1. Management of Adverse Effects of Anti-TB drugs (part I)
Dr. Ashraf Abdulhaseeb
Chest Diseases Consultant
Chief of DR-TB center, Abbassia Chest Hospital

2. Presentation outline:
Monitoring adverse effects
Main adverse effects and suspected drugs.
General considerations of adverse effects management.
Commonly used ancillary drugs.

3. Monitoring of adverse effects:
Aims at:
Early detect and treat adverse effects
Prevent /minimize toxic effects or organ damage

4. Monitoring should consider the following factors:
Patient factors:
Age,
initial clinical condition,
HIV testing,
Socioeconomic condition
Providers:
trained and alert to early detect adverse effects
Specialists and consultants in referral centers are available.

5. Monitoring schedule I) Initial pretreatment screening and evaluation:
Initial evaluation serves to:
Establish a baseline clinical view of the patient
identify patients who are at increased risk for adverse effects or poor outcomes.

6. Initial pretreatment monitoring includes:
Thorough medical history and physical examination.
History of concomitant conditions which can contribute occurrence of drug intolerance
History of adverse drug reactions.
History of allergic reactions
Complete blood count
Liver functions:
Total serum Bilirubin
SGPT & SGOT
Total serum albumin, total serum protein and A/G ratio.

7. Serum Creatinine, blood urea, complete urine analysis with estimation of total urine protein content
Serum uric acid.
Fasting and PP blood sugar.
Pregnancy test.
Initial chest x-ray
Visual acuity, color vision
Audiometry
Direct smear examination
DST for first and second line anti-TB drugs.

8. II) Lab investigation schedule during treatment to monitor adverse effects
Weight
monthly to adjust doses.
Urea & Serum creatinine
monthly while receiving injectable drugs then quarterly. Risk group patients may need more frequent testing e.g. elder, patients with renal troubles.
Serum electrolytes
Monthly while receiving injectable drugs then quarterly, may be more frequent in risk group patients e.g. elder, vomiting & diarrhea
TSH
Every 6 months if receiving ethionamide / prothionamide or PAS and monitor monthly for signs and symptoms of hypothyroidism.
Liver enzymes
Periodic monitoring (every 1month) in patients receiving Pyrazinamide for extended periods or for patients at risk for or with symptoms of hepatitis.
Audiometry
Monthly while receiving the injectable drug
Visual acuity & color discrimination
Monthly
CBC

9. II) Lab investigation schedule during treatment to monitor adverse effects, cont.
Hemoglobin and WBC
If on linezolid, monitor weekly at first, then monthly
Lipase
Indicated for work up of abdominal pain to rule out pancreatitis in patients on linezolid
Lactic acidosis
Indicated for work up of lactic acidosis in patients on linezolid or ART
Serum glucose
If receiving gatifloxacin, monitor glucose frequently (weekly) and educate patient on signs and symptoms of hypoglycaemia and hyperglcycaemia

10. Monitoring of adverse effects should also include:
In high risk patients (over 50 years, renal insufficiency, DM, HIV, underweight), creatinine should be evaluated every week or every other week for at least the first month of treatment.
Creatinine clearance may be needed for high risk group patients.
If Serum potassium is low, check the Magnesium and Calcium levels.

11. Special attention should be paid for:
Liver toxicity.
Vestibular and hearing toxicity with injectable drugs.
Psychiatric disorders with Cycloserine.
Allergic reactions.
Hematological changes.

12. Recording the adverse effects in patient file:
Patient name__________________________________ Patient ID____________________
TB registrations number ___________________________________________________
Description of the
adverse reaction
Date
Severity*
Change
Of treatment
if made
treatment
change
Other actions
Outcome **
Severity code:
*1=asymptomatic 2=does not affect daily activities 3=limits daily activities 4=life threatening hospitalization
 Outcome code:
**1= complete resolution 2= partial resolution 3 = no change 4 = worse
 comments:_______________________________________________________________

13. Adverse effects in cohort 127 patients, Egypt 2009

15. Common adverse effects and suspected drugs
Seizures
Cycloserine & less frequently Isoniazid, Fluoroquinolone
Peripheral neuritis
Cycloserine, Isoniazid & less frequently, Streptomycin, Amikacin, Kanamycin, Capromycin, Viomycin, Fluoroquinlones, Prothionamide/Ethionamide, Linedazole
Hearing loss and vestibular disturbance
All Aminoglycosides, Capreomycin & less frequently clarithromycin
Psychotic symptoms
Cycloserine, Fluoroquinolones, Isoniazid, Prothionamide/Ethionamide
Depression
Maybe due the disease condition of the patient or drugs Cycloserine & less frequently Fluoroquinolones, Isoniazid, Prothionamide/Ethionamide
Hypothyrodism
Prothionamide/Ethionamide, PAS
Nausea and vomiting
PAS, Prothionamide/Ethionamide, Pyrazinamid & less frequently Ethambutol, Isoniazid,

