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B.Pharm (Hon.), M. Sc. In Pharm (Pharmacology)

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Presentation on theme: "B.Pharm (Hon.), M. Sc. In Pharm (Pharmacology)"— Presentation transcript:

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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