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