1. Chemotherapy of Tuberculosis  Medically important mycobacteria  Mycobacterium Tuberculosis  A typical Mycobacterium  Mycobacterium Leprae

2. Treatment Of Tuberculosis  Tuberculosis remains the primary cause of death due to infectious disease.  Organs involved --------- primarily lungs  Drugs are divided into two groups :  First line  Second line

3. Antimycobacterial drugs  First line of drugs:  Isoniazid (INH)  Rifampicin  Ethambutol  Streptomycin  Pyrazinamide

4. Never use a single drug therapy  Isoniazid –rifampicin combination administered for 9 months will cure 95-98% of cases.  Addition of pyrazinamide for this combination for the first 2 months allows total duration to be reduced to 6 months.

5. Isoniazid  Bacteriostatic for resting bacilli.  Bactericidal for rapidly dividing bacilli.  Is effective against intracellular as well as extracellular bacilli

6. Mechanism Of Action  Is a prodrug  Cell wall synthesis inhibitor  Inhibits synthesis of Mycolic acids----  Which are essential components of  Mycobacterial cell walls.

7. Pharmacokinetics  Readily absorbed when given either orally or parenterally.  Aluminum containing antacids interfere with absorption.

8. Distribution  Diffuse rapidly into all body fluids and cells.  Detected in significant concentrations in pleural & ascitic fluids.  Its concentration in CSF is significant in inflammed meninges.  Penetrates well into caseous material.

9. Metabolism & Excretion  75% to 95% of a dose of INH is excreted in urine within 24 hours.  Mostly as metabolities.  The main excretory products in human result from enzymatic acetylation.

10. Clinical uses  Mycobacterial infections (it is recommended to be given with pyridoxine to avoid neuropathy).  Latent tuberculosis in patients with positive tuberculin skin test  Prophylaxis against active TB in individuals who are in great risk as very young or immunocompromised individuals.

11. Adverse effects  Peripheral neuritis  Optic neuritis &atrophy.  Allergic reactions ( fever,skin rash,systemic lupus erythematosus )  Hepatitis

12. Adverse effects (cont.)  Hematological reactions  Vasculitis  Arthritic symptoms

13. Adverse effects (cont.)  CNS toxicity include ;  Lack of mental concentration, memory loss.  Excitability & seizures  Psychosis  ( Respond to pyridoxine)

14. Drug Interactions of INH  Inhibits the hepatic microsomal enzymes, cytochrome P450 & decrease metabolism of other drugs ( especially, Phenytoin )and increase their toxicity.

15. Rifampicin  Bactericidal  Inhibits RNA synthesis----- by binding to the beta –subunit of bacterial DNA dependent RNA polymerase.

16. Site of Action  Intracellular bacilli  Extracellular bacilli  Bacilli in caseous lesions

17. Pharmacokinetics  Well absorbed orally.  Aminosalicylic acid delay the absorption of rifampicin, (They should be given separately at an interval of 8-12 hour ).

18. Metabolism & Excretion  Metabolized in liver by acetylation & enters enterohepatic circulation.  Half-life 1.5-5 hours & increased in hepatic dysfunction.  Eliminated in bile & feces( 60-65% ) & 30% in urine.

19. Distribution  Distributed throughout the body organs & fluids including CSF in effective concentration.

20. Clinical uses  Mycobacterial infections  Prophylaxis of active tuberculosis.  Treatment of serious staphylococcal infections as osteomyelitis and endocarditis.  Meningitis by highly resistant penicillin pneumococci

21. Adverse effects  Harmless red-orange discoloration of body secretions( urine, sweat, tears) & contact lenses ( soft lenses may be permanently stained ).  Skin rash  Fever

22. Adverse Effects ( cont.)  Nausea & vomiting  Hepatotoxicity  ( Hepatitis, cholestatic jaundice)  If administered less than twice weekly causes a flu-like syndrome( fever, chills, myalgias, hemolytic anemia, thrombocytopenia & acute tubular necrosis.

