LAXATIVES

(Aperients, Purgatives, Cathartics)

Definition: These are drugs that promote evacuation of bowels.

Laxative or aperient: milder action, elimination of soft but formed stools.

Purgative or cathartic: stronger action resulting in more fluid evacuation

Classification of Laxatives: Laxatives are classified into

A. Bulk Forming agents

1. Dietary fiber: bran
2. Psyllium (plantago)
3. Ispaghula
4. Methyl cellulose
B. Stool softener
1. Docusates(DOSS)
2. Liquid paraffin
3. Glycerin
C. Osmatic agents
1. Mag. Sulfate hydroxide
2. Sod. phosphate
3. Sod. Pot. tartrate
4. Lactulose
5. Polyethylene glycol
D. Chloride channel activator
1. Lubiprostone
E. Stimulant(Irritant) subdivided into
I. Diphenylmethanes
a. Phenolphthalein
b. Bisacodyl
c. Sod. picosulfate
II. Anthraquinones
a. Senna
b. Cascara Sagrada

1
III. iii. Fixed oil
a. Castor oil
IV. 5-Ht4 agonist

a. Tegaserod

Osmotic purgatives
1. Saline
All inorganic salts used as osmotic (saline) purgatives have similar action
differ only in dose, palatability and risk of systemic toxicity
1. Mag. sulfate (Epsom salt): 5–15 g; bitter in taste.
2. Mag. hydroxide (as 8% W/W suspension milk of magnesia) 30 ml; bland in
taste, also used as antacid.
3. Sod. sulfate (Glauber’s salt): 10–15 g; bad in taste.
4. Sod. phosphate: 6–12 g, taste not unpleasant.
5. Sod. pot. tartrate (Rochelle salt): 8–15 g, relatively pleasant tasting
They should be avoided in young children and patients with renal failure, as they
may cause CNS or cardiac depression. Sodium salts should be avoided in cardiac
patients.

2. Non digestive sugars & alcohol

I. Lactulose , sorbitol & Mannitol
Mechanism of action :

It is a semisynthetic disaccharide of fructose and lactose which is neither digested

nor absorbed in the small intestine → retains water. It is broken down in the colon by
bacteria→ lactic, formic and acetic acids → reduce the pH of stools. → Formation of
soft stool and Inhibition of proteolytic bacteria → decrease formation of ammonia.

Uses Of Lactulose

1. Constipation
2. It can be used to treat constipation in children and pregnant women.
3. It can be used in hepatic coma to reduce blood ammonia levels
The side effects include abdominal discomfort and flatulence

2. Non digestive sugars & alcohol

2
 I. Polyethylene glycol
II. Balanced Polyethylene glycol
 It is available as powder and solution. The powder should be mixed with
water or fruit juice.
 These balanced, isotonic solutions contain an inert, non-absorbable,
osmotically active sugar (PEG) with sodium sulfate, sodium chloride,
sodium bicarbonate, and potassium chloride.
 The solution is designed so that no significant intravascular fluid or
electrolyte shifts occur. The most widely used preparations for colonic
cleansing prior to radiological, surgical, and endoscopic procedures.
Chloride channel activators

1. Lubiprostone
Mechanism of action: Lubiprostone ac by activating chloride channels to increase
fluid secretion in the intestinal lumen → eases the passage of stools and causes little
change in electrolyte balance.
Uses : Chronic constipation
F. Opioid receptor antagonist
Drugs; Methyl naltrexone and naloxegol (oral)
Mechanism of action are peripherally acting μ-opioid receptor antagonists. They
are devoid of central effects;
Uses : used to treat opioid-induced constipation in cancer patients If patient does
not respond to laxative.
Adverse effects are nausea, vomiting and diarrhea

Laxative in Pregnancy
 Bulk-forming agents are not given a specific pregnancy category but have
been safely used during pregnancy.
 Magnesium hydroxide is Pregnancy Category B.
 Polyethylene glycol electrolyte solution is Pregnancy Category C.
 Castor oil is contraindicated in pregnancy because it has been associated
with induction of uterine contractions.
 Cascara derivatives are Pregnancy Category C.
 Bisacodyl is safe to use in pregnancy and is listed as Pregnancy Category
B.

