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LAXATIVES-STIMULANTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Stimulant cathartics act by increasing motor activity in the intestine. Examples include over-the-counter medications containing bisacodyl and senna and herbal medications containing castor oil, cascara sagrada, and aloe.

Specific Substances

    A) BISACODYL (synonym)
    1) 4,4''-(2-pyridylmethylene)di(phenyl acetate)
    2) CAS 603-50-9
    3) CAS 1336-29-4 (bisacodyl tannex)
    CASCARA (synonym)
    1) cascararinde
    2) cascara sagrada
    3) chittem bark
    4) rhamni purshianae cortex
    5) sacred bark
    6) CAS 8047-27-6
    7) CAS 8015-89-2 (cascara sagrada extract)
    CASTOR OIL (synonym)
    1) aceite de ricino
    2) huile de ricin
    3) oleum ricini
    4) rizinusol
    5) CAS 8001-79-4
    DANTHRON (synonym)
    1) antrapurol
    2) chrysazin
    3) dantron
    4) dianthon
    5) dioxyanthrachinonum
    6) 1,8-dihydroxyanthraquinone
    7) CAS 117-10-2
    OXYPHENISATIN (synonym)
    1) dihydroxyphenylisatin
    2) oxyphenisatine
    3) 3,3-Bis(4-hydroxyphenyl)indolin-2-one
    4) CAS 125-13-3
    OXYPHENISATIN ACETATE (synonym)
    1) acetphenolisatin
    2) bisatin
    3) diacetoxydiphenylisatin
    4) diacetyldiphenolisatin
    5) diasatin
    6) diphesatin
    7) isaphenin
    8) oxyphenisatin diacetate (synonym)
    9) phenlaxine
    10) CAS 115-33-3
    PHENOLPHTHALEIN (synonym)
    1) dihydroxyphthalophenone
    2) fenolftaleina
    3) 3,3-Bis(4-hydroxyphenyl)phthalide
    4) CAS 77-09-8
    SENNA (synonym)
    1) CAS 8013-11-4 (senna)
    2) CAS 81-27-6 (sennoside A)
    3) CAS 128-57-4 (sennoside B)
    4) CAS 52730-36-6 (calcium sennoside A)
    5) CAS 52730-37-7 (calcium sennoside B)
    GENERAL TERMS
    1) STIMULANT LAXATIVES

Available Forms Sources

    A) FORMS
    1) Stimulant laxatives come in a number of available forms. Examples include over-the-counter medications containing bisacodyl and senna and herbal medications containing castor oil, cascara sagrada, and aloe.
    2) Danthron was removed from the market in the United States in 1987 because of animal carcinogen data.
    3) In August 1997, the US Food and Drug Administration (FDA) announced a proposal to ban the use of phenolphthalein in non-prescription (over-the-counter) products due to long-term safety concerns and to reclassify phenolphthalein as unsafe based on a review of animal carcinogenicity studies (Anon, 1997). Several United States laxative manufacturers reformulated their phenolphthalein-containing products prior to or in response to the proposal. Effective January 29, 1999, the FDA issued a final ruling establishing that phenolphthalein is not generally recognized as safe and effective and is misbranded as an over-the-counter stimulant laxative ingredient (Anon, 1999).
    B) USES
    1) Laxative-stimulants are used for short-term treatment of constipation and to promote intestinal evacuation for rectal and bowel examination (Prod Info bisacodyl delayed-release enteric-coated oral tablets, 2006; Prod Info SENOKOT(R) S oral tablets, 2004).

