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Chemotherapy of tuberculosis
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Chemotherapy of tuberculosis

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    Chemotherapy of tuberculosis Chemotherapy of tuberculosis Presentation Transcript

    • CHEMOTHERAPY OF TUBERCULOSIS
    • TB is caused by- mycobacterium tuberculosis Drugs:
      • First line drugs
      • Have high antitubercular efficacy as well as low toxicity
      • Isoniazid (H)
      • Rifampicin
      • Pyrazinamide (Z)
      • Ethambutol (E)
      • Streptomycin (S)
    • Second line drugs Either low antitubercular efficacy or high toxicity or both Thiacetazone Paraaminosalicylic acid (PAS) Ethionamide Cyclosporin Kanamycin Amikacin Capreomycin
      • Isoniazid
      • (isonicotinic acid hydrazide, H)
      • It is tuberculocidal
      • MOA
      • -inhibition of synthesis of mycolic acids .
      • Newer drugs
      • Ciprofloxacin
      • Ofloxacin
      • Clarithromycin
      • Azithromycin
      • Rifabutin
      • Dose – 5mg/kg
      • > 50 kg- 300mg/kg
      • RIFAMPICIN
      • -Derivative of rifamycin B
      • -Obtained from- Streptomyces mediterranei
      • - bactericidal
      • MOA
      • Inhibits DNA dependent RNA synthesis
      • Dose - 10mg/kg
      • >50kg- 600mg
      • PYRAZINAMIDE
      • -weakly tuberculocidal
      • MOA
      • It inhibits mycolic acid synthesis, but by interacting with
      • A different fatty acid synthase encoding gene.
      • DOSE- 25mg/kg
      • >50 kg- 1500mg
      • ETHAMBUTOL
      • Tuberculostatic
      • MOA
      • Inhibit arabinogalactan synthesis & mycolic acid
      • incorporation in mycobacterial cell wall.
      • DOSE- 15mg/kg
      • >50 kg- 1000 mg
      • STREPTOMYCIN
      • Tuberculocidal
      • Less effective than INH or rifampin
      • MOA
      • Inhibition of protein synthesis
      • DOSE- 15mg
      • >50 kg- 1000mg
      • Dose is reduced to 750mg in patients above 50 yr age
      • 500 mg in above 65 yr age.
      • The goal of antitubercular chemotherapy are
      • Kill dividing bacilli
      • Kill persisting bacilli
      • Prevent emergence of resistance
      • -combination of two or more drugs must be used
      • -INH and R are most efficacious drugs
      • duration of therapy is shortened from > 12 months
      • to 9 months.
      • Addition of Z for initial 2 months further reduces
      • Duration of t/t to 6 months.
      • Single daily dose of all the first line drugs is prefered
      • The ‘directly observed treatment short course’ (DOTS)
      • was recommended in 1995
      • SHORT COURSE CHEMOTHERAPY (SCC)
      • These are regimens of 6-9 month duration which are
      • Highly efficacious.
      • WHO has framed clear cut t/t guidelines for
      • different categories of TB patients
      • -All regimens have an initial intensive phase lasting
      • 2-3 months to kill the TB bacilli.
      • -followed by continuation phase lasting 4-6 months
      • during which remaining bacilli are eliminated so that
      • Relapse does not occur.
      • T/t of TB is categorized by:
      • Site of disease & its severity
      • Sputum smear positivity/negativity: positive cases are
      • Infectious & have higher mortality.
      • -History of previous t/t.
      • Category I
      • This category includes:
      • New (untreated)smear positive pulmonary TB
      • New smear negative pulmonary TB
      • New cases of severe forms of extrapulmonary TB
      • Viz. meningitis,spinal,intestinal,genitourinary TB.
      • Category II
      • These are smear positive failure, relapse and
      • Interrupted treatment cases
    • Category III These are new cases of smear negative pulmonary TB With less severe form of extrapulmonary TB, viz,skin Bone,peripheral joint TB. Category IV These are chronic cases who have become smear Positive after completing fully supervised retreatment. These are mostly MDR cases.(multi drug resistant)
    • TB Category Initial phase Continuation phase Total duration I 2 HRZE (S) 4 HR/ 4 H 3 R 3 Or 6 HE 6 8 II 2 HRZES + 1 HRZE 5 HRE or 5H 3 R 3 E 3 8 8 III 2 HRZ 4 HR/ 4 H 3 R 3 0r 6 HE 6 8 IV Chronic case
    • In chronic case therapy depends upon the drugs used in the earlier regimen,dosage and regularity with which they were taken, presence of associated disease like AIDS/diabetes/leukemia etc. TB in pregnant women HRZ & E are safe to foetus. Standard 6 month regimen 2HRZ+ 4HR should be given.
