Drugs for constipation & diarrhoea

Pharmacology PPT

1. Pharmacotherapy for constipation and Diarrhoea By dr. Chintan Doshi

2. CONSTIPATION-PATHOPHYSIOLOGY Decreased intestinal and colonic motility and excessive fluid uptake. It is not a disease but a symptom that may result from a broad variety of underlying causes

3. CAUSES Congenital. Inadequate dietary fiber and fluid ingestion. Ignoring defecatory urge. Drugs and toxins. Neurogenic , metabolic and endocrine conditions. Structural abnormalities in the GI tract.

4. Non pharmacological approaches ↑ in roughage in daily diet ↑ in fluid intake ↑ in physical activity Not neglecting natures call Avoidance of constipating drug Correcting under lying pathology : vitamin B 1 deficiency, hypothyroidism, D.M

5. PHARMACOLOGICAL TREATMENT LAXATIVES or APERIENT : milder action , elimination of soft but formed stool. PURGATIVE or CATHARTIC : stronger action , resulting in more watery evacuation.

6. classification BULK FORMING STOOL SOFTENERS OSMOTIC STIMULANT

7. Bulk forming Dietary fiber: Bran, Psyllium ( Plantago ), Ispaghula , Methylcellulose Stool softener Docusates (DOSS), Liquid paraffin Stimulant purgatives (a) Diphenylmethanes Phenolphthalein, Bisacodyl , Sodium picosulfate

8. Contd. (b ) Anthraquinones ( Emodins ) Senna , Cascara sagrada (c) 5-HT4 agonist Prucalopride (d) Fixed oil Castor oil

9. contd Osmotic purgatives Magnesium salts: sulfate, hydroxide Sodium salts: sulfate, phosphate Sod. pot. tartrate Lactulose

10. LAXATIVES INDICATION: To treat constipation To avoid straining at stool in cases like hernia, CVS disease. Before or after any anorectal surgery In bedridden patients Before surgical, radiological and endoscopic procedure where empty bowel is desirable

11. BULK FORMING LAXATIVES 1. Dietary fiber: BRAN Content: unabsorable cell wall + cellulose, lignin, gums , pectins M/A: absorb water in intestine , swells, ↑ water content of faeces – soften it and facilitate colonic transit Bacterial degradation in colon of pectins → osmotically active products → water retention Fiber ↑ bacterial growth in colon: ↑ fecal mass

12. Advantage $ use First line approach for simple constipation Prevention of functional constipation Bind bile acid and ↑ fecal excretion → degradation of cholesterol in liver ↑→ plasma LDL ↓ ↓ recto sigmoid intraluminal pressure: relives symptom of IBS ( pain , constipation)

13. Contd … Side effects and drawbacks: Unpalatable Effect appears in 1-3 days Do not soften already formed stool Flatulence Not to be used in ptn with : gut ulceration, adhesions , stenosis - faecal impaction

14. 2.Physllium and ispaghula Natural colloidal mucilage → absorb water to form gelatinous mass Ispaghual (3-8g) mixed with cold water or juice Effect: 1-3 days Not to be swallowed dry: esophageal impaction

15. 3. methycellulose Semisynthetic Collodial , hydrophilic derivative DOSE:4–6 g/day

16. Stool softener 1. docusates ( dioctyl sodium sulfosuccinate : DOSS) M/A : anionic detergent , soften the stools by net water accumulation in the lumen Emulsifies the colonic content :↑ water entry into feaces Dose : 100-400 mg orally/day Latency period: 1-3 days Use : straining at stool to be avoided

17. Contd … Side effects: Bitter taste: nausea Cramps , abdominal pain Hepatotoxicity ( prolonged use) Caution: ↑ absorption of liquid paraffin , should not be given together

18. 2. Liquid paraffin M/A: pharmacologically inert Feacal lubricant Stool softener:↓ water absorption from stool. Dose: 15-30ml/day Latency: 1-3 days Disadvantages: Unpalatable

19. Contd … Passes from intestinal mucosa→ lymph→ foreign body granulomas in lymph node, spleen , liver Lipid pneumonia Fat soluble vitamin deficiency Interfere with healing in anorectal region