16. Common adverse effects and suspected drugs, cont.
Gastritis
PAS, Prothionamide/Ethionamide, Pyrazinamid
Hepatitis
Pyrazinamid, Isoniazid, Rifampicin & less frequently Fluoroquinolones, Prothionamide/Ethionamide
Renal toxicity
All Aminoglycosides, Capreomycin
Electrolyte disturbance
Capreomycin and Viomycin & less frequently Streptomycin, Kanamycin and Amikacin
Optic neuritis
Mainly Ethambutol & less frequently Prothionamid/Ethionamid
Arthralgia
Mainly Pyrazinamid & less frequently Fluoroquinolones

17. Classification of Adverse Effects
Allergic and dermatological:
Mild
Moderate to severe
Skin pigmentations
Photo-sensitivity
Dry skin
Hypersensitivity
Fever
Rash
Purpura
Allergic dermatitis
Exfoliative dermatitis
Anaphylaxis /Angiodema

18. Classification of Adverse Effects
Gastrointestinal:
Mild
Moderate to severe
Nausea/Vomiting
Anorexia
Metallic taste/salivation
Stomatitis /Glossitis
Diarrhea
Bloating
Abdominal cramps
Gastritis
Gastric ulcer
Hepatitis

19. Classification of Adverse Effects
Neurological and Psychiatric:
Mild
Moderate to severe
Dizziness
Headache
Fatigue
Somnolence
Insomnia
Irritability
Anxiety
Seizure
Peripheral neuropathy
VIII nerve damage: hearing loss, vestibular impairment
Psychosis
Suicidal tendency
Depression
Confusion
Behavior changes

20. Classification of Adverse Effects
Fluid and electrolyte disturbance &others:
Mild
Moderate to severe
Myalgia
Cramps
Arthralgia
Candidiasis, stomatitis
Electrolyte disturbances
Dehydration
Renal failure
Optic neuritis
Anemia

21. Classification of Adverse Effects
Endocrine adverse effects:
Mild
Moderate to severe
Changes in menstrual cycle
Gynecomastia
Impotence
Uncontrolled diabetes
Hypothyroidism

22. Management of adverse effects
General considerations:
majority of adverse effects are easy to recognize.
have a systematic method of patient interviewing to early detect.
Proper management of adverse effects begins with patient education. Inform the patient to report adverse effects.
Monthly evaluation by a physician during ambulatory treatment

23. General considerations, cont.
DOT workers should be trained to screen patients for adverse effects.
Scheduled laboratory screening to detect occult adverse effects e.g. nephrotoxicity.
Electrolyte disturbance is generally a late effect occurring after months of starting treatment.
Complete discontinuation of therapy because of adverse effects is rare.

24. General considerations, cont.
Mild adverse effect is or not dangerous, continue the treatment regimen, with the help of ancillary drugs if needed.
Some adverse effects may disappear or diminish with time, and patients may be able to continue receiving the drug if sufficiently motivated.
adverse effects of a number of second-line drugs are highly dose dependent, reducing the dosage of the offending drug is another method of managing adverse effects

25. General considerations, cont.
Pyridoxine (vitamin B6) should be given to all patients receiving cycloserine or terizidone to help prevent neurological adverse effects. Recommended dose is dose is 50 mg for every 250 mg of cycloserine
Psychosocial support is an important component of the management of adverse effects.

26. General considerations, cont.
Psychosocial support is an important component of the management of adverse effects. A stock of these drugs should be always available.
Timely and intensive monitoring for, and management of, adverse effects caused by second-line drugs are essential components of DR-TB control program.

27. Commonly used ancillary medications
Nausea, vomiting, upset stomach
Metoclopramide, prochlorperazine, promethazine
Heartburn, acid indigestion, sour stomach, ulcer
H2-blockers (ranitidine, famotidine, etc.), proton pump inhibitors (omeprazole etc.) Avoid antacids because they can decrease absorption of Flouroquinolones
Oral candidiasis (non-AIDS patient)
Fluconazole, clotrimazole lozenges ..etc
Diarrhoea
Loperamide or other anti-diarrheal
Depression
Selective serotonin reuptake inhibitors (fluoxetine, sertraline), tricyclic antidepressants (amitriptyline)

28. Commonly used ancillary medications
Prophylaxis of neurological complications of cycloserine
Pyridoxine (vitamin B6)
Peripheral neuropathy
Amitriptyline
vestibular symptoms
Meclizine, dimenhydrinate, prochlorperazine, promethazine
Musculoskeletal pain, arthralgia, headaches
Ibuprofen, paracetamol
Cutaneous reactions, itching
Hydrocortisone cream, calamine, caladryl lotions
Systemic hypersensitivity reactions
Antihistamines (diphenhydramine, chlorpheniramine, dimenhydrinate), corticosteroids (prednisone, dexamethasone)

29. Commonly used ancillary medications
Bronchospasm
Inhaled beta-agonists (albuterol, etc.), inhaled corticosteroids (beclomethasone, etc.), oral steroids (prednisone), injectable steroids (dexamethasone, methylprednisolone)
Hypothyroidism
Levothyroxine
Electrolyte wasting
Potassium and magnesium replacement

30. Commonly used ancillary medications
Severe anxiety
Lorazepam, diazepam, clonazepam
Insomnia
Dimenhydrinate
Psychosis
Haloperidol, thorazine, risperidone (consider benzotropine or biperiden to prevent extrapyramidal effects)
Seizures
Phenytoin, carbamazepine, phenobarbital

31. Thank you