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

2. Tuberculosis  Common sites of infections  Apical areas of lung  Renal parenchyma  Growing ends of bones  Where oxygen tension is high

3. Transmission  Through air ( air borne transmission )  Active tuberculosis kill about two of every three people if left untreated.

4. Latent tuberculosis  The inhaled bacilli are taken into alveolar macrophages and remain viable & multiplying within the cells for extended period of time.  The person is clinically asymptomatic  Positive tuberculin test is the only indication  Individuals with latent TB are not infectious & can not transmit organisms.

5. Active tuberculosis  The goals for the treatment :  - Cure the individual patient  - Minimize the transmission of TB to others  -Kill the tubercle bacilli  - Prevent drug resistance

6. Treatment Of Tuberculosis  Tuberculosis remains the primary cause of death due to infectious disease.  Periods of treatment ( minimum 6 months)  Drugs are divided into :  First line Second line  Third line

7. Antimycobacterial drugs  First line of drugs:  Isoniazid (INH)  Rifampin  Ethambutol  Streptomycin  Pyrazinamide

8. Never use a single drug therapy  The standard “short “ course treatment for TB is isoniazid, rifampin, pyrazinamide, and ethambutol for two months, then isoniazid and rifampin alone for a further four months.

9. Continue  For latent tuberculosis, the standard treatment is six to nine months of isoniazid alone.

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

11. Mechanism Of Action  Is a prodrug, activated by mycobacterial catalase -peroxidase  Cell wall synthesis inhibitor  Inhibits synthesis of mycolic acids----  Which are essential components of  Mycobacterial cell walls.

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

13. Distribution  Diffuse rapidly into all body fluids and cells.  Highly concentrated in pleural fluids.  Its concentration in CSF is significant in inflammed meninges.  Penetrates well into caseous material.

14. Metabolism & Excretion  Metabolized in the liver by acetylation.  Excreted in urine mainly as metabolites.

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

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

17. Adverse effects (cont.)  Hematological reactions  Gastrointestinal upset  Arthritic symptoms

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

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

20. Rifampin  Bactericidal  Inhibits RNA synthesis-by inhibiting bacterial DNA- dependent RNA polymerase enzyme.

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

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

23. 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.

24. Distribution  Distributed throughout the body organs & fluids. Adequate CSF concentration is achieved in meningeal inflammation.

25. Clinical uses  Mycobacterial infections  Prophylaxis of active tuberculosis.  Treatment of deep –seated staphylococcal infections.  Prophylactic agent following exposure to Neisseria meningitids & H.influenzae

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

27. Adverse Effects ( cont.)  Nausea & vomiting  Hepatitis, cholestatic jaundice  Flu-like syndrome  Hemolytic anemia, thrombocytopenia & acute tubular necrosis.

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

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

30. Site Of Action  Intracellular & Extracellular bacilli

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

32. Clinical uses  In combination therapy for : Ttreatment of tuberculosis Mycobactrium avium complex in patients with or without HIV

33. 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

34. Pyrazinamide  Prodrug( converted to pyrazinoic acid,the active form.  Bacteriostatic  Mechanism : unknown  May act through inhibition of mycobacterial fatty acid synthase I gene

35. Site Of Action  More active at an acidic pH ( within macrophages ) and active against Intracellular Bacilli

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

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

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

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

40. 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.

41. Adverse Effects  Ototoxicity  Nephrotoxicity  Neuromuscular block

42. Contraindications  Myasthenia gravis  Pregnancy

43. 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.

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

45. 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

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

47. Adverse Effects  Anorexia, nausea, vomiting, intense gastric irritation.  Poorly tolerated (About 50% of patients are unable to tolerate a single dose more than 500 mg ).

48. Adverse Effects (cont.)  Neurological adverse effects relieved by pyridoxine ( vit.B6 ).  Hypotension  Alopecia  Metallic taste

49. 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.

50. Cycloserine  Inhibitor of cell wall synthesis  Cleared renally  The most serious side effects are peripheral neuropathy and CNS side effects.  Pyridoxine should be given.  Contraindicated in epileptic patients.

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

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

53. Rifabutin  As rifampin, it is RNA polymerase inhibitor.  Cross resistance with rifampin  Enzyme inducer of cytochrome p450.  Effective against typical and atypical mycobacteria.

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

55. Clinical uses  Treatment of T.B. in HIV- infected patients ( received concurrent antiretroviral therapy)  Prevention of tuberculosis  Prevention & treatment of disseminated atypical mycobacterial infections in AIDS patients

56. Adverse Effects  Skin rash  GIT intolerance  Neutropenia  Orange-red discoloration ( skin, urine, ---- -as rifampin ).

57. Drug Interactions  Enzyme inducer of cytochrome P450 enzymes (Less potent than rifampin ).

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

59. Pharmacokinetics  Well absorbed from GIT  Best given after meals  High concentration in pleural fluid & caseous tissues.  Excreted mainly in urine as metabolites.

60. Clinical uses  Treatment of pulmonary & other forms of tuberculosis.

61. Adverse effects  GIT upset  Hypersensitivity reactions  Hematological troubles  Crystalluria

62. Third line  Arginine  Vitamin D  Thioridazine  Macrolides as clarithromycin  Corticosteroids is proven for TB meningitis and pericarditis

63. TB & Pregnancy  Untreated TB represents a far greater risk to a pregnant woman and her fetus than treatment.  Rifampin makes hormonal contraception less effective, so additional precautions to be taken for birth control.  Streptomycin is used as a last alternative

64. TB& Breast Feeding  It is not a contraindication to receive drugs, but caution is recommended

65. Leprosy ( Hansen, s disease)  Deforming disease caused by Mycobactrium leprae.  Affect cooler areas of the body in humans ( skin, nerve segments near to skin, mucous membranes of the upper respiratory tract )

67. Transmission  Respiratory route

68. 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.

69. Clinical uses  Tuberculoid leprosy.  Lepromatous leprosy in combination with rifampin & clofazimine.  To prevent & treat Pneumocystis jiroveci pneumonia in AIDS.

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

71. 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).

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

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