1. B.Pharm (Hon.), M. Sc. In Pharm (Pharmacology)
Antimycobacterial drugs
Pawitra Pulbutr
B.Pharm (Hon.), M. Sc. In Pharm (Pharmacology)

2. วัตถุประสงค์เชิงพฤติกรรม
เมื่อนิสิตศึกษาเอกสารแล้วนิสิตสามารถ
มีความเข้าใจและอธิบายถึงกลไกการออกฤทธิ์, เภสัชจลนศาสตร์, อาการไม่พึงประสงค์ของยา Antimycobacterial
มีความเข้าใจและอธิบายถึงการนำไปใช้ประโยชน์ทางคลินิคของยา Antimycobacterial

3. Mycobacteria Mycobacterium tuberculosis Tuberculosis, TB วัณโรค
Mycobacterium leprae
Leprosy โรคเรื้อน
Atypical mycobacteria
Mycobacterium avium complex (MAC)
Opportunistic infection in AIDS

4. Characteristic of Mycobacteria
Resistance to many antibacterial
Slowly growing or Dormant
Lipid rich cell wall
Intracellular organisms
Able to develop resistance
Impermeable to many agents
Many agents are inaccessible
Hard to be eradicated
Need drug combination

5. Drugs used in tuberculosis
Second line drugs
First line drugs
Ethionamide
Capreomycin
Cycloserine
PAS
Kanamycin & Amikacin
Quinolones
Rifabutin
Rifapentine
Clofazemine
Isoniazid (INH,H, I)
Rifampin [R]
Pyrazinamide [ Z ]
Ethambutol [ E ]
Streptomycin [ S ]

6. Isoniazid (INH) Mechanism of Action Mycolic acid
Essential components of mycobacterial cell wall
INH form complex with
Acyl carrier protein (Acp M)
Beta ketoacyl carrier protein synthase (Kas A)
*Inhibit mycolic acid synthesis*
Need mycobacterial catalase peroxidase (Kat G) to become active

7. Adverse drug reactions (ADRs)
1. INH induced hepatitis
loss of appetite, n/v, jaundice, right upper quadrant pain
can be lethal !!
STOP INH, if occur
risk depend on age of patients
risk patients ex. Alcoholism, pregnancy, feeding mother

8. 2. Peripheral neuropathy
Especially occur in slow acetylator, malnutrition, alcoholism, DM, AIDS, uremia
INH form complex with pyridoxine [pyridoxal hydrazone]
Then, increase pyridoxine excretion in urine
Lack of pyridoxine (Vitamin B6)
Rx : Pyridoxine 10 mg/day

9. Rifampin = Enzyme inducer
Mechanism of action
Binds with beta subunit of bacterial DNA dependent RNA polymerase**
Inhibit RNA synthesis
Mechanism of resistance
Mutation of beta subunit of RNA polymerase
Rifampin = Enzyme inducer

10. Rifampin
ADRs
Orange secretion*** …urine, tear, sweat
Rashes, fever, n/v, thrombocytopenia, nephritis, cholestatic jaundice, hepatitis, flu-like syndrome
Hepatitis [rarely]
Patients at risk …chronic liver disease, alcoholism, elderly

11. Ethambutol Mechanism of action
Inhibit mycobacterial arabinosyl transferase enzyme
Enzyme in arabinoglycan polymerization
Arabinoglycan = Essential component of mycobacterial cell wall
Mechanism of resistance
Mutation of mycobacterial arabinosyl transferase enzyme

12. Contraindication………Children < 5 yrs
Ethambutol
ADRs
1. Optic neuritis
Serious ADRs
Dose-related
Loss of visual acuity ความชัดเจน
Red- green** color blindness
Check visual acuity
Contraindication………Children < 5 yrs

13. Ethambutol
2.Increase uric acid in plasma
Ethambutol decrease uric acid excretion
Caution in gout patients
3. Others
GI disturbances, Arthralgia, Headaches, Giddiness, Mental disturbances

14. Mechanism of action
Unknown
Converted into Pyrazinoic acid (active form)
By enzyme mycobacterial pyrazinamidase
Mechanism of resistance
Mutation of mycobacterial pyrazinamidase
Decrease pyrazinamide uptake into mycobacteria
NO cross resistance with other drugs

15. Pyrazinamide
ADRs
Hepatotoxicity**
Etc., n/v, drug fever, hyperuricemia**

16. Streptomycin
Aminoglycoside antibiotics
Less permeable into the cell … Active extracellular

17. Alternative second line drugs in treatment of tuberculosis
Use when…
Resistance to 1st line drugs
No clinical response with 1st line drugs
Toxic effects with 1st line drugs
Aminosalicylic acid (PAS)
Kanamycin & Amikacin
Quinolones
Ethionamide
Cycloserine
Capreomycin
Rifabutin
Rifapentine

18. Mycobacterium Avium Complex (MAC) Infection
Consists of M. avium & M. intracellulare
Cause of disseminated disease in late stage AIDS… CD4 < 50
Treatment…Drug combination
Azithromycin 500 mg OD or Clarithromycin 500 mg bid +
Ethambutol 15 mg/ kg/ day +
Ciprofloxacin 750 mg bid or Rifabutin 300 mg OD
Other; Amikacin, Ethionamide

19. Drugs used in leprosy
Caused by M. leprae
Dapsone & Other sulfone
Dapsone =Diaminodiphenylsulfone (DDS)
Inhibit folate synthesis [As sulfonamides]
Bacteriostatic

20. Clofazimine
Phenazine dye
Unknown mechanism of action….DNA binding ?
Irregular GI absorption
Excrete in feces
Deposit in reticuloendothelial tissue & skin
Use in …
sulfone resistant leprosy
patients who can not tolerated to sulfone
100 mg/day

21. ADRs; skin discoloration [red brown to black], GI intolerance
Clofazimine
ADRs; skin discoloration [red brown to black], GI intolerance
Rifampin
Bactericidal to M. leprae
600 mg/ day
use in combination with other antileprosy to prevent resistance

22. Additional TB Resources
For additional information on tuberculosis, visit the Division of Tuberculosis Elimination Web site at:

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