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: Laxative-stimulants are used for short-term treatment of constipation and to promote intestinal evacuation for rectal and bowel examination.
    B) PHARMACOLOGY: The mechanism of action is thought to be secondary to irritation of the intestinal mucosa.
    C) EPIDEMIOLOGY: Stimulant laxatives come in a number of available forms. Examples include over-the-counter medications containing bisacodyl, senna, and herbal medications containing castor oil, cascara sagrada, and aloe. Exposures occur but significant acute toxicity is very rare. Chronic overuse can cause colonic dysfunction.
    D) WITH THERAPEUTIC USE
    1) Nausea, vomiting, abdominal pain, and diarrhea may occur with high doses. Blisters and skin sloughing of buttocks were also reported in young children who experienced diarrhea. Rhabdomyolysis has been reported secondary to chronic abuse of senna.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, and diarrhea have been reported.
    2) SEVERE TOXICITY: Fluid and electrolyte depletion, hypotension from extensive fluid losses, blisters, and skin sloughing of the buttocks and perineum with diarrhea.
    3) CHRONIC: Electrolyte abnormalities (eg, hypochloremia, hypokalemia, hypocalcemia, hypomagnesemia), reflex bowel hypofunction, permanent colonic dysfunction (cathartic colon, causing chronic constipation, bloating, and abdominal pain), frank/occult gastrointestinal bleeding and associated anemia, steatorrhea, protein-loss gastroenteropathy, pancreatic dysfunction. Toxic hepatitis and jaundice have been reported following the chronic use of very large doses of senna.
    0.2.20) REPRODUCTIVE
    A) Phenolphthalein is classified as FDA pregnancy category C. The citric acid, magnesium oxide, and sodium picosulfate combination is classified by its manufacturer as FDA pregnancy category B.
    B) One case of spontaneous membrane rupture with amniotic fluid embolism and cardiorespiratory arrest occurred following castor oil ingestion. Senna use during pregnancy is not associated with congenital abnormalities, according to a large population-based case-control study. Stimulant laxatives may pass into the breast milk of lactating women in small amounts but have not produced a cathartic effect in the infant.

Laboratory Monitoring

    A) Plasma levels of these agents are not clinically useful or widely available.
    B) Monitor fluid and electrolyte balance in severely symptomatic patients.
    C) Monitor blood pressure and heart rate.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Diarrhea: Rapid correction of fluid and electrolyte deficits with oral or IV fluid therapy and careful monitoring of intake and output are essential. Restrict solid food and maintain high fluid intake until diarrhea resolves. Oral fluid should consist of polyionic hypotonic solution containing appropriate electrolytes. Hypotension: Infuse isotonic fluid. If hypotension persists, administer pressors (eg, norepinephrine, dopamine).
    B) DECONTAMINATION
    1) Gastrointestinal decontamination is generally not warranted as acute toxicity is self-limited.
    C) AIRWAY MANAGEMENT
    1) Ingestion of these products should not require airway management.
    D) ANTIDOTE
    1) None.
    E) ENHANCED ELIMINATION PROCEDURE
    1) Systemic absorption of these drugs is limited. Methods to enhance elimination are not indicated.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients who are asymptomatic or have mild diarrhea after inadvertent overdose can be monitored at home.
    2) OBSERVATION CRITERIA: Patients with deliberate overdose or severe diarrhea should be observed in a medical facility until free of moderate/severe symptoms.
    3) ADMISSION CRITERIA: All persons with significant toxicity, dehydration, and abnormal electrolyte levels should be admitted. Patients at risk for dehydration who cannot be relied upon for compliance and/or adequate follow-up treatment should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.
    G) PITFALLS
    1) Pitfalls in managing these patients include missing alternative diagnoses or not recognizing iatrogenic overdoses. When managing a suspected overdose, the possibility of multi-drug involvement should be considered. These products may be surreptitiously abused by patients with eating disorders or other psychiatric conditions.
    H) PHARMACOKINETICS
    1) Bisacodyl: Onset of effect: Tablets: 6 to 10 hours. Suppositories: 15 to 60 minutes. Senna: Onset of effect: Tablets: 8 to 12 hours. Suppositories: 15 to 60 minutes.
    I) DIFFERENTIAL DIAGNOSIS
    1) Gastroenteritis, food poisoning, parasites, infectious disease or drugs or chemicals that cause nausea, vomiting, or diarrhea.

