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

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

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

3 วัตถุประสงค์เชิงพฤติกรรม เมื่อนิสิตศึกษาเอกสารแล้วนิสิตสามารถ มีความเข้าใจและอธิบายถึงกลไกการ ออกฤทธิ์, เภสัชจลนศาสตร์, อาการไม่ พึงประสงค์ของยา Antimycobacterial มีความเข้าใจและอธิบายถึงการนำไปใช้ ประโยชน์ทางคลินิคของยา Antimycobacterial

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

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

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

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

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

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

10 Rifampin Mechanism of action DNA dependent RNA polymerase** 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

11 Rifampin ADRs Orange secretion*** …urine, tear, sweat 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

12 Ethambutol Mechanism of action Inhibit mycobacterial arabinosyl transferase enzyme 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

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

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

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

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

17 Streptomycin Aminoglycoside antibiotics Active extracellular Less permeable into the cell … Active extracellular

18 Alternative second line drugs in treatment of tuberculosis Use when…  Resistance to 1 st line drugs  No clinical response with 1 st line drugs  Toxic effects with 1 st line drugs EthionamideCycloserineCapreomycin Aminosalicylic acid (PAS) Kanamycin & Amikacin Quinolones RifabutinRifapentine

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

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

21 Clofazimine Phenazine dye  Phenazine dye DNA binding ?  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

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

23 Additional TB Resources For additional information on tuberculosis, visit the Division of Tuberculosis Elimination Web site at:http://www.cdc.gov/tb

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