This talk discusses GI/liver side effects of commonly used drugs and provides guidance on advising patients and monitoring or preventing adverse effects. It covers factors that may contribute to side effects like drug interactions and underlying diseases. Specific drugs discussed include statins, NSAIDs, aspirin, and ketoconazole. The speaker emphasizes advising patients on medication use and seeking medical help if unwell, considering individual risk factors when prescribing or recommending prophylaxis, and consulting specialists if serious adverse effects occur.

1. GI/liver side effects of
commonly used drugs
What should we advise patients?
How can we monitor for or prevent them?
Speaker: Dr Shim Hang Hock
Gastroenterologist
gutCARE CME series
This talk is accredited for 1 CME Point

2. GI/liver side effects of
commonly used drugs
What should we advise patients?
How can we monitor for or prevent them?
Speaker: Dr Shim Hang Hock
Gastroenterologist
gutCARE CME series

3. Aim
• Most drugs carry some GI/ liver side effects
• Not to cover all drugs
• Factors to be considered that may contribute to
GI/liver side effects.
• General approach on
• advising patients/ prescribers
• how to monitor/prevent them

4. GI and liver related side effects
• Common
• Reported in almost all classes of medications
• Medications are commonly metabolised by the liver
• All medications have gone through trials/ studies to
assess the safe therapeutic dose
• Rarely results in significant harm

5. Adverse outcomes sometimes still occurs:
• Idiosyncratic reaction
• Drug-drug interaction
• Intentional/ unintentional supra-therapeutic dose

6. • Unknown variation of pharmacodynamic outside of
clinical trials
• Extreme age
• Paediatric populations
• Elderly
• Multiple comorbidity
• polypharmacy
• Underlying chronic disease – liver disease
6

7. Liver related side effects (Drug
induced liver injury, DILI)
• Intrinsic (direct) or idiosyncratic (indirect)
Intrinsic Idiosyncratic
Dose dependent Not dose related
Predictable Unpredictable (very small group of
patients)
Onset within short time span (hrs to
days)
Variable onset

10. • US and Europe
• DILI most commonly related to idiosyncratic reaction from
conventional drugs
• Asia
• DILI most commonly related to OTC or supplements
Wai CT, et al. Liver Int 2007;27:465–474.

11. Who may be at risk of DILI?
11

12. Patient related factors
• Children
• Reye’s syndrome (Aspirin use)
• Older age
• Various cutoff across different studies (55-70 years old)
• Female gender
• Ethnicity
• HLA A*33:03 (Japanese): ticlopidine
• HLA-B*15:02 (Asian): anticonvulsants (carbamazepine,
phenytoin, lamotrigine)
• HLA-DRB1*15:02- DQB1*06:01(South Asians): co-amoxiclav
related acute liver failure

13. • Alcohol
• CYP2E1 inducer
• Selected drugs – paracetamol, isoniazid, Methotrexate, halothane
• Pregnancy
• Debatable
• Difficult to be differentiated from intrahepatic cholestasis of pregnancy
• Comorbidities
• Metabolic syndrome
• Drug associated fatty liver disease
• MTX, tamoxifen, amiodarone
• Chronic Hep B and Hep C
• Anti-HIV , anti-TB treatment

14. Drug related factors
• Drugs with significant hepatic metabolism (>50%)
• Higher dose
• Lipophilic
• more likely to have higher liver uptake and require hepatic
metabolism to be eliminated increased amount of
reactive metabolites  DILI

15. • Concomitant drugs
• Through drug-drug interaction
• Induction, inhibition, or substrate competition for CYP
reaction
• Rifampicin + Isoniazid
• Carbamazepine + valproate acid
15

16. 16

17. 17

18. 18

19. When to suspect DILI
• Clinical presentation
• Can be weeks-months from time of ingestion
• Usually asymptomatic, and noted on routine liver blood test
• Nonspecific
• Nausea
• Lack of appetite
• Abdominal discomfort
• Loose stool/ Diarrhoea
• Jaundice
• Liver failure

20. • Careful drug history
• Conventional drugs
• OTC/ supplements
• Dose, duration
• Cessation of unnecessary drugs

