This presentation describes epidemiology of tuberculosis, classification of anti-tubercular drugs based on the efficacy and priority and the pharmacology of the anti-tubercular drugs.

1. Pharmacology of Antitubercular
drugs
Dr Ravi Shankar M
Professor and Head
13.5.2021

2. Specific Learning Objectives
• At the end of the teaching-learning session
the student should be able to
1. Explain the epidemiology of tuberculosis (TB)
2. Classify the antitubercular drugs
3. Describe the pharmacology of antitubercular
drugs

3. Introduction to tuberculosis
• TB is a chronic granulomatous disease which is
especially problematic in developing
countries
• About 1/3 of world’s population is infected
with tubercle bacilli
• 15 to 20% of this one-third develop TB in their
life time

4. Introduction to tuberculosis
• TB is a notifiable disease in India from 2012
• Prevention and treatment of TB is covered under
Revised National Tuberculosis Program (RNTCP)
from 1996
• Latest revised guidelines in 2016
• Treatment is provided free of cost

5. Epidemiology of TB
• 9.6 million new cases in 2014 in the world
• 2.2 million from India
• Maximum burden in India – 600 deaths due to
TB in 24 hours

6. Epidemiology of TB
• In 1980s HIV/AIDS started showing increasing
prevalence of TB
• HIV/AIDS patients showed severe forms of
TB/MAC
• Multi-drug resistant TB (MDR-TB)is the new
challenge

7. Epidemiology of TB
• MDR-TB is resistance to isoniazid and
rifampin and any number of first line drugs
• 3% of newly diagnosed and 18% of retreated
patients are MDR-TB

8. Classification of anti-tubercular drugs
• First line drugs
• Second line drugs
1. Injectables
2. Fluoroquinolones
3. Second line oral drugs
4. Drugs with doubtful efficacy

9. Classification of anti-tubercular drugs
• First line drugs
1. Isoniazid (H)
2. Rifampicin (R)
3. Pyrazinamide (Z)
4. Ethambutol (E)
5. Streptomycin (S)

10. Second line anti-tubercular drugs
• Injectables
1. Kanamycin
2. Amikacin
3. Capreomycin
• Fluoroquinolones
1. Ofloxacin
2. Levofloxacin
3. Moxifloxacin
4. Ciprofloxacin

11. Second line anti-tubercular drugs
• Second line oral drugs
1. Ethionamide
2. Prothionamide
3. Cycloserine
4. Paraaminosalicylic acid
5. Terizidone
6. Rifabutin
7. Rifapentin

12. Classification based on
efficacy/priority

13. Group I (First line oral drugs)
1. Isoniazid
2. Rifampicin
3. Pyrazinamide
4. Ethambutol
Highest efficacy and best tolerability

14. Group II (Injectables)
1. Kanamycin
2. Amikacin
3. Capreomycin
4. Streptomycin
Highly efficacious, cidal but injectables

15. Group III (Fluoroquinolones)
• Ofloxacin
• Levifloxacin
• Moxifloxacin
• Ciprofloxacin
Cidal, efficacious, oral, should always be given
in resistant cases

16. Group IV (Second line oral drugs)
1. Ethionamide
2. Prothionamide
3. Cycloserine
4. Paraaminosalicylic acid
5. Terizidone
6. Rifabutin
7. Rifapentin
Static, less efficacious, more toxic, indicated in
MDR-TB

17. Group V (Drugs with doubtful
efficacy)
1. Clarithromycin
2. Clofazamine
3. Linezolid
4. Amoxycillin with Clavulanic acid
5. Imipenem with Cilastatin
Indicated in XDR-TB

18. Pharmacology of first line anti-
tubercular drugs

19. Isoniazid (H)

20. Isoniazid (H)
• Excellent antitubercular drug
• Should always be present in regimens
• Tuberculocidal, indicated only in TB
• Highly efficacious against rapidly dividing
bacilli

