Drugs Used in Constipation & Diarrhoea

Question 1

List SEVEN major groups of drugs used to treat constipation.

Answer 1

(1) Bulk-Forming Laxatives
(2) Stool Surfactant Agents
(3) Osmotic Laxatives
(4) Stimulant Laxatives
(5) Chloride Channel Activators
(6) Opioid Receptor Antagonists
(7) Serotonin 5-HT4-Receptor Agonists

Question 2

List SIX major classes of drugs used to treat diarrhoea.

Answer 2

(1) Opioid Agonists
(2) Colloidal Bismuth Compounds
(3) Intestinal Adsorbents (e.g., Kaolin and Pectin)
(4) Bismuth
(5) Bile Salt-Binding Resins
(6) Somatostatin-like Peptides
(7) Products of Lactobacillus acidophilus

Question 3

Name examples of bulk-forming laxatives that are (1) natural plant products/fibres; (2) Semi-synthetic plant fibres; and (3) Synthetic fibres

Answer 3

Examples of bulk-forming laxatives that are:

(1) Natural plant products/fibres: Psyllium, Sterculia, Agar, Bran
(2) Semi-synthetic plant fibres: Methylcellulose
(3) Synthetic fibres: Polycarbophil

Question 4

Briefly explain the mechanism of action of bulk-forming laxatives.

Answer 4

• Indigestible, hydrophilic colloids (fibre)
• Absorb water and form bulk, emollient gel that distends colon (increases stool mass)
  
  • Promotes peristalsis

Question 5

What are the most common adverse effects/concerns with bulk-forming laxatives?

Answer 5

• Bacterial digestion of plant fibres within the colon may lead to flatus, bloating and abdominal pain
  
  • Avoid if an obstruction is suspected
• Interaction with the absorption of other drugs

Question 6

List examples of (1) sugar, (2) salt, and (3) balanced osmotic laxatives.

Answer 6

Examples of osmotic laxatives:

(1) Nonabsorbable Sugars: Sorbitol, lactulose
(2) Nonabsorbable Salts: Magnesium hydroxide (milk of magnesia); Magnesium citrate; Sodium phosphate
(3) Balanced: Balanced Polyethylene Glycol (PEG)
* Balanced, isotonic solution of osmotically active sugar (PEG) and various salts

Question 7

Briefly explain the mechanisms of action of osmotic laxatives.

Answer 7

• Osmotically-mediated water movement into the bowel increases stool liquidity (softer stool) and volume
• Increased volume stimulates peristalsis
• High doses can produce bowel evacuation (purgation) within 1 to 3 hours

Question 8

What is the MOST IMPORTANT life-saving step in the management of any patient with severe, acute diarrhoea?

Answer 8

Maintain hydration and electrolyte balance with an oral rehydration salts (ORS) solution.

Question 9

What is the MOST IMPORTANT advice for a patient prescribed an osmotic laxative?

Answer 9

Maintain adequate hydration by increasing oral fluid intake

Question 10

What are the major concerns/adverse effects of osmotic laxatives?

Answer 10

• Colonic bacteria act on sugars → severe flatus & abdominal cramps.
  
  • Note that PEG although an osmotically active sugar does not produce significant cramps or flatus.
• Important to maintain adequate hydration by increasing oral fluid intake.
• Sodium phosphate can cause:
  
  • Hyperphosphataemia, hypernatraemia and hypocalcaemia, hypokalaemia.
  • Normally not clinically significant but may cause cardiac arrhythmias or acute renal failure due to tubular deposition of calcium phosphate (nephrocalcinosis).
  • Should not be used in patients who are frail, elderly, on diuretics, unable to maintain adequate hydration or who have renal insufficiency or cardiac disease.

Question 11

Explain whether lactulose osmotic laxatives are safe for patients with (1) lactose intolerance; or (2) diabetes mellitus.

Answer 11

Lactulose itself does not pose a risk to patients with lactose intolerance or diabetes mellitus.

But caution is necessary as due to the manufacturing process, lactulose osmotic laxative formulations often contain carbohydrate impurities including galactose, lactose, and other sugars (e.g., epilactose, tagatose, and fructose).

