1. The management of adverse effects in tuberculosis treatment
Dr. Özlen Tümer
Süreyyapaşa Chest Diseases and Thoracic Surgery Teaching and Research Hospital
13th Annual Congress of Turkish Thoracic Society-İstanbul 2010

2. Tuberculosis drugs are administered in combination, therefore it is difficult to determine which drug is toxic.
In addition there can be adverse effects due to the combination therapy.
Management of adverse effects :If drugs are not administered properly resistance to drugs can occur.If drugs are not stopped in time the consequences can be life threatening.

3. Risk factors for side effects
Advanced age
Malnutrition
Pregnancy,nursing
Alcolism
Liver failure
Chronic renal failure
HIV infection
Disseminated TB
Atopy
Anemia
D. Mellitus
İnterrupted TB therapy
Familiy history
Additional drug use

4. Speech outline Characteristics of drugs used in TB treatment
The side-effects of TB drugs
Management of minor adverse effects
Management of major adverse effects
Drug interactions

5. Characteristics of drugs used in TB treatment
The side-effects of TB drugs
Management of minor adverse effects
Management of major adverse effects
Drug interactions

6. Isoniazid, Rifampicin, Pirazinamid, Ethambutol Second line drugs
groups
drugs
1. First line drugs
Isoniazid, Rifampicin, Pirazinamid, Ethambutol
Second line drugs
2.Injectable drugs
Streptomycine, Amikacin, Kanamycin, Capreomycin
3.Fluoroquinolone
Ofloxacin, Levofloxacin, Moxifloxacin
4.Other second line drugs
Prothionamide/Ethionamide, PAS, Cycloserine,Terizidon
5.Drugs with unclear role in Tx
Linezolid, Clofazimin, Clavulanat, Thioasetazon, imipenem/cilastatin, high dose INH, Clarithromycine

8. Isoniazid (H)
H was synthesized in 1912, and was rediscovered for TB treatment since 1952.
It is taken orally, is cheap and good tolerable.
It inhibits the mycolic acid synthesis of the cell wall.
After taken on empty stomach high serum concentrations are achieved in 1-2 hours. It penetrates into cerebrospinal fluid.

9. Isoniazid H is used for preventive therapy.
The elimination of H is determined by the acetylator status of the patient. Genetically there are slow and rapid inactivators.
H is metabolized in liver and excreted in urine

10. Side effects of Isoniazid
Hepatotoxicity: Risk is highest in the first 2 months of treatment. It is very rare under age 20. Daily alcohol consumption increases the risk of hepatotoxicity.If AST level is 5 times more than the upper limit of normal drugs are stopped.
Peripheral neuropathy: Daily dosage up to 300 mg does not cause neuropaty . Preventive treatment with small dosages ( max mg) of pyridoxine is recommended.
Pregnancy,alcoholism, advanced age, seizures, uremia and diabetes are risk factors and indicate for preventive therapy.
Hasta semptomatik olduğunda

11. Side effects of Isoniazid
Seizures, hallucinosis, psychosis, optic neuropathy,
Hypersensitivity reactions: Drug fever, asthma, dermatitis, Stevens Johnson syndrome, hematologic disorders (hemolytic anemia,agranulocytosis etc.), vasculitis
Lupus like syndrome, alopecia,monoamine poisoning

12. Rifampicin(R)
R is a semisynthetic, bactericidal drug used since 1966 clinically. R inhibits the synthesis of mRNA by binding to the RNA polymerase.
After oral intake on empty stomach its absorption is rapid and excellent. R penetrates all body fluids well.
R is metabolized in liver , excreted in bile and urine.
Its metabolites color urine, tears, sweat (red).)Patients using contact lenses should be told.

13. Side effects of rifampicin
Mild elevation of serum bilirubin and liver enzymes in the first week of treatment
Hepatotoxicity
Flu-like syndrome: Symptoms like malaise, arthralgia, fever. It occurs when higher doses are implemented.
Pruritus and drug fever
Hypersensitivity reactions: Acute renal failure, thrombocytopenic purpura, hemolytic anemia, anaphylactic shock,
Toxic epidermal necrosis, pseudomembranous colitis, amenorrhea, myopathy

15. Pyrazinamide (Z) Analog of nicotinamide.
The active derivate of Z is pyrazinoic acid.It is bactericidal against intracellularly growing bacteria.
It is an important drug for the initial phase of treatment because of its sterilizing effect.
It has a good penetration into all body fluids. It is inactivated in liver and excreted in urine.