21. Isoniazid (H)
• Extracellular and intracellular activity
• Activity in acidic and alkaline Ph
• Inhibits mycolic acid synthesis in tubercle bacilli
• Fatty acids in mycobacterial cell wall is reduced in
bacilli exposed

22. Isoniazid (H)
• Converted into reactive metabolite by
catalase peroxidase (kat A gene)
• Interacts with inhA and kasA, gene products
involved in mycolic acid synthesis
• 1 in 10 to the power 6 bacilli are resistant

23. Isoniazid (H)
• Used alone, resistant bacilli proliferate
replacing a sensitive with resistant population
• Mutation with kat A gene will require removal
of Isoniazid
• Mutation with inhA gene would require use of
higher dose of Isoniazid

24. Isoniazid (H)
• Incidence of primary resistance is 8.5%
• Daily dose is 5mg/kg, 300 mg for adult

25. Pharmacokinetics of Isoniazid
• Well absorbed orally
• Distributed in cavities, caseous masses, across
placenta, meninges
• Genetic variation in metabolism, fast and slow
acetylators

26. Adverse effects of Isoniazid (H)
• Major adverse effect is hepatotoxicity
• Alcoholics, pre-existing liver disease
• Liver function test (LFT) mandatory before
starting Isoniazid

27. Adverse effects of Isoniazid (H)
• Neurotoxicity manifestations like tingling,
burning sensation, mental confusion and
sometimes convulsions
• Reduced formation of cofactor of pyridoxine,
pyridoxal phosphate and enhanced excretion
• Prophylaxis with 10mg and treatment with
100mg of Pyridoxine, Vit B6

28. Adverse effects of Isoniazid (H)
• Prophylaxis with pyridoxine is mandatory for
alcoholics, malnourished, pregnancy, lactating
and elderly
• Antacids interfere with absorption of Isoniazid
• Microsomal enzyme inhibitor

29. Pharmacogenetics of Isoniazid
• Fast acetylators, t1/2 is 1 hr (30 to 40%
Indians)
• Slow acetylators, t1/2 is 3 hr (60 to 70%
Indians)
• Peripheral neuritis is more common in slow
acetylators

30. Rifampicin (R)

31. Rifampicin (R)
• Obtained from Rifamycin B from Streptomyces
mediterannie
• Equi-efficacious to Isoniazid
• Most efficacious against intermittently dividing
bacilli (spurters)
• Active against intra and extracellular bacilli

32. Rifampicin (R)
• Active in acidic and alkaline Ph
• Acts by inhibiting RNA synthesis
• Binds to and inhibits B subunit of DNA-
dependant RNA polymerase (coded by repo B
gene)

33. Rifampicin (R)
• 1 in 10 to the power 7 bacilli are resistant to
Rifampin
• Primary resistance to Rifampin is rare (2%)
• Resistance is due to mutation in repo B gene
preventing binding of Rifampin

34. Rifampicin (R)
• Useful against few other gram +ve and gram –
ve bacteria
• Meningococci, H.influenza, Brucella,
Legionella, Staphylococcus aureus etc.,
• Atypical mycobacteria also except
M.fortuitum

35. Adverse effects of Rifampicin
• Major is hepatotoxicity
• Pre-existing liver disease is more susceptible
(LFT mandatory)
• Jaundice during treatment is indication to
stop Rifampin

36. Rifampicin (R)
• Rare but serious ADRs also include hemolysis,
shock, purpura and renal failure
• Microsomal enzyme inducer
• Orange-red colouration of body secretions
• Less serious ADRs also includes flu syndrome,
abdominal syndrome, cutaneous syndrome

37. Other uses of Rifampin
1. Leprosy
2. Second line for MRSA, Diphtheroids and
Legionella
3. Prophylaxis in epidemics of meningococcal and
H.influenze meningitis
4. (Rifampin + Doxycycline) in brucellosis is first
line treatment

38. Pyrazinamide (Z)

39. Pyrazinamide (Z)
• Chemically similar to Isoniazid and also in
mechanism of action
• Tuberculocidal, less efficacious than Isoniazid
• Acts best in acidic pH, in inflammatory lesions
and intracellularly
• Preferred in first two months