21. When to suspect DILI
Test Clinical Implication DILI?
Total bilirubin Cholestasis/obstruction,
haemolysis
Not specific
ALP Cholestasis/obstruction, infiltrative
lesion
Not specific
-bone, salivary gland,
intestine, liver
ALT Hepatocellular
AST Hepatocellular Not specific
Muscle, heart, pancreas,
blood
GGT Cholestasis/obstruction Not specific
Kidney, liver, pancreas, GI,
lung

22. Patterns of DILI
• Hepatocellular
• Multiple of ULN of ALT/ALP > 5
• Cholestatic picture
• Multiple of ULN of ALT/ALP <2
• Mixed cholestatic hepatocellular picture
• Multiple of ULN of ALT/ALP between 2-5

24. LiverTox
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25. • Exclude alternative causes

26. • Liver biopsy

27. Case study 1
• Mr Tan, a 50 years old man,
• With
• Hypertension
• DM
• Hyperlipidaemia
• Obesity, BMI 30
• Metformin 1g BD, amlodipine 5mg OM, Simvastatin 40mg ON
• Latest labs: LDL 4.1, TG 1.4
• ALT 110, AST 70

28. Clinical dilemma
Is this of clinical concern?
Are patients with NAFLD at higher risk of DILI with
statin?
What should be done?
a)Stop statin permanently
b)Stop, observe kiv restart again
c)Change simvastatin to atorvastatin/rosuvastatin

29. Raised LFT
Results of
• Fatty liver
• Simvastatin
• Other causes
• Other drugs
• infections

30. NAFLD
• Strong association between NAFLD and
cardiovascular risk factors
• Proatherogenic lipid profile
• Raised TG
• Raised LDL
• Low HDL

31. Statin and DILI
• Irreversible liver injury is exceptionally rare, and
likely idiosyncratic in nature
• <2 : 1 million PY
• DILIN (DILI Network, US)
• Despite significantly increased statin use since 1990,
• No detectable increase in annual rates of severe liver
injury associated with statin

32. • Prospective, intention to treat, randomized study of 1600 patients
• Patients who received statin,
• Improvement in LFT from baseline (p<0.0001)
• Lower risk of CV events (10% vs. 30%, p <0.0001)
• <1% of patients had statin discontinued due to raised ALT (>3x ULN)

33. Position statement from AASLD 2018
• Patients with NAFLD or NASH are not at higher risk
for serious liver injury from statins.
• Thus, statins can be used to treat dyslipidemia in
patients with NAFLD and NASH.
• While statins may be used in patients with NASH
cirrhosis, they should be
• avoided in patients with decompensated cirrhosis.

35. What to advise patients?
• Avoid grapejuice
(interaction)
How to monitor and prevent?
• LFT at baseline, clinically
indicated thereafter

36. Case 2
• 35 years old Chinese lady
• With nil past medical history of note
• Started on prn NSAIDS for migraine
• Would you give PPI prophylaxis?
a) Yes
b) No
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37. Case 3
• 60 years old man
• With underlying history of
• DM
• Hypertension
• Newly diagnosed IHD
• Started on aspirin
• Would you give PPI prophylaxis?
a) Yes
b) No

38. Clinical question
• NSAIDs and Aspirin – risk of dyspepsia/peptic ulcer
disease
• When would you give routine PPI prophylaxis?
• What does the evidence say?
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39. Risk of NSAIDs related PUD
39

40. Risk factors
• Previous GI events
• Age>65
• Concomitant use of
• Anticoagulants
• Steroids
• NSAIDSAspirin
• Chronic disease including IHD
• H pylori infection
40

41. 41 Lanza et al. Am J Gastroenterol 2009; 104:728 – 738

42. NSAIDS
• Difference in ulcerogenic potentials
42 Henry et al. October 1993 Gastroenterology 105(4):1078-8

43. COX2 inhibitor
• Significantly lower risk of PUD than traditional
NSAIDS
• Benefit negated by
• Concomitant use of aspirin
• Risk of IHD/CVA
43 Lanza et al. Am J Gastroenterol 2009; 104:728 – 738

44. Misoprostol
• First agent approved for prevention of NSAIDS
related ulcers
• Significantly more effective than H2RA
• Similar to PPI
44

45. 45
Prospective double blind, RCT
N=537

46. • Limited by GI side effects
• abdominal cramp
• diarrhoea
• Pregnancy category X
• Induce uterine contraction (abortion)
46

47. • H2RA (eg famotidine)
• Only double dose (but not single dose) are effective
in reducing NSAIDS related ulcer
• Significantly inferior to PPI
47

48. • Proton Pump Inhibitor
• More effective than H2RA and misoprostol in preventing
NSAIDS related PUD
48 Yeomans ND et al. N Engl J Med 1998;338:719–26.

