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 “ Symptom based treatment Introduction Acid suppression Phenotyping and classification Antiemetics Prokinetics ■ : GERD(including neurologic deficit, TEF) , AGEAntispasmodics Acid suppression , antiemetics Antibiotics

■ Dysmotility : , Functional 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 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/ 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 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 (even efficacy to enema) For Maintenance 0.5g/kg/d

Lactulose : gas accumulation d/t intra-luminal fermentation Newer agent

■Laxatives PEG3350 Miral LAX PEG4000 Forlax For Disimpaction 1~1.5g/kg/d (even efficacy to enema) For maintenance 0.5g/kg/d

Lactulose : gas accumulation d/t intra-luminal fermentation

■ Prucalopride : 5HT4 agonist, proven for FC management in adult Failed to pediatric efficacy Newer agent-Prucalopride

Bouras EP et al. 2001 Gastroenterology Newer agent – Chloride channel activator

Off label trial Effective, well tolerated in children to adolescents

RCT awaited Introduction Acid suppression Gastroparesis Antiemetics Prokinetics Gastroparesis can present with a constellation of symptoms including Antispasmodics nausea, vomiting, early satiety, anorexia, , and epigastric Antibiotics pain. Defined as the impaired transit of intraluminal contents from the to the duodenum in the absence of mechanical obstruction. Diagnosis of gastroparesis is based on the presentation of gastroparesis-associated symptoms that exist without any gastric outlet obstruction or ulceration and delayed gastric emptying. Delayed gastric emptying is the key diagnostic symptom of gastroparesis resulting from paresis of the stomach, causing its contents to remain in the stomach for a prolonged period of time.

Camilleri M et al. Am J Gastroenterol. 2013;108(1):18-37. Tilman et al. J Pediatr Pharmacol Ther 2016 Vol. 21 No. 2 Introduction Acid suppression Gastroparesis Antiemetics Prokinetics Complications associated with gastroparesis may include Mallory-WeissAntispasmodics tears from repeated vomiting, bezoar formation, , Antibiotics aspiration pneumonia, and electrolyte disorders. gastric motility may be impaired secondary to intestinal surgery, viral infections, neurologic disorders, psychological distress, anticholinergic agents, and overuse of opioids. Clinical guidelines for management of gastroparesis in adults recommend restoring fluids and electrolytes in patients and providing nutritional support, preferably through oral intake.

Camilleri M et al. Am J Gastroenterol. 2013;108(1):18-37. Tilman et al. J Pediatr Pharmacol Ther 2016 Vol. 21 No. 2 Introduction Acid suppression Gastroparesis Antiemetics Prokinetics Currently, there are no standardized clinical guidelines for treating Antispasmodics gastroparesis in pediatrics. Antibiotics Pharmacologic recommendations are individualized and are intended to increase gastric emptying and manage associated symptoms to improve the patient’s lifestyle. Prokinetic therapy is preferred as the first-line medication therapy for gastroparesis as it accelerates intestinal transit; however, studies of medications in this class suggest that they are not as effective in children as they are in adults.

Camilleri M et al. Am J Gastroenterol. 2013;108(1):18-37. Tilman et al. J Pediatr Pharmacol Ther 2016 Vol. 21 No. 2 Introduction Acid suppression Prokinetics – 5HT4 agonist Antiemetics Prokinetics Antispasmodics Serotonin Antibiotics

CNS 5%

GI tract 95% -Enterochromaffin cell -neuronal Introduction Acid suppression Prokinetics – 5HT4 agonist Antiemetics Prokinetics ■ Cisapride : withdrawn at 2000, Antispasmodics for fatal arrhythmia 270 case during 1993-2000 Antibiotics d/t dysregulation of hREG K+ channel, Tegaserod too.

