Antitubercular Therapy PowerPoint PDF

Anti-Tubercular Drugs Dr. Salma Naqvi Asst. Prof., Pharmacology GMU, Ajman  Learning objectives At the end of the class, student should be able to: Classify antimycobacterial drugs into first line and second line drugs. Describe the mechanism of action, clinical uses , mechanism of drug...

Anti-Tubercular Drugs Dr. Salma Naqvi Asst. Prof., Pharmacology GMU, Ajman  Learning objectives At the end of the class, student should be able to: Classify antimycobacterial drugs into first line and second line drugs. Describe the mechanism of action, clinical uses , mechanism of drug resistance and toxicity of: Isoniazid (INH), Rifampicin (RMP), Pyrazinamide (PYZ), Ethambutol (E), Streptomycin(S) Specify the uses of fluroquinolones and macrolides in  A Case of Cough, Night Sweats, and Lethargy A 42-year-old man is seen at a public health clinic. He reports a productive cough, chills, fever, night sweats, loss of appetite, and feeling tired for the past month. He has a history of knife wounds and was jailed for 3 months after a barroom fight 2 years ago. His chest radiograph shows patchy infiltrates in both upper lobes, and a sputum sample is found to contain acid-fast bacilli. He is given a Mantoux tuberculin skin test, which has a positive result with a 15-mm induration 72 h later. After completing laboratory work that will include a complete blood count, liver function tests, and chemistry profile, he will begin standard four-drug therapy for tuberculosis (TB) because the incidence of multiple-drug–resistant TB in his community is low. Liver function tests and a red-green color discrimination test will be conducted every 2 to 4 weeks throughout his treatment. The patient will be isolated until his sputum is negative for tubercle bacilli, and a public health nurse will visit him regularly to provide care and verify adherence to the treatment regimen.  Isoniazid (INH), Rifampicin (R) Pyrazinamide (Z) Ethambutol (E) Streptomycin (S) INH mycolic acid catalase- peroxidase  Mycobacterium tuberculosis TB is caused by M tuberculosis, which initially infects the lungs after transmission via aerosol droplets expelled from an infected person by sneezing and coughing. After infecting pulmonary alveoli, the organism invades macrophages that aggregate with connective tissue to form granulomas and caseous lesions that protect the organism from the immune system and chemotherapy drugs. These often dormant, sequestered organisms contribute to the chronic nature of the infection and its long, difficult treatment. Resistant to most antibiotics because they grow more slowly. Can also be dormant and thus completely resistant to many drugs. Lipid-rich mycobacterial cell wall is impermeable to many agents Intracellular pathogens and organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly. Readily develop resistance Treatment of multidrug-resistant tuberculosis (MDR-TB) cases is challenging because it relies on second-line drugs that are less potent and more toxic than  The solution Always combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy. The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years, depending on which drugs are used. The recommended regimen for MDR-TB is the combination of at least four drugs for a duration of 20 months. The goals of TB chemotherapy are to kill tubercle bacilli rapidly, eliminate dormant and sequestered bacilli, and prevent disease relapse and transmission. Treatment should be guided by drug susceptibility testing of the patient’s infecting organism at the start of therapy, when treatment fails to sterilize the patient’s sputum, and when a relapse of TB occurs after previous treatment. Isolation of patients with TB in single-person rooms is essential until sputum cultures are negative, and extended isolation may be required to prevent the spread of drug-resistant strains.  