AntiTubercular Drugs

1. ANTITUBERCULOUS DRUG

3. Situation in Bangladesh
• Major public health problem in Bangladesh.
• The country ranks sixth among 22 highest burden TB
countries in the world.
• It is estimated that about 70,000 people die every year
due to TB.
• In 2009, 160,735 TB cases were notified to Nation
Tuberculosis Control Program (NTP).
• Only 30 % of expected new cases are detected by
national tuberculosis control program (NTP)
• Other receive treatment from private sectors
• One person get sick in every 2 minutes
• One person dies in every 10 minutes

4. Drug of Neglected Diseases (DNDs)
• Last 25 years, NO anti- TB drug has been
developed
• No anti- TB drugs even in the pipe line
• Whereas, a number of drugs for diseases like
Baldness
Obesity
Erectile dysfunction
Why???

5. • Orphan Disease:
Any disease that affects a small percentage of the
population. condition that affects less than 200,000 people
in the United States
e.g. ribose-5-phosphate isomerase deficiency
• Orphan Receptor:
an apparent receptor that has a similar structure to other
identified receptors but whose endogenous ligand has not
yet been identified. If a ligand for an orphan receptor is
later discovered, the receptor is referred to as an "adopted
orphan.
• Orphan Drug:
a pharmaceutical agent that has been developed
specifically to treat a rare medical condition
condition that affects less than 200,000 people in the
United States,"[2] or about 1 in 1,500 people.

6. Tuberculosis
• Tuberculosis is an infectious disease caused by
Mycobacterium tuberculosis
• Mycobacterium tuberculosis can lead to serious
infections of the lungs, genitourinary tract, skeleton, &
meninges
• The disease may have to be treated for six months to
two years
• Resistant organisms readily emerge, particularly in
patients who have had prior therapy or who fail to
adhere to the treatment protocol.

7. • Mycobacteria are intrinsically resistant to most
Antibiotic, Because they grow slowly compared
with other bacteria, antibiotics that are most
active against growing cells are relatively
ineffective
• Mycobacterial cells can also be dormant & thus
completely resistant to many drugs or killed only
very slowly
• The lipid-rich mycobacterial cell wall is
impermeable to many agents

8. • Mycobacterial species are intracellular
pathogens, & organisms residing within
macrophages are inaccessible to drugs
that penetrate these cells poorly
• Finally, mycobacteria are notorious for
their ability to develop resistance
• Combinations of two or more drugs are
required to overcome these obstacles & to
prevent emergence of resistance during
the course of therapy

9. • The response of mycobacterial infections to
chemotherapy is slow, and treatment must be
administered for months to years, depending on
which drugs are used
• Five first-line antimicrobial agents are currently
recommended for antituberculosis therapy
• Second-line medications are more toxic, or have
not been studied as extensively.
• The second-line medications are useful in patients
who cannot tolerate the first-line drugs or who are
infected with mycobacteria that are resistant to
the first-line agents

10. • First-line drugs –
Isoniazid (bactericidal)
Rifampicin (bactericidal)
Pyrazinamide (bactericidal)
Ethambutol (bacteriostatic)
Streptomycin (bactericidal)
• Second-line drugs –
Amikacin Capreomycin Cycloserine
Kanamycin Thioacetazone
Clarithromycin
Paraamino salicylic acid (PAS) Ciprofloxacin
Levofloxacin Rifabutin Clofazimine

11. Justification of combination therapy
• Different mechanism of action provide additive
antibacterial effect
• Compliance –
Early clinical improvement leads to
discontinuation,duration of therapy reduced as a
result of combination
• Emergence of resistance can be delayed –
– Intracellular, long metabolic inactivity tends to
develop early resistance
• Individual dose reduction –
– Theoretically suppose to minimize the possibility of
adverse effects, however spectrum of adverse
effects has increased

12. • Some obstacles that can be overcome by combination
therapy –
– Most antibiotics are more effective against rapidly
growing organism than against slowly growing
ones. Because mycobacterium are very slowly
growing organisms, they are relatively resistant to
antibiotics. INH inhibit growth of resting microbe &
kills multiplying
– Mycobacterial cells can also be dormant & thus
completely resistant to many drugs – or killed only
very slowly by the few drugs that are active. INH
passes freely into mammalian cells, effective
against intracellular organism. Rifampicin,
pyrazinamide can kill semidormant within cells