23. Drug Interactions  Potent inducer of hepatic microsomal enzymes ( cytochrome P450)  Increase elimination of other drugs including :  Anticoagulants  Anticonvulsants  Contraceptives

24. Ethambutol  Bacteriostatic  Inhibits mycobacterial arabinosyl transferase ( inhibits polymerization reaction of arabinoglycan an essential component of mycobacterial cell wall )

25. Site Of Action  Intracellular & Extracellular bacilli

26. Phrmacokinetics  Well absorbed orally  Half-life 3-4 hours  75% of the drug is excreted unchanged in the urine, 15% as metabolities.

27. Clinical uses  Treatment of tuberculosis in combination with other drugs.

28. Adverse effects  Retrobulbar (optic) neuritis causing loss of visual acuity and red-green color blindness.  Relatively contraindicated in children( under 5 years).  GIT.upset.  Hyperuricemia

29. Pyrazinamide  Prodrug( converted to pyrazinoic acid,the active form.  Bactericidal  Acting on mycobacterial fatty acid synthase I gene involved in mycolic acid biosynthesis.

30. Site Of Action  Intracellular Bacilli

31. Phrmacokinetics  Well absorbed from GIT  Widely distributed including CSF  Half-life 9-10 hours  Excreted primarily by renal route.

32. Clinical uses  Mycobacterial infections (TB) mainly in multidrug resistance cases.  It is important in short –course (6 months ) regimens with isoniazid and rifampicin.  Prophylaxis of TB in combination with ciprofloxacin.

33. Adverse effects  Hepatotoxic  Hyperuricemia( provoke acute gouty arthritis )  Nausea & vomiting  Drug fever & skin rash

34. Streptomycin & Amikacin  Bactericidal  Inhibitors of protein synthesis by biding to 30 S ribosomal subunits.  Acting on extracellular bacilli

35. Clinical uses  Severe, life-threating form of T.B. as meningitis, disseminated disease, infections resistant to other drugs( Multidrug resistance tuberculosis).  In aerobic gram –ve bacterial infections.

36. Adverse Effects  Ototoxicity  Nephrotoxicity  Neuromuscular block

37. Contraindications  Myasthenia gravis  Pregnancy

38. Indication of 2 nd line treatment  Resistance to the drugs of 1 st line.  Failure of clinical response  There is contraindication for first line drugs.  Patient is not tolerating the drugs first line drugs.

39. Ethionamide  Blocks synthesis of mycolic acid.  Prodrug  Is converted to active form (sulfoxide ).

40. Pharmacokinetics  Absorbed from GIT, Given only orally  Rapidly & widely distributed  Half-life 2 hours  Metabolized in liver, less than 1% is excreted in active form in urine  Inhibits the acetylation of INH

41. Clinical uses  Is a secondary agent, to be used concurrently with other drugs when therapy with primary agents is ineffective or contraindicated.

42. Adverse Effects  Anorexia, nausea, vomiting, gastric irritation.  About 50% of patients are unable to tolerate a single dose more than 500mg.

43. Adverse Effects (cont.)  CNS symptoms include :  Mental depression  Drowsiness  Convulsions & peripheral neuropathy  Headache  ( Pyridoxine relieves the neurologic symptoms)

44. Adverse Effects(cont.)  Severe hypotension  Allergic skin reactions  Hepatitis  Alopecia  Metallic taste

45. Capreomycin  Aminoglycosides  It is an important injectable agent for treatment of drug-resistant tuberculosis.  It is nephrotoxic and ototoxic.  Local pain & sterile abscesses may occur.

46. Cycloserine  Inhibitor of cell wall synthesis  Cleared renally  The most serious side effects are peripheral neuropathy and CNS dysfunction, including depression & psychotic reaction.  Pyridoxine should be given.  Contraindicated in epileptic patients.

47. Amikacin  Used as alternative to streptomycin.  Used in multidrug- resistance tuberculosis.  No cross resistance between streptomycin and amikacin.

48. Ciprofloxacin & levofloxacin  Effective against typical and atypical mycobacteria.  Used against multidrug- resistant tuberculosis.  Used in combination with other drugs.

49. Rifabutin  As rifampicin, it is RNA polymerase inhibitor.  Cross resistance with rifampicin but not to all microorganisms.  Enzyme inducer of cytochrome p450.  Effective against typical and atypical mycobacteria.

