LAXATIVES

What is a laxative? What is Constipation? An agent that acts to promote evacuation of the bowel, *a cathartic or purgative. What is Constipation? a decrease in the frequency of fecal elimination and is characterized by the difficult passage of hard, dry stools. The frequency of bowel movements in humans generally ranges from 3 times a day to 3 times a week Constipation cannot be defined solely in terms of the number of bowel movements in any given period. Regularity is what is “regular” for the individual

Physiology of defecation The transverse colon acts as a storage place for fecal matter until defecation At breakfast time mass peristaltic movement propels the fecal matter from transverse colon to rectum This movement results in a desire to defecate HOW?

Physiology of defecation Somatic impulses are sent to the defecation centre in the sacral spinal cord This in turn will send impulses to the internal anal sphincter causing it to relax; A Valsalva maneuver will force the stool down; Voluntary relaxation of the external anal sphincter occurs Elevation of the pelvic diaphragm, which lifts the anal sphincter over the fecal mass, allowing the mass to be expelled Defecation is a spinal reflex, can be voluntarily inhibited by keeping the external sphincter contracted or is facilitated by relaxing the sphincter & contracting the abdominal muscles Children usually defecate after meals, in adults, however, habits may determine the “ proper” time for defecation

Etiology of Constipation Drugs Metabolic & Endocrine disorders Conditions associated with neurogenic constipation Diseases of the large intestine Dietary causes

Etiology- Drugs Analgesics (including NSAIDs) Anesthetics Antacids (Ca & Al compounds) Anticholinergics Anticonvulsants Antidepressants Barium sulphate BDZs Bismuth Diuretics Iron Hyperlimidemia agents AntiHTN Laxative excess opiates Laxative-Drug Interactions Laxatives may absorption of other drugs Drugs with constipating effect may antagonize effects of laxatives Some drugs (e.g. Mg containing antacids, prostaglandins (e.g. misoprostol); and antiadrenergic drugs) may produce laxative side effects (diarrhea)

Etiology of Constipation Dietary Causes Insufficient fluid intake Low-fiber content of the diet Excessive ingestion of food that hardens stool (e.g. processed cheese)

Symptoms Anorexia Dull headache Lassitude Low back pain Abdominal distension Lower abdominal discomfort

Pharmacological Agents Classification of Laxatives: Bulk-forming Emollients Lubricants Saline Hyperosmotics Stimulants

1. Bulk-forming laxatives Agents of choice as initial therapy for most forms of constipation WHY? Natural and semisynthetic hydrophilic polysaccharides & cellulose derivatives that dissolve or swell in the intestinal fluid, forming emollient gels that facilitate passage of intestinal contents Usually effective in 12-24 hours but may require 3 days in some individuals Not absorbed systematically Because they most closely approximate the physiologic mechanism in promoting evacuation

1. Bulk-forming laxatives Examples: Polysaccharides & cellulose derivatives e.g. psyllium (plantago) seed, agar, alginates, guar gum; methylcellulose, carboxymethyl cellulose sodium, Calcium polycarbophil: often used in IBS & diverticular disease Malt soup extract (12-64g)

1. Bulk-forming laxatives Indications People on low-residue diet who cannot be corrected Postpartum women Elderly Patients with colostomies IBS Diverticular disease

1. Bulk-forming laxatives Contraindications People who restrict dietary fluid (e.g. people with significant renal dysfunction) Individuals with intestinal ulceration, stenosis Dextrose-containing products should be avoided in diabetics Sugar-free products containing aspartame should be avoided in phenylketonuria

1. Bulk-forming laxatives Adverse Effects Intestinal obstruction (e.g. elderly, difficulty swallowing, strictures) Bronchospasm from inhalation of dry mucilloid Hypersensitivity reactions (e.g. swollen, watery eyes, & skin rash) Diarrhea, abdominal discomfort, flatulence or excessive fluid loss may occur Usage Considerations Choosing among bulk-forming laxatives is a matter of personal preference Each dose should be taken in a full glass of pleasant tasting fluid (240 ml); Bulk-forming laxatives are safe and appropriate for long-term therapy

2. Emollient Laxatives “stool softeners” Docusate sodium, docusate potassium, docusate calcium Anionic surfactants that when administered orally, increases the wetting efficiency of intestinal fluid & facilitates admixture of aqueous and fatty substances to soften the fecal mass In many cases of fecal impaction, a solution of docusate is added to the enema fluid Onset of action same as bulk laxatives (except docusate K= 2-15 mins) Fluid intake should be increased to facilitate softening of stool

