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Anti tubercular drugs


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  • 3.  Categories of tuberculosis and their treatment regimens have been recommended by WHO.  bone tuberculosis is classified to be a severe form of extrapulmonary tuberculosis and hence should be given Category I treatment (2HRZE & 4HR i.e. 2 months of H,R,Z and E followed by 4 months of H and R).  two phases: an initial ‘Intensive phase’, consisting of four to five drugs to rapidly destroy the majority of the organisms  a ‘continuation phase’ which consists of two to three drugs.
  • 4.  Historically, the recommended duration was - 18 to 24-no scientific basis  Even today there is lack of consensus regarding the ideal duration of treatment for bone TB.  Uncertainty about the penetration of osteoarticular lesions by the available drugs and the fear of early or late recurrence forced the surgeons to continue chemotherapy for prolonged periods.  Modern anti-tuberculous drugs have been shown to penetrate osseous tissue in amounts much higher than the minimal inhibitory concentrations.  Wallace Fox for the first time proved that addition of R or Z to regimens containing H made it possible to shorten the duration of treatment
  • 6. ISONIAZID (INH)  Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains  structural similarity to pyridoxine.  MOA: Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. .
  • 7.  orally administered, well absorbed, widely distributed in body, including cerebrospinal fluid.  INH can also penetrate into macrophages.  Most INH is metabolized in the liver.
  • 8. PHARMACOLOGIC ACTIVITY  bactericidal - actively growing tubercle bacilli. bacteriostatic -resting tubercle bacilli.  Isoniazid is able to penetrate into phagocytic cells and thus is active again both extracellular and intracellular organisms.  DOSE: ADULTS: PO/IM 5 mg/kg/day as single daily dose (max 300 mg/day). INFANTS & CHILDREN: PO/IM 10 to 20 mg/kg/day in single daily dose (max 300 mg/day).
  • 9. ADVERSE EFFECTS  Allergic Reaction: fever,skin rash  Hepatotoxicity : Up to 20% of patients taking INH develop elevated serum amino transferase levels.  Severe hepatic injury occurs more frequently in patients over the age of 35, especially in those who are alcoholic.  Isoniazid is discontinued if symptoms of hepatitis develop or if the aminotransferase activity increases to more than three times normal.
  • 10.  Peripheral and CNS toxicity - toxicity results from an increased excretion of pyridoxine induced by isoniazid, which produces a pyridoxine deficiency.  Peripheral neuritis, urinary retention, insomnia, and psychotic episodes can occur.  Concurrent pyridoxine 25–50 mg/d administration with INH prevents most of these complications.
  • 11.  Isoniazid as a single agent is also indicated for treatment of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice weekly for 9 months.
  • 12. RIFAMPIN  Synthetic derivates of rifamycin B produced by Sterptomyces mediterranei  oral administration, well absorbed, widely distributed in body.  most of the drug is excreted as a deacylated metabolite in feces and in the urine.  half-life is about 4 hours.
  • 13. PHARMACOLOGY  It is bactericidal for mycobacteria.  It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses.  MOA: It binds strongly to the β-subunit of DNA- dependent RNA polymerase and thereby inhibits RNA synthesis.  Drug-resistance is due to target mutations in RNA polymerase, occurs readily.  No cross-resistance to other classes of antimicrobial drugs.
  • 14. ADVERSE EFFECTS  Urine, sweat, tears, and contact lenses may take on an orange color because of rifampin administration, this effect is harmless.  Light-chain proteinuria and impaired antibody response may occur.  Rifampin induces hepatic microsomal enzymes and therefore, affects the half-life of a number of drugs.  When taken erratically in large doses, a febrile “flu-like” syndrome can occur.
  • 15. DOSE  Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug-resistant mycobacteria.
  • 16. ETHAMBUTOL  bacteriostatic  Well absorbed from the gut and widely distributed in all body tissues and fluids.  resistance to ethambutol emerges rapidly when the drug is used alone.  The most common serious adverse effect is dose-related optic neuritis, causing loss of visual acuity and red-green color-blindness, but are reversible.
