Clinical presentation and Management of Diarrhea

1- Osmotic diarrhea
Excess amount of poorly absorbed substances that exert osmotic effect --->> water is drawn into the bowels --->> Diarrhea.
Stool output is usually not massive
Fasting improve the condition.
Stool osmotic gap is high, > 125 mOsm/kg (loss of hypotonic fluid).
Can be the result of:
a- Malabsorption in which the nutrients are left in the lumen to pull in water
e.g. lactose intolerance.
Osmotic laxatives (are medicines that are used to treat constipation, they work by retaining fluid in the large bowel by osmosis).
Hexitols (poorly absorbed): (sorbitol, mannitol, xylitol). (Because hexitols are poorly absorbed).
Secretory diarrhea
There is an increase in the active secretion of water.
High stool output.
Lack of response to fasting.
Normal Stool osmotic gap < 100 mOsm/kg.
Can be the result of:
a- bacterial toxin ( E. coli , cholera) that stimulates the secretion of
anions.(most common) [Active secretion in the small intestine].
b- Enteropathogenic virus e.g. rotavirus and Norwalk virus.
Also seen in neuroendocrine tumors ( carcinoid tumor, gastrinomas)
Rectal villous adenoma

1. Pharmacotherapy for Diarrhea Dr. Govind Rankawat (Gold Medalist) MBBS, MD (General Medicine), FIDM, FICC Assi . Professor, Department of General Medicine SMS Medical College and attached hospital, Jaipur

2. A 53-year-old woman complains of acute diarrhea and severe abdominal pain. She was recently treated with broad-spectrum antibiotics for community- acquired pneumonia. A CBC shows a WBC count of 24,000/ μL . The patient subsequently develops acute gastroenteritis septic shock and dies. These findings are typical of which of the following gastrointestinal diseases? Crohn disease Diverticulitis Ischemic colitis Pseudomembranous colitis

3. D i a r r he a Mind Map: 1 - 2 - 3 - D iarr h ea Acute (<2 weeks) Persistent (2-4weeks) Chronic (>4 weeks) Osmotic Malabsorption Secretory B a c ter i a l t o xins Exudative (i n fl amm a t o r y ) Persists on fasting Motality-related Hy pe r mo t a litiy Diarrhea Causes Com p l i ca ti o n s T e s ts Pathophysiology of Diarrhea Categories

4. Diarrhea Introduction According to (WHO) “Diarrhea” is characterized by: 3 or more loose or liquid stools per day due to “Abnormally high fluid content of stool”. 200-300 gm. /day (of stool ). Why is it (important)? The loss of fluids through diarrhea can cause dehydration and electrolyte imbalances. Easy to treat but if untreated, may lead to death especially in children . The most important treatment in case of diarrhea is fluid replacement (hydration).

5. Fecal osmolality: As stool leaves the colon, fecal osmolality is equal to the serum osmolality. Under normal circumstances, the major osmoles are Na + , K + , Cl – , and HCO 3 - Stool osmotic gap (by measuring the osmotic gap, we can decide if the patient has osmotic diarrhea or not) Stool osmolality - 2 x (stool Na + stool K) REMEMBER: The serum osmolality is 290 mosm/kg. Normal fecal fluid values are : *Osmolality:~290 mOsm/kg *Na+: ~30 mmol/L * K+: ~75 mmol/L This means that the amount of Na+ and K+ is (low) but H2O is (high). “According to the formula”

6. 1- Osmotic diarrhea Excess amount of poorly absorbed substances that exert osmotic effect --- >> water is drawn into the bowels --- >> Diarrhea . Stool output is usually not massive Fasting improve the condition. Stool osmotic gap is high, > 125 mOsm/kg (loss of hypotonic fluid ). Can be the result of : a- Malabsorption in which the nutrients are left in the lumen to pull in water e.g. lactose intolerance. Osmotic laxatives ( are medicines that are used to treat constipation, they work by retaining fluid in the large bowel by osmosis). Hexitols (poorly absorbed): (sorbitol, mannitol, xylitol). (Because hexitols are poorly absorbed). “from Robbins” (in osmotic diarrhea, the diarrheal fluid is more than 50 mOsm more concentrated than plasma).

