Senna

Scientific Name(s): Cassia acutifolia Delile, syn. with Cassia senna L. Also includes references to C. angustifolia Vahl. Family: Fabaceae (beans)

Common Name(s): Senna

Uses

Senna is most commonly used as a laxative.

Dosing

Senna leaves or pods have been used as a stimulant laxative at dosages of 0.6 to 2 g/day, with a daily dose of sennoside B from 20 to 30 mg. The brand Senokot is available in 8.6 and 17.2 mg tablets. A bitter tea can be made containing senna 0.5 to 2 g (ie, ½ to 1 teaspoon). Senna should not be used at higher doses or for extended periods of time.

Contraindications

Senna is contraindicated in patients with intestinal obstruction, ulcerative colitis, appendicitis, and Crohn disease. Senna is not recommended for children younger than 2 years of age.

Pregnancy/Lactation

Category C . Use with caution until more definitive information is known. Some data suggest endometrial stimulation and mutagenic and genotoxic effects with senna usage. Other sources suggest it is the laxative drug of choice in pregnancy.

Interactions

Use of senna with drugs known to deplete potassium, such as diuretics, should be limited or avoided. Because senna may cause diarrhea, caution is warranted in patients receiving warfarin, because diarrhea can reduce the absorption of vitamin K and increase the risk of bleeding.

Adverse Reactions

Senna may cause diarrhea, loss of fluids, hypokalemia, and abdominal pain/cramping. The long-term use of senna has resulted in pigmentation of the colon, reversible finger clubbing, cachexia, and dependency on the laxative. Children, particularly those wearing diapers, may experience severe diaper rash, blister formation, and skin sloughing. Case reports indicate a possible association between long-term administration of senna and hepatotoxicity.

Toxicology

Various case reports of senna toxicity are available and include coma and neuropathy after ingestion of a senna-combination laxative, as well as hepatitis after long-term use of the plant.

Botany

C. acutifolia is native to Egypt and the Sudan while C. angustifolia is native to Somalia, the Middle East, and India. Plants known as wild sennas ( C. hebecarpa Fern. and C. marilandica L.) grow on moist banks and in woods in the eastern United States. This plant should not be confused with cassia, a common name for cinnamon. Senna is a low branching shrub, growing to about 1 m in height. It has a straight woody stem and yellow flowers. 1 The top parts are harvested, dried, and graded. Tinnevally senna is hand-collected, while Alexandria senna is harvested and graded mechanically. There are over 400 known species of Cassia . 1 , 2

History

Senna was first used medicinally by Arabian physicians in the 9th century A.D. 1 The plant derives its name from the Arabic sena and from the Hebrew word cassia , which means “peeled back,” a reference to its peelable bark. It has long been used in traditional Arabic as well as European medicine, primarily as a cathartic. The leaves were brewed into a tea and administered as a strong laxative. Because it is often difficult to control the concentration of the active ingredients in the tea, an unpredictable effect may be obtained. Therefore, standardized commercial dosage forms have been developed, and these concentrates are available as liquids, powders, and nonprescription tablets in over-the-counter laxatives.

Chemistry

Senna contains anthraquinones, including dianthrone glycosides (1.5% to 3%), sennosides A and B (rhein dianthrones), and sennosides C and D (rhein aloe-emodin heterodianthrones). Numerous minor sennosides have been identified, and all appear to contribute to the laxative effect. The plant also contains free anthroquinones in small amounts including rhein, aloe-emodin, chrysophanol, and their glycosides. 3 , 4

Senna pods also contain the same rhein dianthrone glycosides as the leaves.

Carbohydrates in the plant include 2% polysaccharides and approximately 10% mucilage consisting of galactose, arabinose, rhamnose, and galacturonic acid. 3 , 4 Other carbohydrates include mannose, fructose, glucose, pinitol, and sucrose. 3

Flavonols present include isorhamnetin and kaempferol. Glycosides 6-hydroxymusizin and tinnevellin are also found.

Other constituents in senna include chrysophanic acid, salicylic acid, saponin, resin, mannitol, sodium potassium tartrate, and trace amounts of volatile oil. 3 , 5

Uses and Pharmacology

Senna is a potent laxative. Its cathartic effects can be obtained from a tea prepared from 1 or 2 teaspoons of dried leaves or standardized commercial dosage forms. Senna's use in treating constipation is well documented. It is one of the most popular laxatives, especially in elderly patients. 6

Approximately 90% of sennosides are excreted in the feces as polymers. Only 3% to 6% of the metabolites of sennosides are excreted in urine. 7

An in vitro study using Caco-2 monolayers as a model of the human intestinal mucosal barrier suggests that sennosides A and B are transported in a concentration-dependent manner. Transport was higher in the secretory direction compared with the absorptive direction, suggesting the involvement of efflux pumps in the intestine. 8

Laxative
Animal data

Senna has also been studied for long-term laxative treatment in rats. 9 Perivascular nerve stimulation caused a vasconstrictive effect on the mesenteric vascular bed. However, it is thought that myenteric neurons in the rat colon are not destroyed by sennosides, as had been previously suggested. 10 , 11 , 12 , 13 Anthraquinone purgatives in excess were said to have caused degeneration of neurons.

Sennosides exert their cathartic effect through alterations in colonic motility, which occurs indirectly by damage to the epithelial cells. They also change colonic absorption and secretion to cause fluid accumulation. Enhanced permeability is the result of disruption of the tight junctions between the colonic epithelial cells. 14

Metabolism of anthranoid laxatives 15 , 16 and sennosides 17 , 18 , 19 have been reported.

Clinical data

Many reports are available discussing senna's role in constipation 20 , 21 ; its use in elderly patients, 22 , 23 , 24 , 25 , 26 psychiatric patients, 27 and spinal cord injury patients 28 ; and in pregnancy, in which it is the stimulant laxative of choice. 29 In cancer treatment protocols, senna has also been noted to reverse the constipating effects of narcotics, and may prevent constipation if given with the narcotic. 30 However, it may cause more adverse effects than other laxatives, primarily abdominal pain. 31 In terminally ill patients with cancer, it has also demonstrated efficacy in preventing constipation, which may not only be attributable to opioids but potentially due to administration of tricyclic antidepressants or phenothiazines, physical inactivity, deficient nutrition, and/or inadequate fluid intake. 32 Senna has also been studied in long-term constipation. 33 Castor oil was superior to senna for long-term constipation sufferers in another report. 34 In a study of children younger than 15 years of age with constipation, the efficacy and adverse effects of senna were compared with lactulose. Lactulose use resulted in patients passing more normal stools than on the corresponding day of the senna week. Additionally, senna was associated with more adverse effects with greater frequency compared with lactulose. 35

Patients who underwent reconstructive pelvic surgery were randomized to receive senna 8.6 mg/docusate 50 mg or placebo following the surgery. There was a significant difference in time to first bowel movement (3 ± 1.5 vs 4.05 ± 1.5 days; P < 0.002) for patients receiving senna and docusate compared with placebo. Additionally, significantly more patients receiving placebo required magnesium citrate ( P < 0.001). 36 Senna may influence intestinal transit time. 37 , 38 , 39 Its effectiveness as part of a cleansing regimen to evacuate the bowels in preparation for colonoscopies or barium enemas is documented. 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 Results from these studies include reduced ingestion of commercial Golytely solution and simethicone when given with senna 45 and more effective colon cleansing with senna in combination with polyethylene glycol electrolyte lavage solution compared with the solution alone. 46 However, a study comparing the efficacy of PEG 2 L and senna syrup 120 mg with PEG 4 L found that the combination therapy was not as effective as the larger quantity of PEG, though it was better tolerated (ie, 38% could not finish the PEG 4 L compared with 6% receiving combination therapy). 53

A study of 345 patients undergoing colonoscopies assessed the efficacy of magnesium citrate combined with senna versus magnesium citrate alone. In patients receiving magnesium citrate only, 6.9% of the patients had to reschedule the colonoscopy due to inadequate bowel evacuation. In those patients receiving combination therapy, 4.4% required rescheduling ( P = 0.44). Adequate visualization during the colonoscopy occurred in 81.3% of patients receiving combination therapy compared with 67.5% receiving magnesium citrate alone ( P = 0.004). 51 When senna 180 mg was compared with 95 mL of sodium phosphate solution for bowel evacuation prior to colonoscopy, senna was not equivalent to sodium phosphate. However, senna was better accepted compared with sodium phosphate based on taste, and was associated with less nausea and vomiting. 54