Range Of Toxicity

    A) TOXICITY: The acute minimal toxic or lethal dose of these agents is not well established. SENNA: CHILDREN: After the inadvertent ingestion of 10 to 15 Ex-lax (senna-based laxative) chocolate tablets, a child developed superficial partial thickness burns in the perianal area and buttocks within 10 minutes of experiencing diarrhea. A man developed abdominal pain, jaundice, fatigue, and elevated liver enzymes following the daily use of an herbal laxative containing sennoside (15 to 30 mg/day) for over 3 months. Liver enzymes gradually improved and were within normal limits one month after sennoside was discontinued.
    B) THERAPEUTIC DOSE: BISACODYL: ADULTS: ORAL: 5 to 15 mg orally once daily up to 30 mg/day. RECTAL: 10 mg suppository per rectum once daily. CHILDREN: ORAL: 12 YEARS AND OLDER: 5 to 15 mg orally once daily up to 30 mg/day. 6 TO 11 YEARS OF AGE: 5 mg orally once daily. RECTAL: 12 YEARS AND OLDER: 10 mg suppository per rectum once daily. 6 TO 11 YEARS OF AGE: 5 mg (1/2 suppository). SENNA: ADULTS: GRANULES: 15 mg once a day, up to a maximum of 30 mg twice a day. LIQUID: For bowel preparation in adults: An entire content of one 2.5-ounce bottle (130 mg sennosides) on the day prior to the diagnostic procedure. SYRUP: 10 to 15 mL (8.8 mg/5 mL) once a day up to a maximum of 30 mL/day. TABLETS: 2 tablets (15 to 17 mg) once a day at bedtime, up to a maximum of 34 to 50 mg twice a day. SUPPOSITORIES: 1 suppository (652 mg standardized senna concentrate) at bedtime; repeat if necessary.

