PHRM 465: Drug-Induced Diseases

Constipation and Diarrhea

Mallory Carter, PharmD

Objectives:
1. Identify the agents that commonly cause diarrhea and constipation and explain the associated
mechanisms of action.
2. Evaluate patient risk factors and differential diagnoses to identify patients suffering from drug-
induced diarrhea or constipation.
3. Recommend a patient- and drug- specific treatment plan for drug-induced diarrhea or constipation.

Constipation

Constipation occurs when stool remains in the colon for a prolonged amount of time, allowing the colon to
absorb excess water from the stool. The result is infrequent hard, dry stools that can be painful and
potentially serious. Although bowel habits vary quite significantly from person to person, constipation is
defined as having <3 bowel movements per week. Other common symptoms include incomplete
evacuation of stool, bloating, anorexia, nausea, abdominal pain or distention, and straining with defecation.

The prevalence of constipation varies throughout the world, owed in large part to the varied lifestyles and
diets that exist around the globe. In the United States, 2.5 - 6 million doctors’ visits each year are
attributed to constipation. While most people may experience an episode of constipation at least once in
their lifetime, there are some who are at an increased risk of chronic constipation. These risk factors
include:
 Increased age
 Female sex
 Dehydration
 Inactivity
 Diet low in fiber
 Pregnancy
 MEDICATIONS

Many common and frequently used medications are known to cause constipation; however, because of this
condition’s general frequency, it can be difficult to identify a true drug-induced case. Below is a table with
the most common offenders. Each of these drugs is known to have a ≥10% incidence of constipation.

Antibiotics Opioids* Bile Acid Sequestrants

 Dalbavancin  Codeine  Colesevalam
 Fentanyl  Colestipol
 Hydrocodone
 Hydromorphone
 Morphine
Anticholinergics Antineoplastics Diuretics
 Solifenacin  Doxorubicin  Furosemide
 Darifenacin  Bevacizumab
 Antidepressants Antipsychotics Antihypertensives
 Fluoxetine  Aripiprazole  Clonidine
 Paroxetine  Clozapine  Guanfacine
 Bupropion  Quetiapine  Verapamil
 Olanzapine
5HT3 Antagonists Other
 Alosetron  Iron Preparations
 Granisetron  NSAIDs (ibuprofen)
 Atorvastatin

Drug-induced constipation is categorized as a secondary constipation disorder and the mechanisms of

drug-induced constipation vary based on the drug class.
 Diuretics  decreased fluid secretion (dehydration)
 Anticholinergics  decreased parasympathetic action slows down the GI tract
o Antidepressants
o Antipsychotics
o Antihistamines
 *Opioids  inhibit gastric emptying and peristalsis
o Opioid-induced constipation (OID) occurs in 17-67% of patients
o Chronic use of opioids typically requires a prophylactic bowel regimen

It is important to be able to distinguish drug-induced constipation from other causes of constipation in

order to provide appropriate treatment recommendations. When performing a differential diagnosis,
obtain a detailed history that includes:
 Bowel habits
 Onset and duration of constipation
 Hydration status
 Any changes to diet, activity level, or medications/OTC/supplements
 Comorbid conditions

Alarm Symptoms: severe abdominal pain, unintentional weight loss, blood in the stool (or sudden changes
in stool color or consistency), unexplained anemia, family history of colon cancer
 Refer these patients as they require further work up (CT scan, GI endoscopy, colonoscopy, rectal
exam, etc.)

The best treatment starts with prevention. Patients can stay ahead of their drug-induced constipation by
staying active, staying hydrated, eating enough fiber ( ≥25g/day), maintaining a bowel schedule, and
avoiding postponing defecation. Health care providers can help patients stay ahead of their drug-induced
constipation by adjusting doses based on patient-specific factors, slowly escalating doses to maintain
tolerability, using alternative medications when possible, and initiating prophylactic bowel regimens as
needed (OIC).

When lifestyle modifications aren’t sufficient, medications can be used for management.
Drug Class Mechanism of Action
Bulk Forming Laxatives Not digested, absorb liquid in the intestines to increase stool
 Psyllium weight/size and soften the consistency. The increased size
 Calcium Polycarbophil stimulates the intestines to lead to defecation
 Methylcellulose
Emollient Laxatives Act as a surfactant to pull water into the stool and soften it
 Docusate Sodium
Osmotic Laxatives Draw water into the intestines via osmotic effects to stimulate
  Polyethylene Glycol movement
 Glycerin
 Lactulose
 Phosphate Salts
Stimulants Stimulate peristalsis and smooth muscle contraction to induce
 Bisacodyl the urge to defecate
 Senna

Bulk-forming agents and osmotic laxatives are first-line. If patients do not respond appropriately,
stimulant laxatives are often used.

