IBD, Vomiting, Diarrhoea & Constipation PDF

IBD Vomiting, constipation and diarrhoea Prof. L.J. Egan 1 Inflammatory Bowel Disease IBD: Step-wise approach to treatment Infliximab etc. Immune suppressants Systemic Steroids Mesalazine Current Practice Aminosalicylates: mesalazine/5ASA    Structures Topically acting 5-ASA is active moiety COOH...

IBD Vomiting, constipation and diarrhoea Prof. L.J. Egan 1 Inflammatory Bowel Disease IBD: Step-wise approach to treatment Infliximab etc. Immune suppressants Systemic Steroids Mesalazine Current Practice Aminosalicylates: mesalazine/5ASA    Structures Topically acting 5-ASA is active moiety COOH H O N S COOH N OH H2N N N OH O 5-Aminosalicylic acid Sulfasalazine COOH O HO2CH2CH2HNC N Balsalazide N OH COOH HOOC HO N N Olsalazine OH Mesalazine: Pharmacokinetics Absorption 10-40% < 1 mmol/l 10-30 mmol/l Mesalazine: Uses    Mild to moderately active ulcerative colitis Mechanism unknown Oral preparations    Rectal preparations    Delayed release Sustained release Suppository (rectum) Enema (Left colon) Well tolerated Corticosteroids: Uses    Moderate to severely active disease Useful to induce remission but not useful for long-term maintenance Many side effects with long-term use Immunosuppressants     Azathioprine/6-mercaptopurine  Purine analogues  Decrease nucleotide biosynthesis selectively in lymphoid cells  S/Es: Bone marrow suppression, pancreatitis, allergy, lymphoma Methotrexate  Folic acid analogue  Competitive inhibitor of dihydrofolate reductase  Induces apoptosis of activated lymphocytes  S/Es: Liver fibrosis, pneumonitis, bone marrow suppression Slow-acting (months) Reduce flares and corticosteroid use Anti-TNF agents  TNF    Infliximab     Pro-inflammatory cytokine Produced by activated macrophages in inflamed gut Neutralizes soluble and membrane-associated TNF Induces apoptosis of cells expressing TNF Highly effective in induces and maintaining responses in IBD patients Risks    Reactivation of TB Opportunistic infections Lymphoma An important clinical problem: loss of response to anti-TNF antibodies over time Anti-infliximab antibodies speed clearance Development of antibodies to infliximab lowers drug levels and is associated with loss of response Adverse Effects of TNF Inhibitors  Class Effects     Reactivation of latent tuberculosis Increased risk of opportunistic infections Emergence of Multiple Sclerosis Injection and infusion reactions Anti-TNF antibodies in IBD: conclusions    Have revolutionized treatment of IBD Most patients respond very well Loss of response a major limitation   Caused by development of anti-drug antibodies Current therapeutic strategies aim to limit the development of antidrug antibodies Anti-integrin biologics in IBD: Vedolizumab (Entyvio)     Slow acting IV Good efficacy Very few side effects Anti-cytokine biologics in IBD: Ustekinumab (Stelara)         IL-12/23 Derived from many types of immune cells Elevated in many inflammatory diseases Stimulate Th1 and Th17 signalling Monoclonal anti-p40 subunit Good efficacy Well tolerated First dose IV then SC Which statement concerning IBD treatment is false? 1. 2. 3. 4. 5. Corticosteroids should not be prescribed long-term Infliximab blood levels can fall over time due to development of antibodies to infliximab Vedolizumab blocks extravasation of lymphocytes in the gut Mesalazine is a potent inhibitor of cyclo-oxygenase Biologic drugs must be administered parenterally 17 Treatment of vomiting 18 Mechanism of Vomiting: GI irritation Patient: Radiotherapy of gastric cancer Cytotoxic Drugs, Radiation & other GI irritants release 5-HT from the enterochromaffin cells  Stimulation of the 5-HT3 Receptors present on vagal afferents  Stimulation of CTZ  Vomiting 19 Mechanism: Vestibular irritation  Patient: First time sailor…….  The vestibular apparatus generates impulses when body is rotated or equilibrium is disturbed or when ototoxic drugs act. These impulses reach the vomiting centre mainly relayed by the M and the H1 receptors. Various sensory stimuli such as bad odour, ghastly sight, severe pain as well as fear cause nausea and vomiting by direct stimulation of higher centres.   20 Vomiting: Mediators & drugs 21 Mechanism of vomiting 22 Mediators & receptors    5-HT: an important mediator involved in such signals, many other mediators and peptides are also involved. The CTZ expresses a variety of receptors e.g. Histamine H1, Dopamine D2, Cholinergic M, Opioid  and the Serotonin 5-HT3 receptors, through which the emetic signals are relayed. These are the targets of antiemetic drugs 23 Classification       Anticholinergics: Hyoscine, Dicyclomine H1 Antihistamines: Promethazine, Cyclizine, Diphenhydramine, Cinnarizine Neuroleptics: Chlorpromazine, Haloperidol D2 Receptor Antagonist: Domperidone, Metoclopramide 5-HT3 Receptor Antagonist: Ondansetron, Granisetron Others: Dexamethasone, BZD, Cannabinoids 24 Anticholinergics  Hyoscine is an effective drug for motion sickness     Blocks muscarinic receptors suitable for short journeys blocks the conduction of nerve impulses across a cholinergic link pathway leading from the vestibular apparatus to the vomiting centre. anticholinergic side effects such as dry mouth and sedation 25 H1 Antihistamines  Promethazine, Diphenhydramine     Anticholinergic, antihistaminic and sedative effects Protect from motion sickness for 4-6 hrs. Cyclizine, Meclizine, are less sedative Meclizine has a long duration of action used in sea sickness. 