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
4. Endocrine and Metabolic disorders
a) Hypothyroidism
b) Hypercalcemia
c) Hypokalemia
d) Pheochromocytoma
Causes of constipation
5.
Neurologic
a) Parkinson's disease
b) Multiple sclerosis
c) Spinal lesions
d) Damage to sacral parasympathetic nerves
e) Autonomic neuropathy (Diabetes mellitus
6. 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
1)
2)
3)
4)
5)
6)
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
7)
8)
9)
10)
11)
12)
13)
14)
15)
Tricyclic antidepressants
Antacids containing calcium
carbonate or aluminum
hydroxide
Barium sulfate
Calcium channel blockers
Clonidine
Diuretics (nonpotassiumsparing)
Ganglionic blockers
Iron preparations
Muscle blockers (D tubocurarine,
succinylcholine)
Mechanism of drug-induced
constipation
1. 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
3. Electrolyte disturbance as hypokalemia or
hypercalcemia
4. Laxative abuse (leads to atonic intestine)
Treatment of constipation
General measures:
1) 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.
2. Increasing fluid intake.
3. Regulation of bowel habits
4. Regular exercise.
5. Treatment of the cause
6. 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:
1. Fecal impaction
2. Constipation associated with illness, surgery,
pregnancy or poor diet
3. Drug-induced constipation
4. Conditions where bowel strain is undesirable
5. Preparation for surgery or investigations
involving the GIT (e.g. sigmoidoscopy)
Classification of laxatives
1.
2.
3.
4.
5.
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)
1. Methylcellulose
2. Bran
3. 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:
1. They are the first-line treatment of constipation
2. Conditions where dietary intake of fibers can not be increased
Precautions:
 Adequate fluid intake to avoid intestinal obstruction
Adverse effects of bulk-forming laxatives:
1. Abdominal distension (due to fermentation).
2. Intestinal obstruction when not consumed with sufficient fluid
Contraindications:
1. Atony of the colon
2. Intestinal obstruction
3. Fecal impaction (should be corrected before administration of fiber)
4. Immobility
2. Stimulant (irritant) laxatives
Dosage forms::
Bisacodyl
Oral and rectal suppository
Sodium picosulfate
Oral
Senna and Cascara
Oral
Castor oil
Oral
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:
1. Small bowel irritant (hydrolysed in the small intestine by the
action of lipases): castor oil
2. Large bowel irritants (hydrolyzed by colonic bacteria):
a) Bisacodyl and Sodium picosulfate
b) Senna and Cascara
Stimulant (irritant) laxatives
(cont.)
Indications of large bowel irritants:
a)
b)
Bisacodyl and Sodium picosulfate
Senna and Cascara
1. Prevention of straining at stool following
surgery, myocardial infarction or stroke
2. Painful diseases of the anus, e.g., fissure or
hemorrhoids.
Stimulant (irritant) laxatives
(cont.)
1. Bisacodyl and sodium picosulfate:
Dosage forms:
1. Oral (the laxative effects after a dose occurs after 6 – 12
hours; taken at bedtime, it will produce its effect the next
morning)
2. Rectal suppository (for bisacodyl only – the laxative effect
occurs within 30 to 60 min.)
Indications: (also for cascara and senna)
1. Should not be used for more than 10 consecutive days (due
to the possibility of developing atonic colon)
2. Preparation before diagnostic procedures involving the GIT
Stimulant laxatives (cont)
Bisacodyl and sodium picosulfate (cont)
Adverse effects:
1. Abdominal cramps after each dose
2. Over dosage → catharsis and fluid and electrolyte
disturbances.
3. Can damage mucosa and cause inflammation in the
colon.
4. Atonic colon (following years of use)
Contraindications:
1. 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:
1. Unpleasant taste
2. Damage to intestinal epithelium and enteric neurons
Uses:
Strong purgative → evacuation of the bowel before surgery
and diagnostic procedures
Contraindications:
1. Intestinal obstruction
3- Osmotic laxatives
1. Saline laxatives (have cathartic action in large doses)
A. Magnesium salts (sulfate, hydroxide or citrate)
B. Sodium phosphate
Mechanism of action:
1. Poorly absorbed → water retention (osmotic effect) →soft bulky
stools → ↑peristalsis → relief of constipation
2. 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:
1. Flatulence, abdominal cramps, diarrhea
2. Intravascular volume depletion
3. Electrolyte disturbances
Contraindications:
1. Renal insufficiency
2. Severe cardiac disease
3. Preexisting electrolyte abnormalities
4. Patients on diuretic therapy
Osmotic laxatives (cont.)
