Drugs for tuberculosis

1. Pharmacological agents in
tuberculosis
Dr. Marya Ahsan MBBS, MD

2. Learning Outcomes…
At the end of the presentation, students must be able to:
• Classify antitubercular drugs
• Describe the mechanism of action of antitubercular drugs
• Describe the adverse effects of antitubercular drugs
• Describe the treatment regimens for drug-susceptible tuberculosis
• Describe the treatment regimen for drug-resistant tuberculosis

3. Tuberculosis…
• Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis
(MTB)
• In 2010, an estimated 8.8 million incident cases occurred
• Second most common cause of death due to an infective disease.
• It is estimated that around one-third of the world’s population has latent
TB.
• The majority of cases occur in the world’s poorest nations
• In Africa, the resurgence of TB has been largely driven by HIV disease

4. Chronic cough, often with hemoptysis
Pyrexia, of unknown origin
Weight loss, general debility
Unresolved pneumonia
Exudative pleural effusion
Spontaneous pneumothorax
Clinical features of
pulmonary
tuberculosis

5. Systemic
presentations of
extrapulmonary
tuberculosis

6. Mycobacteria
Difficult
to treat
Grow very
slowly
Cell wall
contains
mycolic acid
Reside within
macrophages
Have the
ability to
develop
resistance
Response to
chemotherapy
is slow
resistant to most
antibiotics
impermeable to many
antibiotics
inaccessible to many drugs
combination of drugs are
required to prevent
emergence of resistance
treatment for months
to years is required

7. First line drugs for tuberculosis…
• Isoniazid (H)
• Rifamycins (R)
• Pyrazinamide (Z)
• Ethambutol (E)
• Streptomycin (S)

8. Second line drugs for tuberculosis…
• Para-aminosalicylic acid
• Capreomycin
• Cycloserine
• Ethionamide
• Flouroquinolones
• Macrolides
• Bedaquiline
• Second line drugs are:
Less effective
More toxic

9. Isoniazid (H)
• Most active drug for the treatment of
tuberculosis
Bactericidal for actively growing bacilli
Active against both intracellular and
extracellular organisms
• Structurally similar to
pyridoxine

10. Isoniazid (H)
Mechanism of action:
It is a Prodrug….. activated by mycobacterial catalase-peroxidase (KatG)
inhibits the enzyme acyl carrier protein reductase (encoded by gene
InhA) and beta-ketoacyl-ACP synthase (KasA)….these enzymes are
essential for synthesis of mycolic acid
Inhibition of mycolic acid synthesis disrupts the bacterial cell wall
Inhibits synthesis
of mycolic acid

11. Isoniazid (H)
Antibacterial spectrum
• It is specific for treatment of Mycobacterium tuberculosis
• Particularly effective against rapidly growing bacilli
• Also active against intracellular organisms

12. Isoniazid (H)
Resistance
Chromosomal mutations can cause:
Mutation or deletion of KatG (mutants cannot activate the prodrug)
Mutation of acyl carrier proteins
Overexpression off target enzyme InhA
• Cross resistance may occur between isoniazid and ethionamide

13. Isoniazid (H)
Pharmacokinetics:
Readily absorbed after oral administration
Diffuses into all body fluids….also readily enters CSF
Metabolised in the liver by N-acetylation
(N-acetyltransferase) and hydrolysis
Metabolites are excreted by glomerular filtration
and excretion
• Isoniazid acetylation
is genetically
regulated
Slow acetylators
(t ½ = 4hrs)
Fast acetylators
(t ½ = 90 mins)

14. Isoniazid (H)
Adverse effects
• Hepatitis
• Peripheral neuropathy
• Hypersensitivity reactions
• It can potentiate the adverse effects due to carbamazepine and
phenytoin by inhibiting their metabolism

15. Isoniazid (H)
• Peripheral neuropathy is due to relative pyridoxine deficiency (vit B6)
For prophylaxis: Tab. pyridoxine 10 mg daily
For treatment: Tab. pyridoxine 100 mg daily

16. Rifamycins
RIFAMYCINS : Rifampin, rifabutin and rifapentine are all considered
rifamycins and are first line oral agents for tuberculosis
Rifamycins block RNA
transcription

17. Rifampin (R)
Mechanism of action:
• Bactericidal
• Blocks RNA transcription by interacting with β-subunits of
mycobacterial DNA-dependent RNA polymerase
Antibacterial spectrum:
 Intracellular and extracellular M.tuberculosis,
 Non-tuberculous mycobacteria
 M. leprae
 Meningococci
 H.influenzae

18. Rifampin (R)
Pharmacokinetics:
• Well absorbed orally
• Enters all body fluids
• Taken up by liver and undergoes enterohepatic
circulation
• Excreted through bile into faeces.
• Small amount is excreted in urine
Urine, feces and
other secretions
become orange-
red colour with
rifampin use
Tears can even
stain soft
contact lenses
orange-red

19. Rifampin (R)
Resistance:
• Mutations in the affinity of the bacterial DNA-dependent RNA
polymerase gene

20. Rifamycins
Rifabutin:
Preferred for TB patients co-infected with HIV being treated with
protease inhibitors or NNRTI
Rifapentine:
Longer t ½ than rifampin
Used once weekly in LTBI