  • 17.  Ethambutol hydrochloride, 15–25 mg/kg, is usually given as a single daily dose  50 mg/kg when a twice-weekly dosing schedule
  • 18. PYRAZINAMIDE  Pyrazinamide is a pyrazine analogue of nicotinamide.  pH 5.5 it inhibits tubercle bacilli and some other mycobacteria.  Quickly absorbed after oral administration  Widely distributed in body tissues,including inflamed meninges.  Excreted mainly by glomerular filtration
  • 19. ADVERSE EFFECTS  Major adverse effects of pyrazinamide include hepatotoxicity (in 1–5% of patients)  nausea, vomiting, drug fever, and hyperuricemia.  Hyperuricemia may provoke acute gouty arthritis. DOSE: 40–50 mg/kg is used for thrice-weekly or twice-weekly treatment regimens
  • 20. STREPTOMYCIN  Streptomycin - first antimicrobial drug used to treat tuberculosis.  It is effective against most tubercle bacilli, but its activity is weaker than that of INH and RFP.  Streptomycin penetrates cells poorly-produce drug resistance.  It is always given together with other drugs to prevent emergence of resistance.
  • 21.  The typical adult dose is 1 g/d (15 mg/kg/d). If the creatinine clearance is less than 30 mL/min or the patient is on hemodialysis, the dose is 15 mg/kg two or three times a week
  • 22. MDR TB  Multi-drug-resistant tuberculosis (MDR-TB) is defined as tuberculosis that is resistant to at least isoniazid (INH) and rifampicin.  multidrug-resistant tuberculosis can be cured with long treatments of second-line drugs, but these are more expensive than first-line drugs and have more adverse effects.
  • 24. WHEN CAN IT BE USED  (1) in case of resistance to first-line agents;  (2) in case of failure of clinical response to conventional therapy;  (3) in case of serious treatment-limiting adverse drug reactions;  (4) when expert guidance is available to deal with the toxic effects
  • 25. ETHIONAMIDE  Ethionamide is chemically related to isoniazid  blocks the synthesis of mycolic acids.  It is poorly water-soluble and available only in oral form.  It is metabolized by the liver  Ethionamide is administered at an initial dose of 250 mg once daily, which is increased in 250-mg increments to the recommended dosage of 1 g/d (or 15 mg/kg/d), if possible.
  • 26. ADVERSE EFFECTS  intense gastric irritation , neurologic symptoms  Ethionamide is also hepatotoxic.  Neurologic symptoms may be alleviated by pyridoxine.  Resistance to ethionamide as a single agent develops rapidly in vitro and in vivo.  low-level cross-resistance between isoniazid and ethionamide.
  • 27. CAPREOMYCIN  peptide protein synthesis inhibitor, antibiotic obtained from Streptomyces capreolus.  Daily injection of 1 g intramuscularly  Capreomycin (15 mg/kg/d) is an important injectable agent for treatment of drug-resistant tuberculosis.  Strains of M tuberculosis resistant to streptomycin or amikacin (eg, the multidrug- resistant W strain) are susceptible to capreomycin.  Resistance to capreomycin, may be due to an rrs mutation.
  • 28.  nephrotoxic and ototoxic.  Tinnitus, deafness, and vestibular disturbances occur.  The injection causes significant local pain, and sterile abscesses may occur.  Toxicity is reduced if 1 g is given two or three times weekly after an initial response has been achieved with a daily dosing schedule
  • 29. CYCLOSERINE  Cycloserine is an inhibitor of cell wall synthesis.  Cycloserine is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min.  ADVERSE:peripheral neuropathy and central nervous system dysfunction, depression and psychotic reactions
  • 30.  Pyridoxine 150 mg/d should be given with cycloserine to ameliorates neurologic toxicity. Adverse effects - most common during the first 2 weeks of therapy, occur at higher doses.  Side effects can be minimized by monitoring peak serum concentrations.  The peak concentration is reached 2–4 hours after dosing. The recommended range of peak concentrations is 20–40 mcg/mL
  • 31.  Contraindications- Epilepsy; depression; severe anxiety or psychosis; severe renal insufficiency; excessive concurrent use of alcohol.  Route/Dosage ADULTS: PO 250–500 mg q 12 hr; start with 250 mg q 12 hr for first 2 wk (maximum 1 g/day). CHILDREN: PO 10–20 mg/kg/day administered in 2 equally divided doses (maximum 1 g/day).
