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The management of adverse The management of adverse effects in tuberculosis effects in tuberculosis

treatmenttreatmentDr. Özlen Tümer

Süreyyapaşa Chest Diseases and Thoracic Surgery Teaching and

Research Hospital

13th Annual Congress of Turkish Thoracic Society-

İstanbul 2010

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• 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.

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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

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Speech outline

Characteristics of drugs used in TB treatment

The side-effects of TB drugsManagement of minor adverse effectsManagement of major adverse effectsDrug interactions

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Characteristics of drugs used in TB treatment

The side-effects of TB drugsManagement of minor adverse effectsManagement of major adverse effectsDrug interactions

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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

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Daily dose

(mg/kg/day)

drugs adult child

Max.daily dose

(mg/day)

Isoniazid 5 5-10 300

Rifampicin 10 10-15 600

Pyrazinamide 25 20-40 2000

Morfozinamide 40-50 40-60 3000

Streptomycin 15 20-30 1000

Ethambutol 15-20 15-25 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.

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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

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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 rifampicinSide 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 drugsSecond line drugsAmikacin,kanamycin 15 mg/kg

Capreomycin 15 mg/kg

Ofloxacin 600-800 mg

Levofloxacin 500-750 mg

Moxifloxacin 400 mg

Ethionamide/Prothionamide 500-750 mg

Cycloserine/Terizidon 500-750 mg

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Second line drugs (2)Second line drugs (2)

PAS 8-12 gr

Clofazimine 100-300 mg

Amoxicillin+Clavulanate 2 gr

Clarithromycin 1000 mg

Rifapentin 600mg/2 x wk

Rifabutin 300 mg

Linezolid (Zyvox) 600mg

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Side effects of second line drugsSide effects of second line drugs

GI upset (PAS,ETH)Hearing loss (KM,AMK)Psychotic reaction-depression (CS)

Seizures (CS)

Hepatotoxicity (ETH,PAS)

Arthralgia (Quinolones)

Peripheral neuropathy (CS)

Hypothyroidism (PAS,ETH)

Discoloration of skin (Clofazimine)

Electrolyte abnormalities (CM,AMK,KM)

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Characteristics of drugs used in TB treatment

The side-effects of TB drugsManagement of minor adverse effectsManagement of major adverse effectsDrug interactions

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Minor Side EffectsMinor 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 neuropathyParasthesia, 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

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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

antihistaminesOrange/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 drugsManagement of minor adverse effectsManagement of major adverse effectsDrug interactions

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Major side effectsMajor 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 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.

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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+E (16 mo)

H+R+Z E+S+Mox(2 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 drugsManagement of minor adverse effectsManagement of major adverse effectsDrug interactions

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ISONIAZID

• Phenytoin

• Carbamazepine

• Warfarin

• Diazepam

• Theophylline

• Prednisolone

• Ketoconazole

İncreases serum concentration

Effects of H opposed

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INH

• PAS

• Insulin

• Carbamazepine

• Theophylline

• Acetominophen hepatotoxicity is increased by INH.

Effects of INH potentiated

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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

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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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