ANTI

ANTI--TUBERCULAR DRUGS

By – Dr. Pramod Sharma

 TB a global problem
 Worldwide: 2 billion infected with TB, i.e. 1
in 3 of global population
 MDR
MDR--TB prevalence in new cases is 3.6%
WHO Global Report, 2006

 India: Incidence: 1.96 million new cases

annually (0.8 million new smear +ve)
 330,000 deaths due to TB each year
– Over 1000 deaths a day
– 2 deaths every 3 minutes
 Classification
First line drugs
- Isoniazid (H), Rifampicin (R), Pyrazinamide
(Z), Ethambutol (E), Streptomycin (S)
Second line drugs
- Thiacetazone, paraaminosalicylic acid (PAS),
Ethionamide, Cycloserine, Kanamycin,
Amikacin, Capreomycin, ciprofloxacin,
levofloxacin, ofloxacin, Rifabutin, Rifapentin
 1st line drugs: more efficacious and better tolerated
 Second line agents are in case of poor tolerance or
resistance to first line agents
 Moxifloxacin is being studied as 1st line drug
 Only combination anti TB therapy is currently
recommended for treatment
 Ethambutol & streptomycin – do not add
substantially to overall activity of the combination
regimen but important in preventing resistance to
rifampicin/isoniazid or both
 Isoniazid
 Most active drug for susceptible strain
 Bactericidal for actively growing bacilli
 Active against extra and intracellular bacilli
 Structurally similar to pyridoxine
 It is a prodrug
MOA:
Enters cell by passive diffusion → Inhibits
synthesis of cell wall mycolic acid
 Converted by KatG (mycobacterial catalase
catalase--
peroxidase) to “nicotinoyl radical “→ radical
interact with mycobacterial NAD & NADP to
produce several adducts → these adduct
inhibit activity of InhA (an ACP reductase) &
KasA (a Keto-
Keto-ACP synthase) → inhibition of
these enzymes inhibits M. acid synthesis →
cell death
 Another adduct inhibits DHFR and thus
interfere with nucleic acid synthesis also
Resistance:
 Due to mutations/deletions in InhA, KasA,
or KatG genes
 Overexpression of InhA → low INH
resistance and cross resistance to (Etm)
 KatG mutants → high INH resistance but
no cross resistance to Etm
 Resistance readily develops if used as
single agent
 Readily absorbed orally, metabolism by
liver N
N--acetyltransferase
acetyltransferase--2 (NAT2), is
genetically determined (slow & rapid
acetylator)
 Plasma conc. In rapid (1/3rd Indians)
acetylators – 1/2 to 1/3rd of slow (2/3rd
Indians) acetylators
 Subtherapeutic concentartion with in fast
acetylators if given once weekly or if
malabsorption
 Good entry in CSF (conc. same as plasma)
 Plasma half life: <1hr (rapid); 3 hr (slow)
 No dose adjustment in renal dysfunction
 Well tolerated by most patients
 Important SEs are peripheral neuropathy
(more in slow acetylators) & hepatotoxicity
Neuropathy (~2%) is due to pyridoxine
deficiency (↑
(↑ excretion, ↓utilization)
Give prophylactic pyridoxine (10 mg/d)
 Hepatitis usually occur after 4-4-8 wks
Incidence ↑es with age (risk ↑ed by Rif)
Contraindicated if it is the cause of hepatitis
 Potent inhibitor of CYP3A, 2C19, 2D6
(weak) but induces CYP2E1
 Rifampicin
 Derivative of rifamycin B
 MOA: binds to β subunit of DNA
dependent RNA polymerase (rpoB) →
suppress chain formation in RNA synthesis
 Bactericidal, as efficacious as INH
 Active against extra and intracellular bacilli
 Well absorbed orally (to be taken empty
stomach) & excreted through liver in bile
 No dose adjustment in liver/renal defect
 Resistance is always due to mutation in rpoB
gene – reduces affinity of drug to the enzyme
 No cross resistance with other TB drugs
 Strong hepatic enzyme inducer (CYP3A4, 2D6,
1A2, and 2C subfamily)
