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Clinical Pharmacology A Case of TB  Tuberculosis (TB) Tuberculosis is a chronic granulomatous disease. In developing countries, it is a major health problem. ≈ 30% of world population is infected with Myc. Tuberculosis infection.  Mycobacterium Infections Common...

Clinical Pharmacology A Case of TB  Tuberculosis (TB) Tuberculosis is a chronic granulomatous disease. In developing countries, it is a major health problem. ≈ 30% of world population is infected with Myc. Tuberculosis infection.  Mycobacterium Infections Common infection sites: Lung (primary site) Intestines (primary site) Brain Lymph nodes Bone Liver Kidney  Mycobacterium Infections Tubercle bacilli are conveyed by droplets Droplets are expelled by coughing or sneezing, then enter the body by inhalation Tubercle bacilli then spread to other body organs via blood and lymphatic systems Tubercle bacilli may become dormant, or walled off by calcified or fibrous tissue  Clinical Manifestations Early stages - Free of symptoms Systemic manifestations: - Fatigue, anorexia, weight loss, low-grade fevers, night sweats - Cough: frequent & mucopurulent sputum - Dull or tight chest pain Some cases: - Acute high fever, chills, pleuritic pain  Diagnostic Studies Tuberculin Skin Testing + ve Reaction 2-12 weeks after the initial infection Chest X-ray Used in conjunction with skin testing Multinodular lymph node involvement with cavitation in the upper lobes of the lungs Calcification Bacteriologic Studies Sputum, gastric washings –early morning specimens for acid-fast bacillus, three consecutive cultures on different days CSF or pus from an abscess  Chemotherapy in TB Goals of anti-tubercular chemotherapy I- Kill dividing bacilli: Patient becomes non-contagious, transmission of TB is interrupted. II- Kill persisting bacilli: for effective cure and prevent relapse. III- Prevent emergence of resistance: so that the bacilli remain susceptible to the drugs. TB is an infection difficult to treat ?? Typical growth characteristics Unique cell wall structure (mycolic acid). Resistance emerges quickly.  Antitubercular Agents First line drugs: Isoniazide (H) Rifampicin (R) Ethambutol (E) Pyrazinamide (Z) (Multiple targets)  Antitubercular Agents Pyrazinamide (Z) (Multiple targets) proposed mechanism of action: 1. Inhibition of fatty acid synthase I interferes with mycolic acid synthesis. 2. Reduction of intracellular pH. 3. Disruption of bacterial membrane transport.  Antitubercular Agents Second line drugs: Para amino salicylic acid (PAS) Ethionamide (Etm) Kanamycin& Amikacin& Capreomycin Cycloserine Streptomycin (S)  Antitubercular Agents Newer Second Line drugs: Ciprofloxacin& Ofloxacin& Levofloxacin& Moxifloxacin Clarithromycin& Azithromycin Clofazimine (Multiple targets) mechanism of action: It targets DNA gyrase, 30s ribosomal subunits and induces formation of ROS attacking cell membrane.  Antitubercular Agents MDR- anti-TB drugs: Bedaquiline Targets mycobacterial ATP synthase, an enzyme that is essential for ATP synthesis which finally affect the supply of energy to bacteria. Linezolid Prevents the formation of 70S complex, so inhibits bacterial protein production.  Antitubercular Agents MDR- anti-TB drugs: Clofazimine Pyrazinamide Moxifloxacin Mechanism of pharmacotherapy in tuberculosis  Regimen of TB treatment 1- Regimen design principles: - Drugs commonly used in the country and resistance should be taken into consideration. - Drug Susceptibility Testing (DST) should be therapy guide. - Regimens should consist of at least four drugs. - The drug dosage is determined by body weight. - Each dose is given as Directly observed therapy (DOT), with a treatment card.  Regimen of TB treatment 2- Duration of treatment: Remarkable change, conventional 1-1½yr is replaced by more effective & less toxic 4–6-month therapy. 3- Drugs used: Multi-Drug Therapy ?? H & R are most efficacious drugs ,their combination is synergistic. The Basis for Multi-Drug Therapy 1 Prevent emergence of resistance 2 Antibacterial INH Rifampin attack against all High Streptomycin Ethambutol subpopulations INH INH, Rifampin А of bacilli. Rapid Continuous (RIF, SM)PZ Ethambutol, growers growth PZ RIF Rifampin Speed of bacteria Slow A growers growth INH Rifapentine B C D Acid Spurts Spurtersof Dormant inhibition metabolism Low (No cure)  Antitubercular Drugs used in subpopulations of TB bacilli a) Rapidly growing with higher bacillary load e.g., wall of the cavity region- highly suscep. to H & lesser extent to R,E,S. b) Slow growing: intracellular & at inflamed sites – vulnerable to Z while H,R,E are lesser active.  Antitubercular Drugs used in subpopulations of TB bacilli c) Spurturs: with in caseous material (where O2 tension is less) the bacilli grow intermittently. R is most active in this sub population. d) Dormant: bacilli remain totally inactive for prolonged periods- suscep. to H & Rifapentine. Treatment regimen of drug sensitive TB (DS-TB) 1- The 6-month regimen (2HRZ (E)/ 4 HR) comprises 2 months of H, R, Z and E, followed by 4 months of H and R. This regimen is recommended in adult populations. Treatment regimen of drug sensitive TB (DS-TB) 2- In children (aged