Clinical Effects

Summary Of Exposure

    A) USES: Laxative-stimulants are used for short-term treatment of constipation and to promote intestinal evacuation for rectal and bowel examination.
    B) PHARMACOLOGY: The mechanism of action is thought to be secondary to irritation of the intestinal mucosa.
    C) EPIDEMIOLOGY: Stimulant laxatives come in a number of available forms. Examples include over-the-counter medications containing bisacodyl, senna, and herbal medications containing castor oil, cascara sagrada, and aloe. Exposures occur but significant acute toxicity is very rare. Chronic overuse can cause colonic dysfunction.
    D) WITH THERAPEUTIC USE
    1) Nausea, vomiting, abdominal pain, and diarrhea may occur with high doses. Blisters and skin sloughing of buttocks were also reported in young children who experienced diarrhea. Rhabdomyolysis has been reported secondary to chronic abuse of senna.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, and diarrhea have been reported.
    2) SEVERE TOXICITY: Fluid and electrolyte depletion, hypotension from extensive fluid losses, blisters, and skin sloughing of the buttocks and perineum with diarrhea.
    3) CHRONIC: Electrolyte abnormalities (eg, hypochloremia, hypokalemia, hypocalcemia, hypomagnesemia), reflex bowel hypofunction, permanent colonic dysfunction (cathartic colon, causing chronic constipation, bloating, and abdominal pain), frank/occult gastrointestinal bleeding and associated anemia, steatorrhea, protein-loss gastroenteropathy, pancreatic dysfunction. Toxic hepatitis and jaundice have been reported following the chronic use of very large doses of senna.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension from extensive fluid losses may occur.
    b) Hypotension has occurred after phenolphthalein poisoning (Buchanan et al, 1976; Sidhu et al, 1989).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema and adult respiratory distress syndrome (ARDS) has developed following phenolphthalein poisoning (Buchanan et al, 1976; Sidhu et al, 1989).
    B) ASPIRATION PNEUMONIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 76-year-old woman developed a persistent cough and hemoptysis following an aspiration of phenolphthalein (grains de Valls). Thoracic radiograph and CT scan showed an atelectasis of the medical segment of the right middle pulmonary lobe. Bronchoscopy did not show any sign of malignancy. Following a lobectomy, the pathology of the resected lobe showed a 'destroyed lung' with hyperactive pneumonia with local bronchial epithelial destruction in the presence of foreign body reactions and microabscesses. Following supportive care, she recovered completely without further sequelae (DeWulf et al, 2005).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may occur as a result of stimulant laxative overdose (Blatt et al, 1943).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea may occur as a result of stimulant laxative overdose (Durani et al, 2006; Darrow, 1982).
    b) CASE REPORT - An 11-year-old boy presented to a hospital with severe diarrhea (over 5 L/day), dehydration and hypernatremia. Upon observation of the child's mother, it was discovered that she was surreptitiously administering a cathartic to her child, and had been doing so for several months. Toxicological analyses of the patient's stool, urine, and serum revealed an ingestion of bisacodyl (Kudo et al, 1998).
    C) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal cramps may occur as a result of stimulant laxative overdose.
    D) PANCREATITIS
    1) Pancreatitis has been reported with excessive phenolphthalein ingestion (Lambrianides & Rosin, 1984).
    E) STOOL FINDING
    1) STOOL COLOR - Phenolphthalein may change stool color to red or pink, if the stool is alkaline (Orland, 1913).
    F) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) CHRONIC TOXICITY
    a) Chronic overuse of stimulant laxatives produces a variety of gastrointestinal effects, including: (Mitchell & Boutacoff, 1986; Weiss & Wood, 1982)
    1) Reflex bowel hypofunction
    2) Constipation
    3) Permanent colonic dysfunction ("cathartic colon", causing chronic constipation, bloating, and abdominal pain)
    4) Frank or occult gastrointestinal bleeding and associated anemia
    5) Steatorrhea, protein-loss gastroenteropathy
    6) Pancreatic dysfunction
    7) Permanent colonic mucosa pigmentation
    b) Other complications include(Mitchell & Boutacoff, 1986; Wright & DuVal, 1987):
    1) Dehydration
    2) Hyperaldosteronism
    3) Peripheral edema
    4) Electrolyte abnormalities (hypocalcemia, hypomagnesemia)