2. Emollient Laxatives Indications: To prevent development of constipation (prophylactic) and are of little or no value in treating long-standing constipation May be used for up to 1 week without physician consultation Indicated in cases of acute perianal disease to soften and inhibit painful elimination of stool or when avoidance of straining at the stool is desirable (e.g. after rectal or abdominal surgery, labor) Dose: docusate Na= 0.05-0.36 g

2. Emollient Laxatives Contraindications: Nausea & vomiting Undetermined abdominal pain (e.g. symptoms of appendicitis) Adverse Effects May increase absorption of poorly absorbed substances (e.g. mineral oil), thus increase their possible toxicity

3. Lubricant Laxatives Liquid petrolatum (mineral oil) & olive oil Soften stool contents by coating them, thus preventing colonic absorption of fecal water Onset of action: 6-8 hrs Dose: 14-45 ml Emulsified products are used to increase palatability

3. Lubricant Laxatives Indications To prevent straining (e.g. after surgery, CVD, MI, HTN, haemorroidectomy) however, stool softeners such as docusate Na are better to use in such cases

3. Lubricant Laxatives Adverse Effects associated with repeated & prolonged use Oil droplets may be absorbed (especially if emulsified products are used), reach mesenteric lymph nodes, liver, spleen elicit a typical foreign body reaction Lipid pneumonia may result from oral ingestion and subsequent aspiration of mineral oil, thus should never be administered at bedtime, or to very young, elderly or debilitated patients May impair the absorption of fat-soluble vitamins (A,D,E,K)

3. Lubricant Laxatives Contraindications Mineral oil may delay gastric emptying and should never be taken with meals Should never be given to pregnant ladies as it may availability of vitamin K to fetus Caution: with anticoagulants Should never be taken with emollient fecal softeners WHY? Because surfactants tends to increase the absorption of otherwise “non-absorbable” oils

4. Hyperosmotic laxatives There are three types of hyperosmotic laxatives taken by mouth—the saline, the lactulose , and the polymer types:

Saline Laxatives (=osmotics) The active constituents are relatively nonabsorbable cations & anions (e.g. magnesium, sulphate, tartrate, phosphate and citrate) The sulphate salts are the most potent The wall of the small intestine acts as semi-permeable membrane that retains the highly osmotic ions inside intestine, which will draw water inside intestine, thus increases intraluminal pressure This increased intraluminal pressure will act as a mechanical stimulus that increases intestinal motility

Saline Laxatives (=osmotics) However, different mechanisms that are independent of the osmotic effect maybe partially responsible; Complex series of reactions on GIT (secretory and motor): e.g. MgSO4 effect on GIT is similar to cholecystokinin-pancreozymin There is evidence that this hormone is released from the mucosa when saline laxatives are administered accumulation of fluid and electrolytes within the lumen

Saline Laxatives Indications Onset: 0.5-3 hr (2-15 min if rectal) Doses: Mg hydroxide: 15-40 mL Mg sulphate: 10-30 g (solid) Na biphosphate: 9.6-12.9 g orally or rectally Indications For use only for acute evacuation of the bowel (e.g. preparing for endoscopy, suspected poisoning) Have no place in the long-term management of constipation

Saline Laxatives Ad. E: (as much as 20% of Mg is absorbed) Precautions If renal function is normal no consequences If renal dysfunction, newborn or elderly toxic accumulation of Mg serious Ad.E: hypotension, muscle weakness, ECG changes, CNS depression, abdominal cramps, N&V and dehydration Precautions Na-containing laxatives patients on Na restricted diet Avoid phosphates in patients with impaired renal function or children < 2 years old hyperphosphatemia, hypocalcemia & tetany

Lactulose It is a semi-synthetic disaccharide which is not absorbed from the GIT. Hydrolysed by the gut bacteria, draw fluid limited evidence from two RCTs that lactulose improved symptoms compared with placebo: http://www.clinicalevidence.com/ceweb/conditions/dsd/0413/0413_I7_harms.jsp Lactulose, a disaccharide, is a sugar like Hyperosmotic Laxative . Lactulose produces an osmotic effect in the colon as bacterial flora breaks down the lactose into lactic, formic and acetic acids. Fluids that accumulate distend the abdomen, promoting peristalsis and bowel evacuation. Lactulose produces results much more slowly than the saline type of hyperosmotic and has been used for long-term treatment of chronic constipation. Evacuation is watery 2. Results usually occur in 24-48 hours lasting no longer than 24 hours.