 Enhances own metabolism and of other drugs
(OCPs, warfarin, steroids, PIs, NNRTIs,
theophylline etc.)
 Rifabutin is less potent inducer of CYP450s
 Rifapentin is intermediate in inducing effects
 Common SEs are – rash, fever, nausea &
vomiting, flu like syndrome
 Hepatitis: usually occur in patients with
preexisting liver disease, alcoholics (stop the
drug if jaundice develops)
 Urine & secretions may become orange-
orange-red
Apart from TB also used in
 Leprosy
 Prophylaxis of meningococcal disease &
H. influenzae meningitis,
 Staphylococcal carrier (Chr furunculosis)
 Brucellosis
 Serious staphylococcal infection
(osteomyelitis, endocarditis)
 Ethambutol
 Bacteriostatic
 MOA: inhibits “arabinosyl transferases” →
inhibits polymerization of arabinoglycans,
an essential component of cell wall
 Resistance is due to mutation in emb
gene → overproduction of enzyme or
structural change in enzyme
 No cross resistance with other TB drugs
 Crosses BBB only when meningeal
inflammation present (highly variable
conc. i.e. 4 - 64% of plasma conc.)
 Accumulate in renal failure – give half the
dose if CrCL is <10ml/min
 Optic neuritis is most important SE (not
to be used <6 yrs of age)
 Pyrazinamide
 Inactive at neutral pH but active at acidic pH
 Kills intracellular bacilli & those at sites of
inflammation (pH is acidic)
 Highly effective during induction phase
 Good sterilizing activity (Kills residual intra-
intra-
cellular bacilli) → shorten duration of
regimen by 1/3rd & ↓ relapse by 2/3rd
 MOA: converted to pyrazinonic acid (active
form) by pyrazinamidase (coded by pncA
gene) – interfere with mycolic acid
synthesis, disrupt membrane transport
 Resistance is due to mutation in pncA
gene (pyrazinamidase with reduced
affinity to drug)
 Good penetration in CSF
 Major adverse effects are hepatotoxicity
(1
(1--5%, stop therapy), hyperuricemia etc.
 Streptomycin
 Tuberculocidal but less effective
 Acts only on extracellular bacilli and poor
action in acidic medium
 Crosses BBB when meninges are inflamed
and achieves therapeutic conc.
 Inhibits protein synthesis by inhibiting 30s
ribosomal subunit
 Resistance develops rapidly when used
alone
 Stop streptomycin at the earliest if
infection is due to Strep resistant strain to
prevent “streptomycin dependence”
 Needs to be given i.m./i.v.
 Ototoxicity, nephrotoxicity - common SEs
 Dose modification in renal failure required
 Second line drugs
 Used in case of resistance to 1st line drugs
 Failure of clinical response to conventional
therapy
 Serious treatment limiting ADRs with 1st
line agents
 Ethionamide: related to INH and block
mycolic acid synthesis
Bactericidal, Good CSF entry (100%)
SEs: Gastric irritation, hepatotoxicity;
neurological (alleviated by pyridoxine)
 Cycloserine: cell wall synthesis inhibitor;
Reduce dose to half if CrCl <50ml/min
Peripheral neuropathy & CNS effects
(depression, psychosis) – give pyridoxine
 PAS: folate synthesis antagonist;
structurally similar to PABA; tuberculostatic
No CSF penetration
GI symptoms very common (give with
meals or antacids), may cause crystalluria
Dose is 8-
8-12 g/day in adults
 Kanamycin, amikacin, capreomycin:
more toxic drugs, reserved if no response
to usual therapy
All show ototoxicity and nephrotoxicity -
not combined among themselves
All act by inhibiting protein synthesis
All are parenteral agents
None penetrate CSF
 Fluoroquinolones: DNA gyrase inhibitors,
bactericidal, kill intracellular bacilli also;
 Rapid resistance if used as a single drug
 Always use in combination

