1. Dr. Ahraf Abdulhaseeb Chest Diseases Consultant Chief of DR-TB Center, Abbassia Chest Diseases Management of Adverse Effects of Anti-TB drugs (part II) 1

2. I) Management of Gastro-intestinal intolerance 2

3. A. Gastritis Symptoms: - epigastric pain or burning sensation, - bitter taste in the mouth, - less pain after eating. - Coffee ground emesis if present means gastrointestinal hemorrhage (hematemesis) 3

4. A.Gastritis, cont. exclude: - infections (e.g. helicobacter pylori) - alcohol intake, - spicy diet, - other drugs e.g. NSAIDs - other diseases e.g. bile reflux, HIV, Auto-immune diseases, renal or liver impairment Investigations: stool analysis for occult blood, maybe gastroscopy needed 4

5. Algorithmic management of Gastritis - Hematemesis +Emergency refer to hospital No Hematemesis, only epigastric pain, burning sensation …etc. Give drugs with or after food, avoid coffee, alcohol, smoking If no improvement, give H2 blocker or proton pump inhibitor If no improvement, give antacid e.g. Mg Hydroxide. Away from Fluoroquinolone at least 3 hours If no improvement, If receiving ethionamide, PAS, clofazimine consider reduction dose. Consider treatment for Helicobacter pylori and GIT consultation 5

6. B.Diarrhea: Diarrhea is frequent (  3-4) &/or watery bowel movements exclude: - infections (giardia, amoebic or bacillary dysentery, or other infectious causes) 6

7. Algorithmic management of Diarrhea: stools frequent &waterystools frequent & loose Encourage fluid intake, check serum electrolytes With blood, mucous, fever No blood, mucous, fever Role out infection Treat accordingly Avoid anti-diarrheal Check electrolytes Infection rolled out Rehydrate Check electrolytes Anti-diarrheal e.g. Loperamide (2 mg orally after each episode of up to 10 mg total / day 7

8. C.Nausea and vomiting Algorithmic management HematemesisUrgent referral to hospitalNo hematemesis Dehydrated Check electrolyte Rehydrate IV Hospitalization to correct fluid electrolyte disturbance If not and hepatitis rolled out Administer oral anti-emetics Use benzodiazepines in anxiety (avoided in Co2 retention) Administer IM/IV anti-emetics if no improvement. Consider reducing the dose or suspending it for a short time 8

9. D.Hepatitis: Nausea, vomiting, jaundice, scleral icterus, tea- colored urine, pale stool, and diminished appetite Serum transaminases &/or Serum bilirubin exceed three times normal level. Causes include: Infections (e.g., viral A B C, amoebic, TB etc.), Autoimmune disease, Alcoholism, Medications, including anti-tuberculosis drugs, anti- epileptics, acetaminophen, sulfa drugs, erythromycin 9

10. I) Management of Gastro-intestinal intolerance (SGOT) ALT (SGPT), direct or bilirubin >3 times normal values Stop all drugs Role out other causes TREATMENT of HEPATITIS  Hospitalization for severely ill patient  Symptomatic treatment as needed or the underlying cause if appropriate  Wait for normalization of serum liver tests prior to considering re-initiation of Anti-tuberculosis medications  If possible, eliminate the most likely agent from the regimen  Reinitiate anti-tuberculosis medications, one by one, with serial monitoring of serum liver tests  Introduce agents most likely to cause hepatitis first  If possible, replace the hepatotoxic medications with equally efficacious anti- tuberculosis medications without compromising the regimen.  Follow up serum liver test every month throughout treatment. 10

11. II) Allergic and dermatological adverse reactions 11

12. Allergic and dermatological adverse reactions Minor Skin pigmentation Photosensitivity Dry skin Moderate to severe adverse reactions Hypersensitivity Rash Purpura Allergic dermatitis Exfoliative dermatitis, Steven Johnson Syndrome Photosensitivity Anaphylaxis /Angiodema 12

13. Symptoms include: – Difficulty of breathing (often with wheezing), – Pruritis,  Hoarseness, sensation of a “lump” in the throat, – Urticaria (with or without angioedema), – Nausea, Vomiting, – Cramps, – Diarrhea – Sometimes, patient also presents with fever, arthralgia, myalgia Signs include:  stridor, wheezing, swelling  of the tongue, hoarseness  Systolic blood pressure  <90mm Hg (shock) A.Anaphylaxis Fatal and appears within minutes of the administration of the offending medication. 13

14. Management EMERGENCY  Evaluate for airway obstruction, exclude foreign body aspiration,  Administer epinephrine 0.2- 0.5 ml 1:1000 SC  Re-administer epinephrine if the symptoms persist after 20 min  Administer antihistamine and corticosteroids  Intravenous fluids to expand intravascular volume  Oxygen  Consider intubation if necessary 14