    5) Osteomalacia
    c) A pseudo-Bartter's syndrome has also been described, with systemic alkalosis, hypokalemia, impaired renal function, and hyperuricemia (Adam & Goebel, 1987; Wright & DuVal, 1987).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) JAUNDICE
    1) Tolman et al (1976) reported liver injury following the ingestion of DANTHRON/dioctyl calcium sulfosuccinate (Doxidan(R)) (Tolman et al, 1976).
    B) TOXIC HEPATITIS
    1) WITH POISONING/EXPOSURE
    a) SENNA - Chronic abuse of senna has caused toxic hepatitis. The dose was more than 10 times normal. When the senna was discontinued, liver enzymes fell 70% within a week (Beuers et al, 1991).
    2) CHRONIC
    a) OXYPHENISATIN - Chronic active hepatitis has been associated with use of oxyphenisatin. The onset is at least 6 months, usually two years, after continuous use (Reynolds et al, 1971; Reynolds & Redeker, 1970; Mallory et al, 1971; Cooksley et al, 1973; Kotha et al, 1980).
    C) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) 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 imporved and were within normal limits one month after sennoside was discontinued (Sonmez & Yilmaz, 2005).
    D) HEPATIC FAILURE
    1) CASE REPORT - Fulminant liver failure was reported in a fatal case of phenolphthalein poisoning (Sidhu et al, 1989).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL URINE
    1) URINE COLOR - Phenolphthalein or danthron ingestion will turn alkaline urine red (Reynolds, 1989). Liver damage from senna caused dark urine (Beuers et al, 1991).
    B) ABNORMAL RENAL FUNCTION
    1) CHRONIC TOXICITY
    a) CHRONIC LAXATIVE ABUSE may result in renal damage from chronic hypokalemia (Wright & DuVal, 1987).
    C) KIDNEY STONE
    1) AMMONIUM URATE RENAL CALCULI were seen in women who had chronic laxative abuse (mostly of phenolphthalein). These patients also had decreased fluid volumes, sodium, citrate, and potassium. These calculi, in sterile urine, may be diagnostic for laxative abuse (Dick et al, 1990).
    D) LEUKORRHEA
    1) VAGINAL COLOR - Orange vaginal secretions have been reported after use of large amounts of DANTHRON (Greer, 1984).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Phenolphthalein poisoning has resulted in lactic acidosis secondary to hypotension (Buchanan et al, 1976).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) CASE REPORT - Tolman et al (1976) reported leukopenia following the ingestion of danthron/dioctyl calcium sulfosuccinate (Tolman et al, 1976).
    B) DISSEMINATED INTRAVASCULAR COAGULATION
    1) CASE REPORT - Disseminated intravascular coagulation was reported in a fatal case of phenolphthalein overdose (Sidhu et al, 1989).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) ERYTHEMA MULTIFORME (STEVENS-JOHNSON) has been associated with phenolphthalein use (Abramowitz, 1918).
    B) FIXED DRUG ERUPTION
    1) WITH THERAPEUTIC USE
    a) FIXED DRUG ERUPTIONS have been reported following use of phenolphthalein (Stroud & Rosio, 1987; Chan, 1984).
    C) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 78-year-old man presented with a diffuse, urticarial rash over his trunk and extremities one day after taking one dose of an OTC laxative containing phenolphthalein 65 mg and docusate sodium 100 mg. Despite supportive care and discontinuation of other medications (furosemide, spironolactone, allopurinol, and hydroxyurea), the patient's lesions worsened five days post-ingestion. Biopsy of a lesion revealed full thickness epidermal necrosis consistent with toxic epidermal necrolysis. The patient gradually recovered following supportive treatment. The patient had developed a similar rash approximately 1.5 years earlier following ingestion of the same laxative product (Artymowicz et al, 1997).
    D) DISCOLORATION OF SKIN
    1) Danthron may color the perianal skin pink or red. A greyish-blue skin discoloration was reported in a nurse taking danthron (Darke & Cooper, 1978).
    E) BURN
    1) WITH POISONING/EXPOSURE
    a) 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).
    b) 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). 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).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) Rhabdomyolysis has been reported secondary to chronic abuse of SENNA laxatives, and is presumably due to hypokalemia (Wright & DuVal, 1987).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) Recurrent hypoglycemia was reported in a patient with severe hepatic injury from phenolphthalein overdose. Hypoglycemia correlated with levels of aspartate transaminase (Sidhu et al, 1989).

