Download Adverse effects in tuberculosis treatment

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
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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
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Advanced age
Malnutrition
Pregnancy,nursing
Alcolism
Liver failure
Chronic renal failure
HIV infection
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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 drugs
Management of minor adverse effects
Management of major adverse effects
Drug interactions
4
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
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
(mg/kg/day)
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
15
20-30
1000
15-20
15-25
1500
Streptomycin
Ethambutol
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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 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
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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
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)
PAS
Clofazimine
Amoxicillin+Clavulanate
Clarithromycin
8-12 gr
100-300 mg
2 gr
1000 mg
Rifapentin
600mg/2 x wk
Rifabutin
300 mg
Linezolid (Zyvox)
600mg
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Side effects of second line drugs
GI upset
Hearing loss
(PAS,ETH)
(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 drugs
Management of minor adverse effects
Management of major adverse effects
Drug interactions
24
Minor Side Effects
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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.
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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
29
Major side effects
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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. (HRZ) or (RHZ)
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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
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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
H
Recommended regimen
Initial phase continuation phase
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)
E+S+Mox(2
mo)
E+ Mox (22 mo)
H+R+Z
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Monitoring of side effects
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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
43
ISONIAZID
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Phenytoin
Carbamazepine
Warfarin
Diazepam
Theophylline
• Prednisolone
• Ketoconazole
İncreases serum concentration
Effects of H opposed
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INH
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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
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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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