The management of adverse effects in tuberculosis treatment

Sreyyapaa Chest Diseases and Thoracic Surgery Teaching and Research Hospital

Dr. zlen Tmer

13th Annual Congress of Turkish Thoracic Society-stanbul 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 nterrupted TB therapy Familiy history Additional drug use
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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

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

drugs
Isoniazid Rifampicin Pyrazinamide Morfozinamide Streptomycin Ethambutol

(mg/kg/day) adult child

Max.daily dose (mg/day)

5 10 25 40-50 15 15-20

5-10 10-15 20-40 40-60 20-30 15-25

300 600 2000 3000 1000 1500

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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.
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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
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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.

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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
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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.

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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

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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.
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Side effects of Ethambutol

Ocular toxicity Aplastic anemia Rash, Lupus erythematosus, Thrombocytopenia Hyperuricemia

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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.
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Side effects of Streptomycin

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

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Second line drugs

Amikacin,kanamycin Capreomycin
Ofloxacin Levofloxacin Moxifloxacin
Ethionamide/Prothionamide

15 mg/kg 15 mg/kg
600-800 mg 500-750 mg 400 mg

500-750 mg 500-750 mg

Cycloserine/Terizidon

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Second line drugs (2)

PAS Clofazimine
Amoxicillin+Clavulanate

8-12 gr 100-300 mg
2 gr 1000 mg 600mg/2 x wk

Clarithromycin Rifapentin

Rifabutin
Linezolid (Zyvox)

300 mg
600mg
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Side effects of second line drugs

GI upset

Hearing loss
Psychotic reaction-depression

(PAS,ETH) (KM,AMK)
(CS) (CS)

Seizures

Hepatotoxicity
Arthralgia Peripheral neuropathy Hypothyroidism Discoloration of skin Electrolyte abnormalities

(ETH,PAS)
(Quinolones) (CS) (PAS,ETH) (Clofazimine) (CM,AMK,KM)
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 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

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Minor Side Effects

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

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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.
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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 (100200 mg/daily) . exercise

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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.
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 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

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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
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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. (HRZ) or (RHZ)

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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
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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.

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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.

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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.
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Psychotic symptoms
INH cycloserine quinolones Initiate antipsychotic drugs Piridoxin 300 mg Patient is under observation Dosage reduced or drug stopped
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pleural effusionparadoxical 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.
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Drug withdrawn H Z E

Recommended regimen Initial phase continuation phase R+Z+E (2 mo) R+E (7 mo) H+R+E (2 mo) H+R+Z (2 mo) H+R (7 mo) H+R (4 mo)

R
R+Z H+R+Z

H+Z+E (2 mo)
H+E+S (2 mo) E+S+Mox(2 mo)

H+E (16 mo)

H+E (16 mo) E+ Mox (22 mo)
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Monitoring of side effects

Asking for visual complaints Asking for hearing complaints Asking for drug-food allergies Asking for additional diseases Liver enzymes Hemogram
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 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

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ISONIAZID
Phenytoin Carbamazepine Warfarin Diazepam Theophylline

ncreases serum concentration

Prednisolone Ketoconazole

Effects of H opposed
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INH
PAS Insulin Carbamazepine Theophylline

Effects of INH potentiated

Acetominophen hepatotoxicity is increased by INH.

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RIFAMPICIN induces several enzymes

in the cytochrome P-450 system
Oral anti-coagulants Oral contraceptives Oral antidiabetics Corticosteroids Digoxin Verapamil Reduces serum Insulin concentrations Antifungals,chloramphenicol Theophylline Protease inhibitors Other anti-viral agents
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RIF
Cotrimoxazole potentiates the effect of RIF . Ketoconazole reduces resorption of RIF and can cause treatment failure.

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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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.. Thanks
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