20. STIMULANT PURGATIVE M/A: Direct ↑ in motility by action on myentric plexus Fluid accumulation in gut by following : inhibit Na-K ATPase of villous cells- impairing electrolyte and water absorption ++ adenyl cyclase in crypt cell- ↑ water and electrolyte secretion ↑ PG synthesis in mucosa : ↑ secretion

21. Contd … ↑ structural injury to absorbing intestinal mucosal cells ↑ NO synthesis : ↑ secretion and inhibit non propulsive contractions in colon

22. disadvantages Larger dose : excessive purgation , fluid and electrolyte imbalance Hypokalemia Long term use: colonic atony C/I in pregnancy C/I : in acute and subacute intestinal obstruction

23. 1.Diphenophthalein Bisacodyl : M/A: activated in intestine by deacetylation Primary site : colon → irritate mucosa, mild inflammation → secretion ↑ Semi formed stool : 6-8hrs Dose : 5-15 mg S/E : abdominal cramps ,Skin rash, FDE

24. CONTD… 2. Sodium picosulfate : Activated in colon → stimulate peristalsis, water and electrolyte reabsorbtion Dose : 5-10mg Latency:6-8 hrs S/E : colonic atony , hypokalemia

25. 2.anthraquinones( senna , cascara) M/A: plant purgative ( anthraquinone glycoside)→ reach colon →bacterial action → anthrol ( active), which act: Locally Absorbed into circulation , excreted in bile and act on small intestine Active principle : myentric plexus to ↑ peristalsis and segmentation Latency: 6-8 hrs

26. Contd … S/E: Skin rashes Fixed drug eruption Colonic atony Mucosal pigmentation

27. OTHER DRUGS PRUCALOPRIDE: M/A: selective 5 –HT4 agonist→stimulate entric neurons → release Ach → cause propulsive contraction in ileum and colon Use : chronic constipation unresponsive to other drugs S/E : headache , dizziness, abdominal pain Dose: 2mg OD

28. TEGASEROD 5-HT4 receptor agoinst Withdrawn : ↑ risk of edema, stroke, heart attack Reason: affinity for 5-HT 1B/1D receptor

29. LUBIPROSTONE M/A : PG analogue →stimulate Cl channel in intestinal mucosa → ↑ secretion Use: constipation-predominant IBS

30. Caster Oil Oldest purgatives Obtained from the seeds of Ricinus communis M/O : Decreased intestinal absorption of water and electrolytes Enhanced secretion

31. Contd. Dose : 15–25 ml (adults) 5–15 ml (children) in morning Disadvantages: Unpalatability Frequent cramping Dehydration after-constipation Regular use: Damage intestinal mucosa

32. Osmotic purgative M/A : solute not absorbed in intestine→ retain water osmotically → distend bowel → ↑ peristalsis indirectly Mg ions release CCK → motility , secretion ↑ Mg sulfate: 5-15g , bitter in taste Mg hydroxide ( milk magnesia): 30 ml , effect in 2-3 hrs Na sulfate : 10-15 g

33. drawbacks Mg salts: C/I in renal insufficiency Na salts: C/I in CHF Fluid and electrolyte imbalance Unpleasant Watery stool and after constipation So, not preferred for treatment of constipation. Used before surgery or colonoscopy, food or drug poisoning, tapeworm infestation

34. lactulose Non absorbable and indigestible disaccharide ↑ fecal bulk by hydrophilic action and osmotic action Dose : 10 g BD Latency : 1-3 days S/E: Flatulence Cramps nausea

35. Diarrhoea Definition : diarrhea is too frequent , often too precipitate passage of poorly formed stools . WHO definition – 3 or more loose or watery stools in a period of 24 hrs Because of : ↓ water and electrolyte absorption ↑ secretion by intestinal mucosa ↑ luminal osmotic load Inflammation of mucosa and exudation into lumen

36. management Treatment of fluid depletion , shock and acidosis Maintenance of nutrition Drug therapy

37. Rehydration 1. intravenous rehydration: Indication : Fluid loss is severe > 10% body weight Patient is loosing fluid>.10ml/kg/hr Unable to take orally DHAKA FLUID: Nacl : 5g(85mM) Kcl : 1g(13mM) 1L of water or 5% glucose NaHCO : 4g(48mM)

