthetic substance, has been withdrawn from the market because of its suspected carcinogenicity (Hardman et al, 1996; Riley, 2000; Godding, 1988).
    1) These laxatives have a direct action on intestinal mucosa, increasing the rate of colonic motility, enhancing colonic transit, and inhibiting water and electrolyte secretion (Hardman et al, 1996; Godding, 1988).
    2) These agents may also act on the intramural nerves and plexes of the colon. They also have stool softening properties and do not disrupt the usual pattern of defecation (Gilman et al, 1990; Godding, 1988).
    B) SENNOSIDES are a highly purified form of senna, which during the purification process eliminates components that may be responsible for causing cramping and griping (Prod Info Gentle Nature(R), sennosides, 1991).
    C) DITHRANOL -
    1) The mechanism of action of dithranol is not completely known. Dithranol, its 10-acetyl analogue, and dimers completely inhibit cell growth and thymidine incorporation in human cultured cells, and inhibit both DNA replication and repair synthesis. The interference is especially true for mitochondrial DNA (JEF Reynolds , 1991; Farber & Nall, 1984).
    2) In vitro experiments on isolated rat liver mitochondria showed that dithranol acted as an uncoupler of oxidative phosphorylation. The authors suggested that dithranol could inhibit the adenosine triphosphate supply in epidermal cells, reducing the energy supply in keratinocytes and producing a therapeutic effect in psoriasis (Morliere, 1985; JEF Reynolds , 1991).

Physicochemical

Physical Characteristics

    A) DITHRANOL: A yellow to orange-yellow or yellowish-brown, odorless, crystalline powder.

Ph

    A) DITHRANOL: The filtrate from a suspension in water is neutral to litmus (S Sweetman , 2001).

Molecular Weight

    A) CHRYSOPHANIC ACID: 254.23
    B) DITHRANOL: 226.2
    C) EMODIN: 270.23

Animal Toxicology

Clinical Effects

    11.1.2) BOVINE/CATTLE
    A) A cow that grazed on a large amount of Frangula alnus (twigs, leaves and berries) developed diarrhea, vomiting, cramps, bradycardia, and a slight fever. The animal died (Sodermark, 1942).
    11.1.3) CANINE/DOG
    A) A dog which overdosed on a laxative containing Rhamnus cathartic developed gastroenteritis, with severe gastrointestinal hemorrhage. The animal died (Volker, 1950).
    11.1.12) RODENT
    A) Cassia obtusifolia seed extracts were found to lower blood pressure when injected into rats (Koo et al, 1976).
    B) Rats given a 32% diet of sicklepod seed (Cassia obtusifolia) died. Symptoms included a red nasal discharge, increased white cell count, mild to moderate bone marrow, testicular lesions, and soft stools (Dugan & Gumbmann, 1990).
    11.1.13) OTHER
    A) OTHER
    1) Animals which ingest anthraquinone containing plants are likely to develop diarrhea (Rowe et al, 1987).

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) CATTLE
    1) When whole Cassia obtusifolia seeds were fed to Holstein calves at 12.5 to 50 percent of their diet, the animals avoided the seeds, developed diarrhea, and decreased their food consumption. The animals lost weight (Putnam et al, 1988).
    2) Cattle which had ingested Cassia obtusifolia leaves, seeds, and stems as approximately 50% of their diet, died after 10 days on the feed. Deaths continued for 10 days after the feed was discontinued (McCormack & Neisler, 1980; Nicholson et al, 1986; Nicholson et al, 1977).
    B) RODENT
    1) MOUSE - Oral administration of 25 to 50 milligrams per kilogram of emodin from Cassia obtusifolia produced a purgative action in mice (Pal & Pal, 1984).
    2) RAT - Animals fed 32% sicklepod seed died within 8 days. One rat with a 16% diet also died. Diets containing 8% or less did not produce toxicity (Dugan & Gumbmann, 1990).

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
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    65) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    66) OTC Product Information: Senokot(R) oral concentrate tablets, senna oral concentrate tablets. Purdue Products L.P., Stamford, CT, as posted to the DailyMed site 02/2013.
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    71) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    72) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
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