Glycerin suppositories Glycerin suppositories/enemas can be used for both adults and children work through osmotic & mild irritant effect of glycerin with the local irritant effect of Na stearate on colon Onset: 0.25-1 hr Dose: 3 g (solid) or 5-15 mL (enema) in adults and children> 6 years old. In infants and children < 6: 1-1.5 g or 2.5-5 mL Pharmacology Reduces IOP by creating osmotic gradient between plasma and ocular fluids (oral form). Promotes bowel evacuation by local irritation and hyperosmotic actions (rectal form). Reduces edema and clears corneal haze by attracting water through semipermeable corneal epithelium (ophthalmic form).

Polyethylene glycol (PEG) solutions with or without electrolytes (very large poorly absorbable eythelene glycol molecules that cause an osmotic effect, resulting in distension and catharsis)

5. Stimulant Laxatives Doses: MOA: (1) irritate the intestinal mucosa to secrete water and electrolytes into the lumen of either small or large intestine or both (mostly large intestine) or (2) directly stimulate the myenteric plexus motility Onset: 6-12 hours (Thus, take at bedtime to produce effect the next morning) Doses: Anthraquinones: 0.12-0.25 g Cascara: 0.3-1 g/day Senna: 0.5-2.0 g (supp 1 at bedtime) Bisacodyl: 10-30 mg Castor oil: 15-60 mL

5. Stimulant Laxatives A. Anthraquinones: Involve: cascara, casanthranol, senna, aloe, aloin, danthron, rhubarb & frangula Rhuburb, aloe & aloin are very irritating and should not be recommended Anthraquinones are hydrolyzed by colonic bacteria into active compounds Action limited to colon Onset: 8-12 hrs (may require up to 24 hr)

5. Stimulant Laxatives Senna may cause a brown discoloration of breast milk and diarrhea in nursing infants Chrysophandic acid, a component of rhubarb & senna colors acidic urine yellowish-brown & colors alkaline urine reddish-violet (should warn patients) Prolonged use of anthraquinones (especially cascara) may cause harmless, reversible pigementation of the colonic mucosa (melanosis coli) Danthron was withdrawn from USA market in 1987 because of reports of its tendency to produce liver tumors in rodents

5. Stimulant Laxatives B. Diphenylmethane Stimulants: (bisacodyl & phenolphthalein) Bisacodyl: administered as a combination of tab/supp or tab/enema Used to clean the bowel before GI surgery etc Effective in patients with colostomies Minimally absorbed systematically (~ 5%) Ad.E (abuse): metabolic acidosis or alkalosis, hypocalcemia, tetany, loss of protein & malabsorption Suppositories may cause burning sensation in the rectum

Phenolphthalein: After a review of reports of the development of carcinogenic tumors and genetic damage in rats, FDA determined that phenolphthamein posed a risk and subsequently has been withdrawn http://www.fda.gov/bbs/topics/NEWS/NEW00589.html

6. Stimulant Laxatives C. Castor Oil Action is due to ricinoleic acid which is produced when castor oil is hydrolyzed by pancreatic lipase Ricinoleic acid will c-AMP mediated fluid secretion in small intestine. The main site of action: small intestine, thus prolonged use excessive loss of fluid & nutrients Most effective on empty stomach (evacuation within 2-6 hrs). Never at bedtime. Administered with a beverage to mask unpleasant taste. The only serious objections to the use of Castor Oil are its flavor and the sickness often produced by it.

5. Stimulant Laxatives Generally, stimulant laxatives are used: Before GIT examination or surgery e.g. Before colonic examination (Bisacodyl orally and rectally ) Used as initial short-term therapy in simple constipation (no more than 1 week) N.B. Docusate sodium acts both as a stimulant & as a softening agent (emollient) Cascara & castor oil are obsolete in the UK now Cascara, Casanthranol and aloe are obsolete in USA

5. Stimulant Laxatives Generally, the Ad.E of stimulant laxatives are: Severe cramping Electrolyte & fluid deficiencies Loss of protein & malabsorption Hypokalemia Frequently abused prolonged abuse may lead to “cathartic colon” Precautions: use with caution when symptoms of appendicitis (abdominal pain, nausea and vomiting) are present & NEVER USE IF DIAGNOSIS OF APPENDICITIS IS MADE

Most laxatives (except saline laxatives) may be used to provide relief: during pregnancy. for a few days after giving birth. during preparation for examination or surgery. for constipation of bedfast patients. for constipation caused by other medicines.

following surgery when straining should be avoided. following a period of poor eating habits or a lack of physical exercise in order to develop normal bowel function (bulk-forming laxatives only). for some medical conditions that may be made worse by straining, for example: Heart disease Hemorrhoids Hernia (rupture) High blood pressure (hypertension) History of stroke

Saline laxatives have more limited uses and may be used to provide rapid results: during preparation for examination or surgery. for elimination of food or drugs from the body in cases of poisoning or overdose. for simple constipation that happens on occasion (although another type of laxative may be preferred). in supplying a fresh stool sample for diagnosis.

