1. Lecture 5 By Prof. dr. Mohammed Fahmy
Pharmacology-3
Lecture 5 By Prof. dr. Mohammed Fahmy

2. Antimycobacterial drugs
Mycobacteria are very slowly growing organisms
Treatment of mycobacteria with chemotherapy needs longer time (6 – 18 months)
Combinations of drugs are required to prevent the development of resistance

3. Tuberculosis (TB)
A disease caused by a bacterium called Mycobacterium tuberculosis
- Highly aerobic
- Infects lung
- Divides every hrs
- Unable to be digested by microphages
- Very resistant to many disinfectants C

4. Lines of treatment of TB
A- First line drugs
Drugs with high efficacy & acceptable side effects
Examples: Isoniazid, rifampicin, ethambutol, pyrazinamide & streptomycin

5. B- Second line drugs
Less effective & more toxic than first line drugs
Used when first line drugs fail and/or contraindicated
Examples: Ethionamide, capreomycin, P-aminosalicylic acid, cycloserine, fluoroquinolones & macrolides

6. First-line drugs for tuberculosis
Isoniazid (Isocid)
Isonicotinic acid hydrazide (INH)
It is the most active drug for treatment of TB
Pharmacokinetics
Well absorbed orally
Distributed all over the body including CSF
Acetylated in liver & excreted in urine

7. Mechanism of action
Isoniazid is a pro-drug that is activated by a mycobacterial catalase peroxidase
The active metabolite inhibits the enzyme enoyl acyl carrier protein reductase involved in the production of mycolic acid
Mycolic acid is essential for the synthesis of mycobacterial cell wall

8. Resistance Therapeutic uses
Deletion in the KatG gene that encodes for a catalase peroxidase involved in the bioactivation of INH
Deletion in the InhA gene that encodes target enzyme an acyl carrier protein reductase
Therapeutic uses
1- Treatment of TB in combination with rifampicin
2- Chemoprophylaxis in persons very close to active cases

9. Adverse effects 1- Peripheral neuritis
INH combines with pyridoxine (vitamin B6) and accelerates its excretion
Corrected by administration of vitamin B6 (10 mg/day)
2- Hepatotoxicity
Caused by chemically reactive metabolite acetylhydrazine

10. Drug interactions 3- Hemolytic anemia in patients with G6PD deficiency
4- Hypersensitivity reactions
Drug interactions
INH inhibits metabolism of phenytoin, carbamazepine & ethosuximide
actions & toxicity

11. Rifampicin (Rifampin, Rifadin, Rimactan)
Has a wider range of antimicrobial activity than INH
Pharmacokinetics
Well absorbed orally
Distributed all over the body including CSF
Deacetylated in liver
Excreted in:
Bile Enterohepatic circulation
Urine Red discoloration

12. Mechanism of action Resistance 1- Bactericidal
2- Inhibits DNA-dependent RNA polymerase enzyme synthesis of Mycobacterium mRNA
3- Does not bind to human RNA polymerase
Resistance
1- Chemical modification in the target DNA-dependent RNA polymerase enzyme
2- Decreased permeability

13. Therapeutic uses
1- Tuberculosis in combination with INH (Rimactazid)
2- Chemoprophylaxis of meningococcal meningitis
3- Staphylococcal endocarditis, in combination with a β-lactam antibiotic
4- Leprosy, in combination with dapsone

14. Adverse effects
Orange-red discoloration of urine, saliva & tears
Liver damage & Jaundice
GIT disturbances
Hypersensitivity reactions
Drug interactions
Enzyme inducer so metabolism of warfarin & tolbutamide

15. Notes:
1- Rifabutine
A derivative of rifampicin
It is the preferred drug for use in TB-infected with the HIV patients who are concurrently treated with protease inhibitors, why?
It is a less potent inducer of cytochrome P450 enzymes

16. 2- Rifapentine
Has activity similar to rifampicin
Has a longer half-life than rifampicin & rifabutine, which allows weekly dosing
Should not be used alone to avoid resistance

17. Ethambutol (Etibi) Mechanism of action Bacteriostatic
Inhibits arabinosoyl transferase enzyme synthesis of arabinogalactan
(a component of Mycobacterial cell wall)
Adverse effects
Optic neuritis & retinal damