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

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.

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

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

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

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

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.

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

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. 10-15 mg) of pyridoxine is recommended. Pregnancy,alcoholism, advanced age, seizures, uremia and diabetes are risk factors and indicate for preventive therapy. Hasta semptomatik olduğunda

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

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.

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

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.

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

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.

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

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.

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

Second line drugs Amikacin,kanamycin 15 mg/kg Capreomycin Ofloxacin Levofloxacin 500-750 mg Moxifloxacin 400 mg Ethionamide/Prothionamide Cycloserine/Terizidon

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

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)

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

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

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.

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 (100-200 mg/daily) . exercise

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.

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

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

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)

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

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.

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.

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.

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

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.

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)

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

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

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

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

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

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

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.

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