Antimycobacterial drugs
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Antimycobacterial Antimycobacterial drugsdrugs
Pawitra PulbutrPawitra Pulbutr
B.Pharm (Hon.), M. Sc. In B.Pharm (Hon.), M. Sc. In Pharm (Pharmacology)Pharm (Pharmacology)
วั�ตถุ�ประสงค์�เชิ�งพฤต�กรรมวั�ตถุ�ประสงค์�เชิ�งพฤต�กรรม
• เม��อนิ�ส�ตศึ�กษาเอกสารแล้�วันิ�ส�ตสามารถุ• ม�ค์วัามเข้�าใจแล้ะอธิ�บายถุ�งกล้ไกการออก
ฤทธิ�( , เภส�ชิจล้นิศึาสตร� , อาการไม+พ�งประสงค์�ข้องยา Antimycobacterial
• ม�ค์วัามเข้�าใจแล้ะอธิ�บายถุ�งการนิ,าไปใชิ�ประโยชินิ�ทางค์ล้�นิ�ค์ข้องยา
Antimycobacterial
MycobacteriaMycobacteriaMycobacteriaMycobacteria
• Mycobacterium tuberculosis Mycobacterium tuberculosis
• Tuberculosis, TB Tuberculosis, TB วั�ณโรค์วั�ณโรค์• Mycobacterium leprae Mycobacterium leprae
• Leprosy Leprosy โรค์เร�/อนิโรค์เร�/อนิ• Atypical mycobacteria Atypical mycobacteria
• Mycobacterium avium complex Mycobacterium avium complex (MAC) (MAC)
• Opportunistic infection in AIDSOpportunistic infection in AIDS
Characteristic of Characteristic of MycobacteriaMycobacteria
• Slowly growing or Slowly growing or DormantDormant
• Lipid rich cell wallLipid rich cell wall
• Intracellular Intracellular organismsorganisms
• Able to develop Able to develop resistance resistance
Hard to be eradicatedHard to be eradicated
Need drug combinationNeed drug combination
Resistance to Resistance to many many
antibacterialantibacterial
Impermeable to Impermeable to many agentsmany agents
Many agents are Many agents are inaccessible inaccessible
Drugs used in tuberculosisDrugs used in tuberculosis
First line First line drugsdrugs
• Isoniazid (INH,H, Isoniazid (INH,H, I)I)
• Rifampin [R]Rifampin [R]
• Pyrazinamide [ Z ]Pyrazinamide [ Z ]
• Ethambutol [ E ]Ethambutol [ E ]
• Streptomycin [ S ]Streptomycin [ S ]
• EthionamideEthionamide
• CapreomycinCapreomycin
• CycloserineCycloserine
• PASPAS
• Kanamycin & Kanamycin & AmikacinAmikacin
• QuinolonesQuinolones
• RifabutinRifabutin
• RifapentineRifapentine
• ClofazemineClofazemine
Second line Second line drugsdrugs
Isoniazid (INH)
Mechanism of ActionMechanism of Action
*Inhibit mycolic acid *Inhibit mycolic acid synthesis*synthesis*
Mycolic Mycolic acidacid
Essential components Essential components of mycobacterial cell of mycobacterial cell
wallwall
• Need mycobacterial catalase peroxidase mycobacterial catalase peroxidase (Kat G)(Kat G) to become active
• INHINH form complex with
• Acyl carrier protein (Acp M)
• Beta ketoacyl carrier protein synthase (Kas A)
Adverse drug reactions Adverse drug reactions (ADRs)(ADRs)
1. INH induced hepatitis1. INH induced hepatitis
• loss of appetite, n/v, jaundice, right loss of appetite, n/v, jaundice, right upper quadrant painupper quadrant pain
• can be lethal !!can be lethal !!