Capsule endoscopies are useful for assessing obscure GI bleeding, suspected small-bowel Crohn disease, celiac disease, polyposis syndromes, and small-bowel tumor detection. Compared with standard preparation (ie, restriction to clear fluids, fasting, simethicone), the addition of purgatives, such as magnesium citrate and senna, did not improve completion rates or view quality and were associated with less patient acceptance. 55

Because sennosides are water-soluble polar molecules with a high molecular weight, they are not resorbed in the small intestine. Specifically, the beta-glycosidic bond provides protection against acid digestion and to alpha-glucosidase activity. Instead, they act as prodrugs as they pass through the small intestine. They are later converted in the large intestine by gut bacteria to the active metabolite, rheinanthrone, which increases colonic motility and fluid secretion. 1 , 7 , 56 , 57

Prostaglandins may also be involved in the laxative actions. 3 The kinetics of senna constituents rhein and aloe-emodin have been investigated in humans. 58

Other uses

The senna constituents, aloe-emodin and beta-sitosterol, possess inhibitory activity against cancer cells in mice. 2 , 9

Senna did not have antidiabetic activity when tested in diabetic mice. 59

Senna extract was not found to be cytotoxic or mutagenic against strains of Escherichia coli . However, senna was able to induce single and double-strand breaks in plasmid DNA, suggesting senna may only be toxic to DNA in cell-free systems. 60

Dosage

Senna leaves or pods have been used as a cathartic laxative at dosages of 0.6 to 2 g/day, with a daily dose of sennoside B from 20 to 30 mg. The brand Senokot is available in 8.6 and 17.2 mg tablets. 61 Effects usually occur within 8 to 12 hours of administration and may last up to 24 hours. 62 A bitter tea can be made containing 0.5 to 2 g (ie, ½ to 1 teaspoon) of senna. 2 Senna should not be used at higher doses or for extended periods of time. 63

Pregnancy/Lactation

Category C . The use of senna during pregnancy is controversial. Due to minimal absorption of senna glycosides by the intestines, a teratogenic effect would not be expected. However, prolonged use may cause fluid and electrolyte imbalances. 62

Some data suggest endometrial stimulation and mutagenic and genotoxic effects with senna usage. 64 , 65 Other sources suggest it is the laxative of choice during pregnancy. In a 2009 case-control epidemiological study, the use of senna was not associated with a higher risk of congenital abnormalities in the offspring of pregnant women with constipation. 62 However, until more definitive information is known, use with caution. 14

Interactions

Use of senna with drugs known to deplete potassium levels, such as diuretics, should be limited or avoided. Patients may be at an increased risk of cardiac complications. 63 Because senna may cause diarrhea, caution is warranted in patients receiving warfarin, because diarrhea can reduce the absorption of vitamin K and increase the risk of bleeding. In a case report, a woman 45 years of age with an aortic valve taking warfarin presented with abdominal pain. She had been taking senna once to twice per week; however, she took “many” tablets (unspecified) to relieve 2 days of constipation when her abdominal pain started. She reported 3 watery stools and 3 bloody stools. At the time of admission, she was hypotensive, tachycardic, and had a distended abdomen. A computed tomography of the abdomen revealed hematomas in the pelvic, paracolic, and subhepatic regions. Her international normalized ratio (INR), which was therapeutic 25 days prior to admission, was 11.9. She was given vitamin K, fresh frozen plasma, and packed red cells, and her INR eventually returned to the target range. 66

Adverse Reactions

Senna may cause loss of fluids, hypokalemia, diarrhea, and abdominal pain and cramping. 14 Prolonged use may alter electrolytes and thereby increase the risk for cardiac complications. Patients with intestinal obstruction should avoid senna. 3

Long-term use of any laxative, in particular irritant laxatives such as senna, often results in laxative dependency syndrome, characterized by poor gastric motility in the absence of repeated laxative administration. Other reports of laxative abuse include laxative-induced diarrhea 67 , 68 and osteomalacia and arthropathy associated with prolonged use of the product. 69