13. – The lipid rich mycobacterial cell wall is
impermeable to many agents
– A substantial proportion of mycobacterial
organisms are intracellular, resting within
macrophages, & inaccessible to drugs that
penetrate poorly. INH can penetrate caseous
TB lesion.
– Mycobacteria are notorious for their ability to
develop resistance to any single drug.
Combination of drugs are required to
overcome these obstacles & to prevent
emergence of resistance during the course
of therapy

14. • Steps of TB management –
–Step 1 BCG Vaccination: 80% world children
vaccinated relatively effective in
preventing serious but non-infective
childhood TB
–Step 2 Chemoprophylaxis: Treating infected
TB people before they get sick.
– INH 5mg/kg by mouth daily for 1 year in –
»Immuno-suppressed patient
»Unvaccinated contact (tuberculin positive)
»Adolescents with high degree of tuberculin
sensitivity
–Step 3 Different Treatment Regimens

15. Treatment Regimens
• DOTS (Directly Observed Treatment, Short-course
chemotherapy)
• Health workers observe patient taking medicine
• A national TB control programme to monitor progress
• Unsupervised daily regimen (6 months regimen)
– Initial phase 2 months
• Pyrazinamide
• Isoniazid
• Rifampicin
• Ethambutol (Likelihood of drug resistance or seriously
ill)
– Continuation phase 4 - 5 months
• Isoniazid
• rifampicin

16. Treatment Regimens & Success rate
• 9 months regimen
– Initial phase 2 months
• Isoniazid Rifampicin Ethambutol
– Continuation phase 7 months
• Isoniazid Rifampicin
• 12 month regimen: inexpensive & reasonably effective
– Twice weekly: nearly 100% effective
• Streptomycin 1 gm I.M.
• INH 15 mg/kg plus pyridoxin 10 mg orally
– Daily: very cheap regimen which is 80-95% effective
• INH 300 mg & thiacetazone 150 mg – single doses by
mouth
• Comparative success rates in Bangladesh
– Smear positive cases with DOTS 80%
– Unsupervised daily regimen 57%

17. TB
Diagnostic
Category
TB patient TB Treatment
Initial phase
(daily)
Regimens
Continuation
phase(3 times
weekly)
I New smear positive;
New smear negative
PTB with extensive
parenchymal
involvement or
severe forms of
extra PTB (e.g.
meningial, miliary,
pericardial,
peritonial, massive
unilateral/bilateral
pleural effusion,
spinal, intestinal,
genitourinary & multi
organ TB)
2 (HRZE)
4 fixed-dose
combination
daily for 1st 2
months followed
by
4 Fixed drug
combinations
R – 150 mg
INH – 75 mg
Pyraz -400 mg
Etham-275 mg
4 (HR)3
2 fixed drug
combination
thrice weekly
for another 4
months
2 FDC contains

Rifam 150mg
INH – 75mg

18. TB
Diagnostic
Category
TB patient TB Treatment
Initial phase (daily)
Regimens
Continuation
phase(3 times
weekly)
II Previously treated
for > 1 month with
sputum smear
positive PTB with
- Relapse/
-Treatment after
interruption/
-Treatment failure
2 (HRZE)S/
1 (HRZE)
4 FDC daily for
1st 3 month plus
streptomycin
injection 500 mg
daily for 1st 2
months followed
by 
The dose of
Streptomycin
should not
exceed 750 mg
daily after the age
of 50 years
5 (HR)3 E3
2 FDC +
Ethambutol
(400 mg)
thrice weekly
for next 5
months

19. TB
Diagnostic
Category
TB patient TB Treatment
Initial phase (daily)
Regimens
Continuation
phase (3 times
weekly)
III New smear negative
PTB (other than
category I),
Less severe form of
extra PTB
(e.g. lymph node,
pleural effusion
{unilateral}, bone
{excluding spine},
peripheral joint, skin
TB)
2 (HRZ)
3FDC daily for 1st
2 months
followed by 
4 (HR)3
2 FDC thrice
weekly for
another 4
months

