Pediatric GI medication Yu Bin Kim Ajou University Medical Center Department of Pediatrics Pediatric GI medication Trials of potential drugs in adults 의사 New drugs in adults Pediatric GI medication Limitation of GI medication d/t Limited safety profile Limited efficacy profile Trials of potential drugs in adults New drugs in adults New drugs in Children Introduction Acid suppression Available Pharmacotherapy Antiemetics Prokinetics Laxatives Antispasmodics Dopamine antagonis Antibiotics Anticholinesterase inhibitors 5HT4RA – Cisapride, Tegaserod / Prucalopride Motilin agents Opioid receptor antagonists Chloride channel activators Risk Antibiotics Probiotics Immunomodulation Benefit Off the label Indication Introduction Acid suppression We don’t know about disease Antiemetics Prokinetics FGID : ROME IV 2016 Antispasmodics Antibiotics Neurogastoenterologic evidence -> Brain-gut axis Increasing IBD, Eosinophilic GI disorders Omics study Allergic & environmental association GI manifestation of underlying disease (ex. Immune deficiency) Introduction Acid suppression We don’t know about disease Antiemetics Prokinetics Antispasmodics GI medication in Emergent Room setting Antibiotics Indication “Exclusion of surgical abdomen “ Symptom based treatment Introduction Acid suppression Phenotyping and classification Antiemetics Prokinetics ■ Vomiting : GERD(including neurologic deficit, TEF) , AGEAntispasmodics Acid suppression , antiemetics Antibiotics ■ Dysmotility : Gastroparesis, Functional constipation Prokinetics ■ Pain dominant FGID : Functional dyspepsia, IBS, FAP, Abdominal migraine Antispasmodics, Prokinetics ■ Bacterial AGE : Post infectious IBD, Antibiotics Antibiotics, Antispasmodics Context Introduction Acid suppression Antiemetics Prokinetics Antispasmodics Antibiotics Introduction Acid suppression Acid suppression with PPI Antiemetics Prokinetics Irreversible inhibition, H+/K+-ATPase pump in the gastric parietal cells Antispasmodics Antibiotics Primary Tx agent in GERD ■ Long term use indication TEF maintenance : up to 1yr FDA approval : Lansoprazole (12mo~ ), omeprazole(2yrs ~), Esomeprazole(12yrs ~), pantoprazole Introduction Acid suppression Acid suppression with PPI Antiemetics Prokinetics Irreversible inhibition, H+/K+-ATPase pump in the gastric parietal cells Antispasmodics Antibiotics Primary Tx agent in GERD ■ Long term use indication TEF maintenance : up to 1yr J Pediatr Gastroenterol Nutr. 2016 Nov;63(5):550-570. Introduction Acid suppression Acid suppression for Reflux children Antiemetics Prokinetics ■2018 revised GERD guideline Antispasmodics PPIs as first-line treatment of reflux-related Antibiotics erosive esophagitis in infants and children. PPI doses of 1 to 1.7 mg/kg/d H2RAs in infants and children if PPIs are not available or contra-indicated. 4- to 8-week course of PPI or H2RAs Not to use H2RA or PPI for the treatment of crying/distress, visible regurgitation and extraesophageal symptoms such as cough, wheezing,asthma in otherwise healthy infants. Infant Children to adolescent Introduction Acid suppression Broad indications of Acid suppression Antiemetics Prokinetics ■ Anti-secretory drug (J Clin Gastroenterol. 1992;14 Suppl 1:S94-7) Antispasmodics Antibiotics Total mucus secretion ▼▼ > Acid secretion ▼ (daily total secretion 9L / gastric juice 2L / Food 800g) Reducing volume -> Sx Improvement FGID(Functional dyspepsia), GI bleeding control ■ Neutralizing agent Reflux esophagitis PUD with H.Pylori eradication Camilleri M, et al. Nat Rev Gastroenterol Hepatol 2013;10:187 Introduction Acid suppression Is PPI Safe? Antiemetics Prokinetics Bone metabolism Antispasmodics Gastric morphological changes Antibiotics : Atrophic gastritis, Fundic gland polyps, Parietal hyperplasia Hypomagnesemia, Vit B12 deficiency Dysbiosis - C.difficile infection - Small Intestinal Bacterial Overgrowth Defective Allergen desensitization Change in commensal flora Imhann F, et al. Gut 2016;65:740–748. Bruno G et al. World J Gastroenterol. Jun 14, 2019; 25(22): 2706-2719 Introduction Acid suppression Antiemetics Antiemetics Prokinetics Antispasmodics Antibiotics Romano C et al. JPGN 2019;68: 466–471 Introduction Acid suppression Adverse effects of antiemetics Antiemetics Prokinetics ■ 5-HT3 receptor antagonists : Headache/lightheadedness Antispasmodics Constipation/diarrhea Prolonged QT interval Antibiotics ■ NK1 receptor antagonists : Headache Hiccough Asthenia ■ D2 receptor antagonists : Extrapyramidal symptoms(> metoclopramide) Akathisia Tardive dyskinesia Prolonged QT interval ■ H1 receptor antagonists : Sedation Dry mouth Introduction Acid suppression Treatment Target of Antiemetics Antiemetics Prokinetics ■Abortive treatment Antispasmodics Antibiotics 1. Cyclic Vomiting Syndrome (CVS) – NASPGHAN guideline : IV