Therapeutics Treatment of irritable bowel syndrome (IBS) and constipation

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Transcript of Therapeutics Treatment of irritable bowel syndrome (IBS) and constipation

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Therapeutics Treatment of irritable bowel syndrome (IBS) and constipation Slide 2 Definition IBS is an idiopathic chronic relapsing disorder characterized by: 1) Abdominal discomfort (pain), bloating or distension 2)Alteration in bowel habits (diarrhea, constipation or both) Abdominal pain / discomfort Bloating / distension Change in bowel habit Slide 3 Alarm features = investigations 1.Predominant constipation 2.age older than 50 years 3.symptom duration less than 6 months 4.weight loss 5.nocturnal symptoms 6.family history of colon cancer 7. rectal bleeding 8.Anemia 9.recent antibiotic usage. Slide 4 Treatment of IBS Aims of treatment: 1)Relieve abdominal pain and discomfort: 1. Anticholinergic drugs (commonly used are; dicyclomine and hyoscyamine) MOA: block M receptors 2. Low doses of TCA (e.g. amitriptyline or desipramine). Low doses have no effect on mood. 2) Relieve distension / bloating 3)Improve bowel function 1.For patients with predominant diarrhea: anti-diarrheal agents (especially loperamide) and serotonin 5-HT-receptor antagonists 2.For patients with predominant constipation: laxatives (bulk- forming or osmotic laxatives especially Mg oxide) and serotonin 5-HT-receptor agonist K Slide 5 Antispasmodic drugs in IBS Action: relieve smooth muscle spasm relieve pain and bloating in IBS) 1.Anticholinergic drugs: Mechanism of action: Block muscarinic receptors (M on smooth muscles in case of hyoscine or presynaptic M in case of dicyclomine) Adverse effects: 1.Blurred vision (may lead to glaucoma) 2.Dry mouth 3.Tachycardia 4.Urinary retention 5.Constipation 6.Heat intolerance 7.Confusion Slide 6 Antispasmodic drugs in IBS Contraindications of anticholinergic drugs 1.Patients with glaucoma 2.Prostatic hyperplasia (elderly) Drug interactions of anticholinergic drugs: 1.With other drugs having anticholinergic effects Slide 7 Antispasmodic drugs in IBS 2.Mebeverine: (less effective than anticholinergic drugs) Mechanism of action: Not known (? calcium channel blocker or ? Direct acting) Adverse effects: 1.Hypersensitivity reactions 2.In high doses: anticholinergic side effects Slide 8 Antispasmodic drugs in IBS (for bloating/pain) Anticholinergic drugsMebeverine Hyoscine or dicyclomine- Indications: 1.Female or young male patients (no prostatic enlargement) 2.IBS with predominant diarrhea 3.Symptoms of pain or bloating Indications: 1.Symptoms of pain or bloating 2.IBS with predominant diarrhea or predominant constipation Contraindications: 1.Glaucoma 2.Prostatic enlargement Contraindications: 1.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? Slide 9 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) Slide 10 Tricyclic antidepressants Drugs: Amitriptyline or Desipramine (10 50 mg/d). (N.B. the usual antidepressant dose = 75 200 mg) Adverse effects: 1.Blurred vision 2.Dry mouth 3.Constipation 4.Retention of urine 5.Orthostatic hypotension 6.Arrhythmia 7.Cardiac conduction disturbances Slide 11 Tricyclic antidepressants Contraindications: Glaucoma Elderly patients Patients with cardiac diseases Slide 12 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: 1.Nausea and vomiting 2.Diarrhea or constipation 3.Anorexia and weight loss 4.Sexual dysfunction Slide 13 Laxatives Classification: 1.Bulk-forming 2.Osmotic laxatives 3.Stimulant laxatives 4.Fecal softeners / emollients (little role in chronic constipation) Slide 14 Laxatives 1.Bulk-forming laxatives: Containing more soluble fibers (more flatulence) Containing more insoluble fibers (less flatulence) 1.Methylcellulose 2.Psyllium 1.Bran Precautions: Adequate fluid intake to avoid intestinal obstruction Adverse effects: 1.Abdominal distension (due to fermentation). 