Tuberculosis is completely curable disease now a days but one should follow the treatment regimens correctly .so for under graduate MBBS students it is clearly explained with animations.Hope you all this will be helpful.

3. • TUBERCULOSIS is an infectious disease caused by
Mycobacteria; Mycobacterium tuberculosis &
Mycobacterium bovis.
MODE OF TRANSMISSION
 Inhalation of droplets
 Ingestion --self swallowing of infected sputum/ or
ingestion of unpasteurised milk of infected cow
 Inoculation – of organism in to skin may occur
rarely from infected postmortem tissue.
Transplacental – ie tuberculosis of foetus from
mother.

4. Macrophage
with tubercle
bacilli
• Major portion of tubercle bacilli
become intracellular(i.e reside in
macrophage),so it is inaccessible for
majority of antibiotics as they cannot
penetrate easily in to the
macrophage.
• It was once considered to be an
incurable disease but now it is
curable by a number of
chemotherapeutic agents.

5. Classification of anti TB drugs
1st Line Essential
drugs
1st Line
supplemental
drugs
2nd Line drugs
Eg-
RIFAMPICIN
ISONIAZID
PYRIZINAMIDE
ETHAMBUTOL
(RIPE)
Eg-
Rifabutin
Rifapentin
streptomycin
Eg-
Fluroquinolones
Amikacin
Capreomycin
Ethionamide
p-Aminosalicylic
acid
Cycloserine
(FACEPaC)

6. • 1st line essential drugs– most effective & basic
components of anti tubercular treatment.
• 1st linesupplemental drugs– are quite effective &
posseses an acceptable limit of toxicity. These are
kept as reserved drugs & used in special settings.
• 2nd line drugs—these drugs are used if there is
resistance to 1st line drugs or if 1st line drugs are
contraindicated for some reason. These drugs are
less effective & slightly more toxic than Ist line
drugs(except Fluoroquinolones)
• NEWER DRUG UNDER INVESTIGATION--
LINEZOLID

7. CATEGORY PATIENT TYPE DURATION OF
TREATMENT
DRUG REGIMEN
CATEGORY 1 NEW UNTREATED
SMEAR +VE
PULMONARY T.B
6 MONTHS RIPE FOR 2
MONTHS , THEN
R I FOR 4
MONTHS
CATEGORY 2 SMEAR +VE
RETREATMENT
GROUP(RELAPSE
OR TREATMENT
FAILURE)
8 MONTHS RIPE +
STREPTOMYCIN
FOR
2MONTHS;THEN
RIPE FOR 1
MONTH; THEN RIE
FOR 5 MONTHS
CATEGORY 3 SMEAR –VE
PULMONARY T.B
OR LESS SEVERE
EXTRA
PULMONARY TB
6 MONTHS RIP FOR 2
MONTHS THEN
R I FOR 4
MONTHS

8. Treatment of tuberculosis
• One of the main reason for threrapeutic failure
has been patients poor compliancen after having
symptomatic relief.
• WHO , therefore has recommended
DOTS(Directly Observed Therapy for Short
course) wherein the anti-TB drugs are given
under direct supervision of medical professional 3
days a week.
• This helps to ensure the right drugs are taken at
the right time for the full duration of treatment

9. • A Standardized recording and reporting
is maintained by health worker or
medical professional. This helps to keep
track of each individual patient and to monitor
overall programme performance.
• T.B therapy normally begins with 4 1st line
drugs: rifampicin + isoniazid + pyrizinamide +
ethambutol for 2months followed by a course
of isoniazid + rifampicin for next 4 months.
• Combination of drugs ensures prevention of
resistance by mycobacteria

10. Individual drugs.
Isonicotinic acid hydrazide
• INH is a pro drug & is converted into active
form by bacterial enzyme catalase peroxidase.
• SITE OF ACTION– Both intracellular &
extracellular ; also in casseous lesions.
• It is bactericidal to actively growing tubercle
bacilli but not to dormant organisms which
are only inhibited.
• It is active against mycobacterium tuberculosis
& mycobacterium kansasii

11. MECHANISM OF ACTION
INH is converted to active form by catalase
peroxidase (produced by mycobacterium) .
The active form inhibits mycolic acid in outer layer
of cell wall.
Also inhibits DNA, RNA & various oxidative
enzymes.
It is equally active in acidic & alkaline medium

12. Mycobaterium cell wall has the following layers viz.
– mycosides, mycolic acid, arabinoglycan,
peptidoglycan.INH inhibits mycolic acid synthesis
while ethambutol inhibit arabinoglycan layer
ARABINOGLYCAN
INH
(PRODRUG)
Catalase peroxidase
INH
(ACTIVE)
MYCOLIC
ACID
SYNTHESIS
INHIBITED
PEPTIDOGLYCAN
CELL MEMBRANE