      • ANTIFUNGAL DRUGS
      • CLASSIFICATION
      • Antibiotics
      • a) Polyenes: Amphotericin B, Nystatin
      • b) heterocyclic benzofuran: Griseofulvin
      • 2. Antimetabolite
      • Flucytosine
      • 3. Azoles
      • a) Imidazoles(topical)- Clotrimazole, miconazole
      • (systemic)- ketoconazole
      • b) Triazoles (systemic)- Fluconazole,itraconazole
      • 4. Allylamine
      • Terbinafine
    • Other topical agents Tolnaftate, benzoic acid, sodium thiosulfate. Amphotericin B Source- streptomyces nodosus. MOA- Combine with the ergosterol present in the fungal cell membrane and form a micropore thus increase the cell permeability. USE Topically for oral and cutaneous candidiasis.
      • DOSE- orally 50-100 mg QID
      • Heterocyclic benzofurans
      • Griseofulvin
      • Source- Penicillium griseofulvum
      • Active against Epidermophyton,Trichophyton,
      • Microsporium etc.
      • MOA -
      • Interferes with mitosis
      • Causes abnormal metaphase configurations.
      • USE
      • Systemically only for dermatophytosis
      • DOSE
      • 125- 150 mg QID with meals
      • Imidazole and triazoles
      • Have broad spectrum antifungal activity
      • MOA
      • Inhibit funga cytochrome P450 enzyme lanosterol
      • 14-demethylase & thus impair ergosterol synthesis
      • leading to a cascade of membrane abnormalities in the
      • fungus.
    • DISEASE DRUGS 1 st choice 2 nd choice Candidiasis FLU/NYS/CLO ITR Histoplasmosis AMB FLU Blastomycosis ITR/AMB KTZ/FLU Sporotrichosis AMB ITR
      • ANTIVIRAL DRUGS
      • Viruses not only take the nutrition from host cell but
      • also direct its metabolic machinery to synthesize new
      • virus particles.
      • CLASSIFICATION
      • Anti-Herpes virus
      • Idoxuridine, Acyclovir, Ganciclovir, Foscarnet
      • Anti-Retrovirus
      • a) Nucleoside reverse transcriptase inhibitors (NRTIs)
      • Zidovudine,stavudine
      • b) Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
      • Nevirapine,efavirenz
      • c) Protease inhibitors
      • Ritonavir, Nelfinavir
      • 3. Anti-influenza virus
      • Amantadine,rimantadine
      • 4. Nonselective antiviral drugs
      • Ribavirin,Lamivdine,Interferon α
    • ACYCLOVIR (deoxyguanosine analogue) MOA Acyclovir Herpes virus specific thymidine kinase Acyclovir monophosphate Cellular kinase Acyclovir triphosphate Inhibits herpes virus DNA Gets incorporated in viral DNA Polymerase competatively & stops lengthening of DNA strand.the terminated DNA inhibits DNA-polymerase irreversibly.
      • Anti-retrovirus
      • NRTIs
      • Zidovudine (Thymidine analogue)
      • MOA-
      • Single stranded viral RNA
      • virus directed reverse transcriptase
      • (-)
      • zidovudine triphosphate
      • Double stranded viral DNA
    • b) NNRTIs Nevirapine & Efavirenz MOA - They directly inhibit HIV reverse transcriptase without the need for intracellular phosphorylation. Their locus of action on the enzyme is also different. c) Protease inhibitors Ritonavir, Nelfinavir MOA- protease act at the late step in HIV replication. They bind to protease molecule and interfere with its cleaving function.
    • HIV treatment guidelines HAART - highly active antiritroviral therapy Combination of 3 or more drug replace monothrerapy. Therapeutic regimens 2-NRTIs + 1-PI 2-NRTIs + 1-NNRTI 3- NRTIs
    • Anti-influenza virus Amantadine Inhibits replication of influenza A virus Nonselective Antiviral Drugs Ribavirin - Purine nucleoside analogue - Its mono & triphosphate derivatives generated Intracellularly inhibit GTP and viral RNA synthesis.
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