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Pharmacotherapy of tuberculosis
The document provides a comprehensive overview of antitubercular drugs, including their classification, mechanisms of action, pharmacokinetics, adverse effects, and drug interactions. It details treatment regimens for tuberculosis, including drug-sensitive and multi-drug resistant forms, and discusses the role of chemoprophylaxis in preventing tuberculosis infection. Additionally, it highlights the importance of compliance and the use of multiple drug therapy in tuberculosis management.
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Pharmacotherapy of tuberculosis
- 1.
- 2. OBJECTIVES • Classify antituberculardrugs • Discuss mechanism of action, adverse effects, drug interactions and contraindications of antitubercular drugs • DiscussWHO regimens for treatment of tuberculosis • Define multi-drug resistant (MDR) Tuberculosis and XDR tuberculosis • Describe treatment of MDR-TB and XDR-TB • Discuss chemoprophylaxis in tuberculosis • Explain role of corticosteroids inTB
- 3.
- 4. MYCOBACTERIA • Mycos: wax(Greek) • Very difficult to treat Mycobacterial infections • First layer of defense: 60 % cell wall is made of lipids • Second layer of defense: abundant efflux pumps • Third layer of defense: can hide inside patients' cells
- 5. KEY POINTS INTREATMENT OF TUBERCULOSIS • Multiple drug therapy • Compliance • Adequate period
- 6. CLASSIFICATION OF ANTITUBERCULARDRUGS First Line drugs Second line drugs Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin Moxifloxacin Levofloxacin Ofloxacin Ciprofloxacin Kanamycin Amikacin Capreomycin Ethionamide Prothionamide Cycloserine Terizidone PAS Rifabutine Rifapentine
- 7.
- 8. ISONIAZID (H) • Tuberculocidal •Fast multiplying organisms rapidly killed • Acts on extracellular and intracellularTB bacilli • Equally effective in acidic and alkaline medium • Cheapest • Not effective against atypical Mycobacteria except M. Kansasi
- 9. MECHANISM OF ACTION Convertedto active form by catalase peroxidase enzyme Forms adducts with NAD Targets and inhibits inhA & KasA genes Inhibit synthesis of mycolic acids
- 10. MECHANISM OF RESISTANCE •Mutation in KatG gene • Most common • High level of resistance • Mutation in KasA gene • Mutation in inhA gene (Overproduction)
- 11. PHARMACOKINETICS • Good absorptionand distribution • Extensively metabolized in liver by N –acetylation • Fast acetylators • Slow acetylators • Inhibitor of CYP2C19 & CYP3A4 • Metabolites excreted in urine
- 12. ADVERSE EFFECTS • Peripheralneuritis • Paresthesia, numbness, mental disturbances, rarely convulsions • Hepatotoxicity • More in elderly and alcoholics • Lethargy, rashes, mild anemia, arthralgia
- 13. RIFAMPICIN • Tuberculocidal • Bestaction against slowly or intermittently dividing M.Tuberculosis • Also effective against variety of other Gm +/- infections • Effective against M. Leprae • Effective against atypical bacteria like MAC but not M. fortuitum • Both extracellular and intracellular affected
- 14. MECHANISM OF ACTION •Inhibits DNA dependent RNA polymerase and interrupts bacterial RNA synthesis.
