This document discusses the classification, mechanisms of action, resistance, and treatment guidelines for first- and second-line antitubercular drugs. It classifies drugs as first-line (isoniazid, rifampicin, pyrazinamide, ethambutol) or second-line (fluoroquinolones, aminoglycosides, cycloserine) and describes the WHO regimens for treating drug-sensitive, multidrug-resistant, and extensively drug-resistant tuberculosis. It also covers chemoprophylaxis, drug interactions, and the role of corticosteroids in tuberculosis treatment.

1. Antitubercular drugs
Dr Chintan Doshi

2. Objectives
• Classify antitubercular drugs
• Discuss mechanismof action,adverse effects,drug interactions and
contraindications of antitubercular drugs
• Discuss WHO regimens for treatmentof tuberculosis
• Define multi-drug resistant(MDR) Tuberculosis andXDR
tuberculosis
• Describe treatmentof MDR-TB and XDR-TB
• Discuss chemoprophylaxis in tuberculosis
• Explain role of corticosteroids inTB

3. TUBERC
ULOSIS

4. MYCOBCTERIA
• Mycos: wax(Greek)
• Very difficultto treat Mycobacterial infections
• First layer of defense:60 % cell wallis made of lipids
• Second layer of defense:abundant efflux pumps
• Third layer of defense:can hide inside patients' cells

5. • Multiple drug therapy
• Compliance
• Adequate period
KEY POINTS IN TREATMENT
OF TUBERCULOSIS

6. CLASSIFICATION OF
ANTITUBERCULAR DRUGS
First Line
drugs
Second line drugs
Isoniazid
Rifampicin
Pyrazinamide
Ethambutol
Streptomyn
Moxifloxacin
Levofloxacin
Ofloxacin
Ciprofloxacin
Kanamycin
Amikacin
Capreomycin
Ethionamide
Prothionamide
Cycloserine
Terizidone PAS
Rifabutine
Rifapentine

7. CLASSIFICATION OF
ANTITUBERCULAR DRUGS

8. ISONIZID (H)
• Tuberculocidal
• Fast multiplying organisms rapidly killed
• Acts on extracellular and intracellularTB
bacilli
• Equally effectivein acidic and alkaline
medium
• Cheapest
• Not effectiveagainstatypicalMycobacteria
except M. Kansasi

9. MECHANISMOF
ACTION
Converted to active form by catalase peroxidase enzyme
Forms adducts with NAD
Targets and inhibits inhA &KasA genes
Inhibit synthesis of mycolic acids

10. MECHANISM OF RESISTANCE
• Mutation in KatG gene
– Most common
– High level of resistance
• Mutation in KasA gene
• Mutation in inhA gene

11. PHARMACOKINETICS
• Good absorption anddistribution
• Extensively metabolized in liver by N
–acetylation
• Fast acetylators
• Slow acetylators
• Inhibitor of CYP2C19 &CYP3A4
• Metabolites excreted in urine

12. Adverse effects
• Peripheral neuritis
– Prophylactic:pyridoxine 10 mg/day
– Treatment:pyridoxine :100 mg /day
• Hepatotoxicity
• More in elderly and alcoholics
• Reversible on stopping drug
• Lethargy, rashes, fever, acne and arthralgia

13. RIFAMPICIN
• Tuberculocidal
• Best action againstslowly or intermittently
dividing M.Tuberculosis
• Also effectiveagainstvariety of other Gm +/-
infections
• Effective againstM. Leprae
• Effective againstatypicalbacteria like MAC but
not M.fortuitum
• Both extracellular and intracellular affected

14. PHARMACOKINETICS
• 70 % bioavailability (↓ withfood)
• Should be takenon empty stomach
• Widely distributed
• Metabolized in liver
• Excreted mainlyin bile
• Undergoes enterohepatic circulation
• Microsomal enzyme inducer

15. MECHANISOF
ACTION
• Inhibits DNA dependent RNA polymerase and interrupts
bacterial RNA synthesis.

16. MECHANISM OF
RESISTANCE
• Mutation in rpoB gene

17. ADR
• Hepatitis: Major adverseeffect
• Minor reactions
• Cutaneous: flushing, pruritis, rash, rednessand watering of eyes
• Flu like symptoms
• Abdominal syndrome
• Urine and secretions may become orange-red
• Rare reaction
– Respiratory syndrome: breathlessness which may be associated with
shock and collapse
– Purpura, haemolysis, shock and renal failure

18. USES OF RIFAMPICIN
• Tuberculosis
• Leprosy
• Prophylaxis of meningococcal meningitis &
H.influenza meningitis & prevention of carier
state
• Second/ third choice for MRSA,
legionella,Diptheroids
• Combination of doxycycline and rifampicin is
first line therapy for brucellosis

