Drug-Induced Gastrointestinal Diseases (ADRs)

GASTROiNTESTINAL DISEASES

ADVERSE DRUG REACTIONS

OUTLINE

I. DysgeusiaII. Upper GIT UlcerationIII. Dyspepsia IV. GIT HemorrhageV. Antibiotic-induced diarrhea and

antibiotic-associated (pseudomembranous) colitis (AAC)

I. DYSGEUSIA

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

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

Dysgeusia

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

Medications known to cause Dysgeusia

• Captopril and Zofenopril (sulfhydryl compounds)Impaired or salty taste is common

complaint, common cause of taste disturbances

• Systemic GriseofulvinRenders particular foods tasteless,

with worsening symptoms corresponding to duration of drug administration


• 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


• Metronidazole & Chlorhexidine have been found to interact with metal ions that associate with the cell membrane.

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

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

II. UPPER GASTROINTESTINAL ULCERATION

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

UPPER GASTROINTESTINAL ULCERATION

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

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

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

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.

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

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

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

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

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

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

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.

Mechanisms of Drug-Induced Upper GI Ulceration


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

II. Treatment options for Management of Drug-Induced

Upper GI Ulceration


Medication Action

All Discontinue medication if possible

ASA, NSAIDs Eradicate HPHeal ulcer with PPI, misoprostolConsider 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 mealsAvoid a recumbent position for at least 1 hour after medication, medication with sufficient water

III.DYSPEPSIA

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

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.

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)


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.

IV. GIT HEMORRHAGE

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.

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

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

V. ANTIBIOTIC-INDUCED DIARRHEA AND

ANTIBIOTIC-ASSOCIATED

(PSEUDOMEMBRANOUS) COLITIS

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.

DIARRHEA

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

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

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 intestine2. Premature emptying of the colon3. Bacterial overgrowth

Antibiotic-induced diarrhea • Drug-induced diarrhea

associated with chemotherapeutic agents is well recognized, particularly with Fluorouracil (10-80%) and Irinotecan (50-80%).


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 ADrug-Induced Diseases by Tisdale, J.E.; Miller, D.A.

Other Antibiotics causing DIARRHEA

• Antibiotics–Clindamycin –Macrolides (erythromycin)–Penicillins –Quinolones –Sulfonamides –Tetracycline

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

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

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.

Other Antibiotics that cause AAC

• Ciprofloxacin (<1%)• Chloramphenicol • Cloxacillin • Erythromycin • Gentamicin • Rifampin (1-10%)

Management of AAD & AACManagement 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

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/

003133.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/003260.htm

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Drug-Induced Gastrointestinal Diseases (ADRs)