• Lactose poses a risk to patients with lactose intolerance
• Sugars such as galactose, lactose, and fructose may affect blood glucose levels in patients with diabetes mellitus. However, studies of blood sugar levels following administration of lactulose formulations known to contain carbohydrate impurities have found only minor or no significant changes in blood sugar levels.

Question 12

Name examples of (1) natural product anthraquinone derivative and (2) synthetic diphenylmethane derivative stimulant or cathartic laxatives. State routes of administration and how fast these drugs act.

Answer 12

Examples of stimulant or cathartic laxatives:

(1) Natural product, Anthraquinone Derivatives:

• Aloe, Senna and Cascara (oral or per rectum)
• Produce bowel movements in 6 to 12 hrs (oral) or 2 hrs (rectal)

(2) Synthetic, Diphenylmethane Derivatives

• Bisacodyl (oral or per rectum)
• Tablet or rectal suppository
  
  • Induces bowel movement in 6-10 hours (oral) or 30-60 minutes (rectal)
  • Used in conjunction with PEG for colonic cleansing prior to colonoscopy

Question 13

Explain whether stimulant or cathartic laxatives (1) cause dependence, (2) cause colon cancer or (3) cause cardiac toxicity.

Answer 13

These are all concerns that patients who have searched online may ask about. But none are evidence-based medicine concerns.

(1) Long-term use may be required in patients who are neurologically impaired or bed-bound. This led to concerns that chronic use may lead to dependence and destruction of the myenteric plexus resulting in colonic atony and dilation. However, more recent systematic reviews and meta-analyses do not support this concern.
(2) Chronic use of anthraquinone derivatives leads to brown pigmentation of the colon (melanosis coli). This led to concern regarding carcinogenesis, but epidemiological studies do not support an association with colorectal cancer.
(3) An early diphenylmethane derivative, phenolphthalein, was withdrawn due to cardiac toxicity. However, bisacodyl appears to be safe.

Question 14

To which class of drugs does lubiprostone belong?

Answer 14

Chloride channel activator laxatives

Question 15

Briefly explain the mechanisms of action of lubiprostone.

Answer 15

Lubiprostone:

• Is a bicyclic fatty acid derived from prostaglandin E1
• Stimulates type 2 chloride channels (ClC-2) in the small intestine
• Increases chloride-rich fluid secretions, and water follows the chloride osmotically
• Stimulates motility and shortens intestinal transit time due to increased stool volume and liquidity

Question 16

What are the most significant adverse effects of lubiprostone?

Answer 16

• Nausea due to delayed gastric emptying (approx. 30 % of patients)
• Also stomach/abdominal pain,dizziness, headache, diarrhoea

Question 17

List the TWO indications for lubiprostone.

Answer 17

Lubiprostone is used to treat:

• chronic idiopathic constipation
• irritable bowel syndrome with constipation
• constipation caused by opioid medications (other than diphenylheptane opioids e.g., methadone) in people with ongoing pain due to medical conditions other than cancer.

Question 18

Name a drug indicated as a laxative only to reverse opioid-induced constipation. Briefly, explain how this drug is used and administered.

Answer 18

Methylnaltrexone

• Treat constipation caused by opioids in adults with chronic pain (e.g., patients receiving palliative care)
• Administered subcutaneously once daily or every 2 days

Question 19

Briefly, explain the mechanisms of action of methylnaltrexone.

Answer 19

Effects mainly mediated through blockade of intestinal (peripheral) mu (μ) opioid receptors. Blocks shutdown of GIT motility and secretions and closure of GIT sphincters by opioids.

Question 20

Why is methylnaltrexone preferrable to naltrexone or naloxone for reversal of opioid analgesic-induced constipation

Answer 20

In contrast to naltrexone and naloxone, methylnaltrexone does not readily cross the blood-brain barrier (as it is a quaternary ammonium cation) and so do not block CNS analgesic effects.

Question 21

What are the common side effects of methylnaltrexone?

Answer 21

Stomach/abdominal pain, nausea, diarrhoea, chills/increased sweating, dizziness.

Question 22

To which class of laxatives does prucalopride belong?

