Presentation on theme: "Treatment of irritable bowel syndrome (IBS) and constipation"— Presentation transcript:
1Treatment of irritable bowel syndrome (IBS) and constipation TherapeuticsTreatment of irritable bowel syndrome (IBS) and constipation
2DefinitionIBS is an idiopathic chronic relapsing disorder characterized by:Abdominal discomfort (pain), bloating or distensionAlteration in bowel habits (diarrhea, constipation or both)Abdominal pain / discomfortBloating / distensionChange in bowel habit
3Alarm features = investigations Predominant constipationage older than 50 yearssymptom duration less than 6 monthsweight lossnocturnal symptomsfamily history of colon cancerrectal bleedingAnemiarecent antibiotic usage.
4Treatment of IBS Aims of treatment: KTreatment of IBSAims of treatment:Relieve abdominal pain and discomfort:Anticholinergic drugs (commonly used are; dicyclomine and hyoscyamine) MOA: block M receptorsLow doses of TCA (e.g. amitriptyline or desipramine). Low doses have no effect on mood.2) Relieve distension / bloatingImprove bowel functionFor patients with predominant diarrhea: anti-diarrheal agents (especially loperamide) and serotonin 5-HT₃-receptor antagonistsFor patients with predominant constipation: laxatives (bulk-forming or osmotic laxatives especially Mg oxide) and serotonin 5-HT₄-receptor agonist
5Antispasmodic 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 mouthTachycardiaUrinary retentionConstipationHeat intoleranceConfusion
6Antispasmodic drugs in IBS Contraindications of anticholinergic drugsPatients with glaucomaProstatic hyperplasia (elderly)Drug interactions of anticholinergic drugs:With other drugs having anticholinergic effects
7Antispasmodic drugs in IBS Mebeverine: (less effective than anticholinergic drugs)Mechanism of action:Not known (? calcium channel blocker or ? Direct acting)Adverse effects:Hypersensitivity reactionsIn high doses: anticholinergic side effects
8Antispasmodic drugs in IBS (for bloating/pain) Anticholinergic drugsMebeverineHyoscine or dicyclomine-Indications:Female or young male patients (no prostatic enlargement)IBS with predominant diarrheaSymptoms of pain or bloatingIBS with predominant diarrhea or predominant constipationContraindications:GlaucomaProstatic enlargementHypersensitivity to the drugWhich antispasmodic is preferred in patients with IBS with predominant constipation?Which antispasmodic is indicated in patients with IBS with glaucoma or prostatic enlargement?
9Tricyclic 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)
10Tricyclic antidepressants Drugs:Amitriptyline or Desipramine (10 – 50 mg/d) . (N.B. the usual antidepressant dose = 75 – 200 mg)Adverse effects:Blurred visionDry mouthConstipationRetention of urineOrthostatic hypotensionArrhythmiaCardiac conduction disturbances
11Tricyclic antidepressants Contraindications:GlaucomaElderly patientsPatients with cardiac diseases
12Selective 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 vomitingDiarrhea or constipationAnorexia and weight lossSexual dysfunction
13Laxatives Classification: Bulk-forming Osmotic laxatives Stimulant laxativesFecal softeners / emollients (little role in chronic constipation)
14Laxatives Bulk-forming laxatives: Precautions: Containing more soluble fibers (more flatulence)Containing more insoluble fibers (less flatulence)MethylcellulosePsylliumBranPrecautions:Adequate fluid intake to avoid intestinal obstructionAdverse effects:Abdominal distension (due to fermentation).Intestinal obstruction when not consumed with sufficient fluid
15Laxatives Osmotic laxatives: Saline laxatives (e.g. Mg oxide) Non-digestible sugars or alcohols (e.g. lactulose)Polyethylene glycolGlycerinMg oxide is preferred because it is less expensive and it causes less distensionAdverse effects of Mg oxide:Flatulence, abdominal cramps, diarrheaIntravascular volume depletionElectrolyte disturbances
16Laxatives Contraindications of Mg oxide Renal insufficiency Severe cardiac diseasePreexisting electrolyte abnormalitiesPatients on diuretic therapy
17Treatment 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 solidAntisecretory↑ tone of the internal anal sphincter↓ response to the stimulus of a full rectum (by their central action)
18Antimotility agents (cont) Mechanism of opioid action: Inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses
19Opioiods - 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
20Opioiods - Diphenoxylate Drug interactions:Potentiate the effects of CNS depressantsCo-administration with MAO inhibitors→ hypertensive crisesAdverse 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
21Opioids - LoperamideOpioid 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.
22Role 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 to5HT₄R →↑ release ofACH and CGRP5HT₃R are found on terminals of enteric cholinergic neurons → ↑release of ACh5HT5HT5HT₄RAch5HT↑Proximal bowel contraction↑ Distal bowel relaxationCGRP5HT₁pRSubmucosal intrinsicprimary afferent neuron(IPAN)2nd order enteric cholinergic neuron5HT₃R→ stimulation ofnausea, vomitingand abdominal pain5HT→ CNSExtrinsic afferent nerve
23Serotonin 5HT₃ receptor antagonists Inhibition of 5HT₃ receptors in the GIT→ inhibit nausea, bloating and painInhibition of 5HT₃ receptors in the brain→ inhibit central response to afferent visceral stimuliInhibition of 5HT₃ receptors on terminals of enteric cholinergic neurons → ↓motility in the left colon and ↑colon transit time
24Serotonin 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
25Serotonin 5HT₃ receptor antagonists Alosetron Pharmacokinetics:Rapidly absorbed after oral administrationPlasma t½ = 1.5 h.Long duration of action (dissociates slowly from 5HT₃ receptor)Extensive hepatic metabolism (P450) with renal excretion of metabolitesAdverse effects:ConstipationIschemic colitis (may be fatal)
26Serotonin 5HT₄ receptor partial agonist: Tegaserod Action:↑gastric emptying and enhance small and large bowel transit (no effect on esophagus)↑ stool liquidityMechanism 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
27TegaserodPharmacokinetics: 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
28TegaserodUses: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 therapiesAdverse reactions (rare):DiarrheaHeadache
29Summary of treatment of IBS with predominant constipation DietHigh fiber diet (soluble fiber as in fruits and vegetables is better than insoluble fiber in cereals and bran)ConstipationBulk-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)PainAntispasmodics (mebeverine is preferred. Why?)If no effect: give antidepressants. (SSRI drugs as Cetalopram are preferred. Why?)Bloating with distensionProbioticsBloating without distensionTricyclic antidepressants
30Summary of treatment of IBS with predominant diarrhea DietAvoid excess carbohydrates and dairy productsTreatment of diarrheaAntimotility 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 painAntispasmodics (anticholinergic drugs are preferred. Why?If no effect: give antidepressants. (Tricyclic antidepressant drugs as Imipramine are preferred. Why?)Bloating with distensionProbioticsIf no effect: give 5HT₄ agonist (Tegaserod)Bloating without distensionTricyclic antidepressants
31Case (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.
32Case (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.
33Case (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?
34Case (1) answer A case of IBS with: Predominant constipation Abdominal painBloating
35Case (1) answerPsyllium increased abdominal distension because it contain insoluble fiber which is fermented by colonic bacteria.Side effects of lactulose:DiarrheaAbdominal distensionTaste may be objectionable
36Case (1) answer Treatment: Diet: High fiber diet consisting mainly of fruits and vegetables2. Laxatives:Bulk-forming laxatives such as methylcellulose with increasing drinking of water3. Antispasmodics:Mebeverine or Hyoscine (Mebeverine is preferred because Hyoscine may increase constipation)4. Probiotics5. Tegaserod
37Case (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.
38Case (2) AnswerDiet: 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)
39Case (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)
40Case (2) AnswerTreatment of bloating: Probiotics. (why tegaserod could not be prescribed in this case?)
41Treatment of constipation Acute constipationGlycerine suppositoryIf not effective:Oral sorbitol or lactulose or saline laxatives (e.g., Mg hydroxide)Low doses of bisacodyl or senna or cascara
42Treatment of constipation Chronic constipation:Dietary modifications that increase dietary fiberBulk-forming agents (daily and continued indefinitely)
43Treatment of constipation in special populations Bed ridden, geriatric or chronic constipation patients:1. First line of treatment is bulk forming laxatives2. 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).
44Treatment 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.
45Treatment of constipation in special populations In the hospitalized patient without GI disease:If rapid bowel evacuation is required:Eitherglycerin suppository ororal Mg hydroxideFollowed by: 2.2. Most orally or rectally administered laxatives may be used in these situations.
46Prevention of constipation Prevention of straining during recovery from myocardial infarction or following rectal surgeryDuring pregnancyBulk-forming laxativesDocusateIrritant laxatives (mentioned in some books)
47Other 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 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
48Case (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 suppositoryLactuloseBisacodyl
49Case (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.
50Case (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.
51Constipation 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.