1. Chemotherapy of Tuberculosis

2. TUBERCULOSIS
TUBERCULOSIS is an infectious disease caused by Mycobacteria; Mycobacterium tuberculosis & Mycobacterium bovis.
MODE OF TRANSMISSION
Inhalation of droplets
Ingestion --self swallowing of infected sputum/ or ingestion of unpasteurised milk of infected cow
Inoculation – of organism in to skin may occur rarely from infected postmortem tissue.
Transplacental – ie tuberculosis of foetus from mother.

3. Macrophage with tubercle bacilli
Major portion of tubercle bacilli become intracellular(i.e reside in macrophage),so it is inaccessible for majority of antibiotics as they cannot penetrate easily in to the macrophage.
It was once considered to be an incurable disease but now it is curable by a number of chemotherapeutic agents.
Macrophage with tubercle bacilli

5. Classification of anti TB drugs
1st Line Essential drugs
1st Line supplemental drugs
2nd Line drugs
Eg-
RIFAMPICIN
ISONIAZID
PYRIZINAMIDE
ETHAMBUTOL
(RIPE)
Eg-
Fluroquinolones
Amikacin
Capreomycin
Ethionamide
p-Aminosalicylic acid
Cycloserine
(FACEPaC)
Eg-
Rifabutin
Rifapentin
streptomycin

6. 1st line essential drugs– most effective & basic components of anti tubercular treatment.
1st linesupplemental drugs– are quite effective & posseses an acceptable limit of toxicity. These are kept as reserved drugs & used in special settings.
2nd line drugs—these drugs are used if there is resistance to 1st line drugs or if 1st line drugs are contraindicated for some reason. These drugs are less effective & slightly more toxic than Ist line drugs(except Fluoroquinolones)

7. Individual drugs. Isonicotinic acid hydrazide
INH is a pro drug & is converted into active form by bacterial enzyme catalase peroxidase.
SITE OF ACTION– Both intracellular & extracellular ; also in casseous lesions.

9. MECHANISM OF ACTION
INH is converted to active form by catalase peroxidase (produced by mycobacterium) .
The active form inhibits mycolic acid in outer layer of cell wall.
Also inhibits DNA, RNA & various oxidative enzymes.
It is equally active in acidic & alkaline medium

10. MYCOLIC ACID SYNTHESIS INHIBITED
MECHANISM OF ACTION
Mycobaterium cell wall has the following layers viz. – mycosides, mycolic acid, arabinoglycan, peptidoglycan.INH inhibits mycolic acid synthesis while ethambutol inhibit arabinoglycan layer
INH
(PRODRUG)
MYCOLIC ACID SYNTHESIS INHIBITED C E L W A
MYCOSIDES
MYCOLIC ACID
ARABINOGLYCAN
PEPTIDOGLYCAN
CELL MEMBRANE
INH
(ACTIVE)
Catalase peroxidase

11. MECHANISM OF RESISTANCE
Resistance to INH is due to mutation in CATALASE – PEROXIDASE GENE which is responsible for activation of INH.

12. ADR Allergic reactions: Fever,Skin rashes.
Hepatotoxicity : Increase level of serum enzymes.

13. RIFAMPICIN
RIFAMPICIN is a semisynthetic derivative of macrocyclic antibiotic Rifamycin. Mechanism of action of Rifampicin Rifampicin inhibits bacterial DNA DEPENDENT RNA POLYMERASE. Mammalian RNA polymerase is not inhibited , so RNA synthesis of host cells is not affected

15. MECHANISM OF RESISTANCE Resistance develops mutation in rpo B gene which prevents binding of rifampicin to RNA polymerase. Hence if used alone resistance develops rapidly. It is a potent enzyme inducer Pharmacokinetics Absorption--well absorbed after oral administration Distribution – it penetrates in all tissues , tubercular cavities, placenta. Adequate CSF levels are reached if meninges are inflammed. It is significantly protein bound.

16. Excretion – drug is excreted via bile & undergoes entero hepatic circulation.
ADVERSE EFFECTS
HEPATITIS is major side effect. It is dose dependent & reversible. It is common in patients with underlying liver disease. Risk of hepatitis increses when used in combination with INH.
Occasional side effects include FLU-LIKE SYNDROME characterised by fever chills , myalgias & thrombocytopenia,
Rifampicin imparts RED ORANGE COLOR TO URINE.

