Pharmacology of Drugs Used in GI Disorders Dr Loh Poh Yen 2 November 2019 Advances in Gastroenterogy • IBD • Biologics eg infliximab, adalimumab • Viral hepatitis B • Antiviral eg Tenofovir alafenamide (Vemlidy) with low resistance rate and good safety profile • Viral hepatitis C • From interferon with lots of side effects and poor response rate to direct acting antivirals with high cure rates 2 How about in general gastroenterology? • Vomiting • Diarrhea • Abdominal pain/ cramp • Liver inflammation (non viral hepatitis cause) 3 vomiting 4 Vomiting pathways 5 • five principle neurotransmitter receptors • muscarinic M1 • dopamine D2 • histamine H1 • 5-hydroxytryptamine (HT)-3 serotonin • neurokinin 1 (NK1) substance P 6 • Muscarinic M1 receptor antagonist • Scopolamine (hyoscine hydrobromide) • predominantly used to treat motion sickness • Side effects include • dry mouth, vision changes, or drowsiness 7 • Dopamine D2 receptor antagonist • Phenothiazines • Butyrophenones • Benzamides 8 • Dopamine D2 receptor antagonist (Phenothiazines) • eg. Prochlorperazine • Side effects include dizziness, headache, dystonia and tardive dyskinesia. • Hypotension can occur in older adults or with intravenous infusion 9 • Dopamine D2 receptor antagonists (Butyrophenones) • eg. Haloperidol • can cause dose-dependent QT prolongation • the need for this class of agents and their utilization has declined 10 • Dopamine D2 receptor antagonists (Benzamides) • eg. Metoclopramide • can cause anxiety, dystonia, tardive dyskinesia, and akathisia domperidone penetrates the blood-brain barrier poorly. Has less common side effects than with metoclopramide 11 • Antihistamines (H1 receptor) • eg. Diphenhydramine, promethazine • primarily used for motion sickness and in pregnancy • Side effects: • Sedation • anticholinergic eg dry mouth, dilated pupils, blurred vision, reduced bowel sounds, and urinary retention 12 • Serotonin-receptor antagonists (5 HT-3 receptor) • eg. Ondansetron • Side effects include • Headache (15 to 20 % of patients) • constipation • QT-prolongation • Serotonin syndrome • when used in conjunction with SSRIs, SNRIs, mirtazapine, monoamine oxidase inhibitors(MAOIs) 13 Current available anti-emetic drugs remarks Dopamine D2 prochlorperazine Extrapyrimidal side effects (phenothiazine) Hypotension with IV infusion Dopamine D2 metoclopramide Extrapyrimidal side effects (Benzamides) Histamine H1 Promethazine, Drowsiness Diphenhydramine Anticholinergic side effects 5 HT-3 Ondansetron Headache avoid in patients with prolonged QTc 14 Use of anti-emetic Situation Associated Recommended antiemetic neurotransmitters migraine dopamine Metoclopramide or prochlorperazine Vestibular Histamine, acetylcholine Antihistamines Pregnancy induced Unknown Promethazine (first line), serotonin antagonists Gastroenteritis Dopamine, serotonin Dopamine antagonist, serotonin antagonist 15 diarrhea 16 adsorbent Antimotility agent Antisecretary agent 17 Antidiarrheal class Mechenism of action Adsorbents Binding to other Charcoal intraluminal contents Smecta Bismuth subsalicylate Antimotility agents Inhibit peristalsis Diphenoxylate-atropine loperamide Antisecretary Inhibit the secretion of racecadotril water and electrolytes into Bismuth subsalicylate the intestines 18 • Smecta • Removes toxins and germs • Mucosa coating (mucosal protection and repair) • 6 sachets/day at the beginning, followed by 3 sachets/day as symptoms improve 19 • Opioid Agonist • activates opioid receptors in the enteric nervous system & decrease peristalsis • Available options • Diphenoxylate + atropine (Lomotil) • Loperamide (Imodium) • Side effect: constipation 20 • Diphenoxylate + Atropine (Lomotil) • diphenoxylate crosses the BBB and produces central effects • higher doses do have euphoric CNS effects & prolonged use can lead to opioid dependence. • Loperamide • does not cross the blood-brain barrier, hence no analgesic or addictive properties 21 • Bismuth salicylate • less effective than loperamide • potential for salicylate toxicity (especially in those who take aspirin and pregnant women) • two tablets every 30 minutes until the diarrhea resolves or eight doses have been taken 22 • Racecadotril (hydrasec) • inhibit breakdown of enkephalin (antisecretary peptide) • begins to work within 30minutes • Can be used in paed and adult • Adult dose: 100mg 8 hourly Weight <9kg 9-13kg 13-27kg >27kg (kg) Dose 10mg 20mg 30mg 60mg (mg tds) Sachet/ 1x10mg 2x10mg 1x30mg 2x30mg dose sachet sachets sachet tds sachets tds tds tds 23 Racecadotril vs loperamide in adult • resolution of symptoms occurred with similar speed and efficacy • racecadotril was associated with less rebound constipation and less abdominal discomfort Wolfgang Fischbach Frontiers Medicine October 2016 24 Current anti-diarrhea treatment