49. COX2 inhibitor or
NSAIDS+PPI
49
No prophylaxis
Avoid NSAIDS
COX2 inhibitor + PPI
Lanza et al. Am J Gastroenterol 2009; 104:728 – 738

50. Case 4
• 65 years old Chinese lady with underlying
• IHD
• Hypertension
• On clopidogrel, amlodipine and famotidine
• Complaint of dyspepsia despite famotidine.
• Can she be started on omeprazole?
a) Yes
b) No
50

51. PPI use
• Concern of interaction with clopidogrel?
• Risk of osteoporosis? Cdiff diarrhea, pneumonia,
COVID-19 etc…
• Should I change to H2RA?
• What should I counsel my patients?
51

52. FDA
52

53. PPI and clopidogrel
• Due to concern that antiplatelet activity of
clopidogrel requires activation by CYP 2C19,
the same pathway required for metabolism of
some PPIs
53

54. • N=3761 54

55. 55

56. 56

57. PPI and pneumonia
• 6 case controlled studies
• Increased risk of CAP with PPI use
• OR 1.36 (95% CI 1.12-1.65)
• short duration of use [OR 1.92 (95% CI 1.40-2.63), I(2) 75%, P
= 0.003],
• chronic use [OR 1.11 (95% CI 0.90-1.38), I(2) 91%, P < 0.001]
57
*short duration <30 days

58. PPI and Enteric infection
• Salmonella infections
• RR 4.2 – 8.3 in two studies
• Campylobacter
• RR 3.5 – 11.7 in four studies
• C. difficile infections
• RR 1.2 – 5.0 in 17 / 27 studies

59. American College of
Gastroenterology 2013
59

60. 60
American Journal of Gastroenterology, 2020
Cross sectional survey

61. Take home message
• Long-term PPI use has been associated with
several safety concerns.
• However, few of these concerns are
supported by consistent data demonstrating a
causal relationship.
• To limit use of PPI to the minimum dose
where possible
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62. Case 5
36 years old male
With underlying chronic hepatitis B infection
62
• Not responding to first line
topical treatment
including top ketoconazole
2% cream, terbinafine 1%
lotion and selenium
sulfide 2.5% lotion
• ? Oral antifungal

63. Ketoconazole related liver injury
• First approved in 1981
• Recommendation by EMA and FDA against use of
ketoconazole as first line Rx for any fungal treatment
• Risk of hepatotoxicity
• Adrenal insufficiency
• Drug-drug interaction
• Withdrawn in many countries and replaced by other
safer azole
63

64. • Transient raise in LFT in 4-20% of patients
• Clinically apparent 1:2000-1:15000
• Hepatocellular pattern
• Acute liver failure and death reported
• Recovery delayed, 1-3/12
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65. Fluconazole
• Transient raise in LFT in <5% of patients
• Clinically apparent disease rare
• Most recovered with drug withdrawal
65

66. Summary
66

67. Take Home Message
Advise to patients:
• To report to doctor all concomitant drugs
• Prescriptional/ OTC medications
• Minimise unnecessary drug where possible
• Not to exceed target dose
• Minimise use of alcohol
• To inform doctor if pregnant/ concomitant liver
disease
• To seek medical advice if unwell
67

68. Take home message:
Advice to prescribers:
• Full drug history
• Consider drug-drug interaction
• LiverTox
• Most resolved upon withdrawal of drugs
• Use safer alternative where possible
68

69. • Rechallenge not recommended in patients with
severe reaction unless in the absence of alternative
• No definitive treatment are usually available
• Careful exclusion of alternative aetiologies of liver
disease
• To seek early advice from gastroenterologist when in
doubt
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70. Take Home Message
• Statin related DILI
• Safe
• NSAIDS/Aspirin related PUD
• Use minimal dose, shortest duration as possible
• Consider PPI prophylaxis for patient with moderate
risk and above
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71. Thank you