3
  Although no specific pregnancy category is listed for mineral oil, it should
be avoided during pregnancy because chronic use decreases the
absorption of fat-soluble vitamins and causes hypoprothrombinemia in
the newborn.
 Docusate compounds have not been given a specific pregnancy category
but have been safely used during pregnancy
Therapeutic uses of Laxatives

1. Functional constipation Constipation is infrequent production of hard

stools requiring straining to pass, or a sense of incomplete evacuation.
Constipation is a symptom rather than a disease. Various aspects of the
patient’s lifestyle may contribute
Constipation may be spastic or atonic.
(i) Spastic constipation (irritable bowel): The stools are hard,
rounded, stone like and difficult to pass. The first choice
laxative is dietary fiber or any of the bulk forming agents taken
over weeks/months. Tegaserod is a new option available now.
Stimulant purgatives are contraindicated.
(ii) Atonic constipation (sluggish bowel): mostly due to advanced
age, debility or laxative abuse. Non-drug measures like plenty of
fluids, exercise, regular habits and reassurance should be tried.
In resistant cases a bulk forming agent should be prescribed. In
case of poor compliance or if the patient is not satisfied –
Bisacodyl or senna may be given.
2. Bedridden patients (myocardial infarction, stroke, fractures,
postoperative): bowel movement may be sluggish and constipation can be
anticipated.
I. To prevent constipation: Give bulk forming agents on a regular
schedule; docusates, lactulose and liquid paraffin are alternatives.
II. To treat constipation: Enema (soap-water/ glycerine) is preferred;
bisacodyl or senna may be used.

3. To avoid straining at stools (hernia, cardiovascular disease, eye surgery)

and in perianal afflictions (piles, fissure, anal surgery) it is essential to

4
 keep the faeces soft. One should not hesitate to use adequate dose of a
bulk forming agent, lactulose or docusates
4. Preparation of bowel for surgery, colonoscopy, abdominal X-ray The
bowel needs to be emptied of the contents including gas. Saline purgative,
bisacodyl or senna may be used; castor oil only in exceptional
circumstances.
5. After certain anthelmintics (especially for tapeworm) Saline purgative or
senna may be used to flush out the worm and the anthelmintic drug.
6. Food/drug poisoning The idea is to drive out the unabsorbed
irritant/poisonous material from the intestines. Only saline purgatives are
satisfactory.
All laxatives are contraindicated in:
1. A patient of undiagnosed abdominal pain, colic or vomiting.
2. Organic (secondary) constipation due to stricture or obstruction in bowel,
hypothyroidism, hypercalcaemia, malignancies and certain drugs, e.g.
opiates, sedatives, anticholinergics including antiparkinsonian,
antidepressants and antihistaminics, oral iron, clonidine, verapamil and
laxative abuse itself. So that The primary cause should be treated in these
cases.
Purgative abuse

Dangers of purgative abuse are:

1) Flairing of intestinal pathology, rupture of inflamed appendix.

2) Fluid and electrolyte imbalance, especially hypokalaemia.
3) Steatorrhoea, malabsorption syndrome.
4) Protein losing enteropathy.
5) Spastic colitis.

Principles of management of diarrhea

Therapeutic measures may be grouped into:

5
 1. Treatment of fluid depletion, shock and acidosis.
2. Maintenance of nutrition.
3. Drug therapy.
A. Specific anti-microbial agents.
B. Nonspecific anti-diarrheal agents.
1. Treatment of fluid depletion, shock and acidosis.
2. Dehydration: Means the body lost large amount of fluid and too
many electrolytes and can’t function properly. Dehydration is
more dangerous in children and adults and must be treated rapidly
to avoid serious health problems.
3. Signs of dehydration
1. Thirst
2. Less frequent urination
3. Dry skin
4. Fatigue
5. Light-headed
6. Dark-colored urine
Rehydration can be done orally or i. v.