Opioid-induced constipation (OIC) may employ the use of a PAMORA (peripherally acting mu opioid
receptor antagonist). Opioids bind to mu receptors all throughout the body to exert their analgesic effect;
however, the stimulation of the mu receptors in the GI tract results in constipation. PAMORA agents are
opioid antagonists with specificity for mu receptors in the GI tract to prevent the side effect of
constipation. These agents include alvimopan, methylnaltrexone, and naloxegol.

Diarrhea

Diarrhea is characterized by loose, watery, frequent stools. It is defined as ≥3 bowel movements per 24
hours, decreased stool consistency, and/or increased stool weight >200g per 24 hours. Other signs or
symptoms include dehydration, dizziness, electrolyte imbalance, hypotension, weakness, weight loss, thirst,
tachycardia, and hyperactive bowel sounds. Like constipation, diarrhea can be caused by a variety of
mechanisms: decreased absorption of water from the GI tract, active secretion into the GI tract, increased
GI motility, or infection.

Mechanisms of drug-induced diarrhea include:

 Osmotic: draw water into gut lumen
 Secretory: increase secretion or decrease absorption of water/electrolytes from the gut lumen
 Motility: increase GI motility (decreased time spent in GI tract to absorb water)
 Exudative: destroy intestinal mucosa  discharge of mucus, proteins, and blood into the gut 
changes in water and electrolyte absorption
 Malabsorption of fat: prevent absorption of fatty acids in the intestines  inhibition of fluid
absorption in the colon
 Microbial proliferation: disrupt microbial balance of the GI system  overgrowth of “bad” bacteria
that impacts GI functionality

Everyone, even the healthy, will experience diarrhea throughout their lives, especially as >700 drugs have
been associated with diarrhea. Below is a table with the most common offenders. Each of these drugs is
known to have a ≥10% incidence of constipation. (Highlighted colors indicate the mechanism of induction).

Antibiotics Antidepressants Antihyperglycemics

 Clindamycin  SSRIs  Metformin
 Fluoroquinolones  SNRIs  Acarbose
 Macrolides  GLP-1 Receptor Agonists
 β-Lactams
Antineoplastics Other
 Monoclonal Antibodies  Misoprostol
 Immune Checkpoint  Protease Inhibitors
Inhibitors  Orlistat
Determining the true cause of diarrhea can be challenging as so many conditions, lifestyle behaviors,
illnesses/infections, and medications can be the culprit. Acute diarrhea (lasting ≤72 hours or with episodes
for up to 14 days) is typically self-limiting (90% of cases). Chronic diarrhea involves frequent episodes over a
span of time ≥30 days. While medications should be considered when determining the cause of chronic
diarrhea, these patients will require evaluation for food allergies/intolerances, malabsorption,
inflammatory bowel disease, or infection. When performing a differential diagnosis, obtain a detailed
history that includes:
 Bowel habits
 Onset and duration of diarrhea
o Drug-induced diarrhea can begin weeks after the initiation of a medication and can last
weeks after discontinuation of a medication!
 Alcohol and caffeine intake
 Any changes to diet or medications/OTC/supplements
 Recent travel
 Comorbid conditions

Alarm symptoms: prolonged, voluminous bloody diarrhea, severe abdominal pain, electrolyte imbalances,
acid-base disturbances, unintentional weight loss

Diarrhea can be dangerous, even deadly. Risk factors for drug-induced diarrhea include:
 Age (pediatric and elderly)
 Diet high in fat and/or fiber
 Malnutrition
 Female sex
 Pain
 Unsanitary conditions

The best treatment starts with prevention. Patients can stay ahead of their drug-induced diarrhea by
avoiding foods with artificial sweeteners (sorbitol), eating a proper diet with adequate fluid intake, eating
smaller, more frequent meals, or eating bland, soft foods (bananas, rice, applesauce, toast). Health care
providers can help patients stay ahead of their drug-induced constipation by avoiding medications with high
sorbitol content or high tonicity, identifying drug intolerances/allergies, practicing antimicrobial
stewardship, encouraging probiotics, offering drug-specific counseling points, slowly escalating doses to
maintain tolerability, and using alternative medications when possible.

