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  1. 1. Racecadotril Race to Control Mortality and Morbidity in Diarrhoea
  2. 2. Defining - Diarrhoea / Dysentery <ul><li>Diarrhoea is a passage of 3 or more watery or loose stools within 24-hour period and bloating and abdominal discomfort. </li></ul><ul><li>Maybe with / without fever and dehydration </li></ul><ul><li>But when there is frank blood or tinge of blood in the stools, it is called as dysentery </li></ul><ul><li>In both there are watery stools with or without abdominal pain, and what makes the difference is appearance of blood. </li></ul>
  3. 3. Defining – Intestine / Villi
  4. 4. Causes of Diarrhoea Viral infections Bacterial infections most cases of diarrhea, typically with mild-to-moderate symptoms and frequent, watery bowel movements, abdominal cramps, and low-grade fevers. cause the more serious cases of diarrhea Causes of Diarrhoea Gastro-enteritis is diarrhoea caused by bacteria
  5. 5. Diarrhoea - Current Strategies <ul><li>Preventive Measures </li></ul><ul><li>Oral Rehydration Therapy </li></ul><ul><li>Nutritional Therapy </li></ul><ul><li>Drug Therapy </li></ul>
  6. 6. Preventive Measures of Diarrhoea <ul><li>Breast feeding and improved weaning practices </li></ul><ul><li>Use of plenty, clean water for hygiene including hand washing and use of clean water for drinking </li></ul><ul><li>Promoting Hygiene Education. </li></ul><ul><li>Use of latrines & safe disposal of stools </li></ul>
  7. 7. Oral Rehydration Therapy <ul><li>Management of dehydration using sodium and glucose solution (ORS) in children with acute watery diarrhoea. </li></ul><ul><li>The use of ORS has reduced mortality from 5 million to 1.3 million annually (WHO, May 2002) </li></ul>
  8. 8. Nutritional Therapy <ul><li>Infant breast feeding - exclusive for the first 4-6 months reduce the episode of diarrhoea. Breast feeding should be supplemented with ORT in cases of diarrhoea. </li></ul><ul><li>For children with regular food diet who experience episodes of diarrhoea - continuation of regular food is advocated. </li></ul><ul><li>Recommendation for nutritional therapy depend on age and diet of the child. </li></ul>
  9. 9. Nutritional Therapy <ul><li>Continued feeding during episodes of diarrhoea leads to: </li></ul><ul><ul><li>decrease in stool output, </li></ul></ul><ul><ul><li>shortened duration of illness, </li></ul></ul><ul><ul><li>significant weight gain & </li></ul></ul><ul><ul><li>improved nutritional status. </li></ul></ul>
  10. 10. Drug Therapy <ul><li>Antibacterials / antiamoebics - strongly avoided unless it is confirmed infectious diarrhoea </li></ul><ul><li>Used in diagnosed cases of dysentery (bacillary and amoebic), cholera and typhoid fever. </li></ul><ul><li>Anti-motility properties of Loperamide and Diphenoxylate </li></ul><ul><ul><li>can cause complications in E. coli infections </li></ul></ul><ul><ul><li>may mask dehydration as fluid “pools” in intestine. </li></ul></ul><ul><li>Hence better avoided. </li></ul>
  11. 11. Commonly Used Drug Therapy <ul><li>ORT </li></ul><ul><li>Metronidazole / Tinidazole </li></ul><ul><li>Trimethoprim-sulfamethoxazole </li></ul><ul><li>Quinolones </li></ul><ul><li>Others </li></ul>
  12. 12. HIV Associated Diarrhoea pathogen- specific therapy General treatment to relieve symptoms HAART- Highly active antiretroviral therapy 3 forms of Treatment option
  13. 13. Newer Strategies <ul><li>Reduce the complications of fluid loss without the fear of side effects </li></ul><ul><li>Use Racecadotril </li></ul><ul><li>It exerts its antidiarrhoeal effects by preventing the breakdown of endogenous enkephalins in the gastrointestinal tract. </li></ul>
  14. 14. Racecadotril: What Is It? <ul><li>Racecadotril is an effective and safe treatment for acute diarrhoea in adults and children. </li></ul><ul><li>Racecadotril (acetorphan) is an enkephalinase inhibitor that decreases intestinal hypersecretion but not motility in animals and humans. </li></ul>
  15. 15. Study Details <ul><li>A study was conducted to assess whether i n acute watery diarrhoea, treatment with racecadotril and oral rehydration therapy is more effective than treatment with oral rehydration alone, in hospitalized children </li></ul>N Engl J Med 2000;343:463-7.
