Drug-Induced Diseases/Adverse Drug Reactions on the Gastrointestinal Tract, with references included.

1. GASTROiNTESTINAL DISEASES
ADVERSE DRUG REACTIONS

2. OUTLINE
I. Dysgeusia
II. Upper GIT Ulceration
III. Dyspepsia
IV. GIT Hemorrhage
V. Antibiotic-induced diarrhea and
antibiotic-associated
(pseudomembranous) colitis (AAC)

3. I. DYSGEUSIA

4. DYSGEUSIA
• Distortion in the perception of a
correct taste
• Altered taste sensation
• It may manifest as an unusual, bitter,
metallic taste or distaste for food
• Hypogeusia - blunting or decreased
sense of taste
• Ageusia – total loss of taste

5. Dysgeusia
• The mechanism of drug-related
taste disturbance appears to
involve:
- interference with the chemical
composition or flow of saliva
- direct effects on taste receptor
function or signal transduction

6. Dysgeusia
• Changes in taste are a frequently
reported side effect of a wide
range of medications, including
macrolide antibiotics, antifungals,
ACE inhibitors.

7. Medications known to cause
Dysgeusia
• Captopril and Zofenopril (sulfhydryl
compounds)
Impaired or salty taste is common
complaint, common cause of taste
disturbances
• Systemic Griseofulvin
Renders particular foods tasteless, with
worsening symptoms corresponding to
duration of drug administration

8. Medications known to cause
Dysgeusia
• Penicillamine
Has been known to cause a
partial or total loss of taste
• Lithium carbonate & Tetracycline
–Saliva can have traces of the
drug, giving rise to a metallic
flavor in the mouth

9. Medications known to cause
Dysgeusia
• Metronidazole &
Chlorhexidine have been found to
interact with metal ions that
associate with the cell membrane.

10. Consequences
• Poor compliance with
medications
• Nutritional deficiencies and
weight loss

11. Dysgeusia
• For many drugs where taste
disturbance is a side effect, it
appears to be dose-
related, and resolves within
weeks of discontinuation of
the offending agent.
• Type of ADR: Augmented

12. II. UPPER
GASTROINTESTINAL
ULCERATION

13. UPPER GASTROINTESTINAL
ULCERATION
• Ulcer – a break in the skin extending
to all its layers, or in the mucous
membrane lining the alimentary
tract, that fails to heal and is often
accompanied by inflammation.
• Parts included in upper GI
–Esophagus
–Stomach
–Duodenum
The Bantam Medical Dictionary

14. UPPER GASTROINTESTINAL
ULCERATION
• Drug-induced ulceration of the upper
GIT can be a significant problem
resulting in perforation, obstruction
or bleeding.

15. Medications causing upper GIT
ulceration
• Aspirin and Non-steroidal anti-
inflammatory agents –most frequent
causative agents
• Wax matrix potassium chloride
preparations
• Corticosteroids
• Doxycycline
• Ferrous sulfate
• Bisphosphonates

16. Mechanism
• Aspirin and Non-steroidal anti-
inflammatory agents
–Inhibit gastric mucosal
prostaglandin synthesis by
inhibiting the COX enzyme system
altering prostaglandin-associated
GI defense mechanisms

17. Mechanism
• Aspirin and Non-steroidal anti-
inflammatory agents
–Both COX-1(produces prostaglandins known
to protect the GI mucosa) and COX-2
(primarily present at sites of inflammation)
enzymes are inhibited.

18. Mechanism
• Aspirin and Non-steroidal anti-
inflammatory agents
– inhibition of COX-2 by traditional NSAIDs
accounts for the anti-inflammatory effect of
the drugs while the inhibition of COX-1 can
lead to NSAID toxicity and associated side
effects
–Type of ADR: Continuous

19. Cox-1 and Cox-2 Activity of
Selected NSAIDs
NSAID COX-1 COX-2
In Vitro Inhibitory Activity
Ketorolac +++++ +
Indomethacin ++++ +
Naproxen +++ +
Ibuprofen +++ +
Piroxicam ++ ++
Sulindac ++ ++
Diclofenac ++ +++
Celecoxib + +++
Meloxicam + +++
Etodolac + +++
+ Minimal Activity; ++ Some activity; +++ Significant activity;
++++ High activity; +++++ Very High activity

20. Mechanism
• Bisphosphonates
–Only nitrogen-containing
bisphosphonates (i.e.
Alendronate, risedronate &
pamidronate) have been implicated
–Several mechanisms have been
suggested, but the most probable
mechanism is direct topical irritation
–Ulcers are not seen during IV
administration