20. Drug Clinical setting Daily dose
Rifampicin CHILD 10-20 mg/kg
Adults weighing <50 kg & in the
elderly
450 mg
Adults weighing >50 kg 600 mg
Isoniazid CHILD 10 mg/kg
Adults 200 – 300 mg
Ethambutol CHILD & adults: Initial 8 weeks 25 mg/kg
CHILD & adults: Subsequently 15 mg/kg
Pyrazinamide CHILD & adults 20-35 mg/kg
Streptomycin CHILD 30 mg/kg
Adult 1 gm

21. Isoniazid
• Antibacterial activity limited against
mycobacteria
• Inhibits growth of resting microbes, kills
multiplying
• Passes freely into mammalian cells, effective
against intracellular organisms
• For bacilli in the stationary phase, isoniazid is
bacteriostatic, but for rapidly dividing organisms,
it is bactericidal

22. • Mechanism of action:
– not very clear.
–INH is a prodrug that is Isoniazid is a prodrug that is
activated by mycobacterial catalase-
peroxidase(KatG) which forms a covalent
complex with an acyl carrier protein (AcpM) and
KasA, a beta-ketoacyl carrier protein synthetase,
–which blocks mycolic acid synthesis, an important
constituent of the cell wall of mycobacteria & kills the
cell.

23. Mechanism of action:
Isoniazid is a prodrug
↓
activated by mycobacterial catalase-
peroxidase(KatG)
↓
forms a covalent complex with an acyl carrier
protein (AcpM) and KasA, a beta-ketoacyl carrier
protein synthetase
↓
blocks mycolic acid synthesis(an important constituent
of the cell wall of mycobacteria) & kills the cell.

24. • Pharmacokinetics:
–Rapidly & completely absorbed from GIT.
–Wide distribution including CSF
–Penetrates & accumulates into caseous tuberculous
lesion
–Minimum tuberculostatic concentration is 25 – 30 ng/ml
–Metabolized through N-acetylation
• Slow acetylator half-life would be 3 hour
(Drug causes toxicity, so peripheral neuropathy itself )
• Rapid acetylator ( by drug metabolite) half-life
would be 1 hour (metabolite causes toxicity, so
hepatotoxicity)

25. • Adverse effects:
– Commonest – allergic skin eruption
– Drug fever
– Hepatitis in elderly & patients with liver
disease & in rapid acetylators
– Hemolytic anemia in G6PD deficiency
– Arthritic symptoms
– Decreased metabolism of anti-epileptic drugs
like phenytoin, carbamazepine &
ethosuximide. So their effects are increased

26. – Peripheral neuropathy particularly common in
malnourished patients due to deficiency of
pyridoxine
• Explanation – INH is structurally analogue
to pyridoxine & form a hydrazone ( a highly
water soluble) with pyridoxal with no
vitamin activity & the complex rapidly
excreted in the urine
• Measure to prevent – Pyridoxine 10 mg/day
to prevent anticipated neuropathy

27. Rifampicin
• A semisynthetic derivatives of rifampicin, an antibiotic
produced by streptomyces mediterranei.
• Most active antituberculosis agent
• Effective against
–Different mycobacteria - staphylococci
–N. meningitidis - H. influenzae
• It is a powerful hepatic enzyme inducer -  its own
metabolism as well as other drugs like
–phenytoin, OCP, glucocorticoids,
–clarithromycin, ketoconazole, theophyllline,
–clarithromycin

28. • Two Rifampicin derivatives available
– Rifampicin Rifabutin
• Mechanism of action:
Rifampin binds to the subunit of bacterial DNA-
dependent RNA polymerase and thereby inhibits
RNA synthesis.
• Resistance
Mutation to the β subunit of bacterial RNA
polymerase this result in binding of Refampicin to
RNA polymerase .

29. • Human RNA polymerase does not bind rifampin
and is not inhibited by it.
• Rifampin is bactericidal for mycobacteria.
• It readily penetrates most tissues and into
phagocytic cells & Can kill both extracellular &
intracellular microorganisms
• It can kill organisms that are poorly accessible to
many other drugs, such as intracellular
organisms and those sequestered in abscesses
and lung cavities.
• Attains effective concentration in CSF

30. • Pharmacokinetics:
–Used orally, IV formulations available.
–Well absorbed from GIT
–Widely distributed throughout the whole body including
CSF when meninges are inflammed
–80 – 90% protein bound
–Will cross placenta & distribute into the breast milk
–t½ 3 hours
–Metabolized in the liver. Undergoes enterohepatic
cycling
–Parent drug & metabolites are excreted via the bile &
urine