A. Oral rehydration(ORT)
ORT can be introduced from the very beginning. If the fluid loss is mild (5–
7% BW) or moderate (7.5–10% BW).

The composition of oral rehydration salt/solution.

The general principles are:

1. It should be isotonic or slightly hypotonic.

2. The molar ratio of glucose should be equal to or slightly higher
than Na+
3. Enough K + (15–25 mM) and bicarbonate/ citrate (8–12 mM)
should be provided to make up the losses in stool.
Administration of ORT

 Patients are encouraged to drink ORS at ½–1 hourly intervals

6
  In a weak child who refuses to drink ORS at the desired rate it can be
given by intragastric drip.
 ORT is not aimed to stop diarrhoea, but to restore and maintain
hydration, electrolyte and pH balance until
Non- diarrheal uses of ORT

1. Postsurgical, post burn and post-trauma maintenance of hydration and

nutrition (in place of i.v. infusion).
2. Heat stroke.
 During changeover from parenteral to enteral elimentationdiarrhoea
ceases, mostly spontaneously

Super ORS

It is ORS + actively transported amino acids (alanine, glycine which

cotransport Na+) .

B. Intravenous rehydration: It is needed only

1) When fluid loss is severe, i.e. > 10% body weight
2) If patient is losing > 10 ml/kg/ hr.
3) If patient unable to take enough oral fluids due to weakness, stupor or
vomiting
2. Maintenance of nutrition
 Simple foods like breast milk or ½ strength buffalo milk, boiled potato, rice,
chicken soup, banana, sago, etc.
 Fasting decreases brush border disaccharidase enzymes and reduces
absorption of salt, water and nutrients; may lead to malnutrition if diarrhoea is
prolonged or recurrent.
 Thus feeding during diarrhoea has been shown to increase intestinal digestive
enzymes and cell proliferation in mucosa
3. Drug therapy of diarrhea
A. Specific antimicrobial drugs. By Antimicrobials
I. Antimicrobials are of no value In diarrhoea due to noni-nfective causes,
such as:
1. Irritable bowel syndrome (IBS)

7
 2. Coeliac disease
3. Pancreatic enzyme deficiency
4. Tropical sprue (except when there is secondary
infection)
5. Thyrotoxicosis
II. Antimicrobials are useful only in severe disease (but not in mild cases):
a. Travellers’ diarrhoea: mostly due to ETEC, Campylobacter or virus:
Cotrimoxazole, norfloxacin, doxycycline and erythromycin .
b. EPEC: Cotrimoxazole, colistin, nalidixic acid or norfloxacin.
c. Shigella enteritis: ciprofloxacin, norfloxacin or nalidixic acid;
Cotrimoxazole
d. Salmonella typhimurium enteritis: a fluoroquinolones,
Cotrimoxazole or ampicillin.
e. Yersinia enterocolitica: common in colder places, not in tropics.
Cotrimoxazole, ciprofloxacin
III. Antimicrobials are regularly useful in:
1. Cholera: tetracyclines , Cotrimoxazole, norfloxacin /ciprofloxacin.
2. Campylobacter jejuni: fluoroquinolones, Erythromycin
3. Clostridium difficile: The drug of choice for it is metronidazole,
vancomycin given orally is an alternative.
4. Amoebiasis & Giardiasis: metronidazole, diloxanide furoate
B. Nonspecific(symptomatic) therapy:-
1. Adsorbents: kaolin , Bismuth ,Chalk( & Charcoal .
2. Absorbents: Psyllium, Methyl cellulose, Pectin carboxymethylcellulose
and calcium polycarbophil
3. Astringents: Tannic acid
4. Spasmolytic (Antispasmodic): Hyoscine-N-Butyl bromide. (Buscopan
®),Propantheline(indirect) Mebeverine, Papaverine & Drotaverine
(Direct spasmolytic)
5. Opioids: Diphenoxylate and Loperamide
6. Octreotide
7. Racecadrotil
8. α2 Adrenergic Receptor Agonists
9. Bismuth subsalicylate