21. Pyrazinamide (Z)
• Activated by pyrazinamidase to pyrazinoic acid
• Weakly tuberculocidal and active against TB bacilli in acidic lesions
and in macrophages
Adverse effect:
• Liver toxicity
• Uric acid retention
• The drug is discontinued after 2 months of use

22. Ethambutol (E)
• Bacteriostatic
• Inhibits arabinosyl transferase: required for mycobacterial cell wall
synthesis
Adverse effect:
• Optic neuritis: results in diminished visual acuity, red-green colour-
blindness
• Visual acuity and colour vision should be tested prior to starting
therapy
• Not given to children less than 6 years of age

23. Streptomycin (S)
• One of the first effective agents for TB
• Aminoglycoside antibiotic
• Tuberculocidal
• More active against extracellular organisms
• Recent studies indicate worldwide increase in resistance to
streptomycin
Because of need for i.m.
injections and lower margin of
safety (ototoxicity and
nephrotoxicity, it is used only
as an alternative to or in
addition to other 1st line anti-
TB drugs
Labelled as a ‘supplemental’
1st line drug

24. Goal of antitubercular therapy
• Kill dividing bacilli
to achieve quick symptom relief and render the patient non-
contagious
• Kill persisting bacilli
to achieve cure and prevent relapse
• Prevent emergence of resistance

25. Drug treatment of tuberculosis
• The therapy of tuberculosis has undergone remarkable changes.
• The conventional long treatments have been replaced by more
effective and less toxic 6 month (short course) treatment
• The short course yields higher completion rates

26. Drug treatment of tuberculosis
The combination of drugs and their duration of treatment is divided
into two phases:
Intensive phase:
4–5 drugs are used for 2–3 months aimed to rapidly kill the bacilli, bringing about
sputum conversion and afford fast symptomatic relief.
Continuation phase:
2–3 drugs lasting 4–5 months during which the remaining bacilli are eliminated so
that relapse does not occur.

27. Drug treatment of tuberculosis
• 2 months
• 4–5 drugs are used
• Rapidly kill the bacilli,
sputum conversion,
symptomatic relief
Intensive phase
• 4 months
• 2–3 drugs are used
• Kill remaining bacteria,
prevent relapse
Continuation phase

28. Fixed dose combination of drugs (FDCs)
• The use of fixed-dose combination tablets is recommended over
separate drug formulations in treatment of patients with drug-
susceptible TB: WHO (2017)
Better patient compliance

29. Treatment of drug-susceptible tuberculosis
Type of TB case Intensive phase (months) Continuous phase (months)
Newly diagnosed HRZE (2 months) HRE (4 months)
Previously treated
(recurrence, lost follow up
during treatment, after failure
of recent course)
HRZES (2 months)
+ HRZE (1 month)
HRE (5 months)
In all patients with drug-susceptible pulmonary TB, the use of thrice-weekly dosing
is not recommended in both the intensive and continuation phases of therapy and
daily dosing remains the recommended dosing frequency

30. Treatment of drug-susceptible tuberculosis
Weight category
(kg)
Number of tablets (FDCs)
Inj. Streptomycin
(g)
Intensive phase Continuation
phase
HRZE HRE
75/150/400/275 75/150/275
25-39 2 2 0.5
40-54 3 3 0.75
55-69 4 4 1
>70 5 5 1

31. Drug resistant TB
• Drug-resistant TB is defined by the presence of resistance to any first-
line agent.
Isoniazid resistant (Hr-TB)
Rifampicin resistant (RR-TB)
Multidrug-resistant TB (MDR-TB) is defined by resistance to at least
rifampicin and isoniazid, with or without other drug resistance.
Extensively drug-resistant TB (XDR-TB) is defined as resistance to at
least rifampicin and isoniazid, in addition to any quinolone and at
least one injectable second line agent.

32. • Isoniazid
Hr-TB
• Rifampin
RR-TB
• Isoniazid and/or Rifampin
• Any other drug
MDR-TB
• Isoniazid
• Rifampin
• FQ
• One injectable 2nd
line drug
XDR-TB
X X
X X

33. Isoniazid resistant TB
Regimens for isoniazid-resistant tuberculosis (Hr-TB):
• In patients with confirmed rifampicin-susceptible and isoniazid-
resistant tuberculosis, treatment with rifampicin, ethambutol,
pyrazinamide and levofloxacin is recommended for a duration of 6
months

35. MDR-TB/RR-TB
Longer regimen: (upto 18 months)
Start with total 4 drugs
All three Group A agents and at least one Group B agent should be
included
At least three agents are included for the rest of the treatment after
bedaquiline is stopped
 If only one or two Group A agents are used, both Group B agents are
to be included.
If the regimen cannot be composed with agents from Groups A and B
alone, Group C agents are added to complete it.

37. References
• WHO consolidated guidelines on drug-resistant tuberculosis
treatment. World Health Organization 2019
• Guidelines for treatment of drug-susceptible tuberculosis and patient
care, 2017 UPDATE. World Health Organization 2017
• Lippincott Illustrated Reviews: Pharmacology(6th ed.). Philadelphia,
PA: Wolters Kluwer
• Walker BR, Colledge NR, Penman ID. Davidson's principles and
practice of medicine (22nd ed.). Edinburgh: Churchill Livingstone.