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DRUG RECORD

 

SENNA

(CASSIA SPECIES)

OVERVIEW
Senna

 

Introduction

Senna is a popular herbal laxative that is available without prescription.  Senna is generally safe and well tolerated, but can cause adverse events including clinically apparent liver injury when used in high doses for longer than recommended periods.

 

Background

Senna belongs to a large genus of flowering plants found throughout the tropics, commonly used species being Cassia acutifolio (Alexandrian senna) and C. angustifolio (Indian or Tinnevelly senna).  Extracts of the leaves, flowers and fruit of senna have been used for centuries in folk medicine as a laxative and stimulant.  Senna is also included in several herbal teas, used for purging and in weight loss.  The active components in senna extracts are anthraquinone derivatives and their glucosides, referred to as senna glycosides or sennosides.  They appear to act as a local irritant on the colon, which promotes peristalsis and evacuation.  Senna may also enhance intestinal fluid accumulation and increase the moisture content of stool by inhibiting electrolyte and water reabsorption from the colon.  Senna is minimally absorbed.  Senna is used in many over-the-counter laxatives in combination with other agents under trade names such as Ex-lax, Fletcher’s Castoria and Senokot.  The typical dose is 15 to 30 mg of sennosides twice a day, but is recommended for short term use only (less than one week).  Side effects include abdominal cramps and electrolyte imbalance.  Long term use or abuse can lead to “cathartic” colon with diarrhea, cramps, weight loss and darkened pigmentation of the colonic mucosa.

 

Hepatotoxicity

Use of senna in the recommended doses for a limited period of time has been associated with few side effects, most of which are mild and transient and related to its laxative action.  With longer term and higher dose use of senna, however, adverse events have been described including several cases of clinically apparent liver injury.  The time to onset of liver injury was usually after 3 to 5 months of use, and the pattern of serum enzyme elevations was hepatocellular.  The liver injury was usually mild-to-moderate in severity and resolved rapidly with discontinuation.  In at least one instance, reexposure led to rapid recurrence of liver injury.  Immunoallergic features and autoimmune markers were not present in the published cases.

 

Mechanism of Injury

The liver injury due to senna has been attributed to the anthraquinone derivatives present in the herbal extract, but the clinical characteristics of the published cases suggest an idiosyncratic rather than direct hepatotoxic etiology.  Other anthraquinones used to treat constipation have been implicated in causing liver injury with long term use, including cascarosides (cascara) and hydroxyanthraquinone.

 

Outcome and Management

Liver injury from long term senna use is rare, and most cases have been self-limited and rapidly reversible upon stopping the laxative.  However, cases with a severe course with signs of acute liver failure have been described.  There is no evidence of cross sensitivity to hepatic damage with other laxatives.  Restarting senna has been associated with recurrence of liver injury and should be avoided.

 

Drug Class:  Herbal and Dietary Supplements

 

Other Drugs in the Subclass, Anthraquinones:  Cascara

 

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REPRESENTATIVE TRADE NAMES
Senna – Generic

 

DRUG CLASS
Herbal and Dietary Supplements

 

SUMMARY INFORMATION

Fact Sheet at MedlinePlus/Natural Medicines Comprehensive Database

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Senna 8013-11-4 Herbal mixture Not Applicable

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REFERENCES
Senna and Cascara

 

References updated: 20 December 2013

  1. Zimmerman HJ. Unconventional drugs. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott,1999: pp. 731-4.  (Expert review of hepatotoxicity published in 1999; senna is not discussed).

  2. Seeff L, Stickel F, Navarro VJ. Hepatotoxicity of herbals and dietary supplements. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 631-58.  (Review of hepatotoxicity of herbal and dietary supplements [HDS]; senna is not discussed).

  3. Senna. In, PDR for Herbal Medicines. 4th ed. Montvale, New Jersey: Thomson Healthcare Inc. 2007: pp. 743-7.  (Compilation of short monographs on herbal medications and dietary supplements).

  4. Tolman KG, Hammar S, Sannella JJ. Possible hepatotoxicity of Doxidan. Ann Intern Med 1976; 84: 290-2. PubMed Citation  (24 year old man developed fatigue 6 months after starting Doxidan [containing hydroxyanthraquinone for chronic constipation] and at 12 months developed nausea and syncope [bilirubin 0.8 mg/dL, AST 560 U/L, Alk P 339 U/L, ANA negative, slight neutropenia], liver biopsy showing chronic hepatitis, resolving within 1 month of stopping, recurring upon rechallenge).

