Global Threat of Tuberculosis: Antimycobacterial Agents and Treatment Options

1. Sulphonamides. Antimycobacterial agents

2. 1993 – WHO Epidemy of tuberculosis has started in the world, in the most countries it has spread far beyond control borders and now it is a global danger for humanity

3. Ukraine • During 1995-2000 tuberculosis morbidity grew 30 % higher and equals to 42/10000 of population • Totally – 640 000 sick people, 30 000 of whіch are with open form • mortality also increases and equals to 14/10000 • Every hour 1 patient with tuberculosis dies

4. Ternopil region • During 1995-2000 morbidity grew 44% higher • 58 % – “fresh” patients • 48 % – with comlpicated forms • 25 % – people younger 30 years of age

5. Treatment of patients with tuberculosis • Chemotherapy with tuberculostatic drugs • Hygiene regime • Diet • Fitotherapy • Sanatory treatment • Collaps therapy • Surgical methods • Other drugs

6. Antimycobacterial drugs • Derivatives of HINA: isoniazid, ftivazid etc. • Antibiotics: rifampicin, rifabutin, strepromycin, kanamycin, florimycin, capreomycin, cycloserine • Derivatives of pyrazin-carbonic acid: pyrazinamide • Ethambutol • Tiourens: tioacetazone (tibon), salutizone • Derivatives of tiamide-α-ethylizonicotinic acid: ethionamide, protionamide • Salts of PASA: PASA-Na etc. • Combinated tuberculostatics: • inabutol (isoniazid + ethambutol) • infiricine (rifampicine + isoniazide) • rifater (isoniazide + rifampicine + pyrazinamide)

7. Classification of International Union of tuberculosis treatment

8. Properties of antimycobacterial drug - confidence in high effective treatment: • Good permeability in all organs and tissues, including BBB • Influence on mycobacteria, situated intracellulary • Influence on atypical forms of mycobacteria • Influence on mycobacteria which stay in latent phase of development (L-forms)

9. Isoniazide • Inhibits synthesis of phospholipids and damages membranes of MBT • Forms compositions with two-valent cations • Hurts formation of RNA and DNA • Inhibits oxydating processes • Acts on MBT which is in state of active development, situated intra- and extracellularly • Penetrates through all organs and tissues

10. Isoniazide • Orally – 0,45g 1 time/day (10mg/kg) • I.v. dropply 0,15-0,18% solutions • Endobronchial, irrigation of cavities – 5-10%solutions • 100% bioavailability in case of oral administration

11. Metabolism in liver (acetylation)HINAinactivators (acetylators) (genetics)

12. Side effects of isoniazide (derivatives of HINA) (5-18% of patients) • CNS – headache, euforia, insomnia, dizzyness • peripheral neuritis (derivatives of HINA – antivitamins В6), prophylaxis – 50 mg Vit В6 daily • allergy (treatment – antihistamine) • heart – tachycardia, arythmia • dispeptic disorders, stomatitis • hepatitis

13. Rifampicine • Bactericide action, wide spectrum of action • damages synthesis of proteins of MBT • influences on intra- and extracellular MBT • penetrates through all organs and damaged areas (molecule in not ionized) • concentration in organs is 3-4 times larger than in blood serum

14. Rifampicine

15. Rifampicine • 0,6 g 1 time daily with empty stomach • entero-hepatic recirculation • Increases the activity of microsomal enzyme system of liver→autoinduction→ increasing of rifampicine metabolism

16. Side effects of rifampicine (8-22%) • hepatotoxicity • immune-allergic complications • pseudo-flue syndrome - decreasing of platelets aggregation • haemolysis • acute hepato-renal insufficiency • induction og microsomal enzymes→ decreasing of effectiveness of oral contraceptives etc. • dyspeptic manifestations, stomatitis • change of urine, feaces,sweat, tears etc. color into orange-red

17. Rifabutin (mycobutin) • wide spectrum of action • it is 10 times more effective than rifampicine • influences on intra- and extracellular MBT • concentration in organs is 5-10 times higher than in plasma, in neutrophiles - 9 times higher, in monocytes - 15 times higher • influences on atypical forms of mycobacteria (M. avium complex etc.)

18. Rifabutin • Т1/2 35-40 hours • oral administration– 0,45 g 1 time a day

19. Side effects of rifabutin • dyspeptic disorders, hepatitis, jaundice, • leuco-, thrombocytopenia, anemia (especially if combined with isoniazide) • artralgy, mialgy • allergic reactions (rarely including anaphylactic shock) • reverse uveitis (damage of eye retina)

20. Streptomycin • wide spectrum of action • influences only on MBT situated extracellularly • is not absorbed in GIT • concentration in tissues is 25-40 times lower than in blood • does not penetrate in caverns, through BBB

21. Administration of streptomycin • i.m. (streptomycin sulphate) • endolumbal (streptomycin-chlorcalcium complex) • into cavities, endobronchial • 1 g/day – “fresh” forms of tuberculosis