The long-term use of anthroquinone glycosides has been associated with pigmentation of the colon (melanosis coli). Several cases of reversible finger clubbing (enlargement of the ends of the fingers and toes) have been reported following long-term abuse of senna-containing laxatives. 70 , 71 , 72 One report described a woman who developed finger clubbing following ingestion of 4 to 40 Senokot tablets per day for approximately 15 years. 73 Clubbing reversed after the laxative was discontinued. The mechanism has been postulated to be related to either increased vascularity of the nail beds or a systemic metabolic abnormality secondary to long-term laxative ingestion. A case report describes a patient with anorexia nervosa using 50 to 100 tablets of senna daily for weight loss. She developed nephrocalcinosis, finger clubbing, and hypertrophic osteoarthropathy. Nephrocalcinosis was likely due to long-term ingestion of calcium (each senna tablet contained calcium 12.5 mg) in the presence of dehydration, resulting in low calcium excretion. This, in addition to a low body mass index, contributes to calcium phosphate retention. 74

Senna abuse has been associated with the development of cachexia and reduced serum globulin levels after long-term ingestion. 75

Case reports include occupational asthma and rhinoconjunctivitis from a factory worker exposed to senna-containing hair dyes 76 and asthma and allergy symptoms from workers in a bulk laxative manufacturing facility. 77 Another report describes urticaria, rhinoconjunctivitis, and wheezing occurring within 2 hours of an occupational exposure to airborne senna despite wearing a protective suit and respirator. 78

Senna may cause hepatotoxicity. This may be attributed to the exposure of the liver to high amounts of toxic metabolites of anthraquinone glycosides. 7

In a case report, a woman 42 years of age who boiled dried senna leaves and consumed 200 mL of the product each day for 2 years presented with a 5-day history of epigastric pain, vomiting, anorexia, fever, mildly elevated liver function tests, and iron deficiency anemia. She was diagnosed with portal vein thrombosis based on Doppler findings. Additionally, fluid loss and dehydration associated with long-term use of senna may have exerted negative effects on coagulation. 14

Another case report describes the development of subacute cholestatic hepatitis in a man 77 years of age who used senna 15 to 30 mg/day for 3 months. Discontinuation of the product resulted in a progressive decline in liver enzymes and bilirubin levels. 79

Children, particularly those wearing diapers, may experience severe diaper rash, blister formation, and skin sloughing. In a study of 88 exposures to senna, 33% displayed severe diaper rash, which was significantly worse for those wearing diapers ( P < 0.05). The presence of blisters and skin sloughing was also worse in children wearing diapers ( P < 0.05). Diarrhea occurred 5 to 6 hours after ingestion of senna, with skin lesion appearing 14 to 15 hours following ingestion. Thus, the dermatologic manifestations could be attributed to prolonged skin contact with stool or senna being present in later stools, causing an irritant effect on the skin. 80

Patients who are homozygous for the CYP2D6∗4 variant, and thus poor metabolizers for phase 1 hepatic detoxification reactions, may be at risk of hepatitis. The CYP2D6∗4 variant is common in approximately 10% of white people. 81

Toxicology

Concerns regarding the carcinogenicity of anthranoid laxatives have been raised. In a 2-year study, rats receiving senna dosages of 25, 100, and 300 mg/kg/day did not show any changes in several assessments, including hematology measures, tissue histology, and mortality ratio, when compared with the control rats. High doses of senna were associated with increases in water consumption, electrolyte changes, and increases in tubular basophilia and tubular pigment deposits in the kidneys. In fact, other animal data suggest that senna may have anticancer action. 56 , 82 , 83

An analysis of the literature from 2009 suggests: (1) senna is not associated with structural and/or functional changes in the enteric nerves, (2) long-term administration of senna is not associated with GI tumors or any other type in rats, (3) when dosed up to 300 mg/kg in rats for 2 years, senna was not carcinogenic, and (4) evidence does not show an increased risk of genotoxicity in patients treated with senna. 13

Risk assessment for senna's use during pregnancy has been addressed. 84 One review suggests senna to be the stimulant laxative of choice during pregnancy and lactation. 29 Uterine motility was not stimulated by sennosides in one report in pregnant ewes. 85 None of the breast-fed infants experienced abnormal stool consistency from their mothers' ingestion of senna laxatives. The constituent rhein, taken from milk samples, varied in concentration from 0 to 27 mg/mL, with between 89% and 94% of values no more than 10 mg/mL. 86 , 87 Nonstandardized laxatives are not recommended during pregnancy. 3

Toxicity studies separating toxic components of senna's anthraquinone derivatives have been performed. 88

Various case reports of senna toxicity are available and include coma and neuropathy after ingestion of a senna-combination laxative 89 and hepatitis after long- term use of the plant. 90

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