2. Non-digestible sugars and alcohols
1. Lactulose (disaccharide of galactose and fructose
that resists intestinal disaccharidase activity)
2. Sorbitol (monosaccharide)
Mechanism of action:
Lactulose → metabolized by colonic bacteria into short
chain fatty acids → osmotic effect → stimulate
propulsive activity
Adverse effects:
1. Abdominal distention
2. Diarrhea
Osmotic laxatives (cont.)
Uses:
 Lactulose: (24-48h)
1. Used for treatment of hepatic encephalopathy (↓ blood
ammonia by lowering fecal pH →↓growth of ammoniaproducing bacteria and conversion of ammonia in the
colon to ammonium ion).
2. Constipation in the elderly patient
3. Alternative for acute constipation
 Sorbitol:
1. 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:
1. 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 .
2. 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
1. Docusate salts (sodium or calcium) (weak laxatives)
Mechanism of action:
1. Reduces surface tension of stools → increases penetration of fluids into feces →
soft bulky stools
2. Stimulate intestinal fluid and electrolyte secretion (by altering mucosal
permeability)
Dosage forms:
1. Oral form (active within 1-3 d)
2. Rectal form has a rapid onset of action but is contraindicated in
hemorrhoids and anal fissure.
Uses:
1. Used in hospitalized patients following myocardial infarction or surgery,
when straining at defecation should be avoided but activity and fluid
intake may be restricted.
2. 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:
1. Indigestible and with minimal absorption. Coat stool and allow
easier passage.
2. 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:
1. May be absorbed systemically → foreign-body
reaction in lymphoid tissue.
2. May be aspirated (in debilitated or recumbent
patients) → lipoid pneumonia
3. Decreases absorption of fat-soluble vitamins (A, D,
E, and K)
4. 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:
1. Headache
2. 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
1. Infectious (viral or bacterial)
2. Non infectious
Pathophysiologic mechanisms of
diarrhea
Pathophysiologic mechanism
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)
2)
3)
4)
Laxatives
Antacids containing magnesium
Antineoplastic drugs
Antibiotics
a) Clindamycin
b) Tetracyclines
c) Sulfonamides
d) Any broad-spectrum antibiotic
5) Antihypertensives
a) Methyldopa
b) Angiotensin-converting enzyme inhibitors
c) Angiotensin receptor blockers
d) α-adrenergic receptor blockers
Drugs causing diarrhea (cont)
6) Cholinergic drugs
1. Neostigmine
7) Cardiac agents
1. Quinidine
2. Digoxin
8) Nonsteroidal antiinflammatory drugs
9) Misoprostol
10) Colchicine
11) Proton pump inhibitors
12) H2-receptor blockers
Treatment of diarrhea
Non-pharmacologic therapy:
Dietary management:
1. Discontinue consumption of solid foods and dairy products
for 24 h (valuable in osmotic diarrhea)
2. For patients who are experiencing nausea and/or vomiting, a
mild, digestible, low-residue diet should be administered for
24 hours.
3. 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:
1. Patients with mild to moderate acute diarrhea
2. 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
1. Antimotility agents
2. Adsorbents
3. Antisecretory compounds
4. Antibiotics
5. Enzymes
6. Intestinal microflora.
Antimotility agents (opioids)
Opioids agonists:
Action in the GIT (mediated by binding to opioid
receptors)
1. Increase segmentation and a decrease propulsive
movement → ↑ intestinal transit time → ↑
absorption of water and electrolyte → feces become
more solid
2. Antisecretory
3. ↑ tone of the internal anal sphincter
4. ↓ 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:
1. Children below 2 y (toxicity at lower doses than adults)
2. Obstructive jaundice
Drug interactions:
1. Potentiate the effects of CNS depressants
2. Co-administration with MAO inhibitors→ hypertensive crises
Adverse effects:
1. Caused by the atropine in the preparation and include anorexia, nausea,
pruritus, dizziness, and numbness of the extremities.
2. Prolonged use of high doses may cause dependence
Opioids - Loperamide
Opioid agonist that does not cross the bloodbrain 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:
1. 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:
1.
2.
3.
4.
5.
6.
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:
1. Patients with +ve stool culture
2. Patients presented with dysentery
3. Patients with suspected exposure to bacterial
infection → Quinolones (as ciprofloxacin)