Antidiarrheal class remarks Adsorbents Charcoal Smecta Bismuth subsalicylate Beware salicylate toxicity Antimotility agents Diphenoxylate-atropine constipation loperamide Antisecretary racecadotril Adult form not available Bismuth subsalicylate Beware salicylate toxicity 25 Abdominal pain/ cramp 26 Antispasmodic • Actions • Antimuscarinics/ anticholinergics • eg. Hyoscine butylbromide • Smooth muscle relaxants • eg. Alverine, mebeverine, peppermint oil 27 Antispasmodic • Buscopan • Mebeverine • Meteospasmyl • Trimebutine • Librax • Etc No study to suggest one is superior than the other More drugs, more effective to control pain? 28 Descending pain inhibitory pathway Antidepressant eg. TCA, SSRI/SNRI 29 30 • Choice of abdominal pain treatment according to the dominant bowel symptom Constipation diarrhea lubiprostone antispasmodics linaclotide TCA antispasmodics SSRI/SNRI SSRI/SNRI 31 Liver inflammation 32 • Treating the underlying cause is the primary goal in managing liver disease 33 • Non alcoholic fatty liver disease (NAFLD) and alcoholic liver disease are common lifestyle diseases • No safe and effective treatment for NAFLD yet Drug Rx vs placebo Side effect Vitamin E 43% vs 19% Increased overall mortality, hemorrhagic stroke, prostate cancer pioglitazone 34% vs 19% Weight gain, bone fractures, congestive heart failure Liraglutide 39% vs 9% GI side effects Obeticholic acid 45% vs 21% Pruritus, increased LDL 34 Liver supplements/ CAM type examples dose S-adenosylmethionine heptral 1-2 tabs/ day (SAMe) Essential phospholipids Essentiale forte N 2 caps 3 times per day (EPL) (1800mg/d) maintenance: 1 cap 3 times per day (900mg/d) Silymarin Legalon 420mg/d maintenance 280mg/d 35 S-adenosylmethionine (SAMe) • Amino acid derivative of methionine • SAMe synthesis is depressed in chronic liver disease • functions: • methyl donor (cellular function and structure) • synthesis of glutathione (antioxidant) • synthesis of polyamine (liver cell regeneration) 36 Essential phospholipids (EPL) • highly purified extract of polyenylphosphatidylcholine molecules (PPC) from soybean • Functions • Repair and regenerate damaged liver cell membranes • help membrane-dependent cellular functions • antioxidative, and antifibrotic effects 37 Silymarin • active ingredient extracted from Silybium marianum (milk thistle) • Functions • Protect the liver from oxidative stress and sustained inflammatory processes • the supplement is poorly absorbed, and content of preparations is highly variable 38 Evidence of liver supplements • some positive controlled studies • Limited by heterogeneity of studies • many were small, observational studies with significant design flaws • Different doses used in studies • vary considerably in trial duration 39 40 Alcoholic liver disease • SAMe • may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease (child A/B) Mato J Hepatol 1999 • Cochrane 2001 review • No benefit in mortality, transplantation rate 41 Alcoholic liver disease • EPL • A improving trend of transaminases and bilirubin in subgroups with heavy drinkers Lieber CS Alcohol Clin Exp Res, 2003 42 Alcoholic liver disease • Silymarin • normalization of bilirubin, AST and ALT levels, and also improvement in histology in 36 patients with chronic alcoholic liver disease Feher J [Hungarian]. Orv Hetil 1989 • three-month study 31 of 116 patients with histologically proven alcoholic hepatitis randomized to placebo or silymarin showed no significant differences in serum transaminase activity or histologic fibrosis scores. Trinchet JC [French]. Gastroenterol Clin Biol 1989 43 Non alcoholic fatty liver disease • SAMe • resulted in decrease in TC, TG, ALT and AST levels and improvement in symptoms. Boming L. Chinese Hepatol. 2011 • decreased the degree of ALT, AST levels, TG and TC in NASH, and normalization of liver ultra- sonogram in 12 cases (60%) Lei MA Chinese Hepatol. 2011 44 Non alcoholic fatty liver disease • EPL • improved subjective symptoms, hepatomegaly, ultrasonography, liver enzyme levels, liver function and histopathology. • Small studies Karl-Josef Gundermann Pharmacological reports 2011 • meta-analysis showed the clinical efficacy rate was significant, with 83.5% in the treatment group vs. 41.7% under control, however, EPL did not improve the patients’ histology Hu G Liver, 2005 45 Combination of liver supplements • Silybin + vitamin E + phospholipids • Silybin-vitamin E complex given for 1 year showed an improvement in liver enzymes, insulin resistance, and liver histology of NAFLD Loguercio C Free Radic Biol Med 2012 46 Summary • The evidence of benefit is not sufficiently strong to recommend the use of liver supplements • no evidence for a preventive role against liver damage • they appear to be safe • not a substitute for conventional medical therapy 47.