7. Secretory diarrhea There is an increase in the active secretion of water. High stool output. Lack of response to fasting. Normal Stool osmotic gap < 100 mOsm /kg . Can be the result of : a- bacterial toxin ( E. coli , cholera) that stimulates the secretion of anions. (most common) [Active secretion in the small intestine]. b- Enteropathogenic virus e.g. rotavirus and Norwalk virus. Also seen in neuroendocrine tumors ( carcinoid tumor, gastrinomas) Rectal villous adenoma

8. 3- Exudative (inflammatory) Results from the outpouring of blood protein, or mucus from an inflamed or ulcerated mucosa. Presence of blood and pus in the stool. [Using Fecal leucocyte test] Persists on fasting. Occurs with inflammatory bowel diseases, and invasive infections e.g. E. coli, Clostridium difficile and Shigella. Some bacterial infections cause damage by invasion of the mucosa. Many cause diarrhea with blood and pus in the stool (bacterial dysentery). The main organisms are: Campylobacter invades mucosa in the jejunum, ileum and colon, causing ulceration and acute inflammation. Salmonella typhi , S. paratyphi A, B, and C Shigella infections are mainly seen in young children . Enteroinvasive and enterohemorrhagic E. coli . “from Robbins” (Exudative diarrhea is due to inflammatory disease and characterized by purulent, bloody stool that continue during fasting).

9. 4- Motility- related Caused by the rapid movement of food through the intestines (hypermotility). Irritable bowel syndrome (IBS) – a motor disorder that causes abdominal pain and altered bowel habits with diarrhea predominating (is characterized by chronic relapsing abdominal pain and the pathogenesis is poorly defined).

10. Q 2. A 21 year old boy try to avoid his meal as he excuse that after meal frequency of stool increased. Which types of diarrhea you should suspect in this patient. Secretory Diarrhea Osmotic Diarrhea Inflammatory Diarrhea Hypermotiliy Diarrhea

11. Q 3. A 20 year old girl complain of large copious amount of stool 5 times a day from last 3 days. Which types of diarrhea you should suspect in this patient. Secretory Diarrhea Osmotic Diarrhea Inflammatory Diarrhea Hypermotiliy Diarrhea

12. Types of Diarrhea 1- Acute diarrhea: Causes of acute Diarrhea: Approximately 80% of acute diarrheas are due to infections (viruses, bacteria, helminths, and protozoa). o Viral gastroenteritis (viral infection of the stomach and the small intestine) is the most common cause of acute diarrhea worldwide. Food poisoning. Drugs (Antibiotic-Associated Diarrheas) . Others. Antibiotic-Associated Diarrheas: Diarrhea occurs in 20% of patients receiving Broad-Spectrum Antibiotics; about 20% of these diarrheas are due to Clostridium difficile  leading to pseudomembranous colitis. Rotavirus The cause of nearly 40% of hospitalizations from diarrhea in children under 5. Rotaviruses cause 50% of infantile diarrhea . Pseudomembranous colitis Occurs in patients received broad-spectrum antibiotics. Caused by Clostridium difficile (Gram-positive rods) Under the microscope , we will see fibrin and chronic Inflammatory cells.

13. 2- Chronic diarrhea: Causes of Chronic Diarrhea: Infection e.g. Giardia lamblia . AIDS often have chronic infections of their intestines that cause diarrhea. Post-infectious Following acute viral, bacterial or parasitic infections Malabsorption Inflammatory bowel disease (IBD) “ we will talk about it later ”. Endocrine diseases Colon cancer Irritable bowel syndrome (motility diarrhea). Giardia Lamblia: Cryptosporidiosis in AIDS: REMEMBER: Parasitic and protozoal infections affect over half of the world's population on a chronic or recurrent basis.