  5. Beuers U, Spengler U, Pape GR. Hepatitis after chronic abuse of senna. Lancet 1991; 337: 372-3. PubMed Citation  (26 year old nurse taking high doses of senna alkaloids developed jaundice and pruritus [bilirubin not given, ALT 303 U/L, Alk P 227 U/L], resolving within a few weeks of stopping and recurring upon restarting [ALT >280 U/L]).

  6. Franz G. The senna drug and its chemistry. Pharmacol 1993; 47(Suppl 1): 2-6. PubMed Citation  (Senna is dried leaflets or fruits of Cassia senna, either acutifolia [Alexandrian] or angustifolia [Indian senna], native to Northern Africa, middle East and India, similar constituents including anthraquinone glycosides, called sennosides).

  7. Woolf GM. Senna-induced hepatotoxicity. Hepatology 1999; 550A: 1560. PubMed Citation  (48 year old man developed jaundice 3 days after starting cascara sagrada [bilirubin 11.8 mg/dL, ALT 999 U/L, Alk P 309 U/L, ANA 1: 640] developing ascites, but recovering in 3 months).

  8. Nadir A, Reddy D, Van Thiel DH. Cascara sagrada-induced intrahepatic cholestasis causing portal hypertension: case report and review of herbal hepatotoxicity. Am J Gastroenterol 2000; 95: 3653-7. PubMed Citation  (48 year old man developed jaundice 3 days after starting cascara sagrada [bilirubin 11.8 mg/dL, ALT 999 U/L, Alk P 309 U/L, ANA 1: 640], developing ascites, but recovering within 3 months of stopping).

  9. Wurtz AS, Vial T, Isoard B, Saillard E. Possible hepatotoxicity from Copaltra, an herbal medicine. Ann Pharmacother 2002; 36: 941-2. PubMed Citation  (49 year old woman developed jaundice 3 months after starting Copaltra tea [Coutarea latiflora and Centaurium erythreae] for diabetes [bilirubin 20.8 mg/dL, ALT 3010 U/L, Alk P 132 U/L], with recovery in 3 months).

  10. De Smet PAGM. Herbal remedies. N Engl J Med 2002; 347: 2046-56. PubMed Citation  (Review of status and difficulties of herbal medications, including lack of standardization, federal regulation, contamination, safety, hepatotoxicity and drug-herb interactions; specific discussion of 4 herbs with therapeutic promise: ginkgo, hawthorn, saw palmetto and St. John’s wort).

  11. Stedman C. Herbal hepatotoxicity. Semin Liver Dis 2002; 22: 195-206. PubMed Citation  (Review and description of patterns of liver injury due to herbs, including discussion of potential risk factors, and herb-drug interactions; senna is listed as causing liver injury).

  12. Schiano TD. Hepatotoxicity and complementary and alternative medicines. Clin Liver Dis 2003; 7: 453-73. PubMed Citation  (Comprehensive review of herbal associated hepatotoxicity; senna is not listed as causing hepatotoxicity).

  13. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. PubMed Citation  (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, including 7 [5%] for herbal medications, none attributed to senna).

  14. Ernst E. Risks of herbal medicinal products. Pharmacoepidemiol Drug Saf 2004; 13: 767-71. PubMed Citation  (Review of the adverse effects of over-the-counter herbal medications, focusing on the hepatotoxicity of kava, drug interactions with St. John’s wort, and contamination of traditional Chinese medications with heavy metals [arsenic, lead, mercury, thallium] and conventional western medications).

  15. Seybold U, Landauer N, Hillebrand S, Goebel FD. Senna-induced hepatitis in a poor metabolizer. Ann Inter Med 2004; 141: 650-1. PubMed Citation  (28 year old woman developed jaundice after drinking herbal tea containing senna leaves, with positive rechallenge [ALT ~1390 U/L, GGT ~190 U/L], with Rhein anthrone detectable in serum).

  16. Vanderperren B, Rizzo M, Angenot L, Haufroid V, Jadoul M, Hantson P. Acute liver failure with renal impairment related to the abuse of senna anthraquinone glycosides. Ann Pharmacother 2005; 39: 1353-7. PubMed Citation  (52 year old woman developed jaundice, acute liver failure, lactic acidosis, and phosphate loosing nephropathy after ingesting herbal tea made from senna fruits for 3 years [bilirubin 6.2 mg/dL, ALT 9160 U/L, INR 5.3], requiring temporary ventilator support, ultimately resolving).

