Laxatives and

Antidiarrheal Agents
Dr. Lester M. Partlow
Department of Pharmacology
UUMC
Laxatives vs. Cathartics
Refers to drug effect rather than to the drug
itself because the drug effect varies with dose.
Laxative effect: a soft but formed stool
Cathartic effect: a fluid stool
Drugs are named according to their usual
effect at the standard dose.
bulk-forming laxatives
saline cathartics
Constipation
Decreased frequency of fecal elimination
and/or passage of hard, dry stools
Range = 3/day to 3/week (99% of people)
Whats the record?
Laxative Overuse
Laxative Habit: The compulsive, chronic use of a
laxative or cathartic to achieve regularity.
Individuals with a laxative habit are dependent for bowel
function on a daily dose of laxative. Why?
70% of such dependence is psychological rather than
physiological.
Laxative Abuse: for weight loss
These factors result in purchase
of about $330,000,000/yr of
mostly unnecessary laxative.
Guidelines for Laxative Use
Generally shouldnt be used on a regular basis:
They can cause water and electrolyte loss.
They decreases the ability of the GI tract to work normally.
Shouldnt be used in the presence of abdominal pain,
nausea, vomiting, bloating, or cramping because they
might exacerbate an underlying pathology.
The Usual Pharmacological Concerns Also Apply:
Use the mildest type that is effective & acceptable to the pt.
Use the lowest effective dose.
Use as infrequently as possible.
Terminate as soon as possible.
TREATMENT OF CONSTIPATION
Eliminate any constipating drugs (list in HO; esp.
narcotics, antacids, iron, etc.)
Deal with any underlying medical problems:
Metabolic/endocrine disorders (e.g., hypothyroidism)
Neurogenic disorders (e.g., altered vagal input)
Disorders of bowel structure
Age (Many/most of elderly are chronically
constipated.)
TREATMENT OF CONSTIPATION
Use non-drug therapy: (G&Gs first line of therapy)
Adequate fiber in diet (20-25 gm/day is optimum)
Adequate fluid intake = 4-6 x 8 oz glasses/day
(increases volume, wetness)
Reduce emotional stress (but stress can also cause
diarrhea!)
Children may need training to respond to the urge to
defecate in order to avoid constipation
Physical exercise also promotes increased bowel
activity
Laxative Use for Routine
Constipation:
1. Bulk-forming agents
2. Saline or sugar osmotic laxatives
3. Stimulant or contact cathartics
Class I: Bulk-forming Laxatives
First Choice for Simple Constipation
psyllium (natural; Metamucil)
dietary fiber (natural; bran)
methylcellulose (semisynthetic; Citrucel)
polycarbophil (synthetic; FiberCon, Mitrolan
Chewable Tablets)
polyethylene glycol (synthetic) alone (MiraLax)
or with electrolytes (Colyte, NuLytely, GoLytely
solutions)
Class I: Bulk-forming Laxatives
All are dry powders except [PEG + electrolytes]
Nonabsorbable & Hydrophilic
Subject to Variable Bacterial Degradation
& Gas Formation
o Natural preps = some degradation (usually not too bad
but can reduce compliance)
o Semisynthetic = less
o Synthetic agents =none
Mechanism:
o Absorb & retain water
o Increase fecal volume
o Soften stool
o Increase the rate of transit
Bulk-forming Laxatives Are
Useful in Patients Who:
Need a laxative for simple constipation
Are on low-residue diets
Are postpartum or elderly
Have diverticular disease, spastic colon,
or hemorrhoids
Have alternating constipation & diarrhea
(polycarbophil = Equalactin)
Why does it work so well? Because
Bulk-forming Laxatives
Possible Adverse Effects:
Loss of water and electrolytes with powdered
preparations (prolonged use only)
Possible reduced absorption of drugs/vitamins
Should be introduced gradually over 1-2 weeks
General Characterization: Gentle but slow!
(They require from to 3-4 days for an effect.)
Class II: Saline Osmotic Agents
Active constituents are relatively nonabsorbable ions
magnesium hydroxide (Phillips Milk of Magnesia)
magnesium sulfate (Epson salt)
magnesium citrate (Citroma Solution)
sodium phosphate (Fleet Phospo-Soda and Enemas for children)
Effects are Dose- and Preparation-dependent
Large doses are very rapid but not gentle!
(Phospho-soda produces watery stools after
only 1-3 hours.) [CATHARTIC EFFECT]
Small doses of Phillips MOM may require several days for laxation.
[LAXATIVE EFFECT]
Osmotically draws water into the GI tract volume and
fecal transit rate; works much like bulk fiber preparations.
Fleet
Average water and electrolyte levels in the
normal GI tract. Daily intake assumes 2 L
ingested food + liquid and 7 L of saliva.
Saline Osmotic Agents
Orally administered, empties the entire GI tract.
Rectally administered, only evacuates the
colon.
Some saline suppositories/enemas also
produce CO
2
which exerts pressure in the
rectum and has a gas-lubricant-like effect.