Antitubercular Drugs First-line oral agents Second line agents Isoniazid (INH), Fluoroquinolones: Levofloxacin Rifampicin (R) Gatifloxacin Pyrazinamide (Z) Moxifloxacin Ethambutol (E) Injectables: Streptomycin (S) Amikacin, Capreomycin, Kanamycin (High antitubercular Other oral drugs efficacy & low toxicity) Cycloserine Ethionamide Para-amino salicylic acid, Second-line drugs are reserved to treatClofazimine patients infected with organisms that are resistant to first-line drugs and patients with HIV Second line Drugs Low antitubertular efficacy and High toxicity Usually considered only in case of :  Resistance to first-line agents  Failure of clinical response to conventional therapy  Serious treatment-limiting ADRs Therapeutic approach An isoniazid-rifampin combination administered for 9 months will cure 95–98% of cases of tuberculosis In practice, therapy is usually initiated with a four-drug regimen: Isoniazid, Rifampin, Pyrazinamide and Ethambutol (Note: Fourth drug does not improve efficacy, but only provides additional coverage if the isolate proves to be resistant to isoniazid, rifampin or both) Prevalence of resistance to both isoniazid and rifampin (termed as multidrug resistance) is about 3%.  Isoniazid (INH) Isoniazid (isonicotinic acid hydrazide) is active against both E/C & I/C organisms. Prodrug and its activated metabolite inhibits synthesis of mycolic acids in the organism. Bacteriostatic for resting bacilli, and - cidal for growing bacilli. Less effective against atypical mycobacteria. It’s a Prodrug, activated by catalase Usually given orally, though a parenteral formulation is available. It is well absorbed from the gut and widely distributed, can cross CSF and PB; extensively metabolized, and the parent compound and its metabolites are excreted in the urine. The primary metabolite, acetylisoniazid, is formed by conjugation of acetate with isoniazid in a reaction catalyzed by acetyltransferase. Fast acetylators can easily eradicate M. tuberculosis, while slow acetylators are more likely to have certain adverse drug reactions. A small amount of acetylisoniazid is converted to isonicotinic acid and  Isoniazid - Mechanism of Action and Resistance INH is activated by mycobacterial catalase-peroxidase encoded by the katG gene and forms a complex with reduced nicotinamide adenine dinucleotide (NADH) that inhibits a reductase enzyme involved in the synthesis of mycolic acid. Mycobacterial resistance to isoniazid is increasingly prevalent and is often due to mutations to the katG gene. Isoniazid is part of the standard four-drug regimen for TB for persons without resistance to isoniazid. These drugs are believed to kill different populations of TB bacilli, which include rapidly growing organisms and dormant (stationary phase) bacteria. Isoniazid, together with rifampin and pyrazinamide, eradicates rapidly  ADR of Isoniazid  Hepatotoxicity Immunologic reactions : Hypersensitivity, Fever, hepatitis & rashes, Drug-induced SLE, hemolytic anemia  Direct toxicity : Clinical Hepatitis (Age related risk; 0.3 - 2.3 %) Fatal - Due to formation of monoacetyl hydrazine causing hepatocellular damage and necrosis  Peripheral neuropathy (more in slow acetylators) Due to excretion of pyridoxine (reversed by pyridoxine 25  Rifampicin Bactericidal for both IC & EC (Active on proliferating atypical bacteria) Mechanism: Inhibits DNA-dependent RNA polymerase(β subunit) Resistance due to alteration of the target enzyme (due to mutation of RPO-B gene) Well absorbed (but food dec absorption) and distributed; t1/2: 2-5 hr. It’s a strong enzyme inducer drug.  ADRs of Rifampicin Development of cholestatic Jaundice requires discontinuation. Hepatitis generally occurs in pts. with pre-existing liver disease and is dose related. Abdominal syndrome: GIT disturbances (N,V, abd. cramps, Diarrhea) → discontinuation of the drug Cutaneous syndrome: Flushing, pruritis, rash, redness flu-like syndrome etc. Induces Hepatic microsomal enzyme and reduces the therapeutic effect of oral anticoagulants, oral contraceptives, Steroids, sulfonylureas etc. Harmless orange color to urine, sweat, and tears  Pyrazinamide Weak tuberculo-cidal activity (More active against I/C org.) Converted to pyrazinoic acid (active form) by mycobacterial pyrazinamidase in the bacilli, where it interferes with fatty acid synthase FAS I, inhibits mycolic acid synthesis, an essential component of mycobacterial cell membrane. Acts as a “sterilizing” agent active against residual intracellular organisms that may cause relapse. Well absorbed and widely distributed including CSF (t1l2: 6-10 h) ADR : Hyperuricemia (aggravates gout), Hepatitis, Arthralgia, Pruritis, Rash  Ethambutol Active against all strains of M. tuberculosis & atypical mycobacterium Mechanism: (-) arabinosyl transferases involved in cell wall biosynthesis. 