13. MECHANISM OF RESISTANCE
• Resistance to INH is due to mutation in
CATALASE – PEROXIDASE GENE which is
responsible for activation of INH.
• Another mechanism responsible for resistance
is mutation in PROMOTER GENE , which is
involved in mycolic acid biosynthesis

14. Pharmacokinetics
• Absorption– well absorbed orally
• Distribution– readily distributed in pleural ,
peritoneal & synovial fluids.
CSF concentrations are reached up to 100% if
meninges are inflammed.
• Metabolism – metabolised in liver by N –
acetyl transferase

15. INH N- acetyl transferase Acetyl INH Hepatotoxic
The rate of above reaction varies in different people
i.e the reaction may be rapid or slow.
Accordingly people are classified as RAPID
ACETYLATORS( rate of reaction is rapid forming
acetyl INH eg.- 30-40% Indians, Japanese) &
SLOW ACETYLATORS (rate of reaction is sloweg.-
60-70% Indians, egyptians, jews,swedes).
Plasma half life– a)in rapid acetylators– T ½ = 1h
b)in slow acetylators– T ½ = 3h

16. • The acetylator status of an individual may
influence nature of INH toxicity but not
the anti tubercular response(if INH is
given once daily) because its plasma
concentration normally remains above
inhibitory concentration.
Peripheral neuritis --- commonly in slow
acetylators because accumulated INH
inhibits pyridoxine kinase which converts
pyridoxine to its active form pyridoxyl
phosphate.

17. • Also INH increases excretion of pyridoxine in
urine.
• This side effect can be prevented by giving vit-b6(
pyridoxine) prohylactically in 10-40 mg /
day.
• Hepatotoxicity --- common in fast acetylators
because INH is metabolised in to acetyl INH
which is hepatotoxic.
• Hepatotoxicity is a common side effect by INH
in alcoholics, liver diseases & in people aged
50-65 years.

18. • The drug has to be discontinued at onset of
symptoms like nausea, loss of apetite, abdominal
pain, & on rise of amino transferase enzymes by 3
fold.
• Other side effects are allergic reactions like fever,
rashes, & xerostomia , haematological changes &
convulsions in seizure – prone patients, drug
induced lupus erythematous.
Drug interactions
Aluminium hydroxide inhibits absorption of INH.
 Alcohol increases risk of hepatitis.
 INH inhibits metabolism of phenytoin &
carbamazepine

19. • DOSAGE
In adult– 300mg O.D or 5mg/kg/day
For serious infections or meningitis – 600mg O.D
Duration of treatment is related to drug
combination used.
RIFAMPICIN is a semisynthetic derivative of
macrocyclic antibiotic Rifamycin

20. Anti microbial activity- bactericidal against both
intracellular & extracellular tubercle bacilli. In
addition , it is active against M.leprae,
Staph.aureus, N meningitidis, H. influenza,
Brucella, Legionella.
Mechanism of action of Rifampicin
Rifampicin inhibits bacterial DNA DEPENDENT
RNA POLYMERASE.
Mammalian RNA polymerase is not inhibited , so
RNA synthesis of host cells is not affected.

21. MECHANISM OF RESISTANCE
Resistance develops mutation in rpo B gene which
prevents binding of rifampicin to RNA
polymerase.
Hence if used alone resistance develops rapidly. It is
a potent enzyme inducer
Pharmacokinetics
Absorption--well absorbed after oral administration
Distribution – it penetrates in all tissues , tubercular
cavities, placenta. Adequate CSF levels are
reached if meninges are inflammed.
It is significantly protein bound.

22. • Excretion – drug is excreted via bile &
undergoes entero hepatic circulation.
ADVERSE EFFECTS
• HEPATITIS is major side effect. It is dose
dependent & reversible. It is common in
patients with underlying liver disease. Risk
of hepatitis increses when used in
combination with INH.
• Occasional side effects include FLU-LIKE
SYNDROME characterised by fever chills ,
myalgias & thrombocytopenia,
• Rifampicin imparts RED ORANGE COLOR
TO URINE.

23. DOSAGE
For T.B- 600mg(10mg/kg/day) as a single dose
before breakfast.
For brucellosis – in combination with doxycycline
(first choice combination)
For leprosy – in combination with dapsone
For prophylxis of meningitis caused by
meningococcus—600mg B.D for 2 days.
For prophylxis of meningitis caused by H.influenza–
600mg/day for 4 days.
Rifampicin can also be used for prosthetic valve
endocarditis.

