Drug treatment of tuberculosis, drugs used for TB and pharmacology of first line and second line antitubercular drugs

1. ANTITUBERCULAR
DRUGS
DR NASER ASHRAF TADVI

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

3. TUBERCULOSIS

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

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

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

7. CLASSIFICATION OF ANTITUBERCULAR DRUGS

8. ISONIAZID (H)
• Tuberculocidal
• Fast multiplying organisms rapidly killed
• Acts on extracellular and intracellularTB bacilli
• Equally effective in acidic and alkaline medium
• Cheapest
• Not effective against atypical Mycobacteria except M. Kansasi

9. MECHANISM OF 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 (Overproduction)

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

12. ADVERSE EFFECTS
• Peripheral neuritis
• Paresthesia, numbness, mental disturbances, rarely convulsions
• Hepatotoxicity
• More in elderly and alcoholics
• Lethargy, rashes, mild anemia, arthralgia

13. RIFAMPICIN
• Tuberculocidal
• Best action against slowly or intermittently dividing M.Tuberculosis
• Also effective against variety of other Gm +/- infections
• Effective against M. Leprae
• Effective against atypical bacteria like MAC but not M. fortuitum
• Both extracellular and intracellular affected

14. MECHANISM OF ACTION
• Inhibits DNA dependent RNA polymerase and interrupts bacterial RNA synthesis.

15. MECHANISM OF RESISTANCE
• Mutation in rpoB gene

16. PHARMACOKINETICS
• 70 % bioavailability (↓ with food)
• Should be taken on empty stomach
• Widely distributed
• Metabolized in liver
• Excreted mainly in bile
• Undergoes enterohepatic circulation
• Microsomal enzyme inducer

17. ADVERSE EFFECTS
• Hepatitis: Major adverse effect
• Minor reactions
• Cutaneous: flushing, pruritis, rash, redness and watering of eyes
• Flu like symptoms
• Abdominal cramps
• Urine and other secretions may become orange red

18. USES OF RIFAMPICIN
• Tuberculosis
• Leprosy
• Prophylaxis of meningococcal meningitis
• Second/ third choice for MRSA, legionella
• 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. MECHANISM OF ACTION
• Inhibit arabinosyl transferases involved in arabinogalactan synthesis
• Interferes with mycolic acid incorporation in mycobacterial cell wall

26. MECHANISM OF RESISTANCE
• Mutation in embB gene
• Reduced affinity of 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 patient acceptability
• 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 against extracellular bacilli in alkaline pH
• Adverse effects
• ototoxicity, nephrotoxicity & neuromuscular blockade

30. Mechanism Of Action of first line antitubercular drugs
PROTEIN SYNTHESIS
INHIBITION
CELL WALL
SYNTHESIS
INHIBITION
Transcriptional
level
Translational
level
MYCOLIC ACID
SYNTHESIS
INHIBITION
ARABINOGYLACT
AN SYNTHESIS
INHIBITION
DNA
DEPENDENT
RNA
POLYMERASE
30S
Ribosomal
inhibition
FATTY ACID
SYNTHASE 1
INHIBITOR
RIFAMPICIN STREPTOMYCIN ISONIAZID ETHAMBUTOL
FATTY ACID
SYNTHASE 2
INHIBITOR
PYRAZINAMIDE

32. DRUG RESISTANCE of 1st line drugs
DRUG Mechanism of resistance
ISONIAZID Mutation of the katG gene,
mutation in the inhA gene & kasA gene
RIFAMPICIN Mutation of the rpoB gene
PYRAZINAMIDE Mutation in gene encoding (pncA gene)
ETHAMBUTOL Alteration of drug target gene (embB)
STREPTOMYCIN One step mutation or by acquisition of plasmid

33. DRUGS ABSORPTION DISTRIBUTION METABOLISM EXCRETION
ISONIAZID Well absorbed Penetrates all body tissues,
placenta and meninges.
Hepatic (acetylation)
t½-fast acetylators
(1 hr),slow(3 hrs)
urine
RIFAMPICIN Well absorbed Penetrates all body tissues,
placenta and meninges.
Hepatic
t½ -variable (2- 5 hrs)
Mainly in bile &
some in urine.
PYRAZINAMIDE Well absorbed Widely distributed , good CSF
penetration
Hepatic
t½ - 6-10 hrs
urine
ETHAMBUTOL Well absorbed Widely distributed, penetrates
meninges incompletely,
temporarily stored in RBC’s
Hepatic
t½ ~4 hrs
urine
STREPTOMYCIN GIT-not absorbed
IM-rapid
Penetrates tubercular
cavities;does not cross BBB
Not metabolised
t½ -2-4 hrs.
Urine
(unchanged)
PHARMACOKINETICS

34. ADVERSE REACTIONS of 1st line drugs
DRUG Adverse effects
ISONIAZID Peripheral neuropathy
Hepatitis
RIFAMPICIN Hepatitis
Orange red secretions and urine
PYRAZINAMIDE Hepatotoxicity
Hyperuricemia:gout
ETHAMBUTOL Optic neuritis:Loss ofVisual acuity/colour vision/field
defects
STREPTOMYCIN Ototoxicity, nephrotoxicity