17. Ethambutol is a synthetic tuberculostatic drug active against M
Ethambutol is a synthetic tuberculostatic drug active against M.tuberculosis, M.kamsasii & M.avium intracellulare.
ETHAMBUTOL

18. E MYCOLIC ACIDS ARABINOGLYCAN PEPTIDOGLYCAN CELL MEMBRANE
MECHNISM OF ACTION ETHAMBUTOL inhibits polymerisation of arabinoglycans of cell wall by inhibiting arabinosyl transferase E
MYCOLIC ACIDS
ARABINOGLYCAN
PEPTIDOGLYCAN
CELL MEMBRANE

19. MECHANISM OF RESISTANCE Resistance develops due to point mutations in emb B gene that encodes arabinosyl transferases enzyme involved in mycobacterial cell wall synthesis. Pharmacokinetics Bioavailability– 80% Distribution– widely distributed in all body fluids including CSF

20. Ethambutol should be avoided in in children below 5 years where it is difficult to asses visual activity & red – green color discrimination.
Ethambutol decreases renal excretion of urates & may precipitate gouty arthritis.
Mild GIT intolerance , rashes, fever & dizziness are also possible.

21. Streptomycin It is the first antitubercular drug.
It is bactericidal but because of poor penetration it acts only on extracellular tubercular bacilli.
It is also active against M.kansasii & M.avium intracellulare.
It is less effective than INH or Rifampicin
Pharmacokinetics
Route of administration– I.M , cant be given orally as it is highly polar

22. Distribution – poorly distributed , do not penetrate most cellular compartments.
Metabolism -- as they do not penetrate most cellular compartments , they do not undergo significant metabolism.
Excretion- nearly all of the drug is cleared by kidneys as they do not undergo significant metabolism.
Plasma half life– 1.5 – 3 hrs(24-48 hrs in renal insufficiency)

23. Mechanism of action 1.The mechanism of action of streptomycin is inhibition of protein synthesis of mycobacteria in the ribosome. 2. Interfere with complex peptide formation. 3. Incorporation of incorrect amino acid into Peptide Resulting in Non functional toxic Protein. Adverse effects– nephrotoxicity & ototoxicity.

24. Amikacin It is an aminoglycoside antibiotic.
It is 2nd choice after streptomycin & for multi drug resistant tuberculosis.
Most M.tuberculosis strains are that are resistant to streptomycin are sensitive to amikacin.
MOA- Bind to 30 s ribosomal subunit and bacterial ribosome block protein synthesis. Responsible for growth inhibition.

25. ADR- Neurotoxicity, Nephrotoxicity, Ototoxicity, Cross resistance usually occur between Km and Am is very common.

26. Ciprofloxacin
MOA: Mechanism of Action: Inhibition of topoisomerase (DNA gyrase) enzymes, which Resposible for Nikking of DNA Stand and promotes breakage of double stranded DNA. ADR: headache, insomnia, dizziness; hallucinations, depression.

27. Chemotherapy of Leprosy

28. Leprosy is an infectious disease that causes severe, disfiguring skin sores and nerve damage in the arms and legs
Leprosy is caused by a slow-growing type of bacteria called Mycobacterium leprae (M. leprae). Leprosy is also known as Hansen's disease, after the scientist who discovered M. leprae in 1873.

29. Skin Lesions that are lighter than your normal skin color
Lesions have decreased sensation to touch, heat, or pain
Lesions do not heal after several weeks to months
Muscle weakness
Numbness or lack of feeling in the hands, arms, feet, and legs

30. cLASSIFICATION Sulfone: Dapsone Phenazine Derivatives: Clofazimine
Anti tubercular drugs: Rifampin
Anti biotics : Minocycline (Tertracycline antibiotics)

31. Moa of DAPSONE

32. ADR
Hemolytic anemia
Gastric intolerance
Headache, Mental symptoms

34. Monotherapy cause Resistance in 1-3 yrs.
Dapsone Resistant Respond to Clofazimine.
ADR
Reddish Black Discoloration
Dryness of Skin
Nausea, Vomiting, Abdominal pain.