Saline Osmotic Agents
Therapeutic Uses:
Routine purgation: Phillips MOM is 2
nd
line agent
Acute evacuation of bowel for an endoscopic exam
Elimination of drugs/toxins
Removal of fecal impaction (used in conjunction with
stool softeners or rectally administered mineral oil)
Potential Toxicities:
Electrolyte & volume overload from absorption of
sodium, magnesium, or phosphorus in patients with
renal insufficiency or cardiac dysfunction.
Dehydration
CLASS III: SUGAR OSMOTIC LAXATIVES
Lactulose (Constilac)
Costly but can be used for routine purgation (1-3 d)
especially in the elderly.
A poorly absorbed galactose-fructose disaccharide
which is metabolized by gut bacteria to poorly
absorbed organic acids (lactic, formic, & acetic).
Both the disaccharide & organic acids pull water
into the gut resulting in its laxative effect.
Acidification of the feces increases ammonia
excretion & provides symptomatic relief of portal-
systemic encephalopathy (PSE) (**main use**).
SUGAR OSMOTIC LAXATIVES
Sorbitol (Cystosol)
Like lactulose in its laxative action but cheaper
Like lactulose in that it is favored for the elderly
Oral administration of 70% solution or rectal
administration of a 25-30% solution
Prune Juice: A Natural 12.7% Sorbitol Solution!
5 to 30 fluid ounces = adult oral laxative dose
0.35 oz/kg for children from 2 to 11
Sorbitol is natural & undergoes bacterial fermentation
in the gut causing a bloated, churning feeling & flatus.
This occurs even with prune juice.
*** SIP SLOWLY OVER HALF AN HOUR!! ***
Class IV: Stimulant Laxatives
Laxative/Cathartic Abuse: most often involved
Mechanisms:
All increase peristalsis through the GI tract
Some also increase fluid and electrolyte absorption
resulting in net intestinal fluid accumulation.
Adverse Effects.
Can cause water/electrolyte/nutrient loss
All turn urine pink or red or reddish/brown.
Therapeutic Use:
Used for severe constipation that does not respond to
bulk or osmotic laxatives (3
rd
line agent)
Used to empty the GI tract
For temporary use only
Bisacodyl (Dulcolax): A Common Stimulant Laxative
Oral administration:
5% absorbed
Individually effective doses vary by 4- to 8-fold
Rectal administration: enema or suppositories
Bisacodyl tannex enema (Clysodrast) also
contains potentially hepatotoxic tannic acid.
Used for colon prep for surgery or X-ray exam
Use caution with repeat use
Dont use in pts with colonic ulcers or in
children <10
Anthraquinones: Senna (Ex-Lax) & Cascara
Also common in stimulant laxatives; senna replaced
phenophathalein in Ex-Lax & elsewhere.
Provides a more complete evacuation than bisacodyl.
Shouldnt be used by nursing moms as it is excreted
in breast milk.
Takes 6+ hours as they specifically increase peristalsis
in the colon.
Castor Oil
Triglyceride from castor beans
Releases an anionic surfactant (ricinoleic acid) which
reduces net movement of electrolytes and water out of
the small intestine and increases fecal bulk.
The increased bulk speeds fecal transit.
Also can trigger fairly violent uterine and abdominal
contractions (i.e., cramping). Can cause abortions.
Effective in as little as 2 hours.
Class V: Tegaserod (Zelnorm), A Prokinetic Agent
Selective Partial Agonist of 5HT
4
Serotonin Receptors:
Increases intestinal peristalsis
Reduces sensations of visceral pain
Increases stool frequency & softens feces
As a partial agonist, it is less likely to cause tolerance.
Therapeutic Uses:
Short-term Rx in constipation-predominant IBS in women: only
a modest improvement (12-15%) in assessment of relief.
(Efficacy >12 mo not studied.)
Chronic constipation in men & women <65 (recently approved;
08/21/04)
GERD (off label)
Absolute Contraindications: abdominal pain, breast feeding,
gallbladder/renal/hepatic disease
Adverse Effects: various GI events (6-12%); 2-6% discontinue bec of
diarrhea; no cardiac problems like caused by cisapride (Propulsid)
Class VIa: Lubricant Oils
Oral oil use is limited as
better & safer agents are
available.
Mineral oil enemas are used
to relieve fecal impaction
Lubricates the feces and
distends the rectum
Caution: The resulting
evacuation may be explosive!
(Darwin Award)
Class VIb: Docusate (Colace)
Anionic surfactant
Therapeutic Uses:
Minimal laxative effect at usual doses.
Used as stool softer; esp. in childhood constipation and
postpartum women; requires 1-3 days
Used to relieve fecal impaction; oral or rectal
Safer than mineral oil given orally
Used with a stimulant or saline laxative given rectally
Part 2: Antidiarrheal Agents
*** SKIP INTRODUCTORY COMMENTS
& MOVE TO OPIOID DRUGS ***
Part 2: Antidiarrheal Agents
Diarrhea = increased stool liquidity and/or stool
weight.