2.Intestinal obstruction when not consumed with sufficient fluid Slide 15 Laxatives 2.Osmotic laxatives: a.Saline laxatives (e.g. Mg oxide) b.Non-digestible sugars or alcohols (e.g. lactulose) c.Polyethylene glycol d.Glycerin Mg oxide is preferred because it is less expensive and it causes less distension Adverse effects of Mg oxide: 1.Flatulence, abdominal cramps, diarrhea 2.Intravascular volume depletion 3.Electrolyte disturbances Slide 16 Laxatives Contraindications of Mg oxide 1.Renal insufficiency 2.Severe cardiac disease 3.Preexisting electrolyte abnormalities 4.Patients on diuretic therapy Slide 17 Treatment of diarrhea: Antimotility agents (opioids) Opioids agonists: Action in the GIT Action in the GIT (mediated by binding to opioid receptors) 1.Increase segmentation and a decrease propulsive movement intestinal transit time absorption of water and electrolyte feces become more solid 2.Antisecretory 3. tone of the internal anal sphincter 4. response to the stimulus of a full rectum (by their central action) Slide 18 Antimotility agents (cont) Mechanism of opioid action: Inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses Slide 19 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: 1.Children below 2 y (toxicity at lower doses than adults) 2. Obstructive jaundice Slide 20 Opioiods - Diphenoxylate Drug interactions: 1.Potentiate the effects of CNS depressants 2.Co-administration with MAO inhibitors hypertensive crises Adverse effects: 1.Caused by the atropine in the preparation and include anorexia, nausea, pruritus, dizziness, and numbness of the extremities. 2.Prolonged use of high doses may cause dependence Slide 21 Opioids - Loperamide Opioid agonist that does not cross the blood- brain barrier and has no analgesic properties and no potential for addiction Adverse effects Adverse effects: Abdominal pain and distention, constipation, dry mouth, hypersensitivity, and nausea and vomiting. Slide 22 Role of 5HT and 5HT receptors in GIT motility GIT distension stimulate EC cells in the mucosa of the intestine release of 5HT 5HT 5HTpR Ach CGRP Submucosal intrinsic primary afferent neuron (IPAN) 2 nd order enteric cholinergic neuron Proximal bowel contraction Distal bowel relaxation 5HTR Binding of 5HT to 5HTR release of ACH and CGRP 5HT 5HTR CNS Extrinsic afferent nerve stimulation of nausea, vomiting and abdominal pain 5HTR are found on terminals of enteric cholinergic neurons release of ACh Slide 23 Serotonin 5HT receptor antagonists 1.Inhibition of 5HT receptors in the GIT inhibit nausea, bloating and pain 2.Inhibition of 5HT receptors in the brain inhibit central response to afferent visceral stimuli 3.Inhibition of 5HT receptors on terminals of enteric cholinergic neurons motility in the left colon and colon transit time Slide 24 Serotonin 5HT receptor antagonists Alosetron Action: relieves lower abdominal pain, urgency and diarrhea (no effect on stomach) Mechanism of action: 5HT receptor antagonist Uses: Female patients with severe IBS with diarrhea with no response to other therapies Slide 25 Serotonin 5HT receptor antagonists Alosetron Pharmacokinetics: Rapidly absorbed after oral administration Plasma t = 1.5 h. Long duration of action (dissociates slowly from 5HT receptor) Extensive hepatic metabolism (P450) with renal excretion of metabolites Adverse effects: Constipation Ischemic colitis (may be fatal) Slide 26 Serotonin 5HT receptor partial agonist: Tegaserod Action: 1.gastric emptying and enhance small and large bowel transit (no effect on esophagus) 2. stool liquidity Mechanism of action of tegaserod: Serotonin 5HT partial agonist. Binding to 5HT receptors on the terminals of the 2 nd 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 Slide 27 Tegaserod Pharmacokinetics: Low bioavailability (further reduced by food) 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 Slide 28 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): 1.Diarrhea 2.Headache Slide 29 Summary 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) Constipation1.Bulk-forming laxatives such as methylcellulose (contain more soluble fiber) + increase water intake. improve constipation. What is the effect on abdominal pain? 2.If no effect: give osmotic laxatives (Mg oxide is preferred to Lactulose (cheaper and causes less abdominal distension) 3.If no effect: give 5HT agonist (Tegaserod) Pain1.Antispasmodics (mebeverine is preferred. Why?) 2.If no effect: give antidepressants. (SSRI drugs as Cetalopram are preferred. Why?) Bloating with distension 1.Probiotics 2.If no effect: give 5HT agonist (Tegaserod) Bloating without distension 1.Probiotics 2.Tricyclic antidepressants Slide 30 Summary of treatment of IBS