Used mainly in MDR TB, or as supplement

when HRZ stopped due to hepatotoxicity
 Types of TB bacilli subpopulation
 Rapidly growing: as in the wall of a cavitary
lesion (O2 tension is high and pH is neutral)
highly susceptible to H and less to R, E and S
 Slow growing: located intracellularly and at
inflamed sites where pH is low; vulnerable to Z,
while H, R and E are less active & S is inactive
 Spurters: (within caseous material) grow
intermittently - R is most active
 Dormant: inactive for prolonged periods
 Goals of therapy
 Kill dividing bacilli - reduce bacillary load -
quick sputum negativity reduces transmission
of TB in community; quick symptom relief

 Kill persisting bacilli - To effect cure and

prevent relapse (depends on sterilizing
capacity of the drug)

 Prevent emergence of resistance

 Principles of chemotherapy
 Emergence of resistant organisms (relapse
in almost 3/4th patients) with single drug
- A combination of two or more drugs
must be used to prevent resistance
 Single dose in a day of all 1st line drugs is
preferred
 Treatment should be directly observed
(DOTS)
 All regimen should have intensive &
continuation phase
 Category wise : Short course
chemotherapy (SCC)
Category I:
 New smear +ve PTB; smear -ve PTB with
extensive parenchymal involvement
 New cases of severe forms of EPTB (meningitis,
miliary, pericarditis, peritonitis, etc.)
 2H3R3Z3E3 + 4H3R3 (Total for 6/7 months)

*If sputum +ve for AFB at 2 months, the intensive

phase should be extended by another month; then
continuation phase is started regardless of sputum
status at 3 months
Category II:
 Smear +ve treatment failure, relapse, interrupted
treatment cases, and others (smear -ve/EPTB with
failure or relapse - culture & histology required)

 2H3R3Z3E3S3+1H3R3Z3E3
+ 5H3R3 (total for 8/9 months)

*4 drug treatment is continued for another month if sputum

is positive at 3 months
 Treatment failure: Patient who remains or
again becomes smear +ve 5 months or later
after commencing treatment. Also one who was
smear -ve at start of therapy and becomes
smear +ve after the 2nd month
 Relapse: patient cured from any form of TB in
the past after receiving one full course of
therapy and now has become sputum +ve
 Defaulter: A patient who interrupts treatment
for 2 months or more and returns with sputum-
positive or clinically active TB
Category III:
 New cases of smear -ve PTB with limited
parenchymal involvement or less severe
forms of EPTB, i.e. lymph node TB, unilateral
pleural effusion, peripheral joint etc.

 2H3R3Z3 + 4H3R3 (Total for 6 months)

Category IV:
 Chronic cases who have remained or have
become smear +ve after completing fully
supervised treatment (Category II)
 These are most likely MDR cases
 Multidrug-resistant (MDR) TB is defined
as in-vitro resistance to at least H and R
 Extensively drug resistant (XDR) TB:
resistance to H, R, a FQ, + one of Km/Ami/ Cp
 Treatment regimen consist of
Intensive phase (IP): 6-9 months with
6 drugs (Km, Ofx/Lvx, Eto, Cs, Z, E)
Continuation phase (CP): 18 months of
(Ofx/Lvx, Eto, Cs, & E)
 If culture results from 4th month remain
+ve, IP may be extended by 1 months;
extension beyond 1 month will be decided
on the results of sputum culture of 5th
and 6th months
 PAS can be used as a substitute drug if
any of the drug used is not tolerated

 All drugs should be given in a single daily

dosage (directly observed for 6 days) and
on Sunday Km injection is omitted but
rest oral drugs are taken unsupervised

 Pyridoxine should be administered to all

patients being treated
 Treatment in special case
Pregnancy:
2 HRE + 7HR (total 9 months)
HIV infected:
2HRZE + 4HR (total 6 months) OR
If slow or suboptimal response, prolongation
of CP to 7 months

Treatment of MDR-TB is same as for HIV -ve

*Rifabutin is used in place of rifampicin
 Chemoprophylaxis
 The purpose is to prevent progression of
latent tubercular infection to active disease
 INH 300 mg (10 mg/kg in children) daily for
6-12 months OR
 Combination of INH (5 mg/kg) and R (10
mg/kg) daily for 6 months
THANK YOU