Reproductive

    3.20.1) SUMMARY
    A) Phenolphthalein is classified as FDA pregnancy category C. The citric acid, magnesium oxide, and sodium picosulfate combination is classified by its manufacturer as FDA pregnancy category B.
    B) One case of spontaneous membrane rupture with amniotic fluid embolism and cardiorespiratory arrest occurred following castor oil ingestion. Senna use during pregnancy is not associated with congenital abnormalities, according to a large population-based case-control study. Stimulant laxatives may pass into the breast milk of lactating women in small amounts but have not produced a cathartic effect in the infant.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) Senna use during pregnancy is not associated with congenital abnormalities, according to a large population-based case-control study. The case group involved 22,843 malformed fetuses or neonates (from the data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities), of whom 506 mothers (2.2%) were treated with oral senna at doses between 10 to 30 mg, most took 20 mg per day. There were 38,151 controls (newborns without congenital abnormalities), of these 937 (2.5%) were born to mothers treated with oral senna tablets (adjusted odds ratio (OR), 1; 95% confidence interval (CI), 0.9 to 1.1). Of the 836 malformed control cases with Down syndrome, 26 (3.1%) had mothers who used senna during the study (crude OR, 0.71; 95% CI, 0.47 to 1.05) (Acs, 2009).
    B) ANIMAL STUDIES
    1) Oral doses of the citric acid, magnesium oxide, and sodium picosulfate combination up to 2000 mg/kg/day (about 1.2 times the recommended human dose based on the body surface area) in pregnant rats did not result in any harm to the fetus or any adverse effect on pre and postnatal development. In rabbits, treatment-related mortalities were observed at all doses, however, the reproduction study was not adequate (Prod Info PREPOPIK(TM) oral solution, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) ABORTION
    1) CASE REPORT - Ingestion of 30 mL of castor oil to induce labor in a 33-year-old woman of 40-week gestation resulted in spontaneous membrane rupture 60 minutes postingestion. Amniotic fluid embolism and cardiorespiratory arrest ensued. The infant was stillborn and the mother remained in a persistent vegetative state secondary to anoxic injury (Steingrub et al, 1988).
    B) PREGNANCY CATEGORY
    1) Phenolphthalein is classified as FDA pregnancy category C (Briggs et al, 1998). The citric acid, magnesium oxide, and sodium picosulfate combination is classified by its manufacturer as FDA pregnancy category B (Prod Info PREPOPIK(TM) oral solution, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) MAGNESIUM OXIDE, CITRIC ACID, AND SODIUM PICOSULFATE COMBINATION
    a) It is unknown whether the citric acid, magnesium oxide, and sodium picosulfate combination is excreted in human milk (Prod Info PREPOPIK(TM) oral solution, 2012).
    B) BREAST MILK
    1) Stimulant laxatives may pass into the breast milk of lactating women in small amounts but have not produced a cathartic effect in the infant (Takyi, 1970).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma levels of these agents are not clinically useful or widely available.
    B) Monitor fluid and electrolyte balance in severely symptomatic patients.
    C) Monitor blood pressure and heart rate.
    4.1.2) SERUM/BLOOD
    A) Plasma levels of these agents are not clinically useful or widely available.
    B) Monitor fluid and electrolyte balance in severely symptomatic patients.
    C) Monitor blood pressure and heart rate.
    4.1.3) URINE
    A) URINARY LEVELS
    1) Qualitative urine screening using thin layer chromatography has been reported to be successful in detecting patients with surreptitious laxative abuse (Bytzer et al, 1989).
    a) Single doses of bisacodyl, phenolphthalein, or anthraquinones can be detected in urine for at least 32 hours (de Wolff et al, 1981).
    b) After chronic ANTHRAQUINONE ingestion, urine tests can be positive for up to 96 hours after the last dose (Bytzer & Klitgaard, 1986).

Methods

    A) CHROMATOGRAPHY
    1) A gas chromatographic-mass spectrometric (GC-MS) method was used to identify and quantitate a bisacodyl metabolite (bisacodyl diphenol) in the serum and urine of an 11-year-old boy. The lower limits of detection were 1 ng/0.2 mL for urine and 2 ng/0.2 mL for serum (Kudo et al, 1998).
    B) OTHER
    1) Alkalinization of 10 mL of urine with 2 mL of 0.1 N sodium hydroxide will produce a pink color in the presence of PHENOLPHTHALEIN. Further addition of alkali, to raise the pH above 9, will result in disappearance of the color (Devore et al, 1982).
    2) A purple Clinitest reaction with stool may also raise suspicion of the presence of PHENOLPHTHALEIN, but is not as reliable since the pH may exceed the indicator range (Devore et al, 1982).
    3) Definitive confirmation can be obtained by examining the urine with thin-layer chromatography.

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) All persons with significant toxicity, dehydration, and abnormal electrolyte levels should be admitted. Patients at risk for dehydration who cannot be relied upon for compliance and/or adequate follow-up treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients who are asymptomatic or have mild diarrhea after inadvertent overdose can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate overdose or severe diarrhea should be observed in a medical facility until free of moderate/severe symptoms.

Monitoring

    A) Plasma levels of these agents are not clinically useful or widely available.
    B) Monitor fluid and electrolyte balance in severely symptomatic patients.
    C) Monitor blood pressure and heart rate.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is generally not warranted as acute toxicity is self-limited.
    6.5.2) PREVENTION OF ABSORPTION
    A) Gastrointestinal decontamination is generally not warranted as acute toxicity is self-limited.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Plasma levels of these agents are not clinically useful or widely available.
    2) Monitor fluid and electrolyte balance in severely symptomatic patients.
    3) Monitor blood pressure and heart rate.
    B) DIARRHEA
    1) Rapid correction of fluid and electrolyte deficits with oral or IV fluid therapy and careful monitoring of intake and output are essential. Restrict solid food and maintain high fluid intake until diarrhea resolves. Oral fluid should consist of polyionic hypotonic solution containing appropriate electrolytes.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Systemic absorption of these drugs is limited. Methods to enhance elimination are not indicated.

