ANTI MYCOBACTERIAL DRUGS

1. ANTI MYCOBACTERIAL DRUGS Dr.SaeedAhmad Department of Pharmacology King Saud University PHARMA TEAM !!

2. Tuberculosis • Tuberculosis is one of the world’s most widespread and deadly illnesses. • Mycobacterium tuberculosis, the organism that causes tuberculosis infection and disease, infects an estimated 20 – 43% of the world’s population. • 3 milion people worldwide die each year from the disease

3. Tuberculosis • Tuberculosis occurs disproportionately among disadvantaged populations such as the malnourished, homeless, and those living in overcrowded and sub – standard housing. • There is an increased occurance of tuberculosis among HIV +ve individuals.

4. Tuberculosis • Infection with M tuberculosis begins when a susceptible person inhales airborne droplet nuclei containing viable organisms. Tubercle bacilli that reach the alveoli are ingested by alveolar macrophages. Infection follows if the inoculum escapes alveolar macrophage mirobicidal activity.

5. Tuberculosis • Once infection is established, lymphatic and hematogenous dissemination of tuberculosis typically occurs before the development of an effective immune response. This stage of infection, primary tuberculosis is usually clinically and radiologically silent.

6. Tuberculosis • In most persons with intact cell – mediated immunty, T cells and macrophages surround the organisms in granulomas that limit their multiplication and spread. The infection is contained but not eradicated, since viable organisms may lie dormant within granulomas for years to decades.

7. Tuberculosis • Individuals with this latent tuberculosis infection do not have active disease and can not transmit the organism to others. However, reactivation of disease may occur if the host’s immune defenses are impaired.

8. Tuberculosis Symptoms and Signs: • Malaise • Anorexia • Weight loss • Fever • Night sweats • Chronic cough, blood with sputum • Rarely, dyspnea

9. Tuberculosis • Investigations: • Chest radiograph shows pulmonary infilterates most often apical • Positive tuberculin skin test reaction (most cases) • Acid fast bacilli on smear of sputum or sputum culture positive for Mycobacterium tuberculosis

10. Anti Mycobacterial Drugs • Mycobacteria are intrinsically resistant to most antibiotics. • They grow slowly compared with other bacteria, antibiotics that are most active against growing cells are relatively ineffective. so, that’s why we use cobination of drugs. • Mycobacterial cells can also be dormant and thus completely resistant to many drugs or killed only very slowly.

11. Anti Mycobacterial Drugs • The lipid rich mycobacterial cell wall is impermeable to many agents(e.g. drugs). • Mycobacterial species are intracellular pathogens, and organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly. • Finally,mycobacteria are notorius for their ability to develop resistance.

12. Combinations of two or more drugs are required to overcome these obstacle 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.

14. Anti Mycobacterial Drugs • Drugs Used in Tuberculosis First-line drugs : • Rifampin, • Isoniazid (INH), • Pyrazinamide, • Ethambutol, and • Streptomycin These drugs are the first-line agents for the treatment of tuberculosis. • Isoniazid and Rifampin are the two most active drugs. • Mnemonics  RIPES

15. Anti Mycobacterial Drugs • An isoniazid - rifampin combination administered for 9 months will cure 95-98% of cases of tuberculosis caused by susceptible strains. • The addition of pyrazinamide to an isoniazid rifampin combination for the first two months allow the total duration of therapy to be reduced to 6 months without loss of efficacy.

16. Anti Mycobacterial Drugs • In practice therapy is initiated with a four drug regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin to determine susceptibility to the clinical isolate.

17. 1-ISONIAZID (INH) • It is a chemo not antibiotic. • Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains. • It is small (MW137) and freely soluble in water. • It has the structural similarity to pyridoxine = (Vit.B6) • It is bactericidal for actively growing tubercle bacilli.

18. ISONIAZID (INH) • It is less effective against atypical mycobacterial species. • Isoniazid penetrates into macrophages and is active against both extra- and intracellular organisms.

19. Mechanism of Action and Basis of Resistance INH, a prodrug Mycolic acid, essential component of cell wall KatG enzyme, a mycobacterialcatalaseperoxidase enzyme, activates INH DNA

20. The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a ß-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis and kills the cell.

