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