Abstracts

Case Reports

    A) ADULT
    1) A 32-year-old woman with a history of laxative abuse presented after an overdose of a combination product containing phenolphthalein 60 mg, cascara 30 mg, aloin 2 mg, senna leaf 15 mg, and bisacodyl 2 mg per tablet. She had rectal bleeding secondary to a rectal polyp, iron-deficiency anemia, profuse diarrhea, vomiting, grand mal seizures, and coma. Disseminated intravascular coagulation subsequently developed, as well as fulminant liver failure, renal failure with myoglobinuria, adult respiratory distress syndrome, and myocardial failure. She expired 40 days later after a prolonged course of multi-organ failure (Sidhu et al, 1989).

Range Of Toxicity

Summary

    A) TOXICITY: The acute minimal toxic or lethal dose of these agents is not well established. SENNA: CHILDREN: After the inadvertent ingestion of 10 to 15 Ex-lax (senna-based laxative) chocolate tablets, a child developed superficial partial thickness burns in the perianal area and buttocks within 10 minutes of experiencing diarrhea. A man developed abdominal pain, jaundice, fatigue, and elevated liver enzymes following the daily use of an herbal laxative containing sennoside (15 to 30 mg/day) for over 3 months. Liver enzymes gradually improved and were within normal limits one month after sennoside was discontinued.
    B) THERAPEUTIC DOSE: BISACODYL: ADULTS: ORAL: 5 to 15 mg orally once daily up to 30 mg/day. RECTAL: 10 mg suppository per rectum once daily. CHILDREN: ORAL: 12 YEARS AND OLDER: 5 to 15 mg orally once daily up to 30 mg/day. 6 TO 11 YEARS OF AGE: 5 mg orally once daily. RECTAL: 12 YEARS AND OLDER: 10 mg suppository per rectum once daily. 6 TO 11 YEARS OF AGE: 5 mg (1/2 suppository). SENNA: ADULTS: GRANULES: 15 mg once a day, up to a maximum of 30 mg twice a day. LIQUID: For bowel preparation in adults: An entire content of one 2.5-ounce bottle (130 mg sennosides) on the day prior to the diagnostic procedure. SYRUP: 10 to 15 mL (8.8 mg/5 mL) once a day up to a maximum of 30 mL/day. TABLETS: 2 tablets (15 to 17 mg) once a day at bedtime, up to a maximum of 34 to 50 mg twice a day. SUPPOSITORIES: 1 suppository (652 mg standardized senna concentrate) at bedtime; repeat if necessary.

Therapeutic Dose

    7.2.1) ADULT
    A) SENNA
    1) GRANULES: 15 mg once a day, up to a maximum of 30 mg twice a day (Prod Info Senokot(R), 2000).
    2) LIQUID: For bowel preparation in adults: An entire content of one 2.5-ounce bottle (130 mg sennosides) on the day prior to the diagnostic procedure (Prod Info X-Prep(R), 2000).
    3) SYRUP: 10 to 15 mL (8.8 mg/5 mL) once a day up to a maximum of 30 mL/day (Prod Info Senokot(R) Syrup, 2003).
    4) TABLETS: 2 tablets (15 to 17 mg) once a day at bedtime, up to a maximum of 34 to 50 mg twice a day (Prod Info SENNA PLUS oral tablets, 2006; Prod Info Senokot(R), 2000; Prod Info Ex-Lax(R), 2000).
    5) SUPPOSITORIES: 1 suppository (652 mg standardized senna concentrate) at bedtime; repeat if necessary (Prod Info Senokot(R), 2000).
    B) BISACODYL
    1) ORAL: 5 to 15 mg orally once daily up to 30 mg/day (Prod Info bisacodyl delayed-release enteric-coated oral tablets, 2005; Prod Info Dulcolax(R), 2004).
    2) RECTAL: 10 mg suppository per rectum once daily (Prod Info DULCOLAX(R) rectal suppositories, 2004).
    7.2.2) PEDIATRIC
    A) BISACODYL
    1) ORAL: 12 YEARS AND OLDER: 5 to 15 mg orally once daily up to 30 mg/day (Prod Info bisacodyl delayed-release enteric-coated oral tablets, 2005; Prod Info Dulcolax(R), 2004).
    2) ORAL: 6 TO 11 YEARS OF AGE: 5 mg orally once daily (Prod Info bisacodyl delayed-release enteric-coated oral tablets, 2005; Prod Info Dulcolax(R), 2004).
    3) RECTAL: 12 YEARS AND OLDER: 10 mg suppository per rectum once daily (Prod Info DULCOLAX(R) rectal suppositories, 2004).
    4) RECTAL: 6 TO 11 YEARS OF AGE: 5 mg (1/2 suppository) (Prod Info DULCOLAX(R) rectal suppositories, 2004).