31. • Adverse effects:
– Rash, Thrombocytopenia, Flu like syndrome, Dizziness,
Confusion, Hemolysis
– Red discoloration of urine, tear & sputum is a useful
indication that patient is taking the drug
– Fatal hepatitis mainly being associated with prior liver
disease
• Indications:
– TB
– Leprosy
– Pneumonia
– Gonorrhoea
– Chemoprophylaxis of meningococcal meningitis
– Staphylococcal endocarditis(staphylococcal
infections )
– Osteomylitis

32. Pyrazinamide
• Synthetic, orally effective, bactericidal, antitubercular agent
used in combination with INH & rifampicin
• Prodrug, converted to pyrazinoic acid by pyrazinamindase
of the m. tuberculosis
• Inactive in neutral pH, tuberculostatic in acidic pH
• It is bactericidal to actively dividing organisms, but the
mechanism of its action is unknown

33. • Can kill persisters, i.e., semidormant
mycobacteria within the cell lysosome as well as
in macrophages after phagocytosis because pH
of phagolysosome is low.
• Distribute throughout the body, penetrate
adequately to CSF, hence the drug is valuable in
tuberculous meningitis
• an important front-line drug used in conjunction
with isoniazid and rifampin in short-course (ie,
6-month) regimens as a "sterilizing" agent active
against residual intracellular organisms that may
cause relapse.
• Safe to use in pregnancy

34. • Adverse effects:
-hepatotoxicity (v.high dose -in 1–5% of
patients),
–Arthralgia
–Urate retention can also occur & may precipitate a
gouty attack
–GI upset – anorexia, nausea, vomiting
–Malaise
–Fever
–Urticaria, skin rash

35. Ethambutol
• Dextroisomer, has antitubercular effect
• Bacteriostatic & specific for most strains of M.
tuberculosis & M. kansasaii
• M/A:
Inhibits mycobacterial arabinosyl transferases
which involved in the polymerization reaction of
arabinoglycan, an essential component of the
mycobacterial cell wall.
• Used as an alternative to streptomycin

36. • Resistance emerges rapidly if used alone,
always given in combination with other
antituberculous drugs.
• well absorbed from the gut.
• Taken up by the erythrocytes & slowly
released.
• About 20% of the drug is excreted in feces
and 50% in urine in unchanged form.
• Ethambutol crosses the blood-brain barrier
only if the meninges are inflamed & Can
penetrate CSF , use in TB meningitis.

37. • Adverse effects:
– Optic neuritis (retrobulbar neuritis):
dose related side effect, initially
red/green color blindness followed by a
 in visual acuity. Disappear following
withdrawal of drug
So,baseline opthalmic assesment is
required.
– Other adverse effects: Arthralgia, GI
disturbance, Headache & mental
disturbance
– Peripheral neuritis: rare
– Hypersensitivity: skin rash, fever, itching

38. Streptomycin
• First antibiotic effective in the treatment of
tuberculosis
• Penetrates into cells poorly & is active
mainly against extracellular tubercle bacilli
• Crosses the BBB & achieves therapeutic
concentrations with inflamed meninges
• Nontuberculosis species of mycobacteria
other than M. avium complex (MAC) & M.
kansasaii are resistant to streptomycin

39. • Used when an injectable drug is needed or
desired, principally in individuals with
severe, possibly life-threatening forms of
TB, e.g. meningitis & disseminated
disease, & in treatment of infections
resistant to other drugs
• Adverse effect: dose related, & the risk is
 in elderly
–Ototoxicity & nephrotoxicity. Vertigo &
hearing loss are most common & may
be permanent.

40. 2nd line drug for tuberculosis
Recommended In case of
• Resistance to first-line agents;
• Failure of clinical response to
conventional therapy;
• Serious treatment-limiting adverse drug
reactions; and
• When expert guidance is available to deal
with the toxic effects.

41. • MDR –TB : is a form of TB caused by
bacteria that do not respond to at least
INH & refampicin, the @ most powerful
anti TB drug
• Extensively Drug Resistant( XDR-TB) is a
form of MDR TB that respond to even
fewer available medicine , including the
most effective 2nd line anti TB drug.