Slide 1: Dr iqbal khan
Chapter
Antituberculosis drugs
Slide 2: Tuberculosis
Tuberculosis is a kind of communicable chronic disease caused by M.tuberculosis.
Slide 3: History
Before 1930’s 1944 streptomycin 1950’s Isoniazid 1970’S Rifampin 1990’s Fluoroquinolones
Slide 4: Antituberculosis drugs
First-line drugs
• Isoniazid, rifampin, pyrazinamide,
ethambutol and streptomycin
Second-line drugs
• Aminosalicylic acid （ PAS ） , kanamycin
Slide 5: Isoniazid
1952, the most active drug for the treatment of tuberculosis
Mechanism of action
• Inhibit the synthesis of mycolic acid which is essential components of mycobacterial cell walls
Antimicrobial activity
• High activity against both extracellular and intracellular tubercle bacilli
Slide 6: Isoniazid
Pharmacokinetics
• Diffuse readily into all body fluids and tissues • Metabolized by acetylation • Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the urine.
Clinical uses
• First choice for all types of tuberculosis
Slide 7: Isoniazid
Adverse reactions
• Peripheral neuropathy • more likely to occur in patients with predisposing conditions such as malnutrition, alcoholism,diabetes, AIDS, and uremia. • Due to a relative pyridoxine deficiency
Slide 8: Isoniazid
• CNS toxicity: memory loss, psychosis, seizures • Hepatoxicity: the most frequent, increase in aminotransferase, hepatitis The risk of hepatitis depends on age is greater in alcoholics and possibly during pregnancy and the postpartum period. • Allergic reactions related to dosage and duration of administration.
Slide 9: Rifampicin (rifampin)
Antimicrobial activity
• Mycobacteria, some G+ and G- cocci, chlamydiae and some virus
Mechanism of action
• Bind to β-subunit of bacterial DNAdependent RNA polymerase and inhibit RNA synthesis
Slide 10: Rifampicin
Pharmacokinetics
well absorbed after oral administration Distributed widely in body fluids and tissues Exerted mainly through the liver into bile
Slide 11: Rifampicin
Clinical uses
• Tuberculosis and leprosy • Infections caused by stapylococci and other ripfampicin-susceptible bacteria
Adverse reactions
• • • Gastrointestinal disturbance Liver toxicity: cholestatic jaundice, hepatitis Harmless orange color urine, sweat,tears,and contact lenses
Slide 12: Ethambutol
Mechanism: Pharmacokinetics
well absorbed from the gut. crosses the blood-brain barrier only if the meninges are inflamed. About 20% of the drug is excreted in feces and 50% in urine in unchanged form. Ethambutol accumulates in renal failure, and the dose should be reduced.
interfering with synthesis of RNA by combination with Mg2+
Slide 13: Ethambutol
Used in combination with INH or rifampicin Adverse effect
• Loss of visual acuity, optical neuritis, red-green color blindness
Slide 14: Streptomycin
• Penetrate into cell poorly, active mainly against extracellular tubercle bacilli
Slide 15: pyrazinamide
Pharmacokinetics
After orally administered, pyrazinamide is quickly absorbed and then widely distributed in body tissues,including inflamed meninges.it is also able to penetrate into maxrophages. Pyrazinamide is excreted mainly by glomerular filtration. The half life is 8~11hours.
Slide 16: pyrazinamide
• Clinicle use
• No cross-resistance with other antituberculosis drugs • In conjunction with INH and rifampicin in short-course regimens to prevent relapse
Slide 17: pyrazinamide
Adverse effect
hepatotoxicity nausea, vomiting, drug fever, and hyperuricemia. Hyperuricemia may provoke acute gouty arthritis.
Slide 18: New antituberculosis drugs
Rifandin Rifapentine Sparfloxacin
Slide 19: Use as early as possible Growing vigorously are sensitive to drugs Enough blood supply in focal location makes drugs enter into tuberculotic foci easily The stronger disease-resistance of body is beneficial to wipe out organisms Drug combination The combination therapy not only reduces the drugresistance and increases the curative effect ,but can alternately kill the tubercle bacilli that have been resist to other drugs
Rationale for the use of antituberculosis drugs
Slide 20: Rationale for the use of antituberculosis drugs
Short-time therapy
traditionally,the duration for treatment of tubercululosis is normally required 2 years or longer Isoniazid + rifampin for 9 months cure 95~98% of cases of tubercululosis Isoniazid+rifampin+pyrazinamide (the first 2 months) permits shortenting the total duration of therapy to 6 months without loss of efficacy
Slide 22: Chopin
（ 18101849 ）