■ Mosapride : Diabetic gastroparesis no pediatric study

■ Prucalopride : FC for adults, controversial to Children Enhancing Gastric emptying, colon transit time 0.04mg/kg (>50kg, 2mg qd) Introduction Acid suppression Prokinetics – D2 antagonist Antiemetics Prokinetics ■ MCP : 0.1 ~ 0.2 mg/kg (maximum, 10mg/dose) 4x daily Antispasmodics Antibiotics cannot use >12weeks

■ Domperidone : 0.1-0.2 mg/kg (maximum, 10 mg/dose) 4× daily QT interval, neonatal EKG monitoring

■ Itopride : D2 R antagonist + Acetylcholinerase inhibitor Unknown, Not available in United States Limited evidence for GERD adult Introduction Acid suppression Prokinetics – Antibiotics Antiemetics Prokinetics ■Erythromycin : Improved gastric motility in infants at 15-30 mg/kg Antispasmodics per day; 3 mg/kg 4× daily Antibiotics did not resolve symptoms in children (4-15 yrs old), but 0.15 mg/kg is effective in reducing post-operative nausea

Antibiotic resistance, arrhythmia, CYP3A4 interactions, tachyphylaxis

■ Amoxicillin+Clavulonate : resistance, restricted long term usage Introduction Acid suppression Pain dominant FGID Antiemetics Prokinetics ▪ H1. Functional nausea and vomiting disorders Antispasmodics ▫ H1a. Cyclic vomiting syndrome Antibiotics ▫ H1b. Functional nausea and functional vomiting ▫ H1c. Rumination syndrome ▫ H1d. Aerophagia ▪ H2 Functional abdominal pain disorders Spasm! ▫ H2a. Functional dyspepsia ▫ H2b. Irritable bowel syndrome ▫ H2c. Abdominal migraine ▫ H2d. Funtional abdominal pain ▪ H3 Functional defecation disorders ▫ H3a. Functional constipation ▫ H3b. Nonretentive fecal incontinence

Drossman DA et al. Gastroenterology 2016;150:1262–1279 Introduction Acid suppression Abdominal pain in post AGE progress Antiemetics Prokinetics Antispasmodics Antibiotics

prevalence of PI-IBS to range from 5% to 32% Can affect patients for 6 mo or longer after acute infection Introduction Acid suppression Antispasmodics Antiemetics Prokinetics ■ Calcium channel blocking agent Antispasmodics Perppermint oil, menthol component : 2001. Double blind RCT in 50 (8-17 yrs) IBS, 2weeks, effective Antibiotics

■ Papaverine like agent- smooth mucscle relaxant Mebeverine : action on smooth muscle cells and directly blocks sodium channels and inhibits Ca2+ accumulation 2014. RCT 6~18 yrs FAP 44 vs 43 135mg bid, 4weeks, effective

■ Opioid receptor antagonist Trimebutine – inhibit Ca2+ influx to smooth muscle FDA not approved, Canada & other international use, Dry syrup Small sized controlled trial and parent asking report study. Effective Rapid peak concetration : 0.8~1hr, short half life 1~2.7hr

Anticholinergic, anti muscarinic : no pediatric trial Scopolamine : no pediatric trial

Brusaferro A et al. Pediatr Drugs (2018) 20:235–247 Introduction Acid suppression Application for discharge medication Antiemetics Prokinetics ■ Nausea with bloating Antispasmodics Antibiotics Functional dyspepsia – postpradial fullness, epigastric pain syndrome Gastritis -> Prokinetics ( H2 blocker + )

■ Cramping pain IBS, AGE(PI-IBS) -> Antispasmodics Introduction Acid suppression Antibiotics for AGE Antiemetics Prokinetics ■ Limited Efficacy & HUS risk with Antispasmodics STEC infection Antibiotics

Relative high efficacy : Immune-compromised patient, <3 mo infant Dysentery Sx, Septic condition

High risk : bloody diarrhea 90% of bloody diarrhea within 5ds in STEC

Other : Samonella, Campylobacter, Shigella Introduction Acid suppression HUS risk with empirical Abx Antiemetics Prokinetics Controversial Antispasmodics Antibiotics 2002 JAMA : denied 2016 : OR 1.33 -> 2.24

Safdar N et al. JAMA 2002;288:996-1001. Freedman SB et al. Clin Infect Dis 2016;62:1251-8. Introduction Acid suppression Antibiotics for AGE Antiemetics Prokinetics ■ Recommendation of Azithromycin Antispasmodics Antibiotics lesser Shiga toxin releasing agent with Broad efficacy cf) salmonella, Yersinia

■ Evidence Animal based study : shiga toxin release association quinolone, TMP/SMX > azithromycin, rifaximin

Ohara T et al. Chemother 2002;46:3478-83 Introduction Acid suppression Antibiotics for AGE Antiemetics Prokinetics Antispasmodics Antibiotics

Infect Chemother. 2019 Jun;51(2):217-243 경청해주셔서 감사합니다.