21. Mechanism of Resistance: • Resistance can emerge rapidly if the drug is used alone. • Resistance can occur due to either • High-level resistance is associated with deletion in the katG gene that codes for a catalase peroxidase involved in the bioactivation of INH. • Low-level resistance occurs via deletions in the inhA gene that encodes “target enzyme” an acyl carrier protein reductase.

22. PHARMACOKINETICS: • Drug resistant mutants are normally present in susceptible mycobacterial populations at about 1bacillus in 106. PHARMACOKINETICS: • Isoniazid is readily absorbed from the gastrointestinal tract. • Dosage: 300mg daily per oral or 5mg/kg/d for children. Peak plasma concentration 3-5mcg/ml achieved within 1-2 hours.

23. PHARMACOKINETICS: • Isoniazid diffuses readily into all body fluids and tissues. • The concentration in the CNS and CSF ranges between 20% and 100% of simultaneous serum concentrations. • Metabolism of isoniazid, especially acetylation by liver N-acetyl transferase, is genetically determined.

24. Pharmacokinetics of Isoniazid • The average plasma concentration of isoniazid in rapid acetylators is about one third to one half of that in slow acetylators, and average half lives are less than 1hour and 3 hours, respectively. • More rapid clearance of isoniazid by rapid acetylators is usually of no therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentration may occur if drug is administered as a once-weekly dose or if there is malabsorption

25. Pharmacokinetics of Isoniazid • Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the urine. • The dose need not be adjusted in renal failure. • Dose adjustment is not well defined in patients with severe preexisting hepatic insufficiency (isoniazid is contraindicated if it is the cause of the hepatitis).

26. CLINICAL USES 1. Infections caused by mycobacterium tuberculosis along with other antitubercular drugs • Dosage: 300mg/day per oral adults, or 900mg twice/week. 5mg/kg/day in children. 2. INH is the primary drug used to treat latent tuberculosis, 300mg/day alone or 900mg twice/week for 9 months.

27. Adverse Reactions of INH: The incidence and severity of untoward reactions related to dosage and duration of administration. • Immunologic reactions:

28. Adverse Reactions of INH: 2. Direct toxicity • Isoniazid induced hepatitis (most common major toxic effect). Clinical hepatitis with • loss of appetite, • nausea, • vomiting, • jaundice and • right upper quadrant pain, there is histologic evidence of hepatocellulardamage and necrosis. The risk of hepatitis depends on age, rarely occurs under age of 20, 2.3% for aged 50 and above.

29. Adverse Reactions of INH: • The risk of hepatitis is higher in • alcoholics, • pregnancy and • postpartum period. 3. Peripheral neuropathy in 10-20% of patients given dosages greater than 5mg/kg/day but infrequently seen with the standard 300mg adult dose. • It is more likely to occur in slow acetylators and patients with malnutrition, alcoholism, diabetes and AIDS. Neuropathy is due to relative deficiency of pyridoxine.

30. Adverse Reactions of INH: 4. CNS toxicity, which is less common includes memory loss, psychosis and seizures. These may also respond to pyridoxine. 5. Miscellaneous adverse effects: • Provocation of pyridoxine deficiency anemia, tinnitus and gastrointestinal discomfort. • Drug interactions: isoniazid can reduce the metabolism of phenytoin.

31. 2-RIFAMPIN • Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. • It is active in vitro against gram positive and gram negative cocci, some enteric bacteria, mycobacteria and chlamydia.

32. ANTIMICROBIAL ACTIVITY AND RESISTANCE • Rifampin binds to the β subunit of bacterial DNA–dependent RNA polymerase and thereby inhibits RNA synthesis. • Resistance results from any one of several possible point mutations in rpoB, the gene for the β subunit of RNA polymerase.

33. Rifampin • These mutations result in reduced binding of rifampin to RNA polymerase. • Human RNA polymerase does not bind rifampin and is not inhibited by it. • Rifampin is bactericidal for mycobacteria. It readily penetrates most tissues and phagocytic cells.