• STOP INH, if occurSTOP INH, if occur
• risk depend on age of patientsrisk depend on age of patients
• risk patients ex. Alcoholism, risk patients ex. Alcoholism, pregnancy, feeding motherpregnancy, feeding mother
2. Peripheral neuropathy2. Peripheral neuropathy
• Especially occur in slow acetylatorslow acetylator, malnutrition, alcoholism, DM, AIDS, uremia
• INH form complex with pyridoxine pyridoxine [pyridoxal hydrazone][pyridoxal hydrazone]
• Then, increase pyridoxine excretion in urine
• Lack of pyridoxine (Vitamin B6)Lack of pyridoxine (Vitamin B6)
• Rx : Pyridoxine 10 mg/dayRx : Pyridoxine 10 mg/day
RifampinRifampin
Mechanism of actionMechanism of action
• Binds with beta subunit of bacterial DNA dependent RNA DNA dependent RNA polymerase**polymerase**
• Inhibit RNA synthesis
Mechanism of Mechanism of resistanceresistance
• Mutation of beta subunit of RNA polymerase
Rifampin = Enzyme inducerRifampin = Enzyme inducer
RifampinRifampin
ADRs
• Orange secretion Orange secretion****** …urine, tear, sweat …urine, tear, sweat
• Rashes, fever, n/v, thrombocytopenia, nephritis, cholestatic jaundice, - hepatitis, flu like syndrome
• Hepatitis [rarely] Hepatitis [rarely]
• Patients at risk …chronic liver disease, alcoholism, elderly
EthambutolEthambutol
Mechanism of actionMechanism of action
• Inhibit Inhibit mycobacterial arabinosyl mycobacterial arabinosyl transferase enzymetransferase enzyme
Enzyme in arabinoglycan Enzyme in arabinoglycan polymerizationpolymerization
Arabinoglycan = Essential Arabinoglycan = Essential component of mycobacterial cell component of mycobacterial cell
wallwallMechanism of resistanceMechanism of resistance
Mutation of mycobacterial arabinosyl Mutation of mycobacterial arabinosyl transferase enzyme transferase enzyme
EthambutolEthambutol
ADRsADRs
1 . Optic neuritis 1 . Optic neuritis
• Serious ADRs
• -Dose related
• Loss of visual acuity ค์วัามชิ�ดเจนิ• RedRed- - greengreen**** color blindness
• Check visual acuity
Contraindication………Children < 5 Contraindication………Children < 5yrsyrs
EthambutolEthambutol
2.Increase uric acid in plasma2.Increase uric acid in plasma
• Ethambutol decrease uric acid excretion
• Caution in goutgout patients
3. Others
• GI disturbances, Arthralgia, Headaches, Giddiness, Mental disturbances
Mechanism of Mechanism of actionaction• Unknown
• Converted into Pyrazinoic acid (active form)
• By enzyme mycobacterial mycobacterial pyrazinamidasepyrazinamidaseMechanism of resistanceMechanism of resistance
• Mutation of mycobacterial pyrazinamidase
• Decrease pyrazinamide uptake into mycobacteria
• NO cross resistance with other drugsNO cross resistance with other drugs
PyrazinamidePyrazinamide
ADRsADRs
• Hepatotoxicity**Hepatotoxicity**
•Etc., n/v, drug fever, hyperuricemia**hyperuricemia**
StreptomycinStreptomycin
• Aminoglycoside antibiotics Aminoglycoside antibiotics
• Less permeable into the cell … Active extracellular Active extracellular
Alternative second line drugs in Alternative second line drugs in treatment of tuberculosistreatment of tuberculosis
Use when… Use when…
Resistance to 1 Resistance to 1 st st line drugs line drugs
1No clinical response with 1No clinical response with stst line d line drugsrugs
Toxic effects with 1 Toxic effects with 1 st st line drugs line drugs
EthionamidEthionamidee
CycloserinCycloserinee
CapreomycCapreomycinin
Aminosalicylic acid Aminosalicylic acid (PAS)(PAS)
Kanamycin & Kanamycin & AmikacinAmikacin
QuinolonesQuinolones
RifabutinRifabutin
RifapentiRifapentinene
Mycobacterium Avium Complex (MAC) Mycobacterium Avium Complex (MAC) InfectionInfection
• Consists of M. avium & M. intracellulare
• Cause of disseminated disease in late stageAIDS… CD4 < 50CD4 < 50
• Treatment…Drug combination
• 500 50Azithromycin mg OD or Clarithromycin 500 50Azithromycin mg OD or Clarithromycin 0mg bid 0mg bid ++
• ddd 1 5 / / ddd 1 5 / / ++
• ddddddddd d d d d d 7 5 0 3 0 0 ddddddddd d d d d d 7 5 0 3 0 0dd dd
• Other; Amikacin, Ethionamide Other; Amikacin, Ethionamide
Drugs used in leprosyDrugs used in leprosy
Caused by M. leprae
Dapsone & Other sulfoneDapsone & Other sulfone
Dapsone =Diaminodiphenylsulfone Dapsone =Diaminodiphenylsulfone (DDS)(DDS)
Inhibit folate synthesis [As Inhibit folate synthesis [As sulfonamides]sulfonamides]
BacteriostaticBacteriostatic
ClofazimineClofazimine
Phenazine dye Phenazine dye
Unknown mechanism of action…. DNA DNA binding ? binding ?
Irregular GI absorption
Excrete in feces
Deposit in reticuloendothelial tissue & ski Deposit in reticuloendothelial tissue & skinn
Use in …
sulfone resistant leprosy sulfone resistant leprosy
patients who can not tolerated to sulfon patients who can not tolerated to sulfonee
100mg/day 100mg/day
ClofazimineClofazimine
ADRs; skin discoloration [red ADRs; skin discoloration [red brown to black], GI intolerancebrown to black], GI intolerance
RifampinRifampin
BactericidalBactericidal to M. leprae
600 mg/ day
use in combination with other antileprosy to prevent resistance
Additional TB Additional TB ResourcesResources
For additional information on tuberculosis,
visit the Division of Tuberculosis Elimination Web site at:
http://www.cdc.gov/tbhttp://www.cdc.gov/tb
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