- 15. MECHANISM OF RESISTANCE •Mutation in rpoB gene
- 16. PHARMACOKINETICS • 70 %bioavailability (↓ with food) • Should be taken on empty stomach • Widely distributed • Metabolized in liver • Excreted mainly in bile • Undergoes enterohepatic circulation • Microsomal enzyme inducer
- 17. ADVERSE EFFECTS • Hepatitis:Major adverse effect • Minor reactions • Cutaneous: flushing, pruritis, rash, redness and watering of eyes • Flu like symptoms • Abdominal cramps • Urine and other secretions may become orange red
- 18. USES OF RIFAMPICIN •Tuberculosis • Leprosy • Prophylaxis of meningococcal meningitis • Second/ third choice for MRSA, legionella • Combination of doxycycline and rifampicin is first line therapy for brucellosis
- 19. PYRAZINAMIDE • Tuberculocidal • Moreactive in acidic medium • More lethal to intracellular bacilli and at sites of inflammation • More effective during first 2 months of treatment • Like INH only effective inTB
- 20. MECHANISM OF ACTION Convertedto active form pyrazinoic acid inside mycobacterial cell Metabolite gets accumulated in acidic medium Inhibit synthesis of mycolic acids
- 21. MECHANISM OF RESISTANCE •Mutation in pncA gene which encodes pyrazinamidase enzyme
- 22. PHARMACOKINETICS • Absorbed orally •Well distributed • Good CSF penetration • Extensively metabolized in liver • Excreted in urine
- 23. ADVERSE EFFECTS • Hepatotoxicity •Most important dose related adverse effect • Hyperuricaemia • Abdominal distress • Arthralgia, • Flushing, rashes, fever • Loss of diabetes control
- 24. ETHAMBUTOL • Bacteriostatic drugbut still used? • Resistance to ethambutol develops slowly • Added to RHZ hastens sputum conversion & prevents development of resistance • Also effective against mycobacteria resistant to INH & streptomycin • Also effective against many atypical mycobacteria • No cross resistance with other anti-TB drugs • In high conc it has tuberculocidal activity
- 25. MECHANISM OF ACTION •Inhibit arabinosyl transferases involved in arabinogalactan synthesis • Interferes with mycolic acid incorporation in mycobacterial cell wall
- 26. MECHANISM OF RESISTANCE •Mutation in embB gene • Reduced affinity of Ethambutol for target enzyme
- 27. PHARMACOKINETICS • 75% oraldose absorbed • Well distributed • Penetrates meninges inconsistently • Less than ½ of E is metabolized • Excreted in urine
- 28. ADVERSE EFFECTS • Goodpatient acceptability • Occular toxicity • Loss of visual acuity/ color vision , field defects • Due to retrobulbar neuritis • Reversible with drug stoppage • Nausea, rashes, fever • Rarely peripheral neuritis
- 29. STREPTOMYCIN • Aminoglycoside antibiotic •First clinically useful drug againstTB • Bactericidal • Must be administered IM • Active against extracellular bacilli in alkaline pH • Adverse effects • ototoxicity, nephrotoxicity & neuromuscular blockade
- 30. Mechanism Of Actionof first line antitubercular drugs PROTEIN SYNTHESIS INHIBITION CELL WALL SYNTHESIS INHIBITION Transcriptional level Translational level MYCOLIC ACID SYNTHESIS INHIBITION ARABINOGYLACT AN SYNTHESIS INHIBITION DNA DEPENDENT RNA POLYMERASE 30S Ribosomal inhibition FATTY ACID SYNTHASE 1 INHIBITOR RIFAMPICIN STREPTOMYCIN ISONIAZID ETHAMBUTOL FATTY ACID SYNTHASE 2 INHIBITOR PYRAZINAMIDE
- 32. DRUG RESISTANCE of1st line drugs DRUG Mechanism of resistance ISONIAZID Mutation of the katG gene, mutation in the inhA gene & kasA gene RIFAMPICIN Mutation of the rpoB gene PYRAZINAMIDE Mutation in gene encoding (pncA gene) ETHAMBUTOL Alteration of drug target gene (embB) STREPTOMYCIN One step mutation or by acquisition of plasmid
- 33. DRUGS ABSORPTION DISTRIBUTIONMETABOLISM EXCRETION ISONIAZID Well absorbed Penetrates all body tissues, placenta and meninges. Hepatic (acetylation) t½-fast acetylators (1 hr),slow(3 hrs) urine RIFAMPICIN Well absorbed Penetrates all body tissues, placenta and meninges. Hepatic t½ -variable (2- 5 hrs) Mainly in bile & some in urine. PYRAZINAMIDE Well absorbed Widely distributed , good CSF penetration Hepatic t½ - 6-10 hrs urine ETHAMBUTOL Well absorbed Widely distributed, penetrates meninges incompletely, temporarily stored in RBC’s Hepatic t½ ~4 hrs urine STREPTOMYCIN GIT-not absorbed IM-rapid Penetrates tubercular cavities;does not cross BBB Not metabolised t½ -2-4 hrs. Urine (unchanged) PHARMACOKINETICS
- 34. ADVERSE REACTIONS of1st line drugs DRUG Adverse effects ISONIAZID Peripheral neuropathy Hepatitis RIFAMPICIN Hepatitis Orange red secretions and urine PYRAZINAMIDE Hepatotoxicity Hyperuricemia:gout ETHAMBUTOL Optic neuritis:Loss ofVisual acuity/colour vision/field defects STREPTOMYCIN Ototoxicity, nephrotoxicity
- 35. Drug Interactions Isoniazid Aluminiumhydroxide inhibits absorption INH inhibits phenytoin, carmazepine, diazepam, and warfarin metabolism Rifampicin Hepatic microsomal enzyme inducer increases metabolism of drugs like warfarin, digoxin, oral contraceptives, dapsone, protease inhibitors, sulfonylureas,steroids,ketoconazole
- 36. Recommended doses ofAntitubercular drugs ISONIAZID 5 300 mg 10 600 mg RIFAMPICIN 10 600 mg 10 600 mg PYRAZINAMIDE 25 1500 mg 35 2000 mg ETHAMBUTOL 15 1000 mg 30 1600mg STREPTOMYCIN 15 1000 mg 15 1000 mg DRUG DAILY DOSE 3 × PER WEEK DOSE mg/kg >50 kg mg/kg >50 kg
- 37.