  17. Sonmez A, Yilmaz MI, Mas R, Ozcan A, Celasun B, Dogru T, Taslipinar A, Kocar IH. Subacute cholestatic hepatitis likely related to the use of senna for chronic constipation. Acta Gastroenterol Belg 2005; 68: 385-7. PubMed Citation  (77 year old male developed jaundice after taking a senna preparation for constipation for 3 months [bilirubin 4.9 rising to 16.9 mg/dL, ALT 657 U/L, Alk P 160 U/L], resolving within 1 month of stopping the herbal).

  18. Bruguera M, Herrera S, Lazaro E, Madurga M, Navarro M, De Abajo FJ. [Acute hepatitis associated with consumption of Copalchi: a summary of 5 cases]. Gastroenterol Hepatol 2007; 30: 66-8. PubMed Citation  (Five cases of hepatotoxicity of Copalchi in 4 men and 1 woman ages 59 to 77 years, taking herb for 2-13 months [bilirubin 0.7-13 mg/dL, ALT 403-865 U/L, GGT 54-116 U/L], resolving after stopping in all 5).

  19. García-Cortés M, Borraz Y, Lucena MI, Peláez G, Salmerón J, Diago M, Martínez-Sierra MC, et al. Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry. Rev Esp Enferm Dig 2008; 100: 688-95. PubMed Citation  (Among 521 cases of drug induced liver injury submitted to Spanish registry, 13 [2%] were due to herbals, including one due to Cassia angustifolia [senna], with onset after 5 months [bilirubin 11.7 mg/dL, ALT 35 times ULN, Alk P 1.4 times ULN], resolving in one month).

  20. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 9% of cases were attributed to herbal medications, but none were linked to senna or cascara).

  21. Freeman HJ. "Melanosis" in the small and large intestine. World J Gastroenterol 2008; 14: 4296-9. PubMed Citation  (Pigment found in small and large intestine with long term anthracene laxative [cascara, senna, aloes and rhubarb], use is usually lipofuscin rather than hemosiderin or melanin and is present in macrophages in the lamina propria).

  22. Soyuncu S, Cete Y, Nokay AE. Portal vein thrombosis related to Cassia angustifolia. Clin Toxicol (Phila) 2008; 46: 774-7. PubMed Citation  (42 year old woman developed abdominal pain and was found to have portal vein thrombosis 2 years after starting daily use of tea made from dried senna leaves [bilirubin normal, ALT 81 U/L]).

  23. Jacobsen C, Semb S, Kromann-Andersen H. [Toxic hepatitis following consumption of the herbal medicinal product Cascara Sagrada]. Ugeskr Laeger 2009; 171: 3367-9. Danish. PubMed Citation  (49 year old woman developed jaundice 4 weeks after starting daily ingestion of cascara sagrada for constipation [bilirubin 8.4 rising to 24.6 mg/dL, ALT 944 U/L, ascites], resolving within 4 months of stopping).

  24. Vitalone A, Menniti-Ippolito F, Raschetti R, Renda F, Tartaglia L, Mazzanti G. Surveillance of suspected adverse reactions to herbal products used as laxatives. Eur J Clin Pharmacol 2012; 68: 231-8. PubMed Citation  (Among 519 adverse events attributed to herbals reported to an Italian registry between 2002 and 2011, 26 were related to herbal laxatives, including 3 cases of liver injury, 1 due to cascara and 2 to senna).

  25. Teschke R, Wolff A, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: a
    tabular compilation of reported cases. Liver Int 2012; 32: 1543-56. PubMed Citation  (A systematic compilation of all publications on the hepatotoxicity of specific herbals identified 185 publications on 60 different herbs, including three reports implicating senna: Beuers [1991], Seybold [2004], Vanderperen [2005]).

  26. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement
    hepatotoxicity. Aliment Pharmacol Ther 2013; 37: 3-17. PubMed Citation  (Systematic review of literature on HDS associated liver injury mentions that senna has been associated with at least 3 published cases of liver injury).

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OTHER REFERENCE LINKS
Senna
  1. PubMed logoRecent References on Senna

  2. Clinical Trials logoTrials on Senna

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