15. B.Steven Johnson syndrome Starts as non-specific upper respiratory tract infection. – This usually is part of a 1- to 14-day prodrome during which fever, sore throat, chills, headache, malaise may be present. – Vomiting and diarrhea are occasionally noted as part of the prodrome. Muco-cutaneous lesions develop abruptly and typically non- pruritic. symptoms are as follows: – Cough productive of a thick purulent sputum – Headache – Malaise – Arthralgia – Fever, reported in 85% of cases. 15

16. Signs include: – Fever – Orthostasis – Tachycardia – Hypotension – Altered level of consciousness – Epistaxis – Conjunctivitis – Corneal ulcerations – Vulvovaginitis or balanitis – Seizures, coma Symptoms include: – Cough productive of a thick purulent sputum – Headache – Malaise – Arthralgia – Fever, reported in 85% of cases. 16

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18. Management EMERGENCY Stop all drugs Administer aggressive hydration Administer antihistamine and/or corticosteroids Refer to hospital 18

19. Other allergic skin reactions Patients may have: Skin rash, itching, dry skin, photosensitivity Management: Consider allergic reaction Administer antihistamine and/or corticosteroids PRN for symptoms Rule out other non-allergic causes e.g. scabies, insect bites..etc. If associated with sun exposure, use sunscreens or avoid exposure 19

20. In all allergic and dermatological reactions: In addition to the specific management: Determine the offending substance (food, medication, insect bites) If an anti-tuberculosis medication is highly suspected and the reaction was life-threatening, discontinue medication and replace with equally efficacious anti-tuberculosis drug. When any of the severe allergic reactions are present, all anti-tuberculosis medications should be suspended. Desensitization should not be performed in patients with a history of Stevens-Johnson syndrome. 20

21. Desensitization, General considerations It is essential to determine which drug caused the reaction. Once the patient has improved, anti- tuberculosis therapy can be restarted as a “ challenge ”– a partial dose – in a serial fashion

22. Start the most likely allergen administered first. Desensitization is only done when other therapeutic options are extremely limited. Challenges is done to medicines in which reactions were mild to moderate. Rarely agent that has caused anaphylaxis can only be introduced through a desensitization protocol under careful, hospital based observation. Desensitization, General considerations

23. Example of desensitization protocols

25. III. Neurological and Psychiatric adverse reactions 25

26. Common mild adverse reactions Dizziness Headache Fatigue Somnolence Insomnia Confusion Irritability Anxiety Behavior changes Moderate to severe adverse reaction Seizure Syncope Peripheral neuropathy VIII nerve damage: hearing loss, vestibular impairment Psychosis Suicidal ideation Depression 26

27. Management of Headaches Rule out meningitis: Neck rigidity, photophobia, fever, confusion, somnolence If positive, refer to hospital Rule out migraines: Prior to treatment similar headaches pulsating, with nausea, vomiting, vision changes? Discrete episodes lasting hours, relieved by darkness, sleep analgesics, low-dose beta-blockers, sumatriptan, Supportive measures TREATMENT analgesics (e.g., acetaminophen, ibuprofen, etc.) Avoid non-steroidal anti-inflammatory agents in patients with hemoptysis or gastritis Psychosocial support Encourage adequate fluid intake Confirm patient on proper dose of pyridoxine If no response, Amitriptyline 50-150 mg at night & consider lowering Cycloserine dosage 27

28. Management of Seizures Presentations Recurrent movement of a part of the body (e.g., finger, hand, face, etc.) with or without loss of consciousness? Loss of consciousness followed by rhythmic contraction of muscles? Tongue biting? Urinary or fecal incontinence? Headache, confusion, drowsiness, or amnesia immediately after the event? Sensory disturbances (numbness, dizziness, auditory or visual hallucinations, sensations of fear or anger, etc.)? Psychotic changes (psychosis, hallucinations, sensations of fear or anger, etc.) 28

29. Rule out other causes e.g. meningitis, encephalitis, alcohol withdrawal, hypoglycemia, hyper- or hyponatremia, hyper- or hypocalcaemia, cerebrovascular accident, or space-occupying lesion. Consider neurology consultation Initiate anti-convulsant therapy (e.g. phenytoin 3-5 mg/kg/d) Increase pyridoxine to 300mg daily Lower dose or discontinue suspected agent, if this can be done without compromising regimen Management of Seizures, cont. 29

30. General considerations: Anti-convulsant is generally continued until MDR-TB treatment completed or suspected agent discontinued. History of prior seizure disorder is not a contraindication to the use of agents listed here if patient’s seizures are well controlled and/or patient is receiving anti-convulsant therapy. Patients with history of prior seizures may be at increased risk for development of seizures during MDR-TB therapy. Seizures not a permanent squeal of MDRTB treatment Management of Seizures, cont. 30