Answer 22

Serotonin 5-HT₄ receptor agonists

Question 23

What are the indications for prucalopride?

Answer 23

Prucalopride is used to treat:

• Chronic idiopathic constipation.
• Constipation refractory to treatment with other laxatives.
• Emerging evidence also suggests may be effective in opioid-induced constipation

Question 24

Briefly describe the mechanisms of action of prucalopride.

Answer 24

Prucalopride:

• Is an agonist at 5-HT₄ receptors
• Has an enterokinetic effect (stimulates GIT motility and movement through the bowel)
  
  • Stimulation of presynaptic 5-HT₄ receptors on submucosal intrinsic primary afferent neurone (IPAN) terminals enhances the release of neurotransmitters
    
    • E.g., calcitonin gene-related peptide (CGRP)
  • Stimulates enteric neurones (ENs) to promote peristaltic reflex and colonic mass movement

Question 25

List the major adverse effects of prucalopride.

Answer 25

Dizziness, fatigue, headache, tremors

Stomach/abdominal pain, nausea, diarrhoea, flatulence

Palpitations

Question 26

What is the MOST IMPORTANT advice for a patient prescribed prucalopride?

Answer 26

Prucalopride may cause dizziness and fatigue. If affected, do not drive, or operate machinery.

Question 27

What is the first-line drug class for symptomatic control of diarrhoea of unidentified cause?

Answer 27

Peripherally acting, opioid receptor agonist e.g., loperamide

Question 28

Name TWO examples of opioid agonist antidiarrhoeals.

Answer 28

Loperamide

Diphenoxylate

Question 29

Briefly explain the mechanisms of action of opioid agonist antidiarrhoeals.

Answer 29

Opioid agonists activate mu or mu and delta opioid receptors in the gastrointestinal system to inhibit motility, inhibit secretions, and shuts down sphincters.

Inhibition of acetylcholine release from enteric interneurons and motor neurons and inhibition of purine/nitric oxide release from inhibitory motor neurons causes inhibition of propulsive motility patterns. Reduction of prostaglandin release has been implicated in reducing secretions.

Question 30

Describe the major differences between loperamide and diphenoxylate.

Answer 30

Loperamide is a mu opioid receptor agonist that does not cross the blood-brain barrier.

Diphenoxylate is a mu and delta opioid receptor agonist with limited blood-brain barrier penetration.

Question 31

Explain why diphenoxylate is formulated together with atropine.

Answer 31

At higher doses, diphenoxylate can cross the blood-brain barrier to and therefore its use is associated with a risk of dependence.

Atropine is formulated together with diphenoxylate to:

• Cause adverse effects on overdose to discourage abuse.
  
  • Adverse effects are anticholinergic parasympatholytic adverse effects such as dry mouth, flushing, etc.
• Anticholinergic effects reducing GIT motility and secretions further add to antidiarrhoeal actions

Question 32

Name an example of a colloidal bismuth compound used for the treatment of diarrhoea.

Answer 32

• Bismuth subsalicylate
• Bismuth subcitrate e.g., bismuth subcitrate potassium

Question 33

Briefly describe the mechanisms of action of colloidal bismuth compounds in the treatment of diarrhoea.

Answer 33

• Precise mechanisms of action not known
• Bismuth has an antimicrobial effect and binds enterotoxins, which has benefit for treating traveller’s diarrhoea
• Specifically for bismuth subsalicylate:
  
  • Rapid dissociation in stomach allowing absorption of salicylate
  • Salicylate inhibits intestinal prostaglandin production and chloride secretion
  • Reduces stool frequency and liquidity in acute infectious diarrhoea

Question 34

Describe the adverse effects and concerns with the use of bismuth compounds for the treatment of diarrhoea.

Answer 34

• Although > 99% of bismuth is eliminated in stool <1% is absorbed and stored in many tissues, elimination is by slow renal excretion
• Prolonged use may rarely produce bismuth toxicity resulting in encephalopathy (ataxia, headaches, confusion, seizures)
  
  • Use only for short periods
  • Avoid in patients with renal insufficiency
• But generally, the safety profile of bismuth formulations is good
• Harmless blackening of the stool, which may be confused for gastrointestinal bleeding
• Harmless darkening of tongue (liquid formulations)
• Specifically for bismuth subsalicylate: Salicylate toxicity with high doses

Question 35

Name an example of a bile salt-binding resin used to treat chronic diarrhoea.

