Treatment of irritable bowel syndrome (IBS) and constipation 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) Abdominal pain / discomfort Bloating / distension Change in bowel habit

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 Aims of treatment: 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). Low doses 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) 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 Contraindications of anticholinergic drugs Patients with glaucoma Prostatic hyperplasia (elderly) Drug interactions of anticholinergic drugs: With other drugs having anticholinergic effects

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) Anticholinergic drugs Mebeverine Hyoscine or dicyclomine - Indications: Female or young male patients (no prostatic enlargement) IBS with predominant diarrhea Symptoms of pain or bloating IBS with predominant diarrhea or predominant constipation Contraindications: Glaucoma Prostatic enlargement Hypersensitivity to the drug 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 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 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 antidepressants Contraindications: Glaucoma Elderly patients Patients with cardiac diseases

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

Laxatives Bulk-forming laxatives: Precautions: Containing more soluble fibers (more flatulence) Containing more insoluble fibers (less flatulence) Methylcellulose Psyllium Bran Precautions: Adequate fluid intake to avoid intestinal obstruction Adverse effects: Abdominal distension (due to fermentation). Intestinal obstruction when not consumed with sufficient fluid

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

Laxatives Contraindications of Mg oxide Renal insufficiency Severe cardiac disease Preexisting electrolyte abnormalities Patients on diuretic therapy

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) 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 sub-therapeutic dose of atropine (to prevent abuse) Contraindications: Children below 2 y (toxicity at lower doses than adults) Obstructive jaundice

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 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 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 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 5HT₃ receptor antagonists Alosetron Action: relieves lower abdominal pain, urgency and diarrhea (no effect on stomach) Mechanism of action: 5HT₃ receptor antagonist Uses: Female patients with severe IBS with diarrhea with no response to other therapies

Serotonin 5HT₃ receptor antagonists Alosetron 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 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 → →↑ Cl secretion from the colon →↑ stool liquidity

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

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

Summary of treatment of IBS with predominant constipation Diet High fiber diet (soluble fiber as in fruits and vegetables is better than insoluble fiber in cereals and bran) Constipation Bulk-forming laxatives such as methylcellulose (contain more soluble fiber) + increase water intake. → improve constipation. What is the effect on abdominal pain? If no effect: give osmotic laxatives (Mg oxide is preferred to Lactulose (cheaper and causes less abdominal distension) If no effect: give 5HT₄ agonist (Tegaserod) Pain Antispasmodics (mebeverine is preferred. Why?) If no effect: give antidepressants. (SSRI drugs as Cetalopram are preferred. Why?) Bloating with distension Probiotics Bloating without distension Tricyclic antidepressants

Summary of treatment of IBS with predominant diarrhea Diet Avoid excess carbohydrates and dairy products Treatment of diarrhea Antimotility agents as Diphenoxylate or Loperamide. (Loperamide is preferred. Why?) - What is the effect on abdominal pain? If no effect: give 5HT₃ antagonist (Alosetron) Treatment of pain Antispasmodics (anticholinergic drugs are preferred. Why? If no effect: give antidepressants. (Tricyclic antidepressant drugs as Imipramine are preferred. Why?) Bloating with distension Probiotics If no effect: give 5HT₄ agonist (Tegaserod) Bloating without distension Tricyclic antidepressants

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. 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 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 A case of IBS with: Predominant constipation Abdominal pain Bloating

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) 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) 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 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) 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) Answer Treatment of bloating: Probiotics. (why tegaserod could not be prescribed in this case?)

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 constipation Chronic constipation: Dietary modifications that increase dietary fiber Bulk-forming agents (daily and continued indefinitely)

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 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 populations In the hospitalized patient without GI 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 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: 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 (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 (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) 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 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.