1. Chemotherapy of Tuberculosis By Prof. Azza El-Medany

2. Tuberculosis  Common sites of infections :  1-Apical areas of lung  2- Renal parenchyma  3- Growing ends of bones Where oxygen tension is high

3. Transmission  Through inanimate جامده objects  Through air ( air borne transmission )

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

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

6. Never use a single drug therapy  Isoniazid –rifampin 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.

7. : اولاIsoniazid  Bacteriostatic for resting bacilli.  مهمهBactericidal قاتل للبكتيريا for rapidly dividing bacilli.  Is effective against intracellular as well as extracellular bacilli لانها تخترق المايكروفيج

8. Mechanism Of Action  Is a prodrug دواء غير نشط قبل التناول يحول للشكل النشط بعد تنشيطه بواسطه بعض الانزيمات بالجسم او من البكتيريا نفسها, activated by mycobacterial enzyme  Inhibits synthesis of mycolic acid---- ( component of mycobacterial cell wall). مهمه جدا جدا

9. Clinical uses مهمه  Mycobacterial infections.  Latent tuberculosis in patients with positive tuberculin skin test  Prophylaxis وقائي against active TB in individuals who are in great risk.

10. Adverse effects  Peripheral neuritis التهاب الاعصاب بالاطراف  يحدث هذا بسبب نقص  Optic neuritis &atrophy. نفس السبب العلاج(Pyridoxine should be given )  Allergic reactions  systemic lupus erythematosus ( SLE)  Hepatitis من علاماتها ( ) مهمه جدا Pyridoxin ( vitamine B6) gondes صفار ناتج عن مرض الكبد

11. Drug Interactions دواء يحظر عمل دواء اخر of INH  Inhibits the hepatic microsomal enzymes, cytochrome P450. ..مما يقلل عمليهmetabolize of other drugs Cont. تحدث الاعراض الجانبيه غالبا للمرضى الذين : It is more likely to occur in slow acetylators and patients with malnutrition, alcoholism, diabetes and AIDS

12. ثانيا : Rifampin  Bactericidal قاتل للبكتيريا  MOA : مهمهInhibits RNA synthesis. بالتاثير على الانزيمات كما شرح بالاسفل  : شرحRifampin binds to the β subunit of bacterial DNA – dependent RNA polymerase اسم الانزيم and thereby inhibits RNA synthesis.  2 nd chioce after INH and do not used alone

13. Site of Action  Intracellular bacilli  Extracellular bacilli

14. Clinical uses  Mycobacterial infections  Prophylaxis وقائي of active tuberculosis.  Treatment of serious staphylococcal infections.  Meningitis مهمه by highly resistant penicillin pneumococci . Atypical mycobacterial infections.  As alternative of isoniazid in prophylaxis of latent tuberculosis

15. Adverse effects  Harmless red-orange discoloration of body secretions. مثل البول والدم  Hepatitis  Flu-like syndrome  Hemolytic anemia  Thrombocytopenia

16. Drug Interactions  Potent قوي inducer منشط – عكس الدواء السابق of hepatic microsomal enzymes مهمه جدا جدا ( cytochrome P450) ..مما يزيد عمليهmetabolize of other drugs مما يعطل عملها Rimpfin excreted by Bile from live as fesses Liver >> bile >> fesses مهمه

17. : ثالثا Ethambutol  Bacteriostatic مهمه جدا عكس السابق – يقلل تكاثر البكتيريا  مهمه جداInhibits mycobacterial arabinoglycan a component of mycobacterial cell wall لذلك يمنع تكوين الجدار الخلوي

18. Site Of Action  Intracellular & Extracellular bacilli

19. Clinical uses  Treatment of tuberculosis in combination with other drugs. الاستخدام الوحيد له

20. Adverse effects  Optic neuritis مهمه جدا causing loss of visual acuity  red-green color blindness. (Relatively contraindicated in children under 5 years).  Hyperuricemia