40. Pyrazinamide (Z)
• It is converted to active metabolite, pyrazinoic
acid by pyrazinamidase (coded by pncA gene)
• Resistance is due to mutation of pncA gene
• Including pyrazinamide reduces duration of
treatment and prevention of resistance

41. Adverse effects of Pyrazinamide (Z)
• Hepatotoxicity, contraindicated in liver
disease
• Hyperuricemia is common, interferes with
uric acid excretion
• Fluctuation of diabetes, need to monitor
plasma glucose

42. Ethambutol (E)

43. Ethambutol (E)
• Selectively tuberculostatic
• Inhibits arabinosyl transferases, inhibits
arabinogalactan synthesis
• Inhibits incorporation of mycolic acid
• Hastens sputum conversion and prevents
emergence of resistance

44. Adverse effects of Ethambutol (E)
• Retrobulbar neuritis, manifests as dimunition
of visual acquity, color vision and field of
vision
• Early reporting and stopping the drug reverses
the situation

45. Streptomycin (S)

46. Streptomycin (S)
• Injectable
• Extracellular action
• Dose related nephrotoxicity and ototoxicity
• Supplemental first line drug

47. Daily dose of first line anti-tubercular
drugs
• Isoniazid – 5 mg/kg
• Rifampicin – 10 mg/kg
• Pyrazinamide – 25 mg/kg
• Ethambutol and Streptomycin – 15 mg/kg

48. Pharmacology of second line
anti-tubercular drugs

49. Injectables
• Amikacin and Kanamycin are aminoglycosides
• Similar to Streptomycin in their pharmacology
• Indicated in MDR-TB
• Audiometry and monitoring of renal function

51. Injectables
• Capreomycin is chemically different to
aminoglycosides
• Nephrotoxicity and ototoxicity is similar
• Preferred in Drug Resistant Tuberculosis (DR-
TB)

53. Fluoroquinolones
• Moxifloxacin, Levofloxacin, Ofloxacin and
Ciprofloxacin
• Moxifloxacin is most efficacious
• Always indicated in MDR-TB
• Oral, good penetration, kills bacilli in
macrophages, good tolerability

56. Second line oral anti-tubercular drugs
• Ethionamide and Prothionamide can be used
interchangeably
• Similar in action to Isoniazid
• Indicated in MDR-TB and MAC infections
• Not well tolerated

58. Second line oral anti-tubercular drugs
• Cycloserine, Terizidone
• Used interchangeably
• Cycloserine is indicated in MDR-TB
• Not well tolerated

60. Second line oral anti-tubercular drugs
• Para-aminosalicylic acid (PAS)
• Similar to sulphonamides
• Indicated in DR-TB
• Not well tolerated

61. Second line oral anti-tubercular drugs
• Rifabutin, Rifapentin
• Rifampin congeners
• Rifabutin is less effective against tubercle bacilli
and more against atypical bacilli
• Rifabutin is weaker microsomal enzyme inducer

62. Second line oral anti-tubercular drugs
• Rifabutin is preferred when patient is on anti-
retroviral drugs (Protease inhibitors and Non-
Nucleoside Reverse Transcriptase Inhibitors)
• Rifabutin is also used in prophylaxis and
treatment of MAC infections in AIDS patients
• Rifapentin is long acting and hence indicated
in continuation phase

64. Bedaquiline
• Diarylquinoline derivative
• Inhibits mycobacterial ATP synthase
• Energy processes are affected
• Tuberculocidal on rapidly dividing and
dormant bacilli

65. Bedaquiline
• Indicated only in MDR-TB to enhance efficacy
of the regimens
• Used for 24 weeks along with at least 3 or 4
effective drugs
• Used with precaution in patients with QT
prolongation

66. Summary
1. Epidemiology of tuberculosis
2. Classification of antitubercular drugs
3. Pharmacology of antitubercular drugs

67. Thank you
Happy reading