- 38. KANAMYCIN & AMIKACIN •Aminoglycosides • Effective against many S resistant and MDR resistant strains of M tuberculosis • Amikacin less toxic than kanamycin • Important components for MDR –TB regimens (Intensive phase) • Audiometry and monitoring of renal function is recommended
- 39. CAPREOMYCIN • Cyclic peptideantibiotic but similar mycobactericidal activity to Aminoglycosides • Used as alternative to Aminoglycosides • Adverse effects • Ototoxicity, nephrotoxicity • Fever, rashes, eosinophilia • Injection site pain
- 40. FLUOROQUINOLONES • Mfx, Lfx,Ofx, Cfx • Active against MAC as well as M. fortuitum • Kill mycobacteria lodged inside macrophage as well • Primarily used for MDR-TB • Resistance develops by mutation in DNA gyrase • Resistance against moxifloxacin is slow to develop (FQs)
- 41. CYCLOSERINE • Analog ofD alanine, Inhibits bacterial cell wall synthesis • Tuberculostatic in addition inhibits MAC and some gm + bacteria, E coli and chlamydia • Good oral absorption and distribution even in CSF • Adverse effects of Cs are mainly neuro-psychiatric • Pyridoxine 100 mg/day can reduce neurotoxicity and prevent convulsions • Included in standardized regimen of MDR-TB
- 42. TERIZIDONE • Contains 2molecules of cycloserine • Less neurotoxic and less adverse effects than cycloserine • Used as substitute of cycloserine especially in genitourinaryTB
- 43. PARA-AMINO SALICYLIC ACID(PAS) • Bacteriostatic and least effective • Inhibits folic acid synthesis • Only advantage is delays resistance • Adverse effects: • Severe anorexia, vomiting , epigastric pain, hypokalemia, goiter • Poorly tolerated • Dose: 10 – 12 gm/day
- 44. RIFABUTIN • Related torifampicin in structure and mechanism • Active against M.Tb more active against MAC • Weak inducer • Use: • prophylaxis of MAC in AIDS • HIV patients along with NNRTI • MAC: Rifabutin + E + Clarithromycin / Azithromycin • Adverse events: • GIT intolerance, Myalgia, granulocytopenia , uveitis
- 45. BEDAQUILINE (BDQ) • Inhibitsmycobacterial ATP synthase thus limits energy production in mycobacterial cell • Strong bactericidal kills rapidly multiplying as well as dormant MTuberculosis • Well absorbed orally and fatty meal increases its absorption • Metabolized by CYP3A4 in liver , excreted mainly in feces • Terminal half life is very long 160 days • Adverse effects: nausea, headache, arthralgia, prolongation of Qtc
- 46. GUIDELINES FOR USEOF BEDAQUILINE • Only in patients > 18 years Age • Non pregnant • Only in combination with 3 other susceptible anti-TB drugs or 4 drugs with likely sensitivity • Only when effective regimen cannot otherwise be provided • Given max for 24 weeks, the other anti-TB drugs should be continued for 24 months • Not used for drug sensitive or extrapulmonaryTB
- 47. GOALS OF ANTITUBERCULARCHEMOTHERAPY • Kill dividing bacilli • Kill persisting bacilli • Prevent emergence of resistance
- 48. SHORT COURSE CHEMOTHERAPY •WHO introduced 6-8 months multidrug short course regimens in 1995 • DOTS strategy • Clear cut guidelines for different categories ofTB patients
- 49. CLASSIFICATION OFTB CASES •Drug sensitiveTB • Multidrug resistantTB (MDR-TB) • Rifampicin resistantTB (RR-TB) • MonoresistantTB • Poly Drug resistantTB (PDR-TB) • Extensive Drug resistantTB (XDR-TB)