24. DRUG INTERACTIONS
Accelerates metabolism of oral contraceptives,
anticoagulants, protease inhibitors used in HIV
patients, which may result in therapeutic
failure.
Ethambutol is a synthetic tuberculostatic drug
active against M.tuberculosis, M.kamsasii &
M.avium intracellulare.

25. MECHNISM OF ACTION
ETHAMBUTOL inhibits polymerisation of
arabinoglycans of cell wall by inhibiting
arabinosyl transferase
MYCOLIC ACIDS
ARABINOGLYCAN
PEPTIDOGLYCAN
CELL MEMBRANE

26. MECHANISM OF RESISTANCE
Resistance develops due to point mutations in
emb B gene that encodes arabinosyl
transferases enzyme involved in mycobacterial
cell wall synthesis.
Pharmacokinetics
Bioavailability– 80%
Distribution– widely distributed in all body fluids
including CSF

27. DOSAGE
Should not be used alone as resistance
develops rapidly.
Usual daily dose is 800-1000mg orally
(15mg/kg/day).
It can also be given in a dose of 1600mg/day
In the treatment of M.avium intracellulare
infection in AIDS patients– ethambutol is used
in combination with rifabutin + clarithromycin.
Higher doses are needed to treat tuberculous
meningitis.

28. ADVERSE EFFECTS
Ethambutol if used in a dose of
25mg/kg/day for more than 9
days can cause RETROBULBAR
NEURITIS IMPAIRING VISUAL
ACTIVITY & RED – GREEN COLOR
DISCRIMINATION.
This effect is dose related reverses
slowly after discontinuing the
drug.
Periodic visual activity testing is
desirable during is desirable
during treatment period.

29. • Ethambutol should be avoided
in in children below 5 years
where it is difficult to asses
visual activity & red – green
color discrimination.
• Ethambutol decreases renal
excretion of urates & may
precipitate gouty arthritis.
• Mild GIT intolerance , rashes,
fever & dizziness are also
possible.

30. Pyrazinamide(PZA)
• It is pyrazine derivative of nicotinamide.
• Because of its hepatotoxicity its use had declined
earlier.
• But recently pyrizinamide in reduced doses & in
combination re emerged as 3rd most important
anti tuberculosis agent.
o It is bactericidal to M.tuberculosis & is active only
at low pH only.
o It is highly effective only on intracellular
mycobacteria(due to acidic environment
intracellularly in macrophages)

31. MECHNISM OF ACTION
PZA is thought to enter enter M.tuberculosis by
passive diffusion & is converted to pyrizinoic
acid (its active metabolite) by bacterial
enzyme pyrizinamidase enzyme.
The active metabolite then inhibits
mycobacterial fatty acid synthase 1 enzyme &
disrupts mycolic acid synthesis needed for cell
wall synthesis.

32. ARABINOGLYCAN
PZA
pyrizinamidase
pyrizinoic
acid
MYCOLIC
ACID
SYNTHESIS
INHIBITED
PEPTIDOGLYCAN
CELL MEMBRANE

33. • Mechanism of resistance
A mutation in the gene (pnc A) that encodes
pyrizinamidase is responsible for drug
resistance which can be minimised by drug
combination therapy.
Pharmacokinetics
Absorption– well absorbed orally
Distribution– widely diustributed in all tissues,
macrophages, tubercular cavities & in
meningitis.
Plasma half life– 9-10hrs.

34. Streptomycin
• It is the first antitubercular drug.
• It is bactericidal but because of poor
penetration it acts only on extracellular
tubercular bacilli.
• It is also active against M.kansasii & M.avium
intracellulare.
• It is less effective than INH or Rifampicin
Pharmacokinetics
Route of administration– I.M , cant be given
orally as it is highly polar

35. • Distribution – poorly distributed , do not
penetrate most cellular compartments.
• Metabolism -- as they do not penetrate most
cellular compartments , they do not undergo
significant metabolism.
• Excretion- nearly all of the drug is cleared by
kidneys as they do not undergo significant
metabolism.
• Plasma half life– 1.5 – 3 hrs(24-48 hrs in renal
insufficiency)

36. Mechanism of action
The mechanism of action of streptomycin is
inhibition of protein synthesis of mycobacteria in
the ribosome
Mechanism of resistance
Spontaneous resistance to streptomycin is related
to point mutation of the genes –rpsl or rrs that
encode for ribosomal proteins & ribosomal tRNA
respectively.
Dosage
1000mg/day I.M (15mg/kg/day)
Should be reduced to 500-750mg in elderly & in
renal insufficiency.