19. PYRAZINAMIDE
• Tuberculocidal
• More active in acidic medium
• More lethal to intracellular bacilli and at sites
of inflammation
• More effective during first 2 months of
treatment
• Like INH only effective inTB

20. MECHANISM OF
ACTION
Converted to active form pyrazinoic acid inside
mycobacterial cell
Metabolite gets accumulated in acidic medium
Inhibit synthesis of mycolic acids

21. MECHANISM OF
RESISTANCE
• Mutation in pncA gene which encodes
pyrazinamidase enzyme

22. PHARMACOKINETICS
• Absorbed orally
• Well distributed
• Good CSF penetration
• Extensively
metabolized in liver
• Excreted in urine

23. ADVERSE EFFECTS
• Hepatotoxicity
• Most important dose related
adverse effect
• Hyperuricaemia
• Abdominal distress
• Arthralgia,
• Flushing, rashes,fever
• Loss of diabetes control

24. ETHAMBUTOL
• Bacteriostatic drug but still used?
• Resistance to ethambutol develops slowly
• Added to RHZ hastens sputum conversion &
prevents development of resistance
• Also effective against mycobacteria resistant to
INH & streptomycin
• Also effective against many atypical mycobacteria
• No cross resistance with other anti-TB drugs
• In high conc it has tuberculocidal activity

25. MECHANISOFACTION
• Inhibit arabinosyl transferases involved in
arabinogalactan synthesis
• Interferes with mycolic acidincorporation in
mycobacterial cell wall

26. MECHANISM OF
RESISTANCE
• Mutation in embB gene
• Reduced affinityof Ethambutol for
target enzyme

27. PHARMACOKINETICS
• 75% oral dose absorbed
• Well distributed
• Penetrates meninges
inconsistently
• Less than ½ of E is
metabolized
• Excreted in urine

28. ADVERSE EFFECTS
• Good patientacceptability
• Occular toxicity
• Loss of visual acuity/color vision
,field defects
• Due to retrobulbar neuritis
• Reversible with drug stoppage
• Nausea, rashes,fever
• Rarely peripheral neuritis

29. STREPTOMYCIN
• Aminoglycoside antibiotic
• First clinically useful drug againstTB
• Bactericidal
• Must be administered IM
• Active againstextracellular bacilliin
alkaline pH
• Adverse effects
• ototoxicity, nephrotoxicity &
neuromuscular blockade

31. Drug ADR
ISONIAZID Peripheral neuropathy , Hepatitis
RIFAMPICIN •Hepatitis
•Orange red secretions and urine
PYRAZINAMIDE •Hepatotoxicity
• Hyperuricemia:gout
ETHAMBUTOL •Optic neuritis:Loss of Visual
acuity/colour vision/field defects
STREPTOMYCIN •Ototoxicity,nephrotoxicity

32. • SECOND LINE
ANTITUBERCULAR DRUGS

33. KANAMYCIN &AMIKACIN
• Aminoglycosides
• Effective against many S resistant and MDR
resistant strains of M tuberculosis
• Amikacin less toxic than kanamycin
• Important components for MDR –TB
regimens (Intensivephase)
• Audiometry and monitoring of renal function
is recommended

34. CAPREOMYCIN
• Cyclic peptide antibiotic but similar
mycobactericidal activity to Aminoglycosides
• Used as alternative to Aminoglycosides
• Adverse effects
• Ototoxicity, nephrotoxicity
• Fever
, rashes, eosinophilia
• Injection site pain

35. FLUOROQUINOLONES
• Mfx, Lfx, Ofx, Cfx
• Active against MAC as well as M. fortuitum
• Kill mycobacteria lodged inside macrophage
as well
• Primarily used for MDR-TB
• Resistance develops by mutation in DNA
gyrase
• Resistance against moxifloxacin is slow to
develop

36. CYCLOSERINE
• Analog of D alanine, Inhibits bacterial cell
wall synthesis
• Tuberculostatic in addition inhibits MAC and
some gm + bacteria, E coli and chlamydia
• Adverse effects of Cs are mainly neuro-
psychiatric
• Pyridoxine 100 mg/day can reduce
neurotoxicity and prevent convulsions
• Included in standardized regimen of MDR-TB

37. TERIZIDONE
• Contains 2 molecules of cycloserine
• Less neurotoxic and less adverse effects than
cycloserine
• Used as substitute of cycloserine especially
in genitourinary TB

38. RIFABUTIN
• Related to rifampicin in structure and
mechanism
• Active against M.Tb more active against
MAC
• Weak inducer
• Use:
• prophylaxis of MAC inAIDS
• HIV patients along with NNRTI
• MAC