  • 32. AMINOSALICYLIC ACID (PAS)  Competitively antagonizes metabolism of para- aminobenzoic acid, resulting in bacteriostatic activity against Mycobacterium tuberculosis.  Adverse:Peptic ulceration and hemorrhage may occur. Hypersensitivity reactions may occur after 3–8 weeks of aminosalicylic acid therapy.
  • 33.  Infrequently used now since better tolerated drugs are available  ADULTS: PO 12 to 16 g/day in 2 to 3 divided doses. CHILDREN: PO 275 to 420 mg/kg/day in 3 to 4 divided doses.  Contraindications; Severe hypersensitivity to aminosalicylate sodium and its congeners
  • 34. KANAMYCIN & AMIKACIN  Aminoglycoside antibiotics  Kanamycin has been used for treatment of TB caused by streptomycin-resistant strains, but the availability of less toxic alternatives (eg, capreomycin and amikacin) has rendered it obsolete  Most MDR strains are amikacin sensitive  Amikacin is also active against atypical mycobacteria
  • 35.  no cross-resistance between streptomycin and amikacin, but kanamycin resistance often indicates resistance to amikacin as well.  Serum concentrations of 30–50 mcg/mL are achieved 30–60 minutes after a 15 mg/kg intravenous infusion.  indication- treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrug-resistant strains.  Amikacin must be used in combination .  The recommended dosages are the same as that for streptomycin.
  • 36. FLUOROQUINOLONES  ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of M tuberculosis  Moxifloxacin is the most active against M tuberculosis by weight  the drug must be used in combination with two or more other active agents-to prevent resistance  standard dosage of ciprofloxacin is 750 mg orally twice a day, levofloxacin is 500–750 mg once a day, moxifloxacin is 400 mg once a day.
  • 37. LINEZOLID  Prevents the formation of a functional 70S initiation complex, which is essential to the bacterial translation process.  It achieves good intracellular concentrations.  Linezolid has been used in combination with other second- and third-line drugs to treat patients with tuberculosis caused by multidrug- resistant strains
  • 38.  adverse effects; bone marrow suppression and irreversible peripheral and optic neuropathy, have been reported with the prolonged courses  600-mg (adult) dose administered once a day  it should be considered a drug of last resort for infection caused by multidrug-resistant strains.
  • 39. RIFABUTIN  Inhibits DNA-dependent RNA polymerase in susceptible strains of bacteria.  Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete.  Rifabutin is both substrate and inducer of cytochrome P450 enzymes.
  • 40.  it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or NNRTI (eg, efavirenz)  DOSE; ADULTS: PO 300 mg once daily. INFANTS AND CHILDREN: PO Up to 5 mg/kg/day.
  • 41. RIFAPENTINE  Rifapentine is an analog of rifampin  it is a bacterial RNA polymerase inhibitor.  potent inducer of CYT P450  600 mg (10 mg/kg) once weekly is indicated for treatment of tuberculosis caused by rifampin- susceptible strains during the continuation phase only .  Rifapentine should not be used to treat HIV- infected patients because of an unacceptably high relapse rate with rifampin-resistant organism.
  • 42. XDR TB  XDR-TB is defined as TB that has developed resistance to at least rifampicin and isoniazid , as well as to any member of the quinolone family and at least one of the following second-line anti-TB injectable drugs: kanamycin, capreomycin, or amikacin
  • 43. TB AND HIV CO-INFECTION  3–5 % of patients with pulmonary TB develops musculoskeletal lesions but the incidence of musculoskeletal lesions increases to 60 % in patients who are HIV positive.  Direct observational therapy is even more important for HIV-positive tuberculosis patients and is known to significantly decrease mortality in these patients
  • 44.  addition of rifampicin to the drug regimens in HIV patients significantly reduces mortality ,  protease inhibitors and NNRTI interact with rifampicin and therefore should not be prescribed along with rifampicin.  PARADOXICAL WORSENING- when antiretroviral therapy is started in a patient being treated with tb, there is rapid worsening of symptoms- improvement in inflamatory response
  • 45.  anti-retroviral is known to activate latent tuberculosis in HIV-positive patients which is supposed to be due to the immune reconstitution syndrome