Treatment of constipation and diarrhea Lecture Treatment of constipation and diarrhea

Constipation Definition: Chronic constipation is a disorder characterized by unsatisfactory defecation that results from infrequent stools, difficult stool passage, or both over a time period of at least 12 weeks

Causes of constipation 1. In most cases of chronic constipation, no specific cause is found (chronic idiopathic constipation) 2. Lifestyle Factors    a) Inadequate fluid intake    b) Decreased food intake    c) Inappropriate bowel habits    d) Immobility 3. Medications Endocrine and Metabolic disorders   a) Hypothyroidism   b) Hypercalcemia c) Hypokalemia d) Pheochromocytoma

Causes of constipation Neurologic    a) Parkinson's disease    b) Multiple sclerosis    c) Spinal lesions    d) Damage to sacral parasympathetic nerves    e) Autonomic neuropathy (Diabetes mellitus 6. Psychological    a) Depression    b) Eating disorders (e.g., anorexia nervosa) 7. GI disorders: a) Irritable bowel syndrome b) Diverticulitis c) Hemorrhoids and anal fissures d) Tumors e) Hernia f) Hirschsprung’s disease. 8. Pregnancy

Drugs causing constipation NSAIDs (inhibit prostaglandin synthesis) Opiates: Orally administered opiates have greater inhibitory effect than parenterally administered agents Anticholinergics Antihistamines Antiparkinsonian agents (e.g., benztropine or trihexyphenidyl) Phenothiazines Tricyclic antidepressants Antacids containing calcium carbonate or aluminum hydroxide Barium sulfate Calcium channel blockers Clonidine Diuretics (nonpotassium-sparing) Ganglionic blockers Iron preparations Muscle blockers (D -tubocurarine, succinylcholine)

Mechanism of drug-induced constipation Drugs with anticholinergic action (e.g. first generation antihistaminic drugs, tricyclic antidepressants, benztropine, phenothiazines,..): GIT motility is under parasympathetic (cholinergic) control. Parasympathetic stimulation → ↑motility Drugs with anti-cholinergic effect (whether it is their main action or a side effect) →↓motility → constipation

Mechanism of drug-induced constipation 2. Opioids: Opioids cause constipation by: A) Increasing the smooth muscle tone, suppressing forward peristalsis, raising sphincter tone at the ileo-cecal valve and anal sphincter. This delays passage of feces through the GIT → increase in absorption of electrolytes and water in the small intestine and colon → constipation B) Reducing sensitivity to rectal distension.

Mechanism of drug-induced constipation Electrolyte disturbance as hypokalemia or hypercalcemia Laxative abuse (leads to atonic intestine)

Treatment of constipation General measures: Increase the amount of fiber consumed daily fruits, vegetables, bran and cereals). Definition: Fiber is that part of food that resists enzymatic digestion Effect of fiber: Fiber reaches the colon unchanged. Colonic bacteria → Fermentation → Short-chain fatty acids (→ prokinetic effect) Increased bacterial mass (→ increased stool bulk). Fiber that is not fermented → osmotic effect →increases stool bulk. Increasing fluid intake. Regulation of bowel habits Regular exercise. Treatment of the cause For drug causes of constipation, a non constipating alternatives should be used. If no alternatives exist, lower the dose.

Treatment of constipation If general measures alone are inadequate or not applicable (e.g., because of old age), they may be supplemented with bulk-forming agents, osmotic laxatives or stimulant laxatives. When stimulant laxatives are used, they should be administered at the lowest effective dosage and for the shortest period of time to avoid abuse

Definitions Laxatives Cathartics Drugs that help evacuation of formed fecal material from the rectum Drugs that help evacuation of unformed, usually watery fecal material from the entire colon.

Drug treatment of constipation (laxatives) General indications: Fecal impaction Constipation associated with illness, surgery, pregnancy or poor diet Drug-induced constipation Conditions where bowel strain is undesirable Preparation for surgery or investigations involving the GIT (e.g. sigmoidoscopy)

Classification of laxatives Bulk-forming laxatives Stimulant laxatives Osmotic laxatives Emollient laxatives (fecal softeners) Lubricants

1- Bulk-forming agents (active after 12-36h) Drugs: (taken as granules, powders or tablets) Methylcellulose Bran Psyllium Mechanism of action of bulk-forming agents: They increase stool bulk and water content (make stools bulky (→ stimulate peristalsis) and soft → easy to pass) (similar to natural fiber)