38. ORAL REHYDRATION THERAPY (ORT) Indication: in mild (5-7%BW) or moderate (7-10% BW) fluid loss Rationale of ORS composition : 1. should be isotonic and hypotonic 2.molar ratio of glucose should be more then sodium 3 enough K and bicarbonate should be provided to make up the losses Tri sodium citrate included in place of sodium bicarbonate

39. New formula WHO-ORS NaCl : 2.6 g KCl : 1.5g Trisod .citrate: 2.9 g Glucose : 13.5 g Water : 1L Total osmolarity: 245mOsm/L Na: 75mM K: 20mM Cl : 65mM Citrate: 10mM Glucose: 75 mM

40. Mechanism It capitalizes on the intactness of glucose coupled Na+ absorption, even when other mechanisms have failed or when intestinal secretion is excessive

41. CONTD… Advantages of the New ORS: lower osmolarity improves the efficacy of ORS reduces the need for unscheduled intravenous infusions lowers stool volume causes less vomiting compared with standard ORS

42. Contd. contents concentrations NaCl : 2.6 g Na+ — 75 mM KCl : 1.5 g K+ — 20 mM Trisod . citrate : 2.9 g Cl ¯ — 65 mM Glucose : 13.5 g Citrate — 10 mM Water : 1 L Glucose — 75 mM Total osmolarity 245mOsm/L

43. Non- diarrhoeal uses of ORT (a)Postsurgical, postburn and post-trauma maintenance of hydration and nutrition (in place of i.v . infusion). (b) Heat stroke. (c) During changeover from intravenous to enteral alimentation.

44. CONTD… . Administration: Initially 5-7% BW volume equivalent is given in 2-4hrs AIM: to restore and maintain hydration, electrolyte until diarrhoea stops

45. Zinc in pediatric diarrhoea reduces severity and duration of diarrhea  reduces stool output and frequency  reduces need for hospitalization prevents subsequent episodes of diarrhea Treatment Dose of Elemental Zinc: (14 days)  20 mg/kg/day children 6 month & above  10 mg/kg/day infants below 6 month

46. Mechanism Of Zinc Reduce fluid secretion in the intestine by indirectly inhibiting cAMP dependent Cl ¯ transport across the mucosa Strengthen the immune response Help regeneration of intestinal epithelium.

47. Drug therapy 1. antimicrobials in diarrhoea . A) no use : non infective diarrhoea Rota virus Coelic disease IBS Thyrotoxicosis

48. CONTD… B) useful only in severe cases : 1) travelers diarrhoea : ETEC Drugs: cotrimoxazole , norfloxacin RIFAXIMIN : oral rifamycin Recently approved by US-FDA for emperic therapy of travellers diarrhoea Dose: 200 mg TDS S/E: Flatulence, abdominal pain, headache

49. Contd.. Sheigella : when blood and mucus in stool Drugs: cipro / norfloxacin , cotrimaxzole Non typhoid salmonella : Fluroquinolones , cotrimaxzole Yersinia enterocolitica Cotrimoxazole , Ciprofloxacin

50. cholera Vibrio cholerae Tetracycline Ciprofloxacin Chloramphenicol Furazolidone Cotrimoxazole Erythromycin -

51. CONTD… Campylobacter jejuni : Drugs: norfloxacin , erythromycin Clostridium difficle : Antibiotic associated pseudomembranous colitis DOC: metronidazole Amoebiasis and giardiasis : metronidazole , diloxanide furoate

52. Probiotics … Commonly used: Lactobacillus sp. , bifidobacterium , streptococcus , enterococcus , Saccharomyces boulardii S/E: Infection Acidosis Caution in immunocompromised ptn

53. Antidiarrhoeal agents

54. OPOIDS( Contd …) M/A: stimulate mu receptor (↓ motility) and delta receptor (↓ intestinal secretion) Drugs: Loperamide : does not cross BBB, no addiction liability Dose: 4mg → 2mg after each loose stool Action onset: 1-2 hrs

55. Mechanism Of Action Peripheral μ opioid and additional weak anticholinergic property Inhibits secretion Adverse effects Abdominal cramps and rashes Paralytic ileus and Toxic megacolon with abdominal distension is a serious complication in young children

56. CONTRAINDIATIONS Children < 4 yr Acute infective diarrhoeas they delay clearance of the pathogen from the intestine Invasive organisms ( Shigella , EPEC, EH, etc.) are present increasing the risk of systemic invasion.