- 50. TREATMENT REGIMEN FORNEW AND PREVIOUSLYTREATED PATIENTS OF PULMONARY TB PRESUMEDTO BE DRUG SENSITIVE Type of patient Intensive phase Continuation phase Total duration New 2 HRZE 4 HRE 6 Previously treated 2 HRZES + 1 HRZE 5 HRE 8
- 51. STANDARD RNTCP REGIMENFOR MDR-TB Intensive phase (6-9 months) Continuation phase (18 months) 1. Kanamycin (Km) - 2. Levofloxacin (Lfx) 1. Levofloxacin (Lfx) 3. Ethionamide (Eto) 2. Ethionamide (Eto) 4. Cycloserine (Cs) 3. Cycloserine (Cs) 5. Pyrazinamide (Z) 4. Pyrazinamide (Z) 6. Etambutol (E) - +Pyridoxine 100 mg/day
- 52. MDR-TB is definedas resistance to isoniazid plus rifampin. XDR-TB is defined as resistance to at least rifampin & isoniazid plus resistance to the fluoroquinolones and to at least one of the injectable drugs capreomycin, kanamycin and amikacin. Dr Arif
- 53. EXTENSIVE DRUG RESISTANTTB Intensive phase (6-12 months) Continuation phase (18 months) 1. Capreomycin (Cm) - 2. Moxifloxacin (Mfx) 2. Moxifloxacin (Mfx) 3. High dose Isoniazid (H) 3. High dose Isoniazid (H) 4. Para Amino salicylic acid (PAS) 4. Para Amino salicylic acid (PAS) 5. Clofazimine (Clo) 5. Clofazimine (Clo) 6. Linezolid 6. Linezolid 7.Amoxicillin clavulanate 7.Amoxicillin clavulanate
- 54. TUBERCULOSIS IN PREGNANTWOMEN • 2 HRZE+4 HRE • Streptomycin is contraindicated
- 55. INDICATIONS OF CHEMOPROPHYLAXIS 1.Contactsof open cases who show recent Mantoux conversion. 2.Children with a TB patient in the family. 3.Neonate of a tubercular mother. 4.Patients of leukemia, diabetes, silicosis or HIV+ve 5.HIV infected contacts of sputum positive index cases
- 56. CHEMOPROPHYLAXIS OFTUBERCULOSIS • -INH300mg (10 mg/kg in children)daily for 6 months). -INH(5 mg/kg/day) + RMP(10 mg/kg/day) for 6 months in patients with INH resistance.
- 57. TUBERCULOSIS IN AIDSPATIENTS • HIV + TB infection is serious problem • Short course chemotherapy should be immediately started • Treatment given: 2 HRZE + 7 HR •Rifabutin can be used in place of Rifampin as it has lesser interaction with protease inhibitors
- 58. CORTICOSTEROIDS IN TUBERCULOSIS •Seriously ill patients (miliary or severe pulmonaryTB) • Hypersensitivity reactions occur to anti tubercular drugs • Meningeal, renalTB or pleural effusion- to ↓ exudation • In AIDS patients with severe manifestations ofTuberculosis. • Contraindicated in intestinalTB for fear of silent perforation. • Withdrawn gradually when the general condition of the patient improves
- 59. MYCOBACTERIUM AVIUM COMPLEX(MAC) INFECTION • Clarithromycin and Azithromycin are most active drugs • Opportunistic infection in HIV-AIDS patients • Intensive phase (4 drugs) (2-6 months) • Clarithromycin or Azithromycin + E+ Rifabutin + one FQ • Continuation Phase (12 months) • Clarithromycin or Azithromycin + E/Rifabutin/FQ
- 60. SUMMARY • Classify antituberculardrugs • Discuss mechanism of action, adverse effects, drug interactions and contraindications of first line antitubercular drugs • DiscussWHO regimens for treatment of tuberculosis • Explain multi-drug resistant (MDR) Tuberculosis mechanisms and available drugs for MDR and XDR tuberculosis
- 61. FURTHER READING • Essentialsof Medical Pharmacology 8th edition, by KD Tripathi