22. Side effects of streptomycin • Allergic reactions • Ototoxic action • Peripheral neuritis • Nephrotoxic action

23. Ethambutol • Influences on atypical mycobacteria • On intra- and extracellular MBT, which rapidly reproduce • Gets accumulated in erythrocytes • Penetrates into all organs and tissues, into caverns

24. Ethambutol orally 1,2-1,6 g 1 time a day

25. Side effects of ethambutol(1-2%) • Retrobulbar neuritis of optic nerve (disorders of color vision – green, red, inaccuracy) – shouldn’t be administered for children under the age of 12 • Bronchial spasm

26. Ethionamid • Acts on resistant MBT • Atypical MBT • Extra- and intracellular MBT • Activity grows in acid medium, of caseous masses • Penetrates into all the organs and tissues

27. Ethionamid perorally 0,5 –0,75 g/day Side effects • Allergic reactions • Disturbances of GI tract • Toxic hepatitis • Neurotoxicity (CNS, peripheral neurites) • Endocrine disorders (gynecomastia, menorrhagia, impotence, hypoglycemia)

28. Pyrasinamid • Acts on MBT, which are in condition of metabolic rest • On intra- and extracellular MBT • Penetrates into all organs and tissues • Activity grows in acid medium of caseous masses

29. Pyrasinamid • 1,5-2,0 g orally • Especially in a case of torpidcurrent of tuberculosis, in case of heavy achievable and caseous sources, during the period of finishing treatment

30. Side effects of pyrasinamid • hepatotoxicity • early – 7th day • late – after 6-8 months • dyspeptic disorders • arthralgia (retains uric acid in the organism – pyrasine-carbon acid is its antagonist) • Photosensibilization

31. Ciprobai (cyprofloxacin)

32. Abactal (pefloxacin)

33. Nolicin (norfloxacin)

34. Other fluoroquinolones • Lomefloxacin • Levofloxacin • Moxyfloxacin

35. Standard regimes of anti-tuberculosis treatment according to WHO

36. Principles of rational chemotherapy of tuberculosis • Appropriate in time administration of chemical drugs • Administration of combinations of drugs • Long-lasting treatment • Brakeless treatment • Administration of optimal doses • Choice of way of introduction (orally, i.v. dropply or bolus, i.m., endolymphatically, by inhalations, endotracheally, endopleurally, intracavernously)

37. 3 main schemes of administration of anti-tuberculosis drugs • І. Traditional long lasting (brakeless) treatment • ІІ. Intermitting chemotherapy • 3 times a week • 1 time a week (HINAin slow acetylators) • mixed chemotherapy (interchange of one drug in a certain combination - 3-4 drugs daily from 5-6 of the administered) – 1-3 times a week the combination is changed • ІІІ. Short lasting courses of brakeless treatment

38. Permeability of anti-tuberculosis drugh through the BBB

39. FLUOROQUNOLONES

40. І generation Ciprofloxacin * Ofloxacin * Norfloxacin * Pefloxacin * Lomefloxacin * Fleroxacin ІІ generation Grepafloxacin Sparfloxacin Gatifloxacin Clinafloxacin Moxifloxacin* Trovafloxacin Levofloxacin * Classificatoin of fluoroquinolones

41. Ciprolet (Ciprofloxacin)

42. Nolicine (Norfloxacine)

43. Mechanism of actoin • penetration into microbial cell, where they inhibit DNA-gyrase • disadvantage of DNA replication • performing of postantibiotic effect

44. Fluoroquinolones get accumulated in macrophages and neutrophiles in concentrations which overcome concentration in blood serum 4-8 times, they penetrate in all organs and tissues well (low level of molecular ionisation)

45. Fluoroquinolonesmay be used1-2 times daily Orally – all drugs I.V. – ciprofloxacinum, pefloxacinum, ofloxacinum, levofloxacinum, moxifloxacinum

46. Drugs of І choice Acute attack of chronic bronchitis Acute and chronic sinusitis Malignant otitis Hospital pneumonia Pneumonia and bronchitis in patients with tuberculosis Pneumonia in patients with mucoviscidosis Cholecystitis/ cholangitis Chronic pielonephritis Chronic prostatitis Bacterial diarrhea Diarrhea of travellers Alternative drugs Acute medial otitis Community-acquired pneumonia Sepsis Intraabdominal infections Osteomyelitis Postoperative arthritis Gynecological infections Meningitis Indications for fluoroquinilones administration

47. Side effects offluoroquinilones • photosensibilization • seizures (if combined with metronidazole, NSAIDs) • dyspeptic disorders • changes of mood, insomnia, depression • allergic reactions • ulcerations of cartilages in children and teenagers

48. Interaction • pefloxacin, grepafloxacin inhibit metabolism of euphyllin, manifestation of intoxication • Zn2+, Ca2+, Mg2+, Al3+ (antacids etc.), bismuthi salts, iron drugs, sukralfat depress absorption of fluoroquinolones in gastrointestinal tract

49. Fluoroquinolones are contraindicated: - for pregnant women - in lactation period - for children and teenagers

50. Sulfonamides