57. Uses Non infective diarrhoea Mild traveller’s diarrhoea Diarrhoea is exhausting Idiopathic diarrhoea in AIDS Low doses may be used for chronic diarrhoea in IBS

58. Contd. Induce short-term constipation-after anal surgery to reduce the volume, fluidity and bag cleaning frequency in ileostomy /colostomy patients

59. Contd.. Diphenoxylate : Dose : 2.5mg Along with atropine (0.025mg): to discourage abuse potential Use: travellers diarrhoea , prevent non specific diarrhoea .

60. Contd … S/E: Abdominal discomfort Dry mouth Not to be used with patients having colilits Children below 2 years (paralytic ileus )

61. Contd … Racecadotril : M/A: enkephalinase inhibitor→ ↑ local enkephlin conc → stimulate delta receptor in intestinal mucosa →↓ secretion without affecting motility Dose: 100-300mg TDS Use: acute secretary diarrhoeas S/E: nausea Constipation Headache.

62. 2 . anticholinergic M/A: ↓ bowel motility →↑fluid absorption →abdominal cramps↓ Drugs: Hyoscyamine Dicyclomine

63. Alpha 2 adrenergic receptor agoinst Clonidine (0.1mg BD, oral) facilitates absorption , inhibit secretion, ↑ intestinal transit time

64. octreotide M/A: Inhibit release of 5HT, gastrin , secretin , CCK →↓ GIT motility, intestinal fluid and electrolyte Use: for secretory diarrhoea Dose: 100 microgram BD S/E: nausea,abdominal discomfort Stone formation, hypothyroidism(long term use)

65. adsorbents Kaolin and pectin: Hydrated Mg –Al silicate M/A: adsorb bacteria, enterotoxin and fluid to ↑ consistency of fluid matter. Bismuth subsalicylate: M/A: ↓ Stool frequency in acute diarrhoea due to inhibition of PG synthesis and Cl secretion

66. Drugs for irritable bowel syndrome Introduction Constipation Diarrhoea Abdominal pain Bloating

67. Contd. Constipation predominant Diarrhoea predominant

68. Treatment Antidiarrhoeal drug Loperamide or diphenoxylate Fedotozine : Kappa antagonist Avoid of CNS side effect

69. CONTD. Pain Dicyclomine or hyoscine Inhibit M3 receptor Mebeverine: reserpine analogue Antispasmodic and devoid of anticholenergic side effects

70. Constipation Fiber Osmotic purgative :milk of magnesia Stool softener

71. Other drug Antidepressant Low doses of tricyclic antidepressants Amitriptiline or desipramine : Don’t affect mood but reduce pain by act on visceral afferent nerve fibers Also decrease motility: ↓ stool frequency

72. 5HT3 receptor antagonist Involved in visceral hyperalgesia Blockade ↓pain Alosetron is used:1 mg OD or BD S/E :constipation, sleep disturbances, abdominal discomfort Fatal ischemic colitis has restricted its use

73. Tegaserod 5 HT4 agonist Use: constipation predominant IBS Dose:6 mg BD 10% bioavailability and food further reduce It was withdrawn: stroke and heart attack

74. Other drug Lubiprostone: chloride channel activator Use: constipation predominant IBS Dose:8 microgram BD S/E:nausea C/I:pregnancy

75. Contd. Clonidine α 2 agonist ↓ visceral hyperalgesia ↑ water absorption and prevent diarrhoea Disadvantage: Hypotension

76. Contd. Buspirone 5-HT 1A partial agonist Anxiolytic Reduce gastric and colonic sensitivity Use as adjuvant drug

77. Contd. CCK1 antagonist like loxiglumide and dex-loxiglumide 5 HT-1 agonist- sumatriptan Little clinical success Alvimopan Inhibitors of peripheral u opioid receptor antagonist Use:constipation

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