Anti Tuberculosis

Laboratorium Farmakologi dan Terapeutik

Jurusan Kedokteran FKIK UNSOED

Classification of Drugs
3 Groups depending upon the degree
of effectiveness and potential side
effects
First Line: (Primary agents)
are the most effective and have lowest
toxicity. Isoniazid, Rifampin

Second Line:
Less effective and more toxic effects
include (in no particular order): p-amino salicylic
acid, Streptomycin, Ethambutol

Third Line
are least effective and most toxic. Amikacin,
Kanamycin, Capreomycin, Viomycin, Kanamycin,
Cycloserine

Primary agents
Isoniazid

300 mg/d

Rifampin

600 mg/d

Pyrazinamide

25 mg/kg/d

Ethambutol

1525 mg/kg/d

Streptomycin

15 mg/kg/d

Secondary agents
Amikacin

15 mg/kg/d

Aminosalicylic acid

812 g/d

Capreomycin

15 mg/kg/d

Ciprofloxacin

1500 mg/d, divided

Clofazimine

200 mg/d

Cycloserine

5001000 mg/d, divided

Ethionamide

500750 mg/d

Levofloxacin

500 mg/d

Rifabutin

300 mg/d2

Rifapentine

600 mg once or twice weekly

Isoniazid
Considered the drug of choice for the
chemotherapy of TB.
is bacteriostatic for resting bacilli,
bactericidal for growing bacilli.

Mechanism of action
Kerja utama: menghambat
biosintesis asam-asam mikolat.
Kompleks, disertai pemetaan
resistensi thd mutasi pd 5gen yg
berbeda (katG, inhA, ahpC, kasA,
ndh)
Sebagian bukti menunjukkan inhA
sbg target utama obat

 Gen inhA mengkode enoil-ACP

reduktase pd as.lemak sintase II, yg
mengubah asam2 lemak tak jenuh
mjd as.lemak jenuh pd jalur utk
biosintesis as.mikolat
Pajanan isoniasid mengakibatkan
hilangnya sifat tahan asam &
penurunan jml lipid yg dapat
terekstrasi metanol

Resistance
Organism eventually develops resistance.
The mechanism of resistance is
related to the failure of the drug to
penetrate or be taken up by the
micro-organism (by active transport
system),

Mekanisme resistensi yg paling

umum:
Mutasi pd katalase-peroksidase yg
menurun aktivitasnya
Mencegah konversi isoniazid prodrug
mjd metabolit aktifnya
Missense mutation (mutasi yg
mengubah kodon shg mengkodekan
as.amino yg berbeda) di dlm gen
mhA mikobakteri yg terlibat dlm
biosintesis as.mikolat

Pharmacokineti
cs

Absorption: INH rapidly absorbed

either oral or parenteral route.
Antasid yg mengandung alumunium
mengganggu absorbsi
Distribution:
Diffuses readily into all bodily fluids
does not bind to plasma proteins
In the CSF the [conc] is about 20% of
[plasma],
t1/2 =1-3 hrs.

Excretion
75-95% of a dose excreted in the urine in 24 hr.
- Mostly as a metabolite.
- The main excretory product- acetylisoniazid.
This is a result of enzymatic acetylation
Very important in terms of metabolism,
Isoniazid is under genetic control, There are 2
groups of people. Fast and slow acetylators
Laju asetilasi sangat mempengaruhi
konsentrasi obat tsb dalam peredaran darah

Excretion cont.
Frekuensi msg2 fenotipe asetilasi
tergantung pd ras tetapi tdk dipengaruhi
oleh gender atau usia
Asetilasi cepat inuit & jepang
Asetilasi lambat skandinavia, yahudi,
kaukasia Afrika Utara
Aktifitas asetiltransferase yg tinggi
(asetilasi cepat) diturunkan sbg sifat
bawaan dominan autosomal.

Penggunaan terapeutik
Isoniazid merupakan obat plg
penting utk pengobatan semua jenis
Tuberculosis
Tersedia dlm sediaan oral dan
parenteral
Dosis lazim: 5mg/kg, maks 300mg
Piridoksin hrs diberikan bersama
isoniazid utk menekan serendah
mungkin reaksi2 yg merugikan (1550mg per hari)

Adverse Effects
Induced Hepatitis (2% of Population)
due to the buildup of toxic metabolic
products of acetylisoniazid -->
acetylhydrazine. This is more
frequent in slow acetylators.
Hepatic reactions to Isoniazid are
also age dependent
Reaksi plg menonjol: ruam, demam,
ikterus, neuritis perifer

 Jika tdk diberikan bersama piridoksin, reaksi

yg plg lazim adl neuritis perifer
Patients with renal failure, the normal dose
can be given, because it is secreted in the
inactive form.
Patients with hepatic insufficiency - give a
reduced dose of the drug.
Glucose 6- Phosphate deficiency. People with
a deficiency of Glucose-6-phosphate cannot
adequately process the drug.