39. BEDAQUILINE (BDQ)
• Inhibits mycobacterial ATP synthase thus
limits energy production in mycobacterial
cell
• Strong bactericidal kills rapidly multiplying as
well as dormant M Tuberculosis
• Terminal half life is very long 160 days
• Adverse effects: nausea, headache,
arthralgia, prolongation of Qtc

40. GUIDELINES FOR USE OF
BEDAQUILINE
• Only in patients > 18 yearsAge in MDR TB
• Non pregnant
• Only in combination with 3 other susceptible
anti-TB drugs or 4 drugs with likely sensitivity
• Only when effective regimen cannot otherwise
be provided
• Given max for 24 weeks, the other anti-TB drugs
should be continued for 24 months
• Not used for drug sensitive or extrapulmonary
TB

41. Treatment of TB
• GOALS OF ANTITUBERCULAR
CHEMOTHERAPY
• Kill dividing bacilli
• Kill persisting bacilli
• Prevent emergence of resistance

42. SHORT COURSE CHEMOTHERAPY
• WHO introduced 6-8 months multidrug
short course regimens in 1995
• DOTS strategy
• Clear cut guidelines for different categories
of TB patients

43. CLASSIFICATION OFTB CASES
• Drug sensitiveTB
• Multidrug resistant TB (MDR-TB)
• Rifampicin resistant TB
• Monoresistant TB
• Poly Drug resistant TB (PDR-TB)
• Extensive Drug resistant TB (XDR-TB)

44. TREATMENT REGIMEN FOR NEW AND PREVIOUSLY
TREATED PATIENTS OF
PULMONARYTB PRESUMED TO BE DRUG SENSITIVE
Type of
patient
Intensive phase Continuation
phase
Total duration
New 2 HRZE 4 HRE 6
Previously
treated
2 HRZES
+ 1 HRZE
5 HRE 8

45. STANDARD RNTCP REGIMEN FOR
MDR-TB
Intensive phase (6-9 months) Continuation phase (18months)
1.Kanamycin(Km) -
2.Levofloxacin(Lfx) 1.Levofloxacin(Lfx)
3.Ethionamide(Eto) 2.Ethionamide(Eto)
4.Cycloserine (Cs) 3.Cycloserine (Cs)
5.Pyrazinamide(Z) 4.Pyrazinamide(Z)
6.Etambutol(E)
+Pyridoxine 100 mg/day

46. MDR-TB is
defined as
resistance to
isoniazid plus
rifampin.
XDR-TB is
defined as
resistance to at
least rifampin &
isoniazid plus
resistance to the
fluoroquinolones
and to at least
one of the
injectable drugs
capreomycin,
kanamycin and
amikacin.
Dr

47. EXTENSIVE DRUG RESISTANTTB
Intensive phase (6-12months) Continuation phase (18months)
1.Capreomycin (Cm) -
2.Moxifloxacin (Mfx) 2.Moxifloxacin (Mfx)
3.High dose Isoniazid (H) 3.High dose Isoniazid (H)
4.ParaAmino salicylic acid(PAS) 4.ParaAmino salicylic acid(PAS)
5.Clofazimine(Clo) 5.Clofazimine(Clo)
6.Linezolid 6.Linezolid
7.Amoxicillinclavulanate 7.Amoxicillinclavulanate

48. TUBERCULOSIS IN PREGNANT
WOMEN
• 2 HRZE+4 HRE
• Streptomycin is contraindicated

49. INDICATIONS OF
CHEMOPROPHYLAXIS
1.Contacts of open cases who show recent
Mantoux conversion.
2.Children with aTB patient in the
family
.
3.Neonate of atubercular mother
.
4.Patients of leukemia,diabetes, silicosis or
HIV+ve
5.HIV infected contacts of sputum positive index
cases

50. CORTICOSTEROIDS IN
TUBERCULOSIS
• Seriously ill patients (miliary or severe pulmonary
TB)
• Hypersensitivity reactions occur to anti tubercular drugs
• Meningeal,renalTB or pleural effusion- to ↓ exudation
• In AIDS patients with severe manifestations of
Tuberculosis.
• Contraindicated in intestinal TB for fear of silent
perforation.
• Withdrawn gradually when the general condition of the
patient improves

51. SUMMARY
• Classify antitubercular drugs
• Discuss mechanism of action, adverse effects,
drug interactions and contraindications of
• first line antitubercular drugs
• Discuss WHO regimens for treatment of
tuberculosis
• Explain multi-drug resistant (MDR) Tuberculosis
mechanisms and available drugs for MDR
and XDR tuberculosis

52. •THANK YOU