31. Management of Peripheral neuropathy Symptoms: Burning sensation, Numbness of both feet, worse at night or when walking Leg weakness when walking Leg pain Rule out other causes, including: diabetes, alcoholism, vitamin deficiencies, HIV, hypothyroidism, uremia etc. 31

32. Treatment Initiate low-dose tricyclic antidepressant (e.g., amitriptyline 25-75 mg at bed time) Confirm patient is on proper dose of pyrodoxine. If no improvement Decrease dose of responsible medication (e.g., Ethio. to 750 mg, CS to 750 mg, aminoglycoside to 750 mg, or use CM instead etc.), then resume normal dose once pain is controlled Consider acetaminophen and/or NSAIDs for pain relief Management of Peripheral neuropathy, cont. 32

33. Ototoxicity–Hearing loss is confirmed by audiometry. Patients with previous exposure to aminoglycosides may have baseline hearing loss. Hearing loss generally is not reversible. The aim is to Keep patient quality of life to be able to hear people voice Change parenteral to CM if patient susceptibility has documented. Lower dose of suspected agent, (consider administration three times a week). Discontinues suspected agent if this does not compromise the regimen. Patients with renal failure has increased risk 33 Management of VIII cranial nerve toxicity

34. Management of depression Symptoms of major depressive disorder can include:  changes in sleep pattern,  loss of interest in usual activities,  feelings of guilt,  diminished energy,  decreased concentration,  lack of appetite,  psychomotor retardation (slowed movement and thought),  suicidal ideation. 34

35. 35 Management of depression, cont. EVALUATION More than two weeks of persistent sadness, loss of interest, loss of appetite, weight change, insomnia, fatigue, lack of concentration, feelings of worthlessness or guilt. Suicidal or homicidal ideation? EMERGENCY Consider hospitalization Monitor closely to ensure safety Rule out psychosis Delusions, hallucinations, incoherent thoughts or speech, inappropriate or catatonic behavior Rule out hypothyroidism. TREATMENT Consider psychiatric consultation Initiate antidepressant therapy Provide intensive psychological therapy with counseling to patient and family Provide emotional support from the family and treatment supporter aimed at resolution of causes of stress Organize group therapy or informal support groups

36. Management of Psychosis 36 Disintegration of personality or loss of contact with reality EVALUATION Patient sees or hears things that others do not perceive? Unintelligible thoughts or speech? Bizarre behavior? Suicidal or homicidal ideation? EMERGENCY Consider hospitalization Monitor closely to ensure safety TREATMENT discontinue Cycloserine or replace suspected agent with equally efficacious anti-tuberculosis drug Consider psychiatric consultation & initiate anti- psychotic medications Evaluate psychosocial stressors Confirm patient is on proper dose of pyrodoxine. Anti-psychotic medication can be continued to the end of treatment if recurrence occur. Cycloserine can be re-initiated in a lower dose after remission.

37. IV. Management of fluid and electrolyte disturbances 37

38. Management of Hypokalemia 38 Potassium level <3.5 meq/L). Causes: Some of the anti-tuberculosis medications–-in particular the aminoglycosides and Capreomycin—cause renal wasting of potassium and magnesium. Severe vomiting or diarrhea TREATMENT Replete potassium orally or IV Treat associated conditions such as vomiting or diarrhea. Monitor potassium closely to determine when repletion may be discontinued Empiric magnesium repletion or check Mg level and replete as needed Discontinue any arrhythmogenic medications (e.g., digoxin, amytriptyline,) Consider checking calcium and replete as needed. If severe consider stopping the injectable drug.

39. 39 Management of Hypokalemia, cont. Recommended repletion protocol

40. V. Endocrine adverse reactions 40

41. Common mild adverse reactions Poor glycemic control in diabetics Changes in menstrual cycle Gynecomastia Impotence Moderate to severe adverse reactions Hypothyroidism 41 V. Endocrine adverse reactions

42. Management of Hypothyroidism 42 EVALUATION Fatigue, enlarged thyroid, lack of energy, weakness, depression, constipation, cold intolerance, lack of concentration, loss of appetite, weight gain, dry skin, coarse hair, hair loss. Rule out depression and check TSH, Free T4 & T3 TSH >10 mIU/L TREATMENT Administer levo-thyroxine - Adult patients under 60 years without evidence of heart disease may be started on 50-100 mcg daily - Therapeutic dosage often between 100-200 mcg daily - Repeat TSH every month and adjust the dose of thyroxine; adjustment is made in 12.5-25 mcg increments till adjusted then TSH every 3-4 months. - Continue thyroxine and TSH estimation 2-3 months after treatment completion.

43. Thank You 43