1. Chapter 44 Antituberculosis Drugs Department of pharmacology Liu xiaokang( 刘小康） 2010,3

2. Therapeutic Goals: (1) Prevention or prophylaxis. (2) Cure of clinical disease. (3) Requirements: a) Prolonged therapy. b)Combined therapy. c) Compliance. d) Prevention of development of drug resistance. e) Cures, ideally, 95-100%.

3. Properties of Mycobacterium tuberculosis: a) Cell wall -- high lipid (60% dry weight) content. b) Mycolic acid a major component. c)Slow growth. d) Survive within phagocytes.

4. Isoniazid (INH) General comments: (1) Prophylaxis as single agent. (2)Cure -- ALWAYS in combination: Slows development of resistance (to INH alone -- 1 mutation in 10 6 cell divisions; to 2nd drug -- 1 mutation in 10 6 to 10 8 cell divisions; Combination -- Odds of resistance = 1 in 10 6 x 10 6 = 1 in 10 12 !!).

5. Antibacterial activity: Bacteriostatic at most concentrations (is bactericidal to actively growing organisms) Mechanism of action: Inhibits mycolic acid synthesis.

6. Resistance: 1998 - 8-10% of isolates in US are resistant (10-20% in Caribbean and Southeast Asia). Organisms may be Multidrug-resistant.

7. Pharmacokinetics: PO, Well absorbed, Widely distributed (intracellular, CSF, Necrotic material). Elimination mainly acetylation - liver N- acetyltransferase. Fast and slow acetylators: Plasma concentration in fast acetylators may be 1/3 to 1/2 that of slow acetylators. Elimination half- life (Fast = 70 min, Slow = 180 min, Fast/Slow = 50:50 Western countries (whites and blacks), Fast/Slow = 90/10 Eskimos and Japanese.

8. Adverse Effects: (1) Allergic, Including fever, skin eruptions, hepatitis, and various kinds of rashes. Hematological reactions, e.g., thrombocytopenia, agranulocytosis, eosinophilia, and anemia may occur. Reversible vasculitis may occur and arthritic symptoms at various joints may be observed.

9. (2) Most frequent -- Hepatitis -- 2 types: a)minor increase in liver aminotransferases -- not have to stop drug, 10-20% of cases, Not symptomatic. b) Clinical hepatitis in 1% can be fatal -- Stop drug. loss of appetite, nausea, vomiting, jaundice, and upper right quadrant pain.

10. (3) Most notable -- peripheral neuritis (including optic neuritis): in 10-20% if given > 5 mg/kg/d, but infrequent in standard dose of 300 mg/adult (Assuming 70 kg as standard, 300 is 4.3 mg/kg). Predisposing conditions: slow acetylators, malnutrition, alcoholism, diabetes, AIDS, uremia.Supplement with pyridoxine (Vitamin B6)

11. Rifampin Mechanism of Action: Binds to DNA-dependent RNA polymerase, Inhibits initiation -- not elongation. Antibacterial Spectrum: M. tuberculosis, Bactericidal, Broad spectrum of bacteria, Many Gram – bacteria and many chlamydia.

12. Pharmacokinetics: PO -- Well absorbed, Broadly distributed -- even CSF. Orange-red color stains tissues / secretions / urine. Enterohepatic cycling and partially biotransformed in liver. Drug and metabolites eliminated in feces. Autoinduction of metabolism ( Half-life shortens 40% first 14 days of Rx, Hepatic microsomal induction).

13. Clinical uses: (1) Tuberculosis, Never used alone for Therapy of TB. (2) Leprosy. (3) Various bacterial infections, e.g., with a beta-lactam or vancomycin for staphylococcal endocarditis. Meningococcal and staphylococcal carrier states.

14. Adverse reactions: Relatively safe, less than 4% in TB patients have significant reactions. Drug interaction: Hepatic microsomal induction, Shortens half-life of many drugs.

15. Resistance: Frequency of resistance is 1:10 6 organisms (M. tb). Develops quickly, due to changes in the beta subunit of DNA- dependent RNA polymerase. Not use drug alone for TB or other bacteria

16. Ethambutol Activity: No effect on bacteria other than mycobacteria. Suppresses growth (static) of organisms resistant to streptomycin and isoniazid, i.e., no cross resistance. Resistance to ethambutol develops.

17. Mechanism: Not clear. May be interfering RNA synthesis or inhibits synthesis of component of mycobacterial cell wall – arabinogalactan( 阿拉伯半乳糖 ) (This may increase penetration of other drugs into the organisms).

18. Clinical use: Always used in combination. Adverse reactions: Minimally toxic (<2%) at 15 mg/kg per day (usual dose), decreased visual acuity, rash, drug fever. Optic neuritis (reversible) -- most important adverse effect and Dose related: Occurs in 15% of patients receiving 50 mg/kg per day and 5% of those receiving 25 mg/kg per day and <1% 15 mg/day. Decreased visual acuity and red/green color blindness.

19. Pyrazinamide Activity: Bactericidal to tubercle bacilli within monocytes at 12.5 μg/ml. (requires slightly acidic pH), Resistance develops rapidly when used alone. Mechanism: unknown.

20. Pharmacokinetics: Orally administered at 1 gram gives 45 μg/ml at 2 h and 10 μg/ml at 15 h (Normal dose is 20-30 mg/kg po). Broadly distributed. Eliminated primarily by glomerular filtration; also biotransformed. Adverse reactions: most common and serious side effect is liver injury.

21. Other antituberculosis dugs: Streptomycin, rifapentine, rifandin, para- aminosalicylic acid, ethionamide, amikacin, fluoroquinolones. (The end)