LAXATIVES

What is a laxative?

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.

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

1. Somatic impulses are sent to the defecation centre in the sacral spinal cord

2. This in turn will send impulses to the internal anal sphincter causing it to relax;

3. A Valsalva maneuver will force the stool down;

4. Voluntary relaxation of the external anal sphincter occurs

5. Elevation of the pelvic diaphragm, which lifts the anal sphincter over the fecal mass, allowing the mass to be expelled

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

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

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Pharmacological Agents

Classification of Laxatives:

1. Bulk-forming

2. Emollients

3. Lubricants

4. Saline

5. Hyperosmotics

6. 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

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 use1. Oil droplets may be absorbed (especially if

emulsified products are used), reach mesenteric lymph nodes, liver, spleen elicit a typical foreign body reaction

2. 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

3. 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

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) 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

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

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

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

1. Increase both fluid and the bulk content of the child diet. Unbuttered pop-corn is a good bulk-containing snack for children.

2. 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)

3. 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:1. Factitious diarrhea

2. Electrolyte imbalance (eg, hypokalemia, hypocalcemia, and hypomagnesemia)

3. Osteomalacia

4. Protein-losing eneteropathy

5. Steatorrhea

6. Liver disease

7. General loss of muscle tone

8. 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)