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g
ofreactionsto tuberculosis drugs
g
..
?
?
TB
cat. 1 5
?
?
Underlying HIV
Start GPO-vir 2 wks
OI
Bactrim 1 wk
pul TB
HRZE
1
?
?
anti-TB HRZE
1
?
?
anti-TB HRZE
1
?
?
50
.45
45 kg
SGOT/SGPT 229/ 195 U/L, TB/DB 3.2/1.7 mg/dl, ALP
220 U/L
ADR anti-TB
TB
TB underlying
d l
d
dz
ADR
TB
ADR
ADR
ADR anti-TB
anti-TB
anti-TB
i TB
ADR
----- > ADR & TB
(single agent)
(fixed dose combination: FDC)
monotherapy
ADR
Isoniazid
I or H
Tab 100 mg
Rifampicin
Pyrazinamide
Tab 500 mg
Ethambutol
Streptomycin
Inj 1 gm
: 750 mg/day
1st line drug
Kanamycin
Inj 1 gm
15 mg/kg/day
IM 1
Ofloxacin
Tab 100,
100 200,
200 300
mg
7.5
7
5-15
15 mg/kg/day
1-2
Ethionamide
Ethi
Tab 250 mg
10-20 mg/kg/day
2-3
2 3
Cycloserine
Cs
Tab 250mg
10-20 mg/kg/day
2-3
Para-Amino Salicylic P
acid
Tab 1 gm
200 mg/kg/day
2
Amikacin
Inj 250,
250 500 mg
15 mg/kg/day
IM 1
Trade name
Generic name
Rifinah150
Rifinah300
Rifam150/INH100
Rifam300/INH150
3-4 tabs
2 tabs
Rimactazid300/150
Rimactazid150/75
Rifam300/INH150
Rifam150/INH75
2 tabs
4 tabs
Rifampyzid
Rifater
Rifam120/INH80/PZA250mg
Rifam120/INH80/PZA250mg
Rifafour ee-275
275
Rifam150/INH75/PZA400/ ETB275 mg
4 tabs
Rimstar4-FDC
Rifam150/INH75/PZA400/ ETB275 mg
4 tabs
4 tabs
tabs+(ETB
(ETB 2)
ADR
ADR
1
48
cat 1 (2HRZE/4 HR) dose
3
?
.
. rechallenge
.
. domperidone
ADR
5.5-20% cat.1
pyrazinamide (5.8%)
rifampicin
ethionamide
para-aminosalicylic acid (PAS)
fluoroquinolones
ADR
split dose
domperidone
ADR ADR
ADR
1
48
cat 1 (2HRZE/4 HR) dose
3
?
.
. rechallenge
.
. domperidone
ADR
2
45
cat 1 (2HRZE/4
HR) 5
ADR
2
ADR
13.8-40%
mucous membrane involved
1.3%
mucous membrane
b
involved
i
l d
ADR
exclude
anti
antihistamine CPM, hydroxyzine
anti-histamine 3
prednisolone 5 mg BID 5
continue anti-TB drug
ADR
oral antihistamine
topical corticosteroids
rechallenge
SJS, TEN, exfoliative dermasitis
systemic corticosteroids
ADR
rechallenge
2-3
2 3
rifampicin
INH,
3
4
ADR
Reintroduction of anti-TB
anti TB drugs following drug rash
Drug
Challenge dose
Day 1
Day 2
Day 3
INH
50
300
300
RMP
75
300
Full dose
PZA
2 0
250
1 gm
Fullll dose
d
EMB
100
500
Full dose
SM
125
500
Full dose
ADR
Desensitization of anti
anti-TB
TB drugs following drug rash
1 10
1 10
10
desensitization
desensitization anti-TB drugs
desensitization
INH --- > EMB --- > RMP
ADR
2
ADR
3
ADR
3
: mild jaundice
U/S: mild hepatosplenomegaly
:
Lab (normal)
Admission
Day 6
Day 12
142
119
88
ALT (9-43
(9 43 U/L)
60
72
80
465
339
304
TB (0
(0.2
2-1
1.5
5 mg/dl)
22
2.2
45
4.5
62
6.2
DB (0.5-0.8 mg/dl)
1.3
2.47
3.45
immunology: Anti
Anti-HAV
HAV IgM,
IgM HBsAg,
HBsAg
HBeAg, Anti-Hbc, anti-HCV -----> negative
ADR
3
hepatotoxic TB
Liver enzyme function test > 5 upper normal limit
upper normal limit
Liver enzyme function test > 3
hepatitis
: 2551
ADR
3
hepatotoxic ?
Liver enzyme function test > 3 upper normal limit
hepatitis
Lab (normal)
Admission
Day 6
Day 12
142
119
88
60
72
80
465
339
304
TB (0.2-1.5
(0 2
mg/dl)
/dl)
22
2.2
4.5
62
6.2
DB (0.5-0.8 mg/dl)
1.3
2.47
3.45
ADR
3
hepatotoxic ?
j
:
--- > mild jaundice
lab
--- > AST 142/30
= > 4.73 ,
ALT 60/43
=> 1.39 ,
ALP 465/110
= > 4.23
4 23 ,
TB 2.2/1.5
= > 1.47 ,
DB 1.3/0.8
= > 1.63
immunology: Anti-HAV
Anti HAV IgM,
IgM HBsAg,
HBsAg HBeAg,
HBeAg
Anti-Hbc, anti-HCV -----> negative
U/S
--- > mild hepatosplenomegaly
--- >
ADR
3
hepatic injury ?
ADR
3
hepatic injury ?
R ratio = (ALT/ULN)
(ALP/ULN)
= 1.39/4.23 = 0.33
ADR
Fact about anti
anti-TB
TB drug
drug-induced
induced hepatotoxic
INH, Rifampicin PZA
eosinophil
--- >
INH
toxic metabolite
Rifam bilirubin reuptake
hepatocyte
INH+Rifam > INH alone
rifam enzyme inducer reactive
metabolite INH hepatoxic
PZA fulminant hepatic failure --- > doserelated
ADR
Risk Factors anti
anti-TB
TB drug
drug-induced
induced hepatotoxic
Advanced age
Alcoholism
Previous significant liver abnormalities
HBV HCV
HBV,
HCV, HIV infection
Malnourish
ADR
Fact about INH
INH-induced
induced hepatotoxic
onset ---- > 8-12
AST/ALT --- > 10-20%
N/V
~ 0.101
0.6%
INH
~ 0.023%
ADR
INH induced hepatotoxic
INH-induced
INH
acetylation
Acetyl-isoniazid
hydrolysis
Acetylhydrazine
acetylation
Diacetylhydrazine
Reactive metabolite
(hepatotoxic)
ADR
Risk factors for INH
INH-induced
induced hepatotoxic
Acetylator phenotype
Age > 35 years
Alcoholism
Concurrent rifampicin use
female
pre-existing liver disease
pregnancy (>2-4
(>2 4 )
)
hepatotoxic
ADR
Fact about Rifampicin-induced
Rifampicin induced hepatotoxic
onset ---- > 2
liver injury
cholestasis
INH
20% earlier onset
ADR
Fact about Pyrazinamide-induced
Pyrazinamide induced hepatotoxic
most severe case 1
dose-dependent
1% standard dose 10-20% 40-50
mg/kg/dose
~20%
~ 10%
liver injury hepatocellular hepatitis
ADR
3
?
.
. rechallenge
. INH
. rifampicin
monitor
LFT
ADR
Anti-TB
3-5
LFT
: 2551
ADR
Anti-TB
TB
streptomycin + ethambutol
q
quinolone
: 2551
ADR
rechallenge anti
anti-TB
TB
rechallenge
LFT < 2
g/
TB < 1.5 mg/dl
Challenge dose
1
INH
100
200
300
RFP
150
10 MKD
PZA
500
25 MKD
3
monitor LFT
normall
LFT normal
+ add ETB
2HRZE(S)/4HR
: 2551
ADR
1
1-2
2
rechallenge
Alternative regimen
2SHRE/6HR
6RZE
2HRE/7HR
2HZE/10HE
9RE
2SH(R)E/10H(R)E
2SOE/16OE
: 2551
ADR
Management of symptomatic anti
anti-TB
TB drugs-induced
drugs induced hepatitis
PZA, INH
TB/DB RFP
hepatitis / AST/ALT <3
PZA
F/U clinical symptoms LFT
ADR
50
100
150
200
300
300
150
300
300
300
300
300
450
10
300
450
If success
No more PZA?
ADR
3
?
.
. rechallenge
. INH
. rifampicin
monitor
LFT
ADR
Anti-TB
baseline LFT
DI hepatotoxic
: 2551
ADR
Anti-TB
2
1-2
aminoglycoside,
aminoglycoside ethambutol,
ethambutol quinolone
: 2551
(Peripheral Neuropathy)
Optic Neuritis
INH
ETB
PZA
Streptomycin
INH & N
Neuropathy
h
HIV-positive
DM
renal failure
alcoholism
malnourished or chronic liver disease
elderly
children
pregnancy
INH & N
Neuropathy
h
INH vitamin B6 cofactor
synaptic neurotransmitters
dose related neurological side effects
dose-related
peripheral
neuropathy, ataxia paresthesia
pyridoxine 10 mg/day
25-50 mg/day
1 risk high-risk
features
pyridoxine
id i
Optic
p neuritis & Ethambutol
Optic neuritis & Ethambutol
ethambutol
2
reversible process
p
dose-independent
18%
> 35 mg/kg/day
5-6% 25 mg/kg/day
<1%
1%
15 mg/kg/day
/k /d
Ototoxicity&Nephrotoxicity Streptomycin
Damage 8th cranial nerve
auditory
---- > hearing loss
g , ataxia
vestibular
---- > vertigo,
irreversible
Nephrotoxicity
less
l
frequent
f
t th
than other
th aminoglycosides
i
l
id
~2%
reversible
-----------
>
>
>
>
>
SM
RMP
EMB
PZA
any drugs
ADR anti-TB
Major ADR
ADR
Minor ADR
ADR
ADR anti
anti-TB
TB
1.
2.
3.
4.
&ADR
&ADR
MDR-TB
guideline
5.
monitor educate
..