37. • Even for thrice a week dose schedule the
dose structure remains the same.
Adverse effects– nephrotoxicity & ototoxicity.
RIFABUTIN
IT IS a structural analogue of rifampicin.
It shares with rifampicin a common mechanism
of action , common spectrum of activity ,
aginst gram positive & negative organisms,
common molecular basis for development of
resistance.

38. • Hence there is cross resistance between
rifabutin & rifampicin.
• But rifampicin has better activity against
M.avium complex(MAC) .it is active against
rifampicin resistant strains such as M.leprae &
M.fortuitum. It has longer plasma half
life.(45hrs)
• It is used either alone or in combination with
pyrizinamide in the treatment of latent
tubercular infection.

39. • It can be used in place of rifampicin for the
treatmen of tuberculosis in HIV infected
patients.
• Most important use of rifabutin is in HIV
infected population for prevention &
treatment of disseminated MAC.
Dosage
300mg/day(5mg/kg/day)
Adverse effects– red orange color urine, skin
rash, hepatitis, neutropenia,

40. Drug interactions—
• May decrease plasma conc. Of theophylline,
oarl anti coagulants, protease inhibitors & non
nucleoside reverse transcriptase inhibitors
(but less than rifampicin).
• Fluconazole increases plasma concentration of
rifabutin resulting in pseudojaundice &
polymyalgia syndrome.

41. RIFAPENTINE
• Longer acting analogue of rifampicin(T ½ =13-
15hrs ).
• Its mechanism of action , cross resistance,
enzyme inducion, toxic profile & clinical use is
identical to rifampicin.
• It is not used alone but in 3-4 drug
combination regimen.
• Drug interactions are lower than rifampicin
but greater than rifabutin
• Dosage– 600mg once or twice weekly

42. Fluoroquinolones
• Specially used in multidrug resistant strains.
• Very effective when used as a part of
combined regimen in HIV infected patients.
• Ciprofloxacin, ofloxacin, levofloxacin &
moxifloxacin inhibit 90 – 95% of strains of
tubercle bacilli including MAC & M.fortuitum.
• They kill intracellular pathogens because of
good penetration.
• These can be substitued in drug combinations
if any Ist line drugs are contraindicated.

43. Dosage-
Ciprofloxacin– 750mg BD or 500mg TDS
Ofloxacin– 400mg BD
Levofloxacin500mg OD (preferred over
ofloxacin because of once daily dose schedule)
Moxifloxacin—400mg OD recent studies
suggest use of moxifloxacin with other drugs
reduces duration of therapy for drug
susceptible tuberculosis.

44. Amikacin
• It is an aminoglycoside antibiotic.
• It is 2nd choice after streptomycin &
capreomycin for multi drug resistant
tuberculosis.
• Most M.tuberculosis strains are that are
resistant to streptomycin are sensitive to
amikacin.
• It is also used in disseminated MAC
• Dose– 15mg/kg/day IM or IV for 5 days a
week for 2 months. Then 1g/day thrice weekly
for another 4 months.

45. Capreomycin
• It is tuberculocidal polypeptiode antibiotic.
• Effective against M.tuberculosis, M. kansassi,
M.avium .
• It is poorly absorbed from GIT , so should be
given parenterally( 1g/day IM).
• Side effects- ototoxicity & nephrotoxicity

46. • Rarely used tuberculostatic drug.
• It is hepatotoxic, neurotoxic & produces intense
gastric irritation.
• It blocks mycolic acid synthesis.
PARA-AMINO SALICYLIC ACID
It is a structural analogue of PABA.
Acts by inhibiting folate synthesis of bacteria.
Disadvantages – poor compliance due to GIT
intolerance, hypersensitivity reactions like skin rash,
lupus like reactions, drug fever , joint pain, hepatitis
Dose- 8-12g/ day in 2 or 3 divided doses

47. Cycloserine
• It is tuberculostatic drug.
• It is excreted unchanged in urine so it is used
for renal tuberculosis.
• Also Used in multi drug resistant tuberculosis
• Dose- 500 mh BD
• Side effects- psychotic behavioural changes ,
dizziness, peripheral neuropathy

48. NEWER ANTI TUBERCULAR DRUGS
LINEZOLID it is an antibiotic with 100% oral
bioavailability
VERY effective against drug susceptible & drug
resistant strains.
Adverse effects on prolonged use (which becomes
necessary for treatment of tuberculosis) may
limit its usefulness.
Adverse effects– reversible bone marrow
suppresion, peripheral neuropathy.
Dose- 600mg OD

49. R-207910
• it is di aryl quinoline derivative developed in
year 2004 & completed phase II trials.
• It inhibits proton pump for ATP synthase of M.
tuberculosis.
• It remarkably shortens duration of treatment
to 2 months or less.
• It is not yet available in the market.