Minimum Lethal Exposure

    A) SPECIFIC SUBSTANCE
    1) PHENOLPHTHALEIN
    a) A 2-year-old child developed encephalomyelitis after ingesting between 650 and 1300 mg of phenolphthalein. Despite supportive care, the patient subsequently died approximately 8 days post-ingestion (Kendall, 1954).
    2) BISACODYL
    a) A 2-year-old child who ingested 15 to 20 tablets of bisacodyl was reported to develop pneumonia and erythema multiforme 4 days postingestion, and died 3 weeks postingestion of a ruptured coronary artery. The child had also been receiving aspirin and phenobarbital shortly before onset of symptoms (Tech Info, 1970).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) PHENOLPHTHALEIN
    a) ADULTS
    1) Ingestion of 2500 mg of phenolphthalein in an adult resulted in acute colitis, bloody stools and hypokalemia (Darrow, 1982).
    2) Ingestion of 2 grams of phenolphthalein by an adult male caused hypotension and acidosis (Buchanan et al, 1976).
    b) CHILDREN
    1) Ingestion of 1625 and 1800 mg by a 3-year-old, 780 mg and 915 mg by a 2-year-old (Blatt et al, 1943) resulted in mild laxation and abdominal pain (Orland, 1913).
    2) Ingestion of 8450 mg in a 2-year-old and 6240 mg in a 3.5-year-old also resulted in minimal symptoms (Blatt et al, 1943).
    3) Children aged 5 years and younger are at minimal risk of developing dehydration after ingesting one gram or less of phenolphthalein and do not require gastrointestinal decontamination (Mrvos et al, 1991).
    2) SENNA
    a) 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).
    b) 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 imporved and were within normal limits one month after sennoside was discontinued (Sonmez & Yilmaz, 2005).
    c) 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).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) PHENOLPHTHALEIN - A serum level of 0.4 micrograms/liter was reported in a fatal case of acute-on-chronic phenolphthalein overdose (Sidhu et al, 1989).
    b) BISACODYL - A bisacodyl diphenol (bisacodyl metabolite) serum level of 1.05 micrograms/milliliter was reported in an 11-year-old boy who developed severe diarrhea (over 5 liters/day) following continuous administration of bisacodyl by his mother. The patient's peak bisacodyl diphenol urine concentration was reported to be 91.2 micrograms/milliliter (Kudo et al, 1998).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) All of the stimulant cathartics increase motor activity of the intestinal tract and can cause griping, intestinal cramps, increased mucous secretions, and can produce excessive fluid evacuation even in normal doses.
    1) The intensity of the effect is usually proportionate to dosage.
    B) The mechanism of action is thought to be secondary to irritation of the intestinal mucosa.

Physicochemical

Physical Characteristics

    A) BISACODYL: White or almost white, odorless, crystalline powder.
    B) CASTOR OIL: Nearly colorless or slightly yellow, viscid oil with a slight odor and taste.
    C) DANTHRON: Orange, odorless, crystalline powder.
    D) PHENOLPHTHALEIN: White or yellowish-white, odorless, crystalline or amorphous powder.

Molecular Weight

    A) Varies

References

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