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Drugs for constipation & diarrhoea
- 1. Pharmacotherapy for constipation andDiarrhoea By dr. Chintan Doshi
- 2. CONSTIPATION-PATHOPHYSIOLOGY • Decreased intestinaland 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. • Inadequatedietary 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 • LAXATIVESor 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 • Dietaryfiber: 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 • Magnesiumsalts: sulfate, hydroxide • Sodium salts: sulfate, phosphate • Sod. pot. tartrate • Lactulose
- 10. LAXATIVES • INDICATION: • Totreat 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 effectsand 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: • Bittertaste: 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 fromintestinal 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… • ↑ structuralinjury 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 receptoragoinst • 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 • Oldestpurgatives • Obtained from the seeds of Ricinus communis • M/O: • Decreased intestinal absorption of water and electrolytes • Enhanced secretion
- 31. Contd. Dose: 15–25ml (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 absorbableand 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: diarrheais 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 offluid depletion , shock and acidosis • Maintenance of nutrition • Drug therapy
- 37. Rehydration 1. intravenousrehydration: • 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 capitalizeson the intactness of glucose coupled Na+ absorption, even when other mechanisms have failed or when intestinal secretion is excessive
- 41. CONTD… Advantages of theNew 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 usesof 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 pediatricdiarrhoea • 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) usefulonly 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: whenblood and mucus in stool • Drugs: cipro/norfloxacin, cotrimaxzole Non typhoid salmonella: • Fluroquinolones, cotrimaxzole Yersinia enterocolitica • Cotrimoxazole, Ciprofloxacin
- 50.
- 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.
- 54. OPOIDS(Contd…) • M/A: stimulatemu 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 infectivediarrhoea • 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-termconstipation-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: • Abdominaldiscomfort • 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 adrenergicreceptor agoinst • Clonidine (0.1mg BD, oral) • facilitates absorption , inhibit secretion, ↑ intestinal transit time
- 64. octreotide M/A: • Inhibit releaseof 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 andpectin: • 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 irritablebowel 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 orhyoscine Inhibit M3 receptor Mebeverine: reserpine analogue Antispasmodic and devoid of anticholenergic side effects
- 70. Constipation • Fiber • Osmoticpurgative :milk of magnesia • Stool softener
- 71. Other drug Antidepressant Lowdoses 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 HT4agonist • 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 α2 agonist ↓visceral hyperalgesia ↑water absorption and prevent diarrhoea Disadvantage: Hypotension
- 76. Contd. Buspirone 5-HT1A partialagonist Anxiolytic Reduce gastric and colonic sensitivity Use as adjuvant drug
- 77. Contd. • CCK1 antagonistlike loxiglumide and dex- loxiglumide • 5 HT-1 agonist-sumatriptan • Little clinical success Alvimopan Inhibitors of peripheral u opioid receptor antagonist Use:constipation
- 78.
Editor's Notes
- #73 Ondansetron is not used