16. Side effects of Pyrazinamide
Hepatotoxicity
Hyperuricemia: As pyrazinoic acid inhibits uric acid excretion, serum uric acid level is elevated in 40% of patients.
Gout like Arthralgia: Accumulation of uric acid causes polyarthralgia.
Others: Skin rash,vomiting, anemia, lupus, seizures,photodermatitis

17. Ethambutol (E) E was discovered in 1961
It has a bacteriostatic effect.
It is taken orally, its absorption is rapid and not effected by food.
It has poor penetration into the CSF.
It is eliminated by kidney. If there is renal failure its serum concentrations must be followed up.

18. Side effects of Ethambutol
Ocular toxicity
Aplastic anemia
Rash,
Lupus erythematosus,
Thrombocytopenia
Hyperuricemia

19. Streptomycin (S)
Discovered by SA Waksman it is an aminoglycoside used since 1946.
Its administration is intramuscular,occasionally intravenous.
Dosage is reduced in elderly.
S has a limited ability to penetrate membranes and cell walls, but it still penetrates into CSF in case of meningitis.
It inhibates the protein synthesis of bacilli.

20. Side effects of Streptomycin
Ototoxicity: Vertigo,ataxia, hearing loss
Ototoxic to fetus
Nephrotoxicity
Electrolyte abnormalities
Fever and rash
Hypersensitivity reactions, anaphylaxia

21. Second line drugs Amikacin,kanamycin 15 mg/kg Capreomycin Ofloxacin
Levofloxacin mg
Moxifloxacin
400 mg
Ethionamide/Prothionamide
Cycloserine/Terizidon

22. Second line drugs (2) PAS 8-12 gr Clofazimine 100-300 mg 2 gr
Amoxicillin+Clavulanate
2 gr
Clarithromycin
1000 mg
Rifapentin
600mg/2 x wk
Rifabutin
300 mg
Linezolid (Zyvox)
600mg

23. Side effects of second line drugs
GI upset
(PAS,ETH)
Hearing loss
(KM,AMK)
Psychotic reaction-depression
(CS)
Seizures
Hepatotoxicity
(ETH,PAS)
Arthralgia
(Quinolones)
Peripheral neuropathy
Hypothyroidism
Discoloration of skin
(Clofazimine)
Electrolyte abnormalities
(CM,AMK,KM)

24. Characteristics of drugs used in TB treatment
The side-effects of TB drugs
Management of minor adverse effects
Management of major adverse effects
Drug interactions

25. Minor Side Effects Loss of appetite, vomiting, abdominal pain
Arthralgia
Burning of the feet
Fever
Discoloration of urine, tears etc.
Itching

26. Nausea, vomiting, gastrointestinal distress
Administration time can be changed, dosages can be divided, some agents can be given with food.
Antacids (2 hours before or after the drug intake)
Anti-emetics
H2blockers-proton pump inhibitors
Responsible agent is stopped.
Responsible agent can be withdrawn.

27. Peripheral neuropathy
Arthralgia
PZA
Quinolones NSAI drugs,exercise
Peripheral neuropathy
Parasthesia, burning sensation on the extremities are typical.
INH
Aminoglycosides
Cycloserine
Quinolones
Drug can be stopped. Peripheral neuropathy is treated with Pyridoxine ( mg/daily) .
exercise

28. Fever
Fever is drug related if it resolves within 24 hours after stopping all drugs. Agents should be started one by one.
Itching
Symptomatic treatment with antihistamines
Orange/red urine
Patients should be told that this is normal.