50. Phrmacokinetics  Absorbed from GIT  Lipophilic drug  Excreted in urine & bile  Adjustment of dosage is not necessary in patients with impaired renal function.

51. Clinical uses  Treatment of T.B. in HIV- infected patients ( replaced rifampicin, because it is less potent enzyme inducer)  Prevention of tuberculosis  Prevention & treatment of disseminated atypical mycobacterial infections in AIDS patients

52. Adverse Effects  Skin rash(4%)  GIT intolerance (3%)  Neutropenia (2%)  Arthralgia  Orange-red discoloration ( skin,urine, ----- as rifampicin ).

53. Drug Interactions  Enzyme inducer of cytochrome P450 enzymes.

54. Aminosalicylic Acid (PAS).  Similar in structure to sulfonamide and p- aminobenzoic acid.  Bacteriostatic  Folate synthesis inhibitor.

55. Pharmacokinetics  Well absorbed from GIT  Best given after meals  Distributed throughout the total body water & reaches high concentration in pleural fluid & caseous tissues.  CSF levels are low  Half-life one hour  80% of the drug is excreted in urine as metabolities.

56. Clinical uses  AS a second line agent is used in the treatment of pulmonary & other forms of tuberculosis.

57. Adverse effects  GIT upset ( anorexia, nausea, epigastric pain, diarrhea ).  Hypersensitivity reactions  Hematological troubles ( leukopenia, agranulocytosis, eosinophilia)  Crystalluria

58. Clofazimine

59. Drug Regimens  6 months duration  A) First 2 months:  INH+ Rifampin + Pyrazinamide + Ethambutol or Streptomycin  B) Last 4 months  INH + Rifampin

60. 2- Drug Regimens  2- 9 months duration:  A) First 2 months:  INH + Rifampicin + Ethambutol  B) Last 7 months:  INH + Rifampicin

61. Drug Regimens(cont.)  If there is possibility of drug resistance, Ethambutol or Streptomycin or even second line drugs is added  Depending on :  Type of resistance  Sensitivity of microorganisms

62. Drug Regimens (cont.)  We give drug combination to :  1- Avoid the emergence of resistance  2- Increase therapeutic efficacy  3- Decrease : Dose, Frequency of dose administration, adverse effects

63. Treatment Of Tuberculosis In Pregnant Women  AS previously mentioned, but streptomycin is contraindicated because it can cause congenital ototoxicity

64. Drugs used in leprosy Dapsone  Inhibits folate synthesis.  Well absorbed orally,widely distributed.  Half-life 1-2 days,tends to be retained in skin,muscle,liver and kidney.  Excreted into bile and reabsorbed in the intestine.  Excreted in urine as acetylated.  It is well tolerated.

65. Clinical uses  Tuberculoid leprosy.  Lepromatous leprosy in combination with rifampin & clofazimine.  To prevent & treat Pneumocystis pneumonia in AIDS caused by Pneumocystis jiroveci ( Pneumocystis carinii).

66. Adverse effects  Haemolytic anaemia  Methemoglobinemia  Gastrointestinal intolerance  Fever,pruritus,rashes.  Erythema nodosum leprosum

67. Clofazimine  It is a phenazine dye.  Unknown mechanism of action,may be DNA binding.  Antiinflammatory effect.  Absorption from the gut is variable.  Given orally, once daily.  Excreted mainly in feces.  Stored mainly in reticuloendothelial tissues and skin.  Half-life 2 months.  Delayed onset of action (6 weeks).

68. Clinical uses  Multidrug resistance TB.  Lepromatous leprosy  Tuberculoid leprosy in :  patients intolerant to sulfones  dapsone-resistant bacilli.  Chronic skin ulcers caused by M.ulcerans.

69. Adverse effects  Skin discoloration ranging from red-brown to black.  Gastrointestinal intolerance.  Red colour urine.  Eosinophilic enteritis

70. Treatment of TB in pregnant women  INH ( pyridoxine should be given ),  Rifampicin, ethambutol  Pyrazinamide is given only if :  Resistant to other drugs is documented  Streptomycin is contraindicated.  Breast feeding is not contraindication to receive drugs, but caution should be observed.