8
 10. Bile salt-binding resins
11. Probiotics
Astringents: Tannic acid

 Mechanism of action: inhibit release of autacoids and

prostaglandins → inhibit motility and secretion.
Spasmolytic (Antispasmodic)

i. Hyoscine-N-Butyl bromide. (Buscopan ®),Propantheline(indirect)

ii. Mebeverine, Papaverine & Drotaverine (Direct spasmolytic)
Uses

1. Nervous induced diarrhoea

2. Drug induced diarrhoea
3. Symptomatic relief in dysenteries
Opioids

1) Diphenoxylate
 It is a synthetic opioid, chemically related to pethidine
 Mechanism of action:
 Stimulate μ & δ opioid receptor in small intestine and
colon .
 It is always given in combination with atropine to
prevent the abuse
 Uses : Non-infective diarrhea or mild travellers diarrhea, idiopathic
diarrhea in AIDS ,after anal surgery ,colostomy.
 Contraindication: Children below 6 years of age.
 Note: Commercial preparations commonly contain small amounts
of atropine to discourage over-dosage (2.5 mg diphenoxylate with
0.025 mg atropine)
2) Loperamide: It is an opiate analogue
Mechanism of action:
 Stimulate μ (major)& δ(minor) opioid receptor in small intestine and
colon
 Weak anticholinergic property
 Directly interacts with calmodulin → inhibits secretion

9
 Uses : Non-infective diarrhea or mild travellers diarrhea, idiopathic diarrhea in
AIDS ,after anal surgery ,colostomy.
Contraindication: Children below 4 years of age
Octreotide

‾ This long acting(t1/2=90 min) somatostatin analog can be used to decrease

secretory diarrhea and other symptoms of carcinoid syndrome .
‾ In low doses (50 μg, s.c. ), it stimulates motility, whereas at high doses (100-
250 μg, s.c.), it inhibits motility.
‾ In higher doses, it is also useful for the treatment of diarrhea due to
vagotomy, carcinoid and vasoactive intestinal peptide (VIP)secreting tumours,
short bowel syndrome and for refractory diarrhoea in AID
‾ It can also be used for treatment and prophylaxis of acute pancreatitis
Adverse Effects

1- Steatorrhea formation 2-Sludge or gallstones 3-Hyperglycemia or,

less frequently, hypoglycemia 4-Hypothyroidism 5-Bradycardia

Racecadotril

 Mechanism of action: It is enkephalinase inhibitor (inhibits

breakdown of enkephalins; endogenous opioids) decreases intestinal
hypersecretion, without affecting motility.
 Indication
1. The short-term treatment of acute secretory diarrhoeas. In
contrast to Loperamide / diphenoxylate, it is not
contraindicated in children.
 Side effects are nausea, vomiting, drowsiness, flatulence
α2 Adrenergic Receptor Agonists e.g.

Clonidine( Catapres )
 Mechanism of action
Interact with specific receptors on enteric neurons and enterocytes →
stimulating absorption and inhibiting secretion of fluid and electrolytes and ↑
intestinal transit time.
 Clinical uses

10
  It is indicated for diabetics with chronic diarrhea
 Diarrhea caused by opiate withdrawal
 Side effects
 Hypotension, depression, and perceived fatigue may be dose limiting
in susceptible patients.
Bismuth subsalicylate

 Mechanism of action
‾ Act by ↓ PG synthesis in the intestinal mucosa → ↓ Cl¯
secretion.
 Uses
‾ Traveler’s diarrhea
 Adverse effects
‾ Black tongue
‾ Black stools
Bile salt-binding resins

Examples : Cholestyramine, Colestipol, Colesevelam.