Constipation in children 1 Parents should observe their child for frequency of bowel movements, difficulty in passing stools, pain during defecation etc Any deviation from he child normal habits should be noted Infants and children appear to show a decreasing frequency of defecation with increasing age Factors that may change a child’s bowel habits: emotional distress, febrile illness, family conflict, dietary changes (e.g. human to cow milk) or environmental changes such as move or recent travel

Constipation in children 2 Increase both fluid and the bulk content of the child diet. Unbuttered pop-corn is a good bulk-containing snack for children. Glycerin suppositories may be used in a child < 5 yrs. Malt soup extract is safe for infants < 2 mo. Bisacodyl maybe used for moderate to severe constipation. Bulk forming laxatives & Lactulose can be used (BNF, 2004) Generally, stimulant laxatives and excessive use of enemas should be avoided. Enemas not recommended < 2 years of age

Geriatric Laxative Use 1 Many elderly persons have been laxative dependent for many year Causes of constipation: Insufficient fluid and/or bulk intake Abuse of stimulant laxatives Immobility neuromuscular disorders, confusion & depression Medications (e.g. Ca channel blockers, antipsychotics etc)

Geriatric Laxative Use 2 Laxatives may decrease absorption of some medications Straining may predispose to serious complications such as CVD, or hemorrhoids Elderly patients are particularly sensitive to shifts in fluid & electrolytes. Use of some laxatives (especially saline) in patients on diuretics or fluid-restricted diet may put patient at risk for adverse effects

Geriatric Laxative Use 3 Management: Bulk forming laxatives, glycerin suppositories and oral lactulose are generally preferred for elderly Acute episodes may be treated by plain water or saline enemas Polyethylene glycol-electrolyte oral solutions maybe used safely in patients with cardiac or renal diseases Dietary fibers should be increased (e.g. bran, fruits & vegetables). However, pharmacist should advise patients that increasing bran may lead to erratic bowel habits, flatulence & abdominal discomfort during the first few weeks

Laxative Use in Pregnancy Causes of constipation: 1. fetus compression on colon; 2. reduction in intestinal muscle tone; 3. prenatal multivitamin supplements (Ca, Fe etc) Only bulk-forming, lactulose or emollient laxatives should be used WHY?  possible risks! Mineral oil decreased/loss of vitamin absorption Castor oil premature labor Osmotic agents dangerous electrolyte imbalance saline laxatives appreciable GI absorption in the mother toxicity (e.g. Mg) muscle weakness, ECG changes, hypotension

Laxative Use in nursing mothers Same laxatives used in pregnancy Senna & related anthraquinones have been used during breast-feeding despite lack of information regarding concentration in milk Bisacodyl appears in breast milk but may not pose problems for the infant Avoid saline laxatives as it is absorbed through the mother’s GIT toxicity (e.g. Mg) diarrhea, drowsiness, hypotension, respiratory difficulty Pregnant & lactating women should be counseled on proper diet, fluid intake & reasonable exercise

Laxative Abuse Laxative abusers could be either elderly who believe that the bowel should be “cleaned” daily [habitual abuse] or adolescents (especially females) who use laxatives to lose weight [surreptitious abuse] The latter usually suffer from eating disorders e.g. anorexia nervosa or bulimia nervosa Excessive use of laxatives may lead to complications that has been termed “metabolic madness”

Laxative Abuse Complications of laxatives abuse: Factitious diarrhea Electrolyte imbalance (eg, hypokalemia, hypocalcemia, and hypomagnesemia) Osteomalacia Protein-losing eneteropathy Steatorrhea Liver disease General loss of muscle tone Cathartic colon* Metabolic madness

Melanosis coli in laxative abuser

Laxative Abuse Cathartic colon: Develops years after laxative abuse Symptoms: abdominal pain, diarrhea, mucosal inflammation, loss of innervation & atrophy of smooth muscle, Characterized by: dilation of the colon, loss of haustral markings & appearance of pseudostrictures Cathartic colon is irreversible and the only solution is removal of affected parts

Laxative Abuse Management: Affected persons should be educated about laxatives abuse; harmful effects and that any observed weight loss is due to loss of fluid rather than calories Patients should be advised that constipation, weight gain, bloating or abdominal distention may occur following the laxative withdrawal Patients should be encouraged to exercise, increase dietary fibers and maintain fluid intake In case of long term abuse, refer to doctor as abrupt withdrawal may cause problems (e.g. heart failure)