Drug Interaction
Competition between Isoniazid and
Phenytoin (anticonvulsant). They
both compete for drug metabolism
enzymes. Phenytoin interferes with
metabolism of isoniazid by
reduction in excretion or
enhancement of effect of isoniazid

Rifampin
Golongan rifamisin (rifampin,
rifabutin, rifapentin) adl suatu
kelompok antibiotik makrosiklik
kompleks dg struktur yg serupa, yg
dihasilkan oleh Streptomyces
mediterranei
Rifampin adl turunan semisintetis
dari salah satu golongan rifamisin,
yaitu rifamisin B
Konsentrasi bakterisidalnya: 3-

Rifampin
Mechanism of Action
Rifampin menghambat RNA
polimerase yg tergantung-DNA pd
mikobakteri & mikroorganisme lain
dg cara membentuk suatu kompleks
obat-enzim yg stabil, mengakibatkan
supresi pd awal pembetukan rantai
pd saat sintesis RNA

Resistance:
Due to alteration of the target
(DNA dependent RNA
polymerase) of the drug,
prevents further initiation but
not elongation. The microorganism can change the structure of
the enzyme so that the drug no
longer has an effect.

Pharmacokinetics
Absorption
peak levels reached 2-4 hrs. after oral
dose
rapidly eliminated in the bile and
reabsorbed (enterohepatic circulation) It
can be delayed with use of
aminosalicylic acid.
during this time there is a progressive
deacylation of the drug;
the metabolites maintain full effect
Half life is 6 hours.

 Distribution:
Throughout the total body water
Present in effective concentrations in
many organs and body fluids including
CSF,
With Rifampin you must warn patients:
The drug has an orange red color in body
excretions, This color will be imparted to
all body fluids.

Adverse Effects:
Does not cause many side effects in
any great frequency.
G.I. reactions: Anorexia, Nausea
,Vomiting Mild abdominal pain, Hepatic
Reactions in children, pregnant women
and alcoholics, can result in minor
elevations in serum transaminase as some
jaundice

Allergic Reactions
Fever
Skin Eruptions
Rash
Pruritis
Rifampin does induce microsomal drug
metabolizing enzymes. This will decrease
the half-life of some other drugs. (ie.
phenytoin, digitoxin)

Penggunaan terapetik
Tersedia sebagai obat tunggal dan
kombinasi dosis tetap dg isoniazid
(150mg isoniazid, 300mg rifampin)
atau dg isoniazid dan pirazinamid
(50mg isoniazid, 120mg rifampin,
300mg pirazinamid)
Dosis rifampin utk org dewasa:
600mg 1x sehari 1jam sblm makan
atau 2jam stlh makan

WARNING!
Rifampin and Isoniazid are the most
effective drugs for the treatment of TB, The
drug enjoys high patient compliance and
acceptability. But these 2 drugs should
never be given alone!
They are always used in combination
because resistance occurs to one drug alone
very rapidly.
Prophylaxis is with one drug usually
isoniazid.

ETAMBUTOL
Suatu senyawa yg larut dalam air
dan stabil pd suhu panas
Aktivitas antibakteri:
Bersifat tuberkulostatik
Memblok arabinosil transferase yg
terlibat dlm biosintesis dinding sel

Farmakodinamik
75-80% dosis yg diberikan secara oral
diabsorbsi dari saluran pencernaan
Konsentrasi maks dlm plasma tercapai
dlm 2-4jam setelah obat diminum
Waktu paruh 3-4jamEkskresi
Dalam 24jam, dosis etambutol yg
dikonsumsi akan diekskresikan melalui
urin

PENGGUNAAN TERAPETIK
Dosis lazim dewasa 15mg/kg,
diberikan 1x sehari
Anak-anak 6-12th: 10-15mg/kg
Tidak dianjurkan diberikan kpd anak
<5th, krn mempengaruhi ketajaman
penglihatan

EFEK MERUGIKAN
ES yg plg penting: neuritis optik
ES lain: pruritus, nyeri sendi, gangg
GIT, nyeri abdomen, lesu, sakit
kepala, kekacauan mental,
disorientasi, halusinasi

2nd Line Drugs: Not as effective and

have more toxicity
Streptomycin
The first drug used clinically for treatment
of TB 1947-1952; was the only drug
available at that time.
is an aminoglycoside antibiotic
Bacterisidal in vitro
Bacteriostatic in vivo
acts by protein synthesis inhibitor and
decreases the fidelity mRNA and garbles
the message, leads to nonsense proteins.
Streptomycin only binds to the 30s
subunit.