hydration with ondansetron(5HT3 receptor blocker) maintenance <5 : cyproheptadine, >5 amitriptyline propranolol as 2nd preventive 2. Chemo Induced Nausea Vomiting (CINV) : MCP, Steroid, Ondansetron, apprepitant Li BU, et al. J Pediatr Gastroenterol Nutr 2008;47:379 Boles RG, et al. BMC Neurol 2010;10:10 Introduction Acid suppression Treatment Target of Antiemetics Antiemetics Prokinetics 3. ORS success rate Antispasmodics In mild to moderate degree of dehydrated AGE patient Antibiotics To recover effective circulation, to restore imbalanced electrolyte with ORS MCP Domperidone Ondansetron Introduction Acid suppression Metoclopramide(D2 blocker) Antiemetics Prokinetics not specific in the CTZ, acts also on the dopaminergic system of Antispasmodics different CNS areas -> Akathisia, tardive dyskinesia, prolactinemia (Dose, chronicity) Antibiotics Indication : prophylaxis of acute CINV in children who cannot receive steroids no evidence to support the use of metoclopramide in children with vomiting due to AGE 2009 FDA balck box warning 2013 EMA Maximum 30mg/day up to 5days, for adults Forbidden <1yr, Caution <5yrs , limiting use to 5days Lau M et al. The safety of metoclopramide in children: a systematic review and meta-analysis. Drug Saf 2016;39:675–87. Introduction Acid Domperidone usage for ORS suppression Antiemetics Prokinetics Specific, BBB protection QT prolongation Antispasmodics Antibiotics Recently updated RCT (Double blinded study 2019.10) 292 pt (147 0.25mg/kg control vs 145 placebo) 1’ efficacy : no vomiting within 48hrs 2’ efficacy : no nausea within 48hrs Leitz G et al. JPGN 2019;69: 425–430 Introduction Acid Domperidone usage for ORS suppression Antiemetics Prokinetics Antispasmodics Antibiotics Request of Pharmacovigilance Risk Assessment Committee (PRAC) request Negative result study d/t Risk in regular dose(2013) -> No effect in Low dose -> No risk/benefit ratio too Removed label indication in children <12yrs and <35 kg Leitz G et al. JPGN 2019;69: 425–430 Introduction Acid suppression Ondansetron(5HT3 RA) in AGE Antiemetics Prokinetics A very recent(2012) network meta-analysis (37) (including 10 randomized controlled Antispasmodics trials and 1479 patients) found clear evidence that ondansetron was the most likely Antibiotics treatment to allow ORT to commence. Cessation IV Hospital of therapy day Vomiting Carter B, Fedorowicz Z. BMJ Open 2012;2: Introduction Acid suppression Treatment Target of Antiemetics Antiemetics Prokinetics 3. ORS success rate Antispasmodics In Dehydrated AGE patient Antibiotics To recover effective circulation, to restore imbalanced electrolyte with ORS MCP Domperidone Ondansetron Introduction Acid suppression Treatment Target of Antiemetics Antiemetics Prokinetics 3. ORS success rate Antispasmodics In Dehydrated AGE patient Antibiotics To recover effective circulation, to restore imbalanced electrolyte with ORS MCP : Black box warning Canadian Pediatric Society :a single dose Domperidone : no recommendation of oral ondansetron in children aged 6 Ondansetron : evident months to 12 years presenting with - antihistamin, steroid, antimuscarinic : x acute gastroenteritis and vomiting, mild to moderate dehydration, or failed ORT - apprepitant : no available for study Romano C et al. JPGN 2019;68: 466–471 Fecal impaction due to FC 30% to 75% of children with long-standing functional constipation have abdominal fecal impaction and/or rectal fecal impaction (RFI) on physical examination, which results in severe fecal incontinence in 90% of the patients. Bekkali NL et al. Pediatrics 2009, 124 (6) e1108-e1115 Darrow CJ et al. Pediatrics 2014, 133 (1) e235-e239 Functional Constipation Tabbers MM et al.,JPGN 2014;58: 258–274 Functional Constipation Abdominal pain is a frequent associated symptom, but its presence is not considered a criterion for functional constipation. The role that constipation plays in children with predominant abdominal pain is not clear Tabbers MM et al.,JPGN 2014;58: 258–274 FC need early management Peak age: 12mo- weaning diet 24-36mo- toilet training Stool loosening Pain Hard formed stool Fear Self retention 변R을 참는 행동 Vanden Berg MM et al. J Pediart 2006 PEG (Polyethylene glycol), mainstay of treatment nonmetabolizable, nonabsorbable polymer in powder form that is not fermented by bacterial flora. sequestration of water in the lumen of the intestine, thereby increasing osmotic pressure BM per week, stool consistency, reduced time to first BM, and provided significant relief from straining compared with placebo. safe and well tolerated in several short-term (72 hours to 4 weeks) and long-term (6 months to a year) studies. Adverse events (AEs) were minimal and comparable to placebo. Stool Softner ■Laxatives PEG3350 Miral LAX PEG4000 Forlax For Disimpaction 1~1.5g/kg/d