21. Contraindication موانع الاستخدام  It is relatively contraindicated in children too young to permit assessment of visual acuity and red green color discrimination

22. Pyrazinamide  Prodrug يتحول للشكل النشط عند درجه حامضيه منخفضه  يتحول للشكل النشط كما يلي :  Pyrazinamide >> يتحول الى pyrizenic acid at PH= 5.5  Bactericidal  Mechanism of action is unknown. Pharmacodinamic : 1- widley disturputed 2- orally and well absorbed in GIT 3- pass through 1 st pass metabolism in liver then excreted through kidney Half time = 8-11 H

23. Site Of Action  Active against Intracellular Bacilli

24. Clinical uses  Mycobacterial infections mainly in multidrug resistance cases.  It is important in short –course (6 months ) regimen.  Prophylaxis وقائي of TB.

25. Adverse effects  Hepatotoxicity  Hyperuricemia >> cause GOUTY نقرس ARTHRIETS مهمه جدا ( سؤال )  Drug fever & skin rash

26. : رابعا Streptomycin  Bactericidal  Inhibitors of protein synthesis by binding to 30 S ribosomal subunits.  Active mainly on extracellular bacilli يعتبر كبديل لل في الخطه العلاجيه given by injection الوحيد الذي يعطى عبر الحقن عكس كل السابق الذي يعطى عبر الفم erythrobutile

27. Clinical uses  Severe, life-threating form of T.B. as meningitis مهمه, disseminated disease.

28. Adverse Effects  Ototoxicityمهمه  Nephrotoxicity تسمم الكليه  Neuromuscular block

29. 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.

30. اولا Ethionamide  Inhibits the synthesis of mycolic acid هذا الدواء له نفس ميكانيكيه INH ويعتبر شبيه له

31. Clinical uses  As a secondary line agent.

32. Adverse Effects Poorly tolerated Because of : مهمه  Severe gastric irritation &  Neurological manifestations

33. ثانيا : CAPREOMYCIN  يعطى عبر العضل ولذلك من اعراضه الجانبيه  Local pain & sterile abscesses due to injection.  ومن اثاره الجانبيه :  Nepherotoxicity

34. : ثالثا Cycloserine  Inhibitor of cell wall synthesis by inhipite formation of peptiesdoglycan  The most serious side effects are peripheral neuropathy and CNS dysfunction مهمه.  Pyridoxine should be given.  Contraindicated in epileptic صرع patients.

35. : رابعا Fluoroquinolones (Ciprofloxacin &Levofloxacin )  Effective against multidrug- resistant tuberculosis.  Block DNA bacterial synthesis  يستخدم ضد الجرام السالبه

36. Adverse effects  Nausea, vomiting, diarrhea  Prolong QT interval  Damage growing cartilage ( arthropathy) مهمه لذلك لا يعطى للاطفال والحوامل والمرضعات

37. خامسا : Rifabutin  RNA inhibitor. شبيه ال  Cross –resistance with rifampin is complete.  Enzyme inducer for P450 (hepatic enzymes). rifampin

38. Clinical uses  Effective in prevention &treatment of T.B. in AIDS patients.

39. Adverse Effects  GIT intolerance  Orange-red discoloration of body secretions.

40. سادسا : Aminosalicylic Acid (PAS).  قليل الاستخدام هذه الايام بسبب كثره الاعراض الجانبيه  Bacteriostatic  Inhibits Folic acid synthesis.

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

42. Adverse effects  GIT upset ( anorexia, nausea, diarrhea, epigastric pain ).  Hypersensitivity reactions  Crystalluria

43. TB & Pregnancy  Untreated TB represents a great risk to the pregnant woman & her fetus than the treatment itself.  First line drugs are given for 9 months in normal doses  Streptomycin is the last alternative in treatment

44. TB & Breast Feeding  It is not a contraindication to receive drugs, but caution is recommended شكر خااااص لـ غالي عبد الرحمن فهد المطيري ناصر العبيداء