Bulk-forming agents (cont.) (active after 12-36h) Indications: They are the first-line treatment of constipation Conditions where dietary intake of fibers can not be increased Precautions: Adequate fluid intake to avoid intestinal obstruction Adverse effects of bulk-forming laxatives: Abdominal distension (due to fermentation). Intestinal obstruction when not consumed with sufficient fluid Contraindications: Atony of the colon Intestinal obstruction Fecal impaction (should be corrected before administration of fiber) Immobility

2. Stimulant (irritant) laxatives Dosage forms:: Bisacodyl Oral and rectal suppository Sodium picosulfate Oral Senna and Cascara Castor oil

Mechanism of action and classification of stimulant (irritant) laxatives They are given in an inactive form → hydrolyzed in the GIT into active forms → GIT irritation → modify permeability of the mucosal cells → ↑ fluid and electrolyte secretion in the GIT → distension → evacuation of soft (or liquid) bulky stools. They probably cause direct stimulation of the enteric nerves. According to the site of GIT irritation they are classified into: Small bowel irritant (hydrolysed in the small intestine by the action of lipases): castor oil Large bowel irritants (hydrolyzed by colonic bacteria): Bisacodyl and Sodium picosulfate Senna and Cascara

Stimulant (irritant) laxatives (cont.) Indications of large bowel irritants: Bisacodyl and Sodium picosulfate Senna and Cascara Prevention of straining at stool following surgery, myocardial infarction or stroke Painful diseases of the anus, e.g., fissure or hemorrhoids.

Stimulant (irritant) laxatives (cont.) 1. Bisacodyl and sodium picosulfate: Dosage forms: Oral (the laxative effects after a dose occurs after 6 – 12 hours; taken at bedtime, it will produce its effect the next morning) Rectal suppository (for bisacodyl only – the laxative effect occurs within 30 to 60 min.) Indications: (also for cascara and senna) Should not be used for more than 10 consecutive days (due to the possibility of developing atonic colon) Preparation before diagnostic procedures involving the GIT

Stimulant laxatives (cont) Bisacodyl and sodium picosulfate (cont) Adverse effects: Abdominal cramps after each dose Over dosage → catharsis and fluid and electrolyte disturbances. Can damage mucosa and cause inflammation in the colon. Atonic colon (following years of use) Contraindications: Intestinal obstruction

Stimulant laxatives (cont.) 2. Cascara and Senna Dosage forms: Oral (the laxative effects after a dose occurs after 6 – 12 hours; taken at bedtime, it will produce its effect the next morning) Adverse effects of long-term use; Abdominal cramps after each dose Over dosage → catharsis and fluid and electrolyte disturbances. Pigmentation of the colonic mucosa (melanosis coli). (4 – 9 months of use) Atonic colon (years of use) Contraindications: Breast feeding (active compounds are absorbed to a variable degree from the colon and excreted in breast milk) Intestinal obstruction

Stimulant laxatives (cont.) 3. Castor Oil: Dosage form: Oral in a liquid form (laxative effect occurs after 1 – 3h) Adverse effects: Unpleasant taste Damage to intestinal epithelium and enteric neurons Uses: Strong purgative → evacuation of the bowel before surgery and diagnostic procedures Contraindications: Intestinal obstruction

3- Osmotic laxatives 1. Saline laxatives (have cathartic action in large doses) Magnesium salts (sulfate, hydroxide or citrate) Sodium phosphate Mechanism of action: Poorly absorbed → water retention (osmotic effect) →soft bulky stools → ↑peristalsis → relief of constipation Magnesium-containing laxatives may stimulate the release of cholecystokinin, which leads to intraluminal fluid and electrolyte accumulation and to increased intestinal motility Uses: Enema (causes bowel evacuation after 30 min) Oral forms (cause bowel evacuation after 2-5h) Both forms are used for intestinal evacuation before abdominal radiological procedures, sigmoidoscopy or surgery (cathartics)

Osmotic laxatives (cont.) Saline laxatives Adverse effects: Flatulence, abdominal cramps, diarrhea Intravascular volume depletion Electrolyte disturbances Contraindications: Renal insufficiency Severe cardiac disease Preexisting electrolyte abnormalities Patients on diuretic therapy

Osmotic laxatives (cont.) 2. Non-digestible sugars and alcohols Lactulose (disaccharide of galactose and fructose that resists intestinal disaccharidase activity) Sorbitol (monosaccharide) Mechanism of action: Lactulose → metabolized by colonic bacteria into short chain fatty acids → osmotic effect → stimulate propulsive activity Adverse effects: Abdominal distention Diarrhea

Osmotic laxatives (cont.) Uses: Lactulose: (24-48h) Used for treatment of hepatic encephalopathy (↓ blood ammonia by lowering fecal pH →↓growth of ammonia-producing bacteria and conversion of ammonia in the colon to ammonium ion). Constipation in the elderly patient Alternative for acute constipation Sorbitol: Chronic constipation