21. Mechanism
• Bisphosphonates
–Prolonged contact of the tablet with
the esophageal tissue may occur
when the patient takes a tablet in
the supine position or without
sufficient water.
–Type of ADR: Augmented

22. Mechanism
• Potassium Chloride preparations
–May induce GI damage caused by
direct irritation from the high
concentrations of KCl in the GI
mucosa
–Type of ADR: Augmented

23. Mechanism
• Doxycycline and Ferrous Sulfate
• Drug-induced ulceration associated
with these drugs may be the result
of a low pH when the drug is
dissolved, causing erosions and
inflammation of the esophageal
mucosa
• Type of ADR: Augmented

24. Drugs That May Cause Upper GI
Ulceration
Drug Most common site of ulceration Incidence
ASA Stomach 10-15
Bisphosphonates Esophagus 0.2-0.4
Corticosteroids Stomach 0.4
COX-1 NSAIDs Stomach 10-15
COX-2 NSAIDs Stomach 5-8
Doxycycline Esophagus Unknown
Ferrous Sulfate Esophagus, Stomach Unknown
KCl Esophagus, Stomach 8-19
Drug-Induced Diseases by Tisdale, J.E.; Miller, D.A.

25. Mechanisms of Drug-Induced
Upper GI Ulceration
Drug-Induced Diseases by Tisdale, J.E.; Miller, D.A.
Medication Mechanism
ASA COX-1 inhibition
NSAIDs COX-1 inhibition
KCl Direct irritant
Corticosteroids Controversial
Doxycycline Direct irritant
Ferrous Sulfate Direct irritant
Bisphosphonates Direct irritant

26. II. Treatment options for Management of
Drug-Induced Upper GI Ulceration
Drug-Induced Diseases by Tisdale, J.E.; Miller, D.A.
Medication Action
All Discontinue medication if possible
ASA, NSAIDs Eradicate HP
Heal ulcer with PPI, misoprostol
Consider maintenance for prevention of
recurrence with PPI, misoprostol, or an NSAID
with a lower risk of ulceration
Bisphosphonates,
KCl, Tetracyclines
Consider other medications, administer
medication with sufficient water
Bisphosphonates Avoid taking medication with meals
Avoid a recumbent position for at least 1
hour after medication, medication with
sufficient water

27. III.DYSPEPSIA

28. DYSPEPSIA
• Indigestion (dyspepsia) is a vague
feeling of discomfort in the upper belly
or abdomen during or right after eating.
This may include:
–A feeling of heat, burning, or pain in the
area between the navel and the lower part
of the breastbone
–A feeling of fullness that is bothersome
and occurs soon after the meal begins or
when it is over

29. Dyspepsia
• It is important to recognize that
dyspepsia/uninvestigated dyspepsia
relates to a symptom complex rather
than a true diagnosis or single
medical disease/condition. In fact,
dyspepsia may be indicative of a
variety of possible conditions that
may be the cause of the patient's
dyspeptic symptoms.

30. Medications causing Dyspepsia
• Non-steroidal anti-inflammatory drugs
(NSAID) e.g. aspirin, ibuprofen,
naproxen, diclofenac.
• Corticosteroids e.g. prednisolone,
prednisone.
• Estrogens
• Bisphosphonates
• Certain antibiotics (Rifampin)

31. Drug-Induced Diseases by Tisdale, J.E.; Miller, D.A.
DYSPEPSIA & DIU
• The presence of dyspepsia in a
patient taking medications that
produce DIU does not always indicate
that an ulcer is present but should
raise suspicion.

32. IV.GIT HEMORRHAGE

33. GIT HEMORRHAGE
• Gastrointestinal (GI) bleeding refers to
any bleeding that starts in the
gastrointestinal tract.
• Bleeding may come from any site along
the GI tract, but is often divided into:
–Upper GI bleeding: The upper GI tract
includes the esophagus, stomach, and
first part of the small intestine.
–Lower GI bleeding: The lower GI tract
includes much of the small intestine,
large intestine or bowels, rectum, and
anus.

