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Therapeutics. Treatment of irritable bowel syndrome (IBS) and constipation. Definition. IBS is an idiopathic chronic relapsing disorder characterized by: Abdominal discomfort (pain), bloating or distension Alteration in bowel habits (diarrhea, constipation or both).

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therapeutics

Therapeutics

Treatment of irritable bowel syndrome (IBS) and constipation

definition
Definition

IBS is an idiopathic chronic relapsing disorder characterized by:

  • Abdominal discomfort (pain), bloating or distension
  • Alteration in bowel habits (diarrhea, constipation or both)
  • Abdominal pain / discomfort
  • Bloating / distension
  • Change in bowel habit
alarm features investigations
Alarm features = investigations
  • Predominant constipation
  • age older than 50 years
  • symptom duration less than 6 months
  • weight loss
  • nocturnal symptoms
  • family history of colon cancer
  • rectal bleeding
  • Anemia
  • recent antibiotic usage.
treatment of ibs

K

Treatment of IBS

Aims of treatment:

  • Relieve abdominal pain and discomfort:
  • Anticholinergic drugs (commonly used are; dicyclomine and hyoscyamine) MOA: block M receptors
  • Low doses of TCA (e.g. amitriptyline or desipramine). Lowdoses have no effect on mood.

2) Relieve distension / bloating

  • Improve bowel function
  • For patients with predominant diarrhea: anti-diarrheal agents (especially loperamide) and serotonin 5-HT₃-receptor antagonists
  • For patients with predominant constipation: laxatives (bulk-forming or osmotic laxatives especially Mg oxide) and serotonin 5-HT₄-receptor agonist
antispasmodic drugs in ibs action relieve smooth muscle spasm relieve pain and bloating in ibs
Antispasmodic drugs in IBSAction: relieve smooth muscle spasm →relieve pain and bloating in IBS)
  • Anticholinergic drugs:

Mechanism of action:

Block muscarinic receptors (M₃ on smooth muscles in case of hyoscine or presynaptic M₁ in case of dicyclomine)

Adverse effects:

  • Blurred vision (may lead to glaucoma)
  • Dry mouth
  • Tachycardia
  • Urinary retention
  • Constipation
  • Heat intolerance
  • Confusion
antispasmodic drugs in ibs
Antispasmodic drugs in IBS

Contraindications of anticholinergic drugs

  • Patients with glaucoma
  • Prostatic hyperplasia (elderly)

Drug interactions of anticholinergic drugs:

  • With other drugs having anticholinergic effects
antispasmodic drugs in ibs1
Antispasmodic drugs in IBS
  • Mebeverine: (less effective than anticholinergic drugs)

Mechanism of action:

Not known (? calcium channel blocker or ? Direct acting)

Adverse effects:

  • Hypersensitivity reactions
  • In high doses: anticholinergic side effects
antispasmodic drugs in ibs for bloating pain
Antispasmodic drugs in IBS(for bloating/pain)

Which antispasmodic is preferred in patients with IBS with predominant constipation?

Which antispasmodic is indicated in patients with IBS with glaucoma or prostatic enlargement?

tricyclic antidepressants action relieve pain and bloating in ibs
Tricyclic antidepressantsAction: relieve pain and bloating in IBS

Mechanism of action:

Block synaptic amine uptake (both norepinephrine and serotonin) →↑ presence of serotonin and norepinephrine at their post-synaptic receptors (→ anxiety) followed by down regulation of the receptors →(delayed anxiolytic and antidepressant effect)

tricyclic antidepressants
Tricyclicantidepressants

Drugs:

Amitriptyline or Desipramine (10 – 50 mg/d) . (N.B. the usual antidepressant dose = 75 – 200 mg)

Adverse effects:

  • Blurred vision
  • Dry mouth
  • Constipation
  • Retention of urine
  • Orthostatic hypotension
  • Arrhythmia
  • Cardiac conduction disturbances
tricyclic antidepressants1
Tricyclicantidepressants

Contraindications:

Glaucoma

Elderly patients

Patients with cardiac diseases

selective serotonin reuptake inhibitors ssri
Selective Serotonin Reuptake Inhibitors (SSRI)

Mechanism of action:

Selective block of synaptic uptake of serotonin.

Drugs:

Cetalopram (less P450 inhibition → less drug interactions)

Adverse effects:

Mainly GIT including:

  • Nausea and vomiting
  • Diarrhea or constipation
  • Anorexia and weight loss
  • Sexual dysfunction
laxatives
Laxatives

Classification:

  • Bulk-forming
  • Osmotic laxatives
  • Stimulant laxatives
  • Fecal softeners / emollients (little role in chronic constipation)
laxatives1
Laxatives
  • Bulk-forming laxatives:

Precautions:

Adequate fluid intake to avoid intestinal obstruction

Adverse effects:

Abdominal distension (due to fermentation).

Intestinal obstruction when not consumed with sufficient fluid

laxatives2
Laxatives
  • Osmotic laxatives:
  • Saline laxatives (e.g. Mg oxide)
  • Non-digestible sugars or alcohols (e.g. lactulose)
  • Polyethylene glycol
  • Glycerin
  • Mg oxide is preferred because it is less expensive and it causes less distension
  • Adverse effects of Mg oxide:
  • Flatulence, abdominal cramps, diarrhea
  • Intravascular volume depletion
  • Electrolyte disturbances
laxatives3
Laxatives

Contraindications of Mg oxide

  • Renal insufficiency
  • Severe cardiac disease
  • Preexisting electrolyte abnormalities
  • Patients on diuretic therapy
treatment of diarrhea antimotility agents opioids
Treatment of diarrhea:Antimotility agents (opioids)

Opioids agonists:

Action in the GIT (mediated by binding to opioid receptors)

  • Increase segmentation and a decrease propulsive movement → ↑ intestinal transit time → ↑ absorption of water and electrolyte → feces become more solid
  • Antisecretory
  • ↑ tone of the internal anal sphincter
  • ↓ response to the stimulus of a full rectum (by their central action)
antimotility agents cont
Antimotility agents (cont)

Mechanism of opioid action:

Inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses

opioiods diphenoxylate
Opioiods - Diphenoxylate

Opioid agonist that has no analgesic properties in standard doses. Higher doses have central opioid actions. Used in combination with a sub-therapeutic dose of atropine (to prevent abuse)

Contraindications:

  • Children below 2 y (toxicity at lower doses than adults)
  • Obstructive jaundice
opioiods diphenoxylate1
Opioiods - Diphenoxylate

Drug interactions:

  • Potentiate the effects of CNS depressants
  • Co-administration with MAO inhibitors→ hypertensive crises

Adverse effects:

  • Caused by the atropine in the preparation and include anorexia, nausea, pruritus, dizziness, and numbness of the extremities.
  • Prolonged use of high doses may cause dependence
opioids loperamide
Opioids - Loperamide

Opioid agonist that does not cross the blood-brain 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.

role of 5ht and 5ht receptors in git motility
Role of 5HT₃ and 5HT₄ receptors in GIT motility

GIT distension → stimulate EC cells in the mucosa of the intestine → release of 5HT →

Binding of 5HT to

5HT₄R →

↑ release of

ACH and CGRP

5HT₃R are found on terminals of enteric cholinergic neurons → ↑release of ACh

5HT

5HT

5HT₄R

Ach

5HT

↑Proximal bowel contraction

↑ Distal bowel relaxation

CGRP

5HT₁pR

Submucosal intrinsic

primary afferent neuron

(IPAN)

2nd order enteric cholinergic neuron

5HT₃R

→ stimulation of

nausea, vomiting

and abdominal pain

5HT

→ CNS

Extrinsic afferent nerve

serotonin 5ht receptor antagonists
Serotonin 5HT₃ receptor antagonists
  • Inhibition of 5HT₃ receptors in the GIT→ inhibit nausea, bloating and pain
  • Inhibition of 5HT₃ receptors in the brain→ inhibit central response to afferent visceral stimuli
  • Inhibition of 5HT₃ receptors on terminals of enteric cholinergic neurons → ↓motility in the left colon and ↑colon transit time
serotonin 5ht receptor ant agonists alosetron
Serotonin 5HT₃ receptor antagonistsAlosetron

Action: relieves lower abdominal pain, urgency and diarrhea (no effect on stomach)

Mechanism of action: 5HT₃ receptor antagonist

Uses: Femalepatients with severe IBS with diarrhea with no response to other therapies

serotonin 5ht receptor ant agonists alosetron1
Serotonin 5HT₃ receptor antagonistsAlosetron

Pharmacokinetics:

  • Rapidly absorbed after oral administration
  • Plasma t½ = 1.5 h.
  • Long duration of action (dissociates slowly from 5HT₃ receptor)
  • Extensive hepatic metabolism (P450) with renal excretion of metabolites

Adverse effects:

  • Constipation
  • Ischemic colitis (may be fatal)
serotonin 5ht receptor partial agonist tegaserod
Serotonin 5HT₄ receptor partial agonist:Tegaserod

Action:

  • ↑gastric emptying and enhance small and large bowel transit (no effect on esophagus)
  • ↑ stool liquidity

Mechanism of action of tegaserod:

Serotonin 5HT₄ partial agonist. Binding to 5HT₄ receptors on the terminals of the 2nd order enteric neuron

→↑ release of Ach and CGRP →

↑gastric emptying and enhance small and large bowel transit (no effect on esophagus)

→↑ Cl secretion from the colon →↑ stool liquidity

tegaserod
Tegaserod

Pharmacokinetics:

Low bioavailability (further reduced by food)→ should be taken before meals

Metabolized in liver (by glucuronidation)

Excreted in feces (unchanged) and in urine (metabolites)

Contraindications:

Severe renal or hepatic impairment

tegaserod1
Tegaserod

Uses:

Short term treatment (up to 12 weeks) of women with moderate/severe IBS with predominant constipation who have failed to fiber supplementation and laxatives (reduce pain and bloating - ↑ bowel movements and ↓ hardness of stools)

Other uses:

Chronic constipation in patients not responsive or intolerant to other less expensive therapies

Adverse reactions (rare):

  • Diarrhea
  • Headache
case 1
Case (1)

A 34-year-old woman presents with a 6-month history of abdominal pain, bloating, distension, decrease in the number of bowel movements per week (<3 times) and difficulty when passing stools. She also states that the abdominal pain and bloating almost occur continuously throughout the day although her symptoms are alleviated by passing stool. She also states that the symptoms are worse when she has midterm or final examinations.

case 1 cont
Case (1) cont.

She was taking bran till 3 months ago but could not stand the taste and wasn’t sure how much it was helping. She switched to psyllium powder but she felt that distension increased. She was also treated with sorbitol solution but it has some side effects and she resumed taking psyllium again.

Medical examination and investigations were unremarkable apart from slight abdominal distension and slight tenderness over the lower abdomen.

case 1 questions
Case (1) Questions
  • Why did Psyllium caused abdominal distension?
  • What are the most probable side effects of lactulose in this patient?
  • Mention the drugs required for the patient?
  • What are the side effects of each drug prescribed?
case 1 answer
Case (1) answer

A case of IBS with:

  • Predominant constipation
  • Abdominal pain
  • Bloating
case 1 answer1
Case (1) answer

Psyllium increased abdominal distension because it contain insoluble fiber which is fermented by colonic bacteria.

Side effects of lactulose:

  • Diarrhea
  • Abdominal distension
  • Taste may be objectionable
case 1 answer2
Case (1) answer

Treatment:

  • Diet:

High fiber diet consisting mainly of fruits and vegetables

2. Laxatives:

Bulk-forming laxatives such as methylcellulose with increasing drinking of water

3. Antispasmodics:

Mebeverine or Hyoscine (Mebeverine is preferred because Hyoscine may increase constipation)

4. Probiotics

5. Tegaserod

case 2
Case (2)
  • A 40-year-old man presents for the evaluation of abdominal pain and diarrhea. He states that for about 8 months he has had progressively worsening cramping pains, bloating and diarrhea (3 times/day). with loose stools. However, stools never contained blood. He has tried over-the-counter antidiarrheal medications but diarrhea often recurs. He is on no medication regularly and has no significant medical history. Examination of his abdomen revealed it to be distended and diffusely tender with no palpable masses. Otherwise, the patient is normal.
  • What medications could be prescribed to that patient. What are their side effects? Comment on the diet that should be followed by the patient.
case 2 answer
Case (2) Answer

Diet:

Diet should be low in carbohydrates

Drugs:

The patient had IBS with predominant diarrhea with pain and distension.

Treatment of diarrhea: Loperamide. (why not diphenoxylate?) What can you prescribe if loperamide fails? What are the side effects of the new drug? (see the table)

case 2 answer1
Case (2) Answer

Treatment of abdominal pain:

  • Antispasmodics as Hyoscine (what are its side effects and contraindications?). Why hyoscine is preferred to mebeverine in cases of diarrhea?
  • What are the second line drug you can prescribe if Hyoscine fails? What are the side effects of the new drug? (see the table)
case 2 answer2
Case (2) Answer

Treatment of bloating:

Probiotics. (why tegaserod could not be prescribed in this case?)

treatment of constipation
Treatment of constipation

Acute constipation

  • Glycerine suppository

If not effective:

  • Oral sorbitol or lactulose or saline laxatives (e.g., Mg hydroxide)
  • Low doses of bisacodyl or senna or cascara
treatment of constipation1
Treatment of constipation

Chronic constipation:

  • Dietary modifications that increase dietary fiber
  • Bulk-forming agents (daily and continued indefinitely)
treatment of constipation in special populations
Treatment of constipation in special populations

Bed ridden, geriatric or chronic constipation patients:

1. First line of treatment is bulk forming laxatives

2. Second line: more potent agents may be required :

  • Osmotic laxatives (Saline laxatives as Mg hydroxide) or poorly absorbed sugars (sorbitol or lactulose).
  • Irritant laxatives (bisacodyl, senna, cascara)
  • Mineral oil should be avoided, particularly in bed-ridden patients. Why? (because of the risk of aspiration and lipoid pneumonia).
  • When other than bulk-forming laxatives are used, they should be administered in the lowest effective dose and as infrequently as possible to maintain regular bowel function (more than 3 stools per week).
treatment of constipation in special populations1
Treatment of constipation in special populations

Fecal impaction.

Before oral laxatives can be used, the impaction needs to be removed using mechanical methods, including tap-water or saline enemas and digital extraction.

treatment of constipation in special populations2
Treatment of constipation in special populations

In the hospitalized patient withoutGI disease:

  • If rapid bowel evacuation is required:

Either

  • glycerin suppository or
  • oral Mg hydroxide

Followed by: 2.

2. Most orally or rectally administered laxatives may be used in these situations.

prevention of constipation
Prevention of constipation
  • Prevention of straining during recovery from myocardial infarction or following rectal surgery
  • During pregnancy

Bulk-forming laxatives

Docusate

Irritant laxatives (mentioned in some books)

other uses of laxatives
Other uses of laxatives:

Evacuation of bowel before surgery or diagnostic procedures involving the GIT as sigmoidoscopy or barium enema:

Oral forms:

Oral bisacodyl, sodium picosulfate, cascara or senna (active after 6 -12 h) Given the night before operation or procedure)

Oral castor oil (active after 1-3 h)

Oral Mg hydroxide (active after 2-5h)

Rectal suppository:

Bisacodyl rectal suppository (active after 30 – 60 min)

Enema:

Rectal Na sulfate enema (active after 30 min)

Polyethylene glycol - electrolyte solution enema

case 11
Case (1)

A 35-year-old patient on normal diet and exercise presented with Constipation since 2 weeks. Mention three alternative drugs from different groups that could be used to treat his condition giving the side effect of each.

Answer:

  • Glycerine suppository
  • Lactulose
  • Bisacodyl
case 21
Case (2)

You have been asked to prescribe a drug for prevention of straining for a hospitalized patient treated from myocardial infarction. Mention 2 drugs from 2 different groups giving their side effects.

case 3
Case (3)

A patient will undergo sigmoidoscopy in the next morning. Mention drugs which could be given to evacuate his bowel giving the expected time of action and possible adverse effects.

constipation questions
Constipation questions
  • Mention two pharmacological groups of drug that may cause constipation as a side effect giving the mechanism in each case.
  • To which category of drugs does lactulose belong? Comment on its mechanism of action.
  • Comment on the adverse effects which are associated with the use of stimulant laxatives.