29. Characteristics of drugs used in TB treatment
The side-effects of TB drugs
Management of minor adverse effects
Management of major adverse effects
Drug interactions

30. Major side effects Hepatotoxicity Cutaneous reactions
Hearing loss,dizziness
Optic neurotoxicity
Acute renal failure
Thrombocytopenic purpura
Hemolytic anemia
Hypersensitivity reactions-Anaphylaxia
Psychotic reactions
Lupus like syndrome-pleural effusion

31. Hepatotoxicity(Drug induced hepatitis)
INH,RIF, PZA
Ethionamid,Quinolones,PAS
Patient should be hospitalized. Drugs are discontinued, if liver enzymes(ALT,AST) are 5 fold higher or the patient has symptoms. Drugs are restarted when ALT,AST return to normal.
If hepatitis re-occur the drugs are reintroduced gradually one by one. (HRZ) or (RHZ)

32. Cutaneous reactions
Itching and minor rash are frequent. Antihistamine can be used
In case of generalized erythematous rash all drugs should be stopped.when rash is improved drugs can be started one bt one, at intervals of 2-3 days. (RIF should be started first).If no rash appears after the fist 3 drugs the fourth drug shoud not be started.
Hypersensitivity reactions are rare: S, PAS, TH
Exfoliative dermatitis
Stevens-Johnson Syndrome:
Toxic dermal necrosis of skin and mucosal membranes

36. Hearing loss Aminoglycosides Capreomycin is less toxic
It is recommended to obtain audiometry at the initiation of therapy.
Dosage can be reduced or drug can be stopped.

37. Retrobulbar neuritis
usually with high dosages.Reduced visual acuity, central scotoma, loss of ability to see green and red.
E is stopped and withdrawn from treatment. Usually reversible.

38. Hipersensitivity reactions
Hemolytic anemia,
Thrombocytopenic purpura,
Shock,
Acute renal failure
All drugs should be stopped.Rifampin is usually responsible.Treatment is restarted without R when the signes diminish.

39. Psychotic symptoms INH cycloserine quinolones
Initiate antipsychotic drugs
Piridoxin 300 mg
Patient is under observation
Dosage reduced or drug stopped

40. pleural effusion–paradoxical response
Formation of pleural effusion during a successful treatment is called a paradoxical response.
Elevated level of ANA and decreased level of total complement in pleural fluid analysis reveal lupus like syndrome.This could be with or without systemic SLE. Isoniazid might be discontinued.

41. Initial phase continuation phase
Drug withdrawn
Recommended regimen
Initial phase continuation phase H
R+Z+E (2 mo)
R+E (7 mo) Z
H+R+E (2 mo)
H+R (7 mo) E
H+R+Z (2 mo)
H+R (4 mo) R
H+Z+E (2 mo)
H+E (16 mo)
R+Z
H+E+S (2 mo)
H+R+Z
E+S+Mox(2 mo)
E+ Mox (22 mo)

42. Monitoring of side effects
Asking for visual complaints
Asking for hearing complaints
Asking for drug-food allergies
Asking for additional diseases
Liver enzymes
Hemogram

43. Characteristics of drugs used in TB treatment
The side-effects of TB drugs
Management of minor adverse effects
Management of major adverse effects
Drug interactions

44. ISONIAZID Phenytoin Carbamazepine Warfarin Diazepam Theophylline
Prednisolone
Ketoconazole
İncreases serum concentration
Effects of H opposed

45. INH PAS Insulin Carbamazepine Theophylline
Acetominophen hepatotoxicity is increased by INH.
Effects of INH potentiated

46. RIFAMPICIN induces several enzymes in the cytochrome P-450 system
Oral anti-coagulants
Oral contraceptives
Oral antidiabetics
Corticosteroids
Digoxin
Verapamil
Insulin
Antifungals,chloramphenicol
Theophylline
Protease inhibitors
Other anti-viral agents
Reduces serum concentrations

47. RIF Cotrimoxazole potentiates the effect of RIF .
Ketoconazole reduces resorption of RIF and can cause treatment failure.

48. Pyrazinamide
Allopurinol increases plasma level of pyrazinoic acid.Therefore it is not used for Z-induced arthralgias.
Ethambutol
Aluminium-Magnesium antacid reduces E resorption.
Streptomycin
Ototoxicity is increased by diuretics such as furosemide.

49. ..
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