34. Medications causing GIT
Hemorrhage
• NSAIDs
–Ketorolac has the highest COX-1
activity and has the highest risk of
GI bleeding of all the NSAIDs
–Indomethacin & Ibuprofen also
have significant proportion of COX-
1 activity compared to COX-2
–Type of ADR: Continuous

35. Medications causing GIT
Hemorrhage
• Corticosteroids
–Have long been implicated as a cause of
GI hemorrhage but the exact
mechanism is not clear.
–However, it has been proposed that
these agents impair mucosal healing
through reduction of epithelial
regeneration.
–Research suggests that the incidence is
small

36. V. ANTIBIOTIC-INDUCED
DIARRHEA AND
ANTIBIOTIC-ASSOCIATED
(PSEUDOMEMBRANOUS)
COLITIS

37. ANTIBIOTIC-INDUCED DIARRHEA
AND ANTIBIOTIC-ASSOCIATED
(PSEUDOMEMBRANOUS) COLITIS
• Patients with either of these diseases
present with profuse diarrhea (rarely
with blood) consisting of mucoid,
greenish, foul-smelling, watery stools;
abdominal pain; low-grade fever.

38. DIARRHEA
• Diarrhea – increased
frequency of bowel movements
(≥3/d), decreased stool
consistency, and/or increased
stool weight (>200g/d)

39. DIARRHEA
• Arises from two basic mechanisms:
–Decreased absorption of water
and electrolytes
–Increased active secretion of
water and electrolytes in GIT
• Result in a net secretion that
causes an increase in stool volume
& weight

40. DIARRHEA
• Drugs increasing active secretion
alter intestinal motility
–Drug-altered intestinal motility is
attributed to 3 different mechanisms:
1. Reduction of contact time in the small
intestine
2. Premature emptying of the colon
3. Bacterial overgrowth

41. Antibiotic-induced diarrhea
• Drug-induced diarrhea
associated with
chemotherapeutic agents is well
recognized, particularly with
Fluorouracil (10-80%) and
Irinotecan (50-80%).
Drug-Induced Diseases by Tisdale, J.E.; Miller, D.A.

42. Mechanism
• Antineoplastics increase active
secretion and destroy the intestinal
mucosa of the small & large intestines,
causing exudative mechanisms.
• Additionally, they may affect the
absorptive, secretory, or motility
functions of the gut
• Type of ADR: Type A
Drug-Induced Diseases by Tisdale, J.E.; Miller, D.A.

43. Other Antibiotics causing
DIARRHEA
• Antibiotics
–Clindamycin
–Macrolides (erythromycin)
–Penicillins
–Quinolones
–Sulfonamides
–Tetracycline

44. ANTIBIOTIC-ASSOCIATED
(PSEUDOMEMBRANOUS) COLITIS
• Pseudomembranous colitis is
infection of the large intestine
(colon) with an overgrowth
of Clostridium difficile bacteria.
• a cause of antibiotic-associated
diarrhea (AAD),
• It is an inflammation of the colon

45. Mechanism
• The mechanism for diarrhea resulting
from pseudomembranous colitis is
bacterial proliferation. (Clostridium
difficile)
• The bacteria secretes:
enterotoxin A – adheres to the brush-
border membrane of enterocytes,
inducing lesions and an inflammatory
response, and;
cytotoxin B – may also cause GI mucosal
damage

46. Mechanism
• The use of clindamycin, broad-spectrum
antibiotics such as cephalosporin, or any
penicillin-based antibiotic such
as amoxicillin causes the normal
bacterial flora of the bowel to be altered.
In particular, when the antibiotic kills off
other competing bacteria in the
intestine, any bacteria remaining will
have less competition for space and
nutrients.

47. Other Antibiotics that cause AAC
• Ciprofloxacin (<1%)
• Chloramphenicol
• Cloxacillin
• Erythromycin
• Gentamicin
• Rifampin (1-10%)

48. Management of AAD & AAC
Management of antibiotic-induced diarrhea
Discontinue offending drug/change to another drug if
possible
Lower (adjust dose) if possible
Implement low residual diet
Provide rehydration and maintenance of fluid electrolytes
Clostridium difficile must be eliminated as the cause of
diarrhea before implementation of antiperistaltic drugs
For Clostridium difficile and pseudomembranous colitis,
initiate metronidazole (first line) or oral vancomycin

49. References:
• Remington: The Science & Practice of Pharmacy, 19th
Edition
• Drug-Induced Diseases: Prevention, Detection and
Managemet; Drug-Induced Diseases by Tisdale, J.E.;
Miller, D.A.
• McGraw-Hill Drug Handbook; Schull, P.D.
• http://www.nlm.nih.gov/medlineplus/ency/article/003
133.htm
• http://www.dwp.gov.uk/publications/specialist-
guides/medical-conditions/a-z-of-medical-
conditions/dyspeptic-disorders/
• http://www.nlm.nih.gov/medlineplus/ency/article/003
260.htm

50. Thank You
for Being
Attentive!!!