34. Rifampin • It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities. Pharmacokinetics: • Rifampin is well absorbed after oral administration.

35. It is excreted mainly through the liver into bile. • It then undergoes an enterohepaticcirculation, with the bulk excreted as a de-acylatedmetabolite in feces and a small amount in the urine. • Rifampin is distributed widely in body fluids and tissues. • Rifampin is relatively highly protein bound and adequate CSF concentrations are achieved only in the presence of meningeal inflammation.

36. CLINICAL USES: 1. Mycobacterial infections: Rifampin usually600mg/day, 10mg/kg/day, orally must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug resistant mycobacteria.

37. CLINICAL USES: 2. Atypical mycobacterial infections. 3. Leprosy. in these above two conditions rifampin 600mg daily or twice weekly for 6 months is effective in combination with other agents. 4. As alternative of isoniazid in prophylaxis of latent tuberculosis 600mg/day as a single agent for 4 months, in patients with isoniazid-resistance or rifampin-susceptible bacilli.

38. CLINICAL USES: 5. In exposure to a case of active tuberculosis caused by an isoniazid resistant, rifampin susceptible strain. 6. To eliminate meningococcal carriage,600mg, twice daily, for 2 days. 7. To eradicate staphylococcal carriage with combination to other agent.

39. CLINICAL USES: 8. Osteomyelitis and prosthetic valve endocarditis caused by staphylococci in combination therapy with other agent.

40. Adverse effects: 1. Rifampin imparts a harmless orange color to urine, sweat, tears and contact lenses. 2. Occasional adverse effects:

42. Drug interactions: • Rifampin strongly induces most cytochrome p450 isoforms (3A4,2C9,2D6,2C19,1A2). • Anticoagulants, cyclosporine, anticonvulsants, contraceptives, methadone, protease inhibitors, non-nucleoside reverse transcriptase inhibitors. • Administration of rifampin results in significantly lower serum levels of these drugs.

43. 3-Ethambutol Ethambutol is a synthetic water soluble, heat stable compound, the dextro-isomer of the structure dispensed as the dihydrochloride salt. Ethambutol inhibits mycobacterialarabinosyltransferases. Arabinosyltransferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Mechanism of action:

44. Resistance to ethambutol is due to mutations resulting in overexpression of emb gene products or within the emb B structural gene. Pharmacokinetics : • Ethambutol is well absorbed from the gut. • After ingestion of 25mg/kg, a blood level peak of 2-mcg/mL is reached in 2-4 hours.

45. Pharmacokinetics : • About 20% drug excreted in feces and 50% in urine in unchanged form. • Ethambutol crosses the blood brain barrier only if the meninges are inflammed. • Ethambutol accumulates in renal failure and the dose should be reduced by half if creatinine clearance is less than 10mL/min. • Resistance to ethambutol emerges rapidly when used alone, therefore it is always given with other antitubercularagents.

46. Clinical Uses of Ethambutol • Tuberculosis: • Ethambutolhydrochloride 15-25mg/kg/d is usually given as a single daily dose in combination with isoniazid or rifampin. • Adverse effects: • Retrobulbar (optic) neuritis resulting in loss of visual acuity and red green color blindness. Usually occur at doses of 25mg/kg/day continued for several months.

47. Precaution & contraindication • Periodic visual acuity testing is desirable if the 25mg/kg/day dosage is used. • It is relatively contraindicated in children too young to permit assessment of visual acuity and red green color discrimination.

48. 4-PYRAZINAMIDE • Pyrazinamide (PZA) is a relative of nicotinamide, stable and slightly soluble in water. • It is inactive at neutral PH, But at PH 5.5 it inhibits tubercle bacilli, and some other mycobacteria at concentrations of approximately 20mcg/ml.

49. The drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes. • Pyrazinamide is converted to pyrazinoic acid, the active form of the drug, by microbial pyrazinamidase, which is encoded by pncA.

50. The drug target and mechanism of action are unknown. • Resistance may be due to impaired uptake of pyrazinamide or mutations in pncA that impair conversion of pyrazinamide to its active form.