Drug-Induced Gastrointestinal Diseases (ADRs)

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

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  • Perforation –Obstruction-
  • Misoprostol 200 mcg in QID8-12 week course in normal doses of PPI
  • Misoprostol 200 mcg in QID8-12 week course in normal doses of PPI
  • Misoprostol 200 mcg in QID8-12 week course in normal doses of PPI
  • Misoprostol 200 mcg in QID estrogen conjugated and esterified8-12 week course in normal doses of PPI
  • Misoprostol 200 mcg in QID8-12 week course in normal doses of PPI
  • Drug-Induced Gastrointestinal Diseases (ADRs)

    1. 1. GASTROiNTESTINAL DISEASES ADVERSE DRUG REACTIONS
    2. 2. OUTLINE I. Dysgeusia II. Upper GIT Ulceration III. Dyspepsia IV. GIT Hemorrhage V. Antibiotic-induced diarrhea and antibiotic-associated (pseudomembranous) colitis (AAC)
    3. 3. I. DYSGEUSIA
    4. 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. 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. 6. Dysgeusia • Changes in taste are a frequently reported side effect of a wide range of medications, including macrolide antibiotics, antifungals, ACE inhibitors.
    7. 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. 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. 9. Medications known to cause Dysgeusia • Metronidazole & Chlorhexidine have been found to interact with metal ions that associate with the cell membrane.
    10. 10. Consequences • Poor compliance with medications • Nutritional deficiencies and weight loss
    11. 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. 12. II. UPPER GASTROINTESTINAL ULCERATION
    13. 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. 14. UPPER GASTROINTESTINAL ULCERATION • Drug-induced ulceration of the upper GIT can be a significant problem resulting in perforation, obstruction or bleeding.
    15. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 27. III.DYSPEPSIA
    28. 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. 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. 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. 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. 32. IV.GIT HEMORRHAGE
    33. 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. 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. 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. 36. V. ANTIBIOTIC-INDUCED DIARRHEA AND ANTIBIOTIC-ASSOCIATED (PSEUDOMEMBRANOUS) COLITIS
    37. 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. 38. DIARRHEA • Diarrhea – increased frequency of bowel movements (≥3/d), decreased stool consistency, and/or increased stool weight (>200g/d)
    39. 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. 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. 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. 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. 43. Other Antibiotics causing DIARRHEA • Antibiotics –Clindamycin –Macrolides (erythromycin) –Penicillins –Quinolones –Sulfonamides –Tetracycline
    44. 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. 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. 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. 47. Other Antibiotics that cause AAC • Ciprofloxacin (<1%) • Chloramphenicol • Cloxacillin • Erythromycin • Gentamicin • Rifampin (1-10%)
    48. 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. 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. 50. Thank You for Being Attentive!!!

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