26 Neuroleptics Eg prochlorpromazine Potent antiemetics Block D2 receptors in the CTZ. Broad spectrum antiemetic effect and is useful in          Drug induced and postanaesthetic nausea and vomiting Vomiting due to diseases: gastroenteritis, migraine etc. Hyperemesis gravidarum Second line agents Sedation++ 27 D2 receptor antagonist: Metoclopromide    It increases GI peristalsis leading to increased gastric emptying The tone of lower oesophageal sphincter is increased ADR       sedation, dizziness, movement disorders (extrapyramidal) acute dystonias eg spasmodic torticollis occulogyric crisis Managed with antihistamines eg diphenhydramine Long term use can cause Parkinsonism (tardive dyskinesia) Domperidone   Similar but does not cross BBB – fewer side effects but less effective Associated with long QT syndrome deaths 28 5-HT3 Receptor Antagonists         Ondansetron is the prototype Very effective in treating Cancer Chemotherapy/Radiotherapy induced vomiting It is effective in vomiting due to any cause Blocks the emetogenic impulses both at their peripheral origin and their central relay. It has no DA blocking effects It is given orally or i.v Generally well tolerated and very few side effects Granisetron is 10 times potent than Ondansetron 29 Which statement is true? 1. 2. 3. 4. 5. Metoclopromide is a 5HT antagonist Ondansetron is a dopamine receptor blocker Diphenhydramine is a H1 receptor antagonist that crosses the blood brain barrier Chlorpromazine is a dopamine antagonist that does not cause sedation Chemotherapy causes release of 5HT (serotonin) in the vomiting centre 30 Treatment of Constipation 31 Introduction  Patient: Bowel motion once a week……..  Constipation usually the result of slow colonic transit (lazy bowel) Can be due to drug side effects Intermittent constipation is best prevented with a high fibre diet, adequate fluid intake, regular exercise Those not responding to the above measures should be medically evaluated before started on laxatives    32 Drugs that cause constipation   Any opioid analgesic Anti-cholinergics   Cationic drugs    Eg Tricyclic antidepressants Eg iron Aluminium containing antacids Calcium channel blockers 33 Drug Classification  1. 2. 3. 4. Based on the mechanism of action Bulk Forming agents Stool Softeners Osmotic laxatives Motility stimulant 34 Bulk Forming Laxatives   Indigestible, hydrophilic colloids that absorb water, forming a bulky emollient gel that distends the colon and promotes peristalsis Natural plant products     Psyllium husk Methylcellulose Synthetic fibres – Polycarbophil ADR of these preparations include bloating of abdomen 35 Stool Softeners    Soften the stool material, permitting water and lipids to penetrate They are administered orally or rectally. Common agents    Docusate (orally and as an enema) Glycerine suppository Mineral oil is a clear, viscous oil which lubricates faecal material, retarding water absorption from the stool (for treating faecal impaction in children) 36 Osmotic Laxatives  Osmotic laxatives are soluble but nonabsorbable compounds result in increased stool liquidity due to an increase in faecal fluid Magnesium oxide – to be used with caution in patients with renal impairment (may cause hypermagnesemia) Sorbitol & Lactulose –       Treatment of chronic constipation Metabolized by the colonic bacteria May cause severe flatus and cramps 37 Motility stimulant  Prucalopride    5HT4 agonist Stimulates colonic smooth muscle contraction Used when simpler measures have failed 38 Antidiarrhoeal Agents 39 Introduction    Used safely in patients with mild to moderate diarrhoea Should not be used in bloody diarrhoea, high fever (this may worsen the condition) Useful in   Irritable bowel syndrome Travellers diarrhoea 40 Opioid Agonists   These agents have significant constipating effects Inhibition of presynaptic cholinergic nerves in submucosal and myenteric plexus and lead to increased colonic transit time.      Loperamide Diphenoxylate Less CNS effect than conventional opiates (BBB) At higher than recommended doses, CNS effects can occur Codeine can also be used (morphine pro-drug) 41 Anti-cholinergics  Atropine  Combined with opioids in certain pharmaceutical preparations    Low dose Uncertain benefit at such low doses At doses sufficient to inhibit diarrhoea  Dry mouth, tachycardia, sedation ……. 42 Special category: Octreotide    Stomatostatin analogue Stomatostatin is a 14 amino acid peptide that is released in the GIT and pancreas Key action      inhibition of secretion of numerous GIT hormones and peptides Reduction of intestinal fluid secretion Slows GI motility Inhibits secretion of some anterior pituitary hormones It is mainly used in treating symptoms of two GI endocrine tumours 1. 2. 3. Carcinoid tumours Vasoactive intestinal peptidomas High output fistulas and stomas 43