  16. 16. Dose In Study <ul><li>The dose of racecadotril was 1.5 mg per kilogram of body weight. This dose was chosen because it was similar to the adult dose in milligrams per kilogram and because a pharmacokinetic study in children found that plasma concentrations of the active metabolite of racecadotril remained higher than the concentration that inhibited 50 % of enkephalinase activity for up to 8 hours after oral administration. </li></ul>N Engl J Med 2000;343:463-7.
  17. 17. Stool Output <ul><li>Decreased </li></ul>N Engl J Med 2000;343:463-7.
  18. 18. Duration of Diarrhoea <ul><li>Decreased </li></ul>N Engl J Med 2000;343:463-7.
  19. 19. Intake of ORT <ul><li>The need for ORT in the racecadotril group as compared to the placebo group shows a greater reduction in requirements. </li></ul>N Engl J Med 2000;343:463-7.
  20. 20. Conclusions <ul><li>Hence, when used as an adjunct to oral rehydration therapy, racecadotril reduces </li></ul><ul><ul><li>the severity of diarrhea </li></ul></ul><ul><ul><li>the duration of diarrhea </li></ul></ul><ul><ul><li>and even the duration of hospitalization. </li></ul></ul>
  21. 21. New MOA of Racecadotril <ul><li>What is the MOA or the Mechanism Of Action of racecadotril? </li></ul><ul><li>The efficacy of racecadotril in the treatment of acute diarrhea is thought to be due to its inhibition of enkephalinase. </li></ul><ul><li>Racecadotril, through inhibition of enkephalinase, reinforces the physiological activity of endogenous enkephalins and, therefore, shows intestinal antisecretory activity. </li></ul>
  22. 22. What Is Enkephalinase? <ul><li>Enkephalinase is an enzyme, in the intestinal lining cells that bring about the inactivation of endogenous enkephalins and shorten their physiologic action. </li></ul>
  23. 23. What Are Enkephalins? <ul><li>The enkephalins are endogenous opiate substances that act as neurotransmitters in the gastrointestinal tract by activating the delta -opiate receptors and thus reducing the level of cyclic AMP. </li></ul><ul><li>What is the outcome of this action? </li></ul><ul><li>The result is reduced secretion of water and electrolytes without any detectable effect on intestinal motility. </li></ul>
  24. 24. What Are Endogenous Opiates? <ul><li>The body contains 3 types of endogenous opioids but mostly in the nervous system: </li></ul><ul><ul><li>beta-endorphins, </li></ul></ul><ul><ul><li>enkephalins, and </li></ul></ul><ul><ul><li>dynorphins. </li></ul></ul><ul><li>These Endogenous opioid peptides or opiates function as neurotransmitters acting on the opiate receptors </li></ul><ul><li>The enkephalins, are also located in the enteric nervous system and participate in the regulation: </li></ul><ul><ul><li>of visceral sensitivity as well as several </li></ul></ul><ul><ul><li>visceral motor function induced by the myoenteric reflexes. </li></ul></ul>
  25. 25. Types of Opiate Receptors <ul><li>Each receptor type binds differently with the various opioids </li></ul><ul><li>Enkephalins act by binding to the delta receptors </li></ul><ul><li>Loperamide binds to the mu-receptors </li></ul><ul><li>Mu receptors influence motility and delta receptors influence secretion </li></ul>mu - subtypes mu-1 and mu-2 kappa delta sigma 5 distinct types of opioid receptors are found in the body epsilon
  26. 26. What Can Happen… <ul><li>What is the normal role of enkephalinase and what can happen if enkephalins are not destroyed after their physiological action? </li></ul><ul><li>The enkephalins reduce secretion of water and electrolytes and if this happens continuously without stopping [without enkephalinase acting], the patient will get constipated. </li></ul>
  27. 27. Advantages of Racecadotril <ul><li>Racecadotril has antisecretory actions only when hypersecretion is present, not in the basal state. </li></ul><ul><li>The efficacy and safety of racecadotril as an adjuvant to ORT has also been demonstrated in infants and very small children with less severe diarrhea. </li></ul><ul><li>Racecadotril is effective in children with rotavirus-associated diarrhea, a condition caused mainly by malabsorption. </li></ul>
  28. 28. Significance of Racecadotril <ul><li>Racecadotril is effective in rotavirus-associated diarrhea, where there is malabsorption. </li></ul>
  29. 29. Pharmacokinetics of Racecadotril <ul><li>After oral administration, racecadotril is rapidly absorbed and entirely metabolized to its active metabolite thiorphan. </li></ul><ul><li>The activity on plasmatic enkephalinase appears 30 min after the administration. </li></ul><ul><li>The peak plasma concentration of thiorphan is reached 60 min after administration of a single oral dose of racecadotril. </li></ul><ul><li>The biological half-life of enkephalinase activity is 3 h. </li></ul>
  30. 30. Dosage Of Racecadotril <ul><li>In adults, adequate plasmatic levels are maintained with the administration of 100 mg of racecadotril every 8 h, and are not modified by repeated administration or in aged patients. </li></ul><ul><li>A pharmacokinetics study in children indicated that the administration of 1.5 mg/kg of racecadotril every 8 h is adequate. </li></ul>
  31. 31. What About Loperamide? <ul><li>Loperamide is an opiate drug currently recommended for the treatment of diarrhea, and seems to act largely by activating µ-opiate receptors, </li></ul><ul><li>This leads to an increase in intestinal transit time as a result of disruption of normal peristaltic motion. </li></ul><ul><li>Side effects associated with the use of these drugs include constipation, bacterial overgrowth, and toxic megacolon. </li></ul>
  32. 32. Comparison With Loperamide <ul><li>Racecadotril resolves the symptoms of acute diarrhoea rapidly and effectively, with </li></ul><ul><ul><li>more rapid resolution of abdominal symptoms and </li></ul></ul><ul><ul><li>less constipation than loperamide. </li></ul></ul><ul><li>Racecadotril is as effective as loperamide but with fewer adverse effects </li></ul>Scand J Gastroenterol. 2002 Jun;37(6):656-61, A multinational comparison of racecadotril and loperamide in the treatment of acute watery diarrhoea in adult by Prado D; Global Adult Racecadotril Study Group, Hospital Centro Medico, Guatemala City, Guatemala.
  33. 33. Racecadotril: Summary <ul><li>Racecadotril Reduces Hypersecretion </li></ul><ul><li>Racecadotril prevents loss of water and electrolytes </li></ul><ul><li>Racecadotril is effective in acute diarrhoea in infants, children and adults </li></ul><ul><li>Racecadotril has been well tolerated in all age groups </li></ul><ul><li>Racecadotril shows promise in chronic diarrhoea such as in HIV-associated diarrhoea. </li></ul>
  34. 34. Racecadotril: Potential Limitations <ul><li>Supplements rather than replaces the requirement for oral rehydration therapy </li></ul><ul><li>May not be effective against diarrhoea caused by cryptosporidium that occurs in HIV patients. </li></ul>
  35. 35. Conclusion <ul><li>Most of the mortality and morbidity associated with diarrhoea can be avoided if patients & doctors understand: </li></ul><ul><ul><li>The preventive measures </li></ul></ul><ul><ul><li>The theraputic interventions of management; & </li></ul></ul><ul><ul><li>How to recognise the danger signs. </li></ul></ul>