Osmotic laxatives (cont.) 3. Polyethylene Glycol-Electrolyte Solutions. Mechanism of action: Poorly absorbed, and retained in the lumen of the gut → osmotic effect → increase water content of stools. Uses: Cathartic: high volume of aqueous polyethylene glycol - isotonic electrolyte solution (4 liters), used for colonic cleansing for radiological, surgical, and endoscopic procedures . The isotonic electrolyte solution avoids transfer of ions across the intestinal wall. The osmotic activity of the PEG molecules retains the added water . Laxative: small oral doses of polyethylene glycol used for the short-term treatment of occasional constipation in difficult cases (2 weeks or less). This preparation does not contain electrolytes, so larger volumes may represent a risk for ionic shifts. Onset of effect: 2- 4 days

Osmotic laxatives (cont.) 4. Glycerin Dosage form: Suppository (laxative effect > 30 min.) Mechanism of action: Osmotic effect in the rectum. Adverse effects: Occasional rectal irritation. Uses: Intermittent constipation in children.

4- Fecal softeners/emollient laxatives Docusate salts (sodium or calcium) (weak laxatives) Mechanism of action: Reduces surface tension of stools → increases penetration of fluids into feces → soft bulky stools Stimulate intestinal fluid and electrolyte secretion (by altering mucosal permeability) Dosage forms: Oral form (active within 1-3 d) Rectal form has a rapid onset of action but is contraindicated in hemorrhoids and anal fissure. Uses: Used in hospitalized patients following myocardial infarction or surgery, when straining at defecation should be avoided but activity and fluid intake may be restricted. They have little role in the management of chronic constipation, except when the patient is fluid-restricted or incapable of increasing his or her dietary fiber or activity.

Fecal softeners/emollient laxatives (cont.) 2. Mineral oil: Mechanism of action: Indigestible and with minimal absorption. Coat stool and allow easier passage. Inhibit colonic absorption of water → increasing stool weight and decrease stool transit time. Dosage forms: Oral or rectal. Laxative effect is noted after 2 or 3 days of oral use. Indications: Similar to docusates: to maintain a soft stool and avoid straining for relatively short periods of time (a few days to 2 weeks),

Fecal softeners/emollient laxatives (cont.) Mineral oil: Adverse effects: May be absorbed systemically → foreign-body reaction in lymphoid tissue. May be aspirated (in debilitated or recumbent patients) → lipoid pneumonia Decreases absorption of fat-soluble vitamins (A, D, E, and K) When given orally, mineral oil may leak from the anal sphincter.

New agents Lubiprostone Mechanism of action: Opening of chloride channels locally in the GI luminal epithelium, which stimulates chloride-rich intestinal fluid secretion and shortens GI transit time Uses: Chronic idiopathic constipation in adults Adverse effects: Headache Diarrhea, and nausea, as a result of delayed gastric emptying.

Laxative abuse syndrome

Laxative abuse syndrome Mechanism: 1. With the use of strong purgatives, the colon may be so thoroughly evacuated that a bowel movement may not occur normally until a few days later. This delay reinforces the need for more laxative. Eventually the patient may require daily laxatives to maintain bowel function.

Laxative abuse syndrome (cont.) Mechanism: 2.

Diarrhea Definition: diarrhea is an increased frequency and decreased consistency of fecal discharge as compared to an individual’s normal bowel pattern. Classification: Acute <14 d Persistent >14 d Chronic > 30 d

Causes of diarrhea Infectious (viral or bacterial) Non infectious

Pathophysiologic mechanisms of diarrhea Type of diarrhea A stimulating substance (e.g. a laxatives or a bacterial toxin) changes active ion transport in the intestine by either decreased sodium absorption or increased chloride secretion Secretory diarrhea Change in intestinal motility (e.g by overgrowth of bacteria) Altered intestinal motility Increase in intestinal luminal osmolarity due to poorly absorbed substances Osmotic diarrhea Increase in tissue hydrostatic pressure due to inflammatory diseases of the GIT Exudative adiarrhea

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

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

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

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. Glucose concentration > 160 mmol/L will cause osmotic diarrhea. 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

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

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

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)

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

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

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.

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.

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

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.

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. 4. Octreotide has been used in low doses to stimulate small bowel motility in patients with small bowel bacterial overgrowth or intestinal pseudoobstruction secondary to scleroderma.

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 Prolonged treatment may result in hypothyroidism. Octreotide also can Bradycardia.

Antimicrobials Indications: Patients with +ve stool culture Patients presented with dysentery Patients with suspected exposure to bacterial infection → Quinolones (as ciprofloxacin)