When lifestyle modifications or therapy alterations aren’t sufficient, medications can be used for
management.
Drug Mechanism of Action
Loperamide Inhibits peristalsis to prolong transit time, diminishes
fluid/electrolyte loss
Bismuth Subsalicylate Stimulates absorption of fluids/electrolytes, has
antimicrobial activity
Diphenoxylate and Atropine Inhibits excessive GI motility
Octreotide Increases GI transit time and decreases intestinal
secretions
Probiotics Replaces “good” bacteria in the GI tract
Antibiotic-Associated Diarrhea (AAD)
Antibiotics disrupt the natural microbiome of the GI tract by eliminating both “bad” and “good” bacteria.
This disruption alters the digestive process and can cause diarrhea. In some cases, this results in an
overgrowth of “bad” bacteria, like Clostridium dificile. C. dificile secretes toxins that cause inflammation and
mucosal damage leading to a Clostridium dificile Infection (CDI). CDI is characterized by excessive diarrhea
made up of mucoid, greenish, foul-smelling, watery stools. It requires a stool culture for diagnosis and has
a specific treatment algorithm involving other antibiotics (metronidazole and vancomycin). Of note, anti-
diarrheal medications should be avoided in CDI as they can prevent toxin elimination and mask the
symptoms of the infection prior to resolution.

Cancer Treatment-Induced Diarrhea (CTID)

Antineoplastic agents are a well-documented cause of diarrhea. The risk of diarrhea increases as additional
drugs are added to patient regimens. CTID can be life-threatening and typically requires medications as
first-line treatment.
 Loperamide 4mg once, then 2mg q4hrs or after every unformed stool (max 16mg daily)
o Can increase dose to 2mg q2hrs
o Can add oral antibiotic (to prevent superinfection)
 If unresolved, discontinue loperamide, start octreotide 100-150mcg SQ TID (max 500mcg daily)
 If requiring hospitalization for IV fluids, stop chemotherapy until symptoms resolve and restart at a
lower dose

Dehydration is the most common complication of diarrhea. Rehydration is essential.

 For patients with mild-moderate dehydration  oral rehydration solution (ORS)
o Contains sodium, potassium, chloride, citrate, and glucose
o Volume: 50-100 mL/kg
 For patients with severe dehydration  IV fluid (quickly)
o Lactated Ringer’s (avoid normal saline as it does not address necessary acid-base or
electrolyte replacements)
o Volume: 100 mL/kg

References:
 Cleveland Clinic. Constipation. Cleveland Clinic website. Updated November 7, 2019. Accessed February 10,
2023.
 Guzman F. Adverse effects of SSRIs. Pharmacology Institute. Published November 7, 2018. Accessed February
13, 2023.
 Koselke EA, Kraft S. Chemotherapy-induced diarrhea: options for treatment and prevention. J Hematol Oncol
Pharm. 2012; 2(4):143-151
 Nisly SA, Jung CM. Constipation. In: Tisdale JE, Miller DA eds. Drug-Induced Diseases: Prevention, Detection,
and Management. 3rd ed. ASHP; 2018:835-841.
 Nisly SA, Walton AM. Diarrhea. In: Tisdale JE, Miller DA eds. Drug-Induced Diseases: Prevention, Detection,
and Management. 3rd ed. ASHP; 2018:821-831.
 Oliva V, Lippi M, Paci R, et al. Gastrointestinal side effects associated with antidepressant treatments in
patients with major depressive disorder: a systematic review and meta-analysis. Prog Neuropsychopharmacol
Biol Psychiatry. 2021; 109:110266. doi:10.1016/j.pnpbp.2021.110266.
 Philpott HL, Nandurkar S, Lubel J, Gibson PR. Drug-induced gastrointestinal disorders. Frontline Gastroenterol.
2014; 5(1):49-57. doi: 10.1136/flgastro-2013-100316
 Sizar O, Genova R, Gupta M. Opioid induced constipation. In: Aboubakr S, Abu-Ghosh A, Acharya A, et al. eds.
Stat Pearls. StatPearls Publishing; 2022.
 Xu Y, Amdanee N, Zhang X. Antipsychotic-induced constipation: a review of the pathogenesis, clinical
diagnosis, and treatment. CNS Drugs. 2021; 35(12):1265-1274. doi: 10.1007/s40263-021-00859-0.