35. Drug Interactions
Isoniazid Aluminium hydroxide inhibits absorption
INH inhibits phenytoin, carmazepine, diazepam, and
warfarin metabolism
Rifampicin Hepatic microsomal enzyme inducer
increases metabolism of drugs like warfarin, digoxin,
oral contraceptives, dapsone, protease inhibitors,
sulfonylureas,steroids,ketoconazole

36. Recommended doses of Antitubercular
drugs
ISONIAZID 5 300 mg 10 600 mg
RIFAMPICIN 10 600 mg 10 600 mg
PYRAZINAMIDE 25 1500 mg 35 2000 mg
ETHAMBUTOL 15 1000 mg 30 1600mg
STREPTOMYCIN 15 1000 mg 15 1000 mg
DRUG DAILY DOSE 3 × PER WEEK
DOSE
mg/kg >50 kg mg/kg >50 kg

37. SECOND LINE
ANTITUBERCULAR
DRUGS

38. 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 (Intensive phase)
• Audiometry and monitoring of renal function is recommended

39. 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

40. 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
(FQs)

41. CYCLOSERINE
• Analog of D alanine, Inhibits bacterial cell wall synthesis
• Tuberculostatic in addition inhibits MAC and some gm + bacteria, E coli and chlamydia
• Good oral absorption and distribution even in CSF
• 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

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

43. PARA-AMINO SALICYLIC ACID (PAS)
• Bacteriostatic and least effective
• Inhibits folic acid synthesis
• Only advantage is delays resistance
• Adverse effects:
• Severe anorexia, vomiting , epigastric pain, hypokalemia, goiter
• Poorly tolerated
• Dose: 10 – 12 gm/day

44. RIFABUTIN
• Related to rifampicin in structure and mechanism
• Active against M.Tb more active against MAC
• Weak inducer
• Use:
• prophylaxis of MAC in AIDS
• HIV patients along with NNRTI
• MAC: Rifabutin + E + Clarithromycin / Azithromycin
• Adverse events:
• GIT intolerance, Myalgia, granulocytopenia , uveitis

45. BEDAQUILINE (BDQ)
• Inhibits mycobacterial ATP synthase thus limits energy production in mycobacterial cell
• Strong bactericidal kills rapidly multiplying as well as dormant MTuberculosis
• Well absorbed orally and fatty meal increases its absorption
• Metabolized by CYP3A4 in liver , excreted mainly in feces
• Terminal half life is very long 160 days
• Adverse effects: nausea, headache, arthralgia, prolongation of Qtc

46. GUIDELINES FOR USE OF BEDAQUILINE
• Only in patients > 18 years Age
• 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 extrapulmonaryTB

47. GOALS OF ANTITUBERCULAR CHEMOTHERAPY
• Kill dividing bacilli
• Kill persisting bacilli
• Prevent emergence of resistance

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

49. CLASSIFICATION OFTB CASES
• Drug sensitiveTB
• Multidrug resistantTB (MDR-TB)
• Rifampicin resistantTB (RR-TB)
• MonoresistantTB
• Poly Drug resistantTB (PDR-TB)
• Extensive Drug resistantTB (XDR-TB)

50. TREATMENT REGIMEN FOR NEW AND PREVIOUSLYTREATED PATIENTS OF
PULMONARY TB PRESUMEDTO 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

51. STANDARD RNTCP REGIMEN FOR MDR-TB
Intensive phase (6-9 months) Continuation phase (18 months)
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

52. 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 Arif

53. EXTENSIVE DRUG RESISTANT TB
Intensive phase (6-12 months) Continuation phase (18 months)
1. Capreomycin (Cm) -
2. Moxifloxacin (Mfx) 2. Moxifloxacin (Mfx)
3. High dose Isoniazid (H) 3. High dose Isoniazid (H)
4. Para Amino salicylic acid (PAS) 4. Para Amino salicylic acid (PAS)
5. Clofazimine (Clo) 5. Clofazimine (Clo)
6. Linezolid 6. Linezolid
7.Amoxicillin clavulanate 7.Amoxicillin clavulanate

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

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

56. CHEMOPROPHYLAXIS OFTUBERCULOSIS
• -INH 300mg (10 mg/kg in children)daily for 6 months).
-INH(5 mg/kg/day) + RMP(10 mg/kg/day) for 6 months in patients with INH
resistance.

57. TUBERCULOSIS IN AIDS PATIENTS
• HIV + TB infection is serious problem
• Short course chemotherapy should be immediately started
• Treatment given: 2 HRZE + 7 HR
•Rifabutin can be used in place of Rifampin as it has lesser
interaction with protease inhibitors

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

59. MYCOBACTERIUM AVIUM COMPLEX (MAC)
INFECTION
• Clarithromycin and Azithromycin are most active drugs
• Opportunistic infection in HIV-AIDS patients
• Intensive phase (4 drugs) (2-6 months)
• Clarithromycin or Azithromycin + E+ Rifabutin + one FQ
• Continuation Phase (12 months)
• Clarithromycin or Azithromycin + E/Rifabutin/FQ

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

61. FURTHER READING
• Essentials of Medical Pharmacology 8th edition, by KD Tripathi