1. Anti-Tuberculosis Drugs
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture 8
October 17, 2010

2. Tuberculosis Infected by Mycobacterium tuberculosis
Usually occurs in the lungs, but can affect other organs like lymph nodes, meninges, bone, adrenals or the urogenital tract
One third of the world's population is thought to be infected with M. tuberculosis
Treatment for TB (short for tubercle bacillus) uses antibiotics to kill the bacteria
Lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut
The meninges is the system of membranes which envelopes the central nervous system Adrenal gland: endocrine glands, located over kidney.
tubercle bacillus: A rod-shaped aerobic bacterium (Mycobacterium tuberculosis) that causes tuberculosis 2

3. First-Line Drugs
Isoniazid
Rifampicin
Ethambutol
Pyrazinamide 3

4. Isoniazid
One of the most important agents for the treatment of tuberculosis
It is bactericidal only to Mycobacterium tuberculosis
High doses are used in tuberculous meningitis
Often given in combination with ethambutol or rifampicin

5. Isoniazid: Mechanism of Action
It is a prodrug; mycobacterial catalase-peroxidase (katG) converts isoniazid into an active metabolite
A primary action of isoniazid is to inhibit the biosynthesis of mycolic acids (long, branched lipids that form part of the mycobacterial cell wall) 5

6. Isoniazid: Resistance
The most common mechanism resistance is mutation in KatG that decreases its activity, preventing conversion into active metabolite 6

7. Isoniazid: Pharmacokinetics
Readily absorbed from the gut, diffuses well into the body tissues, including the CSF, and penetrates into macrophages so that it is effective against intracellular tubercle bacilli
It undergoes genetically controlled polymorphic acetylation in the liver. The proportion of a given population characterized as fast or slow acetylators depends upon the group´s ethnic make-up
The half-life is less than 80 min in fast acetylators and greater than 140 min in slow acetylators
Fifty to seventy per cent of a dose is excreted in the urine within 24 hours as metabolite or free drug
Macrophages are white blood cells within tissues 7

8. Isoniazid: Adverse Effects
Peripheral neuropathy
Common in patients who are slow acetylators, and which may be prevented by pyridoxine administration of mg daily
Hepatitis
Vitamin B6, also called pyridoxine
Hepatitis is swelling and inflammation of the liver 8

9. Isoniazid: Drug Interactions
Partly metabolized by hepatic cytochrome P450, and inhibits metabolism of certain drugs, for example, phenytoin and carbamazepine, thereby causing toxicity in some patients
Phenytoin: antiepileptic drug 9

10. Rifampicin: Mechanism of Action
Transcription is a cellular process during which RNA is synthesized using DNA as a template. RNA polymerase is the principal enzyme of transcription
Rifampicin acts by inhibiting bacterial DNA-dependent RNA polymerase of mycobateria by forming a stable drug-enzyme complex
Because of its high lipid solubility it diffuses easily through cell membranes to kill intracellular bacteria 10

11. Rifampicin: Pharmacokinetics
Absorption from the gut is almost complete but is delayed by food
Eighty-five to ninety per cent of the drug is protein bound in plasma but rifampicin penetrates well into most tissues, cavities and exudates, although relatively little enters the brain and CSF
Metabolized by deacetylation and is excreted mainly in the bile
The drug and its metabolite undergo prolonged enterohepatic circulation
An exudate is any fluid that filters from the circulatory system into lesions or areas of inflammation 11

12. Rifampicin: Adverse Effects
After a few hours influenza-like symptoms, flushing and rashes occur
Hepatotoxicity: hepatitis and cholestatic jaundice occur
Urine and tears become pink/red which may be a useful guide to compliance with therapy
The presence of elevated serum concentration of conjugated bilirubin is a principal sign of cholestasis 12

13. Rifampicin: Drug Interactions
Markedly induces hepatic microsomal cytochrome P450 activity thereby accelerating the metabolism of several commonly used drugs like Corticosteroids, Warfarin and Estrogens 13

14. Ethambutol: Mechanism of Action
It is an inhibitor of mycobacterial arabinosyl transferases, which are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall 14

15. Ethambutol: Pharmacokinetics
Well absorbed (75-80%) from the intestine
The plasma t1/2 is 5-6 hours
The drug is concentrated in red cells and this provides a depot for entry into the plasma
About 80% is excreted unchanged in the urine
Ethambutol is contraindicated in renal failure
A contraindication is a specific situation in which a drug, procedure, or surgery should NOT be used, because it may be harmful to the patient 15

16. Ethambutol: Adverse Effects
Retrobullar neuritis and loss of visual acuity occurs in 10% of patients on the higher dose. The first signs are loss of red-green perception. Prompt withdrawal of the drug may be followed by recovery
Rashes, joint pains
Nausea, abdominal pain
Retrobulbar neuritis is a form of optic neuritis in which the optic nerve, which is at the back of the eye, becomes inflamed
Scotomata: An area of diminished vision within the visual field 16

17. Pyrazinamide: Mechanism of Action
The enzyme pyrazinamidase in mycobacteria cleaves off the amide portion of the molecule producing pyrazinoic acid which is bactericidal by unknown mechanisms 17

18. Pyrazinamide: Pharmacokinetics
Converted in the liver by an amidase to pyrazinoic acid and this undergoes further metabolism to hydroxypyrazinoic acid by xanthine oxidase
Peak concentrations of the metabolites occur 6 hours after oral administration
Almost completely absorbed and t1/2 is hours
Pyrazinamide and its metabolites are excreted via the kidney, and renal failure necessitates dose reduction
It crosses the blood-brain barrier to achieve therapeutic CSF concentrations and is therefore a drug of first choice in tuberculous meningitis 18

19. Pyrazinamide: Adverse Effects
Hyperuricemia which may precipitate gout
Pretreatment hepatic enzymes must be measured, as about 5-15% of patients develop hepatotoxicity. Measurements must be repeated during treatment
Rashes and photosensitivity
Hyperuricemia is a level of uric acid in the blood that is abnormally high
It should be avoided if there is a history of alcohol abuse and treatment should not be continued for more than 2 months 19

20. Second-Line Drugs
The commonest cause of treatment failure or relapse is non-compliance with therapy
The previous drugs used should be known and current bacterial sensitivity found
If the organisms are still sensitive to the original drugs, then more fully supervised and prolonged therapy with these drugs should be prescribed
If bacterial resistance has arisen then alternative drugs are used, supervised by a clinician with experience in the use of such agents 20

21. Second-Line Drugs Streptomycin Capreomycin Ethionamide Prothionamide
Aminosalicylic acid
Fluroquinolones 21

22. Streptomycin: Mechanism of Action
It is an aminoglycoside, actively transported across the bacterial cell wall and its antibacterial activity is due to it binding to the 30S subunit of the bacterial ribosome and inhibiting protein synthesis 22

23. Streptomycin: Pharmacokinetics
Oral absorption is minimal, given parenterally (IM)
Mainly excreted via the kidney and dosage requires adjustment in renal impairment
The t1/2 varies from 2 to 9 hours
Crosses the blood-brain barrier when the meninges are inflamed 23

24. Streptomycin: Adverse Effects
Same as for other aminoglycosides
The main problems are ototoxicity and nephrotoxicity 24

25. Capreomycin
This is an effective drug but, like other aminoglycosides, it can produce nephrotoxicity and ototoxicity 25

26. Ethionamide and Prothionamide
Structural analogs of isoniazid
Both produce nausea after oral administration
Given as a single daily dose in the late evening with a sedative
Other toxic effects include liver damage, neuropathy and mental disturbance 26