Answer 35

Colestyramine (also known as cholestyramine in the USA), colestipol, or colesevelam

Question 36

Briefly explain the mechanisms of action of bile salt-binding resins in the treatment of diarrhoea

Answer 36

• Diseases of the ileum (e.g., Crohn’s disease) or surgical resection lead to malabsorption of bile salts resulting in colonic secretory diarrhoea
• Bile salt-binding resins bind to bile sales alleviating diarrhoea caused by excess faecal bile salts

Question 37

To what class of antidiarrhoeals does octreotide belong?

Answer 37

Somatostatin-like peptides

Question 38

What is the route of administration and duration of action of octreotide?

Answer 38

Octreotide is a synthetic octapeptide similar to somatostatin but with a half-life of about 1.5 hrs in serum.

To extend the duration of action to 6 to 12 hours it is administered by subcutaneous injection.

It can also be administered as a monthly intramuscular depot formulation.

Question 39

List examples of indications for use of octreotide as an antidiarrhoeal.

Answer 39

• Use for secretory diarrhoea caused by gastrointestinal neuroendocrine tumours (carcinoid and VIP-oma)
• Can also treat diarrhoea due to chemotherapy, vagotomy, gastric dumping syndrome, short bowel syndrome and AIDS

Question 40

What are the adverse effects of somatostatin-like peptides?

Answer 40

Adverse effects of somatostatin-like peptides are numerous as they mimic the endogenous somatostatin hormone.

Major concerns / adverse effects:

• Impaired pancreatic secretion can cause steatorrhoea, which can lead to fat-soluble vitamin deficiency
• Nausea, abdominal pain, flatulence, and diarrhoea
• Formation of gall sludge or gallstones in 50% of patients, rarely leading to acute cholecystitis
• Prolonged treatment can result in hypothyroidism
• Bradycardia

Question 41

Are probiotics effective in the treatment of diarrhoea?

Answer 41

Although frequently taken for bacterial and traveller’s diarrhoea, the use of probiotics is not an evidence-based medical treatment for infectious or bacterial diarrhoea.

Question 42

What is the difference between probiotics and lacteol forte?

Answer 42

Probiotics contain live microorganism, which include Lactobacillus acidophilus in some formulations. Formulations tend to be variable and, as they are not registered pharmaceutical products, consistency between products and batches is not controlled by the regulatory authorities. In contrast, lacteol forte contains standardized freeze-dried (lyophilized), heat-inactivated Lactobacillus acidophilus.

Lacteol forte is an evidence-based treatment for diarrhoea. The lyophilizate of killed Lactobacillus acidophilus binds to the intestinal wall to normalize the intestinal flora preventing over-colonization of invasive microflora by competitive exclusion.

Probiotics attempt to colonize the gastrointestinal tract with live beneficial microflora. However, there is insufficient or inconsistent evidence for efficacy in the treatment of infectious or bacterial diarrhoea.

Question 43

What are the major considerations or adverse effects when using lyophilizate of killed Lactobacillus acidophilus?

Answer 43

• Not systemically absorbed therefore little risk of adverse effects
• Important to maintain hydration
• Contraindicated in patients with lactose intolerance as formulation contains lactose monohydrate

Question 44

Name ONE example of a commonly used intestinal adsorbent.

Answer 44

Diosmectite​ (also known as dioctahedral smectite), kaolin, or pectin

Question 45

How do intestinal adsorbents work in the treatment of diarrhoea?

Answer 45

• Absorbents of bacterial toxins and fluid
• Decrease stool liquidity and number
• Useful in acute diarrhoea but seldom used chronically

Question 46

What are the major concerns and adverse effects when using intestinal adsorbents to treat diarrhoea?

Answer 46

• Not absorbed so little risk of significant adverse effects
• Constipation is only likely adverse effect
• Can bind to and inhibit absorption of other medications:
  
  • Should not be taken within 2 hrs of other medication