Associated with increased frequency (>3/day),
perianal discomfort, urgency, incontinence.
Diarrhea (2)
Acute:
2 weeks or less in duration
Infectious, toxic, drug-induced, or dietary in origin
Serious; it ranks 2
nd
only to respiratory infections as a
cause of morbidity
Chronic:
More than 2 weeks to many months
Often a symptom of serious illness
Can result from 50+ diseases of many different organs
Initial Goals for both Acute and Chronic:
Termination of fluid loss
Replacement of fluid and electrolytes.
Classical OTC Antidiarrheal Drugs
Some are hydrophilic agents & decrease
stool fluidity
Others are absorbents that might bind
pathogens or toxins
Some do both (e.g., kaolin + pectin =
kaopectate)
Generally these agents are of poor
efficacy in treating diarrhea (except for
bismuth salts)
Opioid Drugs
All reduce gut motility by acting on opiate receptors
to reduce Ach release by GI neurons that stimulate
contraction.
Diphenoxylate-atropine (Lomotil): Was most
commonly used agent in this class for yrs but Rx
doses caused dizziness, drowsiness, mild euphoria
while higher doses cause pronounced euphoria &
potentially serious respiration depression.
Therefore, drug companies searched for an opioid
with less potential for analgesia, respiratory
depression, and addiction & found loperamide!
Loperamide (Imodium)
Loperamide is now the preferred opioid antidiarrheal
agent.
Safer because less than 10% leaves the GI tract and less
than 0.04% reaches the brain.
Longer duration of action
Has a unique antisecretory effect not mediated through
opioid receptors. (It reduces fluid accumulation in the
intestine.)
So safe that available OTC in 2 mg tablets and in a 0.2
mg/ml liquid for children. (In contrast, lomotil should
never be used in children because of the atropine.)
5-HT
3
Antagonist: Alosetron (Lotronex)
Blockade of 5-HT
3
Receptors on Enteric Neurons
in the Gut Causes:
sensation of visceral pain
reflex increase in colonic transit rate
water & sodium reabsorption
Therapeutic Use: Used in diarrhea-predominant IBS in
women who experience bowel urgency >50% of the time.
Only causes a modest increase (13-16%) in the median %
of days without bowel urgency.
Unexpected Severe Side Effects: 70 in 4 months
50 with ischemic colitis
5 deaths so Lotronex was voluntarily withdrawn
Alosetron (Lotronex) contd.
Back on market after FDA risk/benefit analysis & user demand
Heavily Restricted!!!
Only used in women for unresponsive severe diarrhea-
predominant IBS
Starting dose was reduced to 1 mg per day
Refills not allowed without follow-up exam
Patient & physician have to sign a risk-benefit statement
Patient & physician must agree to strictly adhere to Rx plan
Physicians must enroll, take training, & use stickers on Rx
Pharmacists must have script with sticker in hand to fill Rx
Absolute Contraindications: Cant have other current or past GI
disease (see partial list in HO) or thrombophlebitis.
Adverse Effects: Constipation (25-30%), 0.1% serious; many
others including cardiac effects; many drug interactions
Traveler's Diarrhea
Occurs with very high frequency in
travelers to some specific foreign countries.
Caused most commonly by toxigenic E.
coli (45-70%)
Other frequent causative agents include:
Campylobacter
Salmonella
Shigella
Viruses and parasites
Treatment of Travelers Diarrhea
Rehydration (fruit juice, Rehydralyte, Pedialyte [grape])
Bismuth subsalicylate (Pepto-Bismol)
1-2 tablets every eight hours for eight doses
Has both a weak antibacterial & an anti-inflammatory action.
Generally controls diarrhea within 24 hr
Side Effects and Toxicities of Pepto-Bismol
Binds tetracyclines including doxycycline which is often used
for prophylaxis of malaria.
Turns stools and tongue black.
Contains salicylate, can cause ringing in ears, and is additive
with aspirin. Dont use in pts allergic to aspirin!
Can cause GI impaction in debilitated patients.
Treatment of Travelers Diarrhea
Loperamide: 4 mg loading dose plus 2 mg per stool
with a max of 16 mg/day (i.e., 8 tablets).
Antimicrobial agents are only appropriate when:
the diarrhea is severe,
the patient is febrile,
bloody diarrhea is present, and/or
the infection is persistent.
Current best antimicrobial choices:
ciprofloxacin (Cipro) or ofloxacin (Floxin) in adults or
trimethoprim-sulfamethoxazole (Bactrim) in children.
Treat with ABs up to 3 days or until symptoms
resolve.
Prophylaxis of Travelers Diarrhea
Bismuth Subsalicylate: (2 tablets x 4/day)
reduces TD incidence from 61% to 23%
Antimicrobial Agents:
The same agents used to treat diarrhea can
be given for prophylaxis.
Dont use ABs for more than three weeks!
Routine use of ABs for prophylaxis should
be discouraged.
Many physicians provide ABs & loperamide
to travelers for use if symptoms appear