2. LAXATIVES

3. 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

5. 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?

7. 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

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

10. 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)

11. 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)

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

14. Treatment Non-drug Measures
In many cases, treatment of underlying medical condition may be sufficient to relieve constipation (e.g. perianal disease, hypothyrodism, depression)
If constipation does not have an organic etiology, it can be alleviated with lifestyle modification such as fiber in diet, adequate fluid intake & exercise

15. Treatment Non-drug Measures
Fiber adds bulk and softens the stool, thus improves function
Increase both insoluble fiber: (wholegrain breads, prunes, raisins and corn) and soluble fiber (beans, oat bran, barley, peas, carrots, citrus fruits and apples)
Constipation mostly affects sedentary people exercise is important
Avoid suppressing the urge to pass the stool

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

17. 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 hours but may require 3 days in some individuals
Not absorbed systematically
Because they most closely approximate the physiologic mechanism in promoting evacuation

18. 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)

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

20. 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

21. 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

22. 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

23. 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= g

24. 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

25. 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: ml
Emulsified products are used to increase palatability

26. 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

27. 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)

28. 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

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

30. 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

31. 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

32. Saline Laxatives Indications Onset: 0.5-3 hr (2-15 min if rectal)
Doses: Mg hydroxide: mL
Mg sulphate: g (solid)
Na biphosphate: 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

33. 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

34. 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:
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 hours lasting no longer than 24 hours.

35. 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: hr
Dose: 3 g (solid) or 5-15 mL (enema) in adults and children> 6 years old. In infants and children < 6: g or 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).

36. 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)

37. 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: g
Cascara: g/day
Senna: g (supp 1 at bedtime)
Bisacodyl: mg
Castor oil: mL

38. 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)

39. 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

40. 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

41. 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

42. 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.

43. 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

44. 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

45. 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.

46. 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

47. 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.

48. Dosage Forms
Enemas
Used routinely to prepare patients for surgery, child delivery and GI radiologic or endoscopic examination & to treat certain cases of constipation
The enema fluid determines the mechanism by which evacuation is produced
The most effective are phosphate containing enemas (saline laxative). Used only for short-term
Proper administration requires that the diagnosis, the enema fluid and the technique of administration be correct
Improper administration of enema may result in fluid & electrolyte disturbance, mucosal changes or intestinal spasm, abrasion of the anal canal & rectal wall or colonic perforation

49. Dosage Forms Technique of enema administration:
The patient should lie or be placed on the left side with knees bent or in the knee-to-chest position
One pint (500mL) usually produces complete evacuation if retained until definite abdominal cramping is felt
As long as 1 hour may be needed for the entire procedure

50. 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

51. 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

52. 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)

53. 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

54. 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

55. 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

56. 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

57. 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”

58. 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

59. Melanosis coli in laxative abuser

60. 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

61. 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)

62. Laxative Selections Guidelines
The initial choice is usually a bulk-forming laxative
Acute constipation is the primary indication for OTC laxatives. They are also used for preparing for diagnostic GI procedures
Laxative use is supervised by a physician in patients in whom straining should be avoided (after surgery or MI) or in chronic constipation
Laxative use is inappropriate in case of intestinal pathology

63. Patient Counseling Firstly, You should discuss with the patient:
Dietary habits (fluid 4-6 glasses daily, fiber-rich diet)
Physical exercise
The ability to respond to the urge to defecate (no ignoring of urge to defecate)
General emotional well-being
When counseling patients on rational laxative use, you should stress on certain points:

64. Patient Counseling The rational Laxative use:
Should not be used regularly, more natural methods should be used instead
If not effective after 1 week, consult doctor
If a skin rash appears after phenolphtalein use, it should be stopped and a doctor consulted
Saline agents should not be used daily, not be used under 6 yrs or rectally under 2 yrs

65. Patient Counseling The rational laxative use:
Mineral oil should be avoided in children < 6 yrs, during pregnancy, in elderly patients, in those taking anticoagulants and should not be given in conjunction with emollient laxatives
Laxatives should not be used in presence of abdominal pain, perianal lesions, nausea, vomiting, bloating or cramping without consulting a doctor
Laxatives containing phenolphthalein may discolor urine. Phenolphthalein may discolor urine and feces pink to red, depending in alkalinity