 Uses
1. Diarrhea caused by excess fecal bile acid (Steatorrhea)
2. Cholestyramine resin is helpful for the relief of pruritus associated
with partial biliary obstruction
 Adverse effects
1. Bloating 2.Flatulence 3.Constipation 4. Fecal impaction.
 Drug interaction
1. Decrease absorption of many drug
2. Colesevelam does not effects on absorption of other drugs.
Probiotics

 The administration of nonpathogenic bacteria to recolonize the gut is an area

of intense investigation(Sartor, 2005).
 Probiotic preparations containing a variety of bacterial strains have shown
some degree of benefit in acute diarrhea conditions, antibiotic-associated
diarrhea, and infectious diarrhea.

11
Inflammatory bowel disease (IBD)

Commonly used drugs

1. Aminosalicylates: Sulphasalazine, mesalamine, olsalazine, balsalazide.

2. Glucocorticoids: Prednisolone, methylprednisolone, hydrocortisone,
budesonide.
3. Immunomodulators: Azathioprine, 6-mercaptopurine (6-MP),
methotrexate, cyclosporine.
4. Biological response modifiers: Infliximab.
5. Antibiotics: Metronidazole, ciprofloxacin, clarithromycin.
6. Others: Probiotics.
Methotrexate oral, i.m, s.c

Pharmacokinetics: Methotrexate may be given orally, subcutaneously, or

intramuscularly. Reported oral bioavailability is 50–90% at doses used in chronic
inflammatory diseases. Intramuscular and subcutaneous methotrexate exhibit nearly
complete bioavailability.
Mechanism of action Inhibition of dihydrofolate reductase, an enzyme important
in the production of thymidine and purines. At the high doses used for
chemotherapy, methotrexate inhibits cellular proliferation. However, at the low
doses used in the treatment of inflammatory bowel disease (12–25 mg/ wk), the
antiproliferative effects may not be evident. Methotrexate may interfere with the
inflammatory actions of interleukin-1. It may also stimulate increased release of
adenosine, an endogenous antiinflammatory autacoid. Methotrexate may also
stimulate apoptosis and death of activated T lymphocytes.

Adverse Effects At higher dosage, methotrexate may cause bone marrow

depression, megaloblastic anemia, alopecia, and mucositis. At the doses used in
the treatment of inflammatory bowel disease, these events are uncommon but
warrant dose reduction if they do occur. Folate supplementation reduces the risk
of these events without impairing the anti-inflammatory action.

In patients with psoriasis treated with methotrexate, hepatic damage is common;

however, among patients with inflammatory bowel disease and rheumatoid

12
arthritis, the risk is significantly lower. Renal insufficiency may increase risk of
hepatic accumulation and toxicity.

Drugs used to treat variceal hemorrhage

1) Intravenous Somatostatin (250 Mcg/H) or Octreotide (50 mcg/h) for 3–5

days
Mechanism of action: Act via Inhibition of release of glucagon and other
gut peptides that alter mesenteric blood flow.
2) Vasopressin & terlipressin: Mechanism of action: When administered
intravenously by continuous infusion, vasopressin causes splanchnic
arterial vasoconstriction that leads to reduced splanchnic perfusion and
lowered portal venous pressures.
Adverse effects Systemic and peripheral vasoconstriction can lead to
hypertension, myocardial ischemia or infarction, or mesenteric infarction.
3) Beta-receptor antagonists: Mechanism of action: Beta-receptor
antagonists reduce portal venous pressures via a decrease in portal venous
inflow. This decrease is due to a decrease in cardiac output (β 1 blockade)
and to splanchnic vasoconstriction (β 2 blockade) caused by the
unopposed effect of systemic catecholamines on α receptors. Thus,
nonselective β blockers such as propranolol and nadolol are more
effective than selective β 1 blockers in reducing portal pressures

13