14. Q 4. A 1-year-old girl is brought to the emergency room by her parents who report that she had a fever and diarrhea for 3 days. The child’s temperature is 38°C (101°F). The CBC shows a normal WBC count and increased hematocrit. Which of the following microorganisms is the most likely cause of diarrhea in this young child? Cytomegalovirus Rotavirus Salmonella typhi Shigella dysenteriae

15. Q 5. Which of the following is the most common cause of chronic diarrhea Viral gastroenteritis Inflammatory bowel disease Food poisoning Antibiotic-Associated Diarrheas

16. Causes Of Diarrhea Acute Diarrhea Bacterial Viral Drug induced Nutritional Protozoal Chronic Diarrhea Tumors Diabetes Addison’s disease Hyperthyroidism Irritable bowel syndrome

17. COMMON CAUSES OF DIARRHEA- BACTERIA Vibrio cholera Shigella Escherichia coli Salmonella Campylobacter jejuni Yersinia enterocolitica Staphylococcus Vibrio parahemolyticus Clostridium difficile

18. COMMON CAUSES OF DIARRHEA- VIRUS Rotavirus Adenoviruses Caliciviruses Astroviruses Norwalk agents and Norwalk-like viruses

19. COMMON CAUSES OF DIARRHEA- PARASITE Entameba histolytica Giardia lamblia Cryptosporidium Isospora

20. COMMON CAUSES OF DIARRHEA-OTHERS Metabolic disease Hyperthyroidism Diabetes mellitus Pancreatic insufficiency Food allergy Lactose intolerance Antibiotics Irritable bowel syndrome

21. Drugs causing diarrhea 1) Laxatives 2) Antacids containing magnesium 3) Antineoplastic drugs 4) Antibiotics Clindamycin Tetracyclines Sulfonamides Any broad-spectrum antibiotic 5) Antihypertensives Methyldopa Angiotensin -converting enzyme inhibitors Angiotensin receptor blockers α -adrenergic receptor blockers

22. Drugs causing diarrhea (cont) 6) Cholinergic drugs Neostigmine 7) Cardiac agents Quinidine Digoxin 8) Nonsteroidal antiinflammatory drugs Misoprostol 10) Colchicine 11) Proton pump inhibitors 12) H2-receptor blockers

23. Q 6. Diarrhea that starts suddenly, often with vomiting and within 4 to 8 hours of eating, is a common feature of:   A. Inflammatory bowel disease   B. Appendicitis   C. Colon cancer   D. Food poisoning

24. Q 7. When a doctor tests a patient’s stool for fat, he or she suspects which of the following as the cause of the patient’s diarrhea?   A. Malabsorption   B. Gastroenteritis   C. Food poisoning   D. Irritable bowel syndrome

25. Complications of Diarrhea: Chronic diarrhea: Fecal Le u k o c y tes Present I n f l ammat o ry Diarrhea Fluids  Dehydration. Electrolytes  Electrolytes imbalance. Sodium bicarbonate  Metabolic acidosis. If persistent  Malnutrition. Tests useful in the evaluation of diarrhea: Acute diarrhea: Shigellosis, salmonellosis, Campylobacter or Yersinia infection, amebiasis). Toxin ( C difficile, E coli O157:H7). Inflammatory bowel diseases. Not P rese n t Noninflammatory Diarrhea Small bowel source Or colon but without mucosal injury. S t ool a na l ys i s O va, p a ras it es Positive Infection Nega t i ve Stool fat test Po s i t iv e Ma l absorp t i on N egat iv e Secretory or Noninfectious i n f l am m a t ory d i arrhea Quantitative stool for fat: Best screening test 72-hour collection of stool Positive test > 7 g of fat/24 hours. DO: -Serum Anti-tissue transglutaminase antibodies. -Anti-endomysial IgA antibodies. -Antigliadin antibodies to check for celiac disease. -Duodenal biopsy.

26. TRANSMISSION Most of the diarrheal agents are transmitted by the fecal-oral route Cholera: water-borne disease; transmitted through water contaminated with feces Some viruses (such as rotavirus) can be transmitted through air Nosocommial transmission is possible Shigellosis (blood dysentery) is mainly transmitted person-to-person.