75 - 80% is absorbed: t1/2 3 - 4 hours. 75% → excreted unchanged in the urine requiring dose adjustment during impaired renal function. Can cross BBB and can be used for Meningitis ADR: Retrobulbar neuritis (loss of visual acuity and red-green color blindness) rash, drug fever, Hyperuricemia Contraindicated in children  Streptomycin Indicated as the fourth drug when other anti-TB are contraindicated due to toxicity or intolerance. Streptomycin, an aminoglycoside antibiotic, inhibits protein synthesis by irreversibly binding to the small 16S rRNA of the 30S ribosomal subunit. Given i.m. which diffuses readily into the extracellular component of most body tissues and attains bactericidal concentrations, particularly in tuberculous cavities ADR: Ototoxicity, Nephrotoxicity, Hypersensitivity, headache, vertigo, tinnitus  Fluoroquinolones Important as substitute agents for those who are intolerant of first- line TB agents. Novel anti-TB drugs to be used when a patient is infected with a MDR-TB strain. Fluoroquinolones prevent DNA synthesis by inhibitng two enzymes- topoisomerases-II (DNA gyrase) and topoisomerase IV (Topo IV). Both targets allow one double‐stranded DNA molecule to pass through another, followed by religation of the original strand. Levofloxacin, Gatifloxacin & Moxifloxacin are highly active against M. tuberculosis. Macrolide Clarithromycin, is defined as a group 5 anti-TB drug by WHO. However, its efficacy in the treatment of MDR-TB is unclear. Potential benefits: Accumulation in the relevant compartments and cells in the lungs Immuno-modulatory effects Synergistic activity with other anti-TB drugs. Azithromycin preferred in → HIV Pts. as it is least likely to  Drug Resistance-TB Occur when the drugs used to treat TB are misused or mismanaged e.g., when:  patients do not complete the course of treatment  Health care providers prescribe the wrong treatment, dose, or duration for taking the drugs  Supply of drugs is not always available; or  Drugs are of poor quality  Drug Resistance Multidrug Resistant TB (MDR-TB): Resistance to Isoniazid and rifampicin (with or without resistance to other anti-TB drugs) Extensively drug resistant TB (XDR-TB): Resistance to Isoniazid and rifampicin + One fluoroquinolone + One of the 3 injectable 2nd line drugs ( Amikacin, kanamycin or capreomycin)  Chemotherapy-Short course WHO introduced 6–8 month multidrug ‘Short course’ regimens in 1995 under the DOTS program. For initial empiric treatment , start patients on a 4-drug regimen: Isoniazid, Rifampin, pyrazinamide, and either Ethambutol (or streptomycin). Once the TB isolate is known to be fully susceptible, ethambutol (or streptomycin), can be discontinued. New patient (Min. 6 months): Acceptable if DOT ensured I + R+ Z+ E daily for 2 months followed by I + R thrice weekly for 4 months Recommended doses for anti-TB drugs Prophylaxis Isoniazid 300 mg (10 mg/kg in children) daily for 6 months. Because of spread of Isoniazid resistance, a combination of isoniazid (5 mg/kg) and Rifampicin (10 mg/kg, maximum 600 mg) daily given for 3 months is preferred in some areas. Isoniazid alone (300mg daily for 9 months) has been given for treatment of latent tuberculosis  Case Discussion Tubercle bacilli are transmitted on microdroplets expelled by coughing from persons with active infections. Person-to-person transmission requires close contact with an active case and usually leads to a latent infection. Active infections typically occur months or years later when latent TB emerges as a result of decreased immune function, poor nutrition, physical stress, or other insults. The man in the present case has classic signs and symptoms of TB. The definitive diagnosis is based on finding acid-fast bacilli in sputum and a positive tuberculin test result. Effective therapy will sterilize respiratory secretions in a few weeks or less, but eradication of dormant organisms from infected tissues requires lengthy exposure to antitubercular drugs. Reference Stevens CW. Antimycobacterial drugs for treating tuberculosis and other diseases. In: Brenner and Stevens’ Pharmacology. 6th ed., Elsevier; 2023. p. 475- 82. (Available in Clinical key: https://www-clinicalkey-com.gmulibrary.com/#!/content/ book/3-s2.0-B9780323758987000419 ) Than k you