 Adverse Effects:
affects C. Nerve 8: auditory and
vestibular functions. - this drug is
now 2nd 'line because of its
toxicity.
Nephrotoxicity, ototxicity,tinnitus,
vertigo
Can cause fetal harm when
administered to a pregnant woman

para- Aminosalicylic Acid

a structural analog of PABA (p-aminobenzoic
acid) is bacteriostatic inhibits de novo folate
synthesis
half life = 1 hour after 4 g. dose
you can give this drug up to 12 grams per day.
80% of the drug is excreted in the urine and 50%
of that is as an acetylated metabolite which is
insoluble. You must make sure the patient's
urine is normal or alkaline.

Penggunaan Terapetik
Oral, dosis harian 10-12g
Iritatif thd lambung, shg diberikan
setelah makan dan dosis harian
dibagi dlm 2-4 dosis
Dosis anak-anak 150-300mg/kg per
hari dibagi dlm 3-4 dosis

Adverse effects
GI irritation due to the amount of drug given
(high doses) nausea, vomiting, bleeding, occurs
in 30-40% of the patients. be careful with those
who have peptic ulcers
Hypersensitivity reactions Rash, Fever some
hepatotoxicity
All will disappear when the drug is stopped
This drug has poor patient acceptability and
compliance:

Third Line Drugs - least effective

and most toxic

Third line drugs are used when

resistance is developed to 1st and
2nd line drugs; these drugs are also
used in combination.
Aminoglycosides
Capreomycin - Viomycin Kanamycin

Adverse effects
These drugs are: Nephrotoxic - will
cause Proteinuria, Hematuria, Nitrogen
metabolism, and Electrolyte disturbances
However effect is reversible when drug is
stopped.

 Ototoxic will result in deafness and

some loss of vestibular function, leads to
cranial nerve 8 damage. The nerve
damage is permanent.
Capreomycin has replaced viomycin
because of less toxic effects, but all
three drugs have the same effects.

Cycloserine
Mrpkan antibiotik spektrum luas yg
dihasilkan oleh Streptococcus orchidaceus
can cause CNS disturbances
Therapeutic States
Cycloserine should be used when retreatment is necessary or when the microorganism is resistant to the other drugs.
It must be given in combination with other
anti-tuberculosis drugs.

 Mechanism of Action:
An analog of D-alanine synthetase
(mrpkn suatu asam amino), will block
bacterial cell wall synthesis.

 Pharmacokinetics: Rapidly absorbed

Peak [plasma] occurs in 3-4 hours
Distributed throughout all body fluids,
including CSF About 50% is excreted in
unchanged form in the urine during the
first 12 hours. Only about 35% of the drug
metabolized This drug can accumulate to
toxic conc in patients with renal
insufficiency

 Toxicity:
Most common in the CNS: Headache,
Tremor, Vertigo, Confusion, Nervousness,
Psychotic states with suicidal
tendencies , Paranoid reactions,
Catatonic and depressed reactions
Kontraindikasi pd pasien epilepsi

Chemoprophylaxis of TB
Used only in high risk groups

Household members and other close

contacts of a patient with active TB.
A positive skin test in persons less
than 35 years.
A positive skin test reactive in the
immunosuppressed, persons with
leukemia, and Hodgkin's Disease,
HIV + patients with a positive TB
test,

 The drug of choice for

chemoprophylaxis is isoniazid.
Prophylaxis uses only one drug.
In patients who are HIV+ and TB+ and
have the disease; they are treated for a
minimum of 9 months, The first 2
months using isoniazid and rifampin and
for the next 7 months or longer, use
only 2 or 3 of the 2nd/3rd line drugs and
Isoniazid/Rifampin.

Treatment
Isoniazid, Ethambutol, & Rifampin are given
for 2 months.
Isoniazid & Rifampin are given for 4 months.
If you suspect resistance to isoniazid use
Isoniazid, Ethambutol, Rifampin &
Parazinamide. Incidence of drug
resistance is 2-5% in the U.S.
Prolonged bed rest is not necessary or
helpful in obtaining a speedy recovery. The
patient must be seen at regular and
frequent intervals to follow the course of the
disease and treatment. Look for toxic effects