27. LABORATORY DIAGNOSIS Stool microscopy Dark field microscopy of stool for cholera Stool cultures ELISA for rotavirus Immunoassays, bioassays or DNA probe tests to identify E. coli strains

28. Treatment of diarrhea Non-pharmacologic therapy: Dietary management: Discontinue consumption of solid foods and dairy products for 24 h (valuable in osmotic diarrhea) For patients who are experiencing nausea and/or vomiting, a mild, digestible, low-residue diet should be administered for 24 hours. If vomiting is present and uncontrollable with antiemetics , nothing is taken by mouth. As bowel movements decrease, a bland diet is begun. Rehydration and maintenance of water and electrolytes

29. Treatment of dehydration Increase fluid intake (fruit juice – contain glucose and potassium) Oral rehydration solution (ORS). The WHO formula contains glucose, sodium, potassium, chloride and bicarbonate in an isotonic fluid. Glucose concentrations between 80 – 120 mmol /L are needed to optimize sodium absorption in the small intestine. Sodium concentration = 75 mmol /L (higher concentrations may cause hypernatremia ) Dose in mild/moderate diarrhea for adults: 2L/first 24 h followed by 200 ml per each loose stool

30. Why Reduced osmolarity ORS? 39% reduction in need for IVF 19% reduction in stool output 29% lower incidence of vomiting Risk of hyponatremia not significant in any type of diarrhea . 39

31. Home-Made ORS Home-made ORS: Sugar or molasses (40 g) can be used as a substitute for glucose to prepare home-made ORS. Common salt (5 g) will be added to it and dissolved in one liter of clean water. Rice-ORS: Rice powder (50 g) can replace the sugar or glucose. The amount of the other salts will remain the same. These will be dissolved in one liter of clean water to prepare rice-based ORS. Studies showed that rice-based ORS can reduce vomiting and diarrhea more in some cases compared to the conventional ORS prepared with glucose.

32. Zinc in Diarrhea Zinc has an additional modest benefit Reduces stool volume. Reduces duration of diarrhea. 29/08/2024 Takvani 42

33. Zinc in Diarrhea Dose: Elemental Zinc 20 mg/day for 6months and older for 14 days 10 mg/day Between 2-6 months. Any of zinc salts e.g ., sulphate , gluconate or acetate may be used.

34. Antidiarrheal agents Indications of antidiarrheal agents: Patients with mild to moderate acute diarrhea Control chronic diarrhea caused by IBS or IBD Contraindications: Patients with bloody diarrhea, fever or systemic toxicity (risk of worsening of the underlying condition) Discontinued in patients whose diarrhea is worsening despite therapy

35. Treatment of diarrhea Pharmacologic therapy: Drugs used for the treatment of diarrhea include Antimotility agents Adsorbents Antisecretory compounds Antibiotics Enzymes Intestinal microflora .

36. Antimotility agents ( opioids ) Opioids agonists: Action in the GIT (mediated by binding to opioid receptors) Increase segmentation and a decrease propulsive movement → ↑ intestinal transit time → ↑ absorption of water and electrolyte → feces become more solid Antisecretory ↑ tone of the internal anal sphincter ↓ response to the stimulus of a full rectum (by their central action)

37. Antimotility agents (cont) Mechanism of opioid action: Inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses

38. Opioiods - Diphenoxylate Opioid agonist that has no analgesic properties in standard doses. Higher doses have central opioid actions. Used in combination with a subtherapeutic dose of atropine (to prevent abuse) Contraindications: Children below 2 y (toxicity at lower doses than adults) Obstructive jaundice Drug interactions: Potentiate the effects of CNS depressants Co-administration with MAO inhibitors→ hypertensive crises Adverse effects: Caused by the atropine in the preparation and include anorexia, nausea, pruritus , dizziness, and numbness of the extremities. Prolonged use of high doses may cause dependence

39. Opioids - Loperamide Opioid agonist that does not cross the blood-brain barrier and has no analgesic properties and no potential for addiction Adverse effects : Abdominal pain and distention, constipation, dry mouth, hypersensitivity, and nausea and vomiting.

40. Antidiarrheals: Mechanism of Action Adsorbents Coat the walls of the GI tract Bind to the causative bacteria or toxin, which is then eliminated through the stool Examples: bismuth subsalicylate (Pepto-Bismol), kaolin-pectin, activated charcoal, attapulgite (Kaopectate)

41. Adsorbents 1. Kaolin and Pectin: Kaolin (hydrated magnesium aluminum silicate), often combined with pectin (indigestible carbohydrate). Mechanism of action: Adsorb bacterial toxins and fluid Indications: Acute diarrhea (given after each loose bowel movement) Adverse effects: Not absorbed and has no adverse effects.

42. Adsorbents (cont) 2. Bismuth subsalicylate: Insoluble complex of bismuth and salicylate Mechanism of action: Bismuth: antimicrobial Salicylate : antisecretory Adverse effects: blackening of tongue and stools

43. Octreotide ( somatostatin analogue) Mechanism of the anti-diarrheal action: 1. It inhibits the secretion of many GIT hormones, including gastrin, cholecystokinin, glucagon, insulin, secretin, pancreatic polypeptide, vasoactive intestinal peptide, and 5-HT3. 2. It reduces intestinal fluid secretion and pancreatic secretion. 3. It slows gastrointestinal motility and inhibits gallbladder contraction. 4. It induces direct contraction of vascular smooth muscle, leading to a reduction of portal and splanchnic blood flow.

44. Octreotide ( somatostatin analogue) Indications in diarrhea: Secretory diarrhea due to carcinoid tumor 2. Diarrhea due to vagotomy 3. Diarrhea caused by short bowel syndrome or AIDS.

45. Octreotide ( somatostatin analogue) Adverse effects: Steatorrhea leading to fat-soluble vitamin deficiency (due to impaired pancreatic secretion) Nausea, abdominal pain, flatulence, and diarrhea due to alterations in gastrointestinal motility Gall bladder sludge, gall stones or cholecystitis due to inhibition of gallbladder motility Hyperglycemia Bradycardia .

46. Antidiarrheals: Mechanism of Action (cont'd) Anticholinergics Decrease intestinal muscle tone and peristalsis of GI tract Result: slowing the movement of fecal matter through the GI tract Examples: belladonna alkaloids (Donnatal), atropine

47. Antidiarrheal Agents: Side Effects (cont'd) Anticholinergics Urinary retention, hesitancy, impotence Headache, dizziness, confusion, anxiety, drowsiness Dry skin, rash, flushing Blurred vision, photophobia, increased intraocular pressure

48. Intestinal Flora Modifiers( Probiotics ) Nonpathogenic micro-organisms. Exert a positive influence on the health or physiology of the host. They consist of either yeast or bacteria, Lacto-bacillus Acidophilus

49. Probiotics in the Treatment of Diarrhea Mechanisms: Protect the intestine by competing with pathogens for attachment. Strengthening tight junctions between enterocytes 3. Enhancing the mucosal immune response to pathogens.

50. Antimicrobials Indications: Patients with + ve stool culture Patients presented with dysentery Patients with suspected exposure to bacterial infection.

51. Antibiotic in Acute Dysentery Cotrimoxazole has been recommended as the first line drug for acute bloody diarrhea. High resistance of shigella to cotrimoxazole has been reported. 29/08/2024 Takvani 62

52. Antibiotic in Acute Dysentery Resistance rates to cotrimoxazole exceed 30% Cefixime 20mg/kg/day 5-7 days should be used instead of quinolones . If No response to cefixime in 3 days:; Ceftriaxone 50-100mg/kg od for 2-5 days. 29/08/2024 Takvani 63

53. Antibiotic in Acute Dysentery Metronidazole/Tinidazole should be used when cases of acute dysentery fail to respond to second line drugs for dysentery such as cefixime or when a stool examination has confirmed trophozoites of Entamoeba hystolitica.

54. Antidiarrheal Agents: Interactions Adsorbents decrease the absorption of many agents, including digoxin , clindamycin , quinidine , and hypoglycemic agents Adsorbents cause increased bleeding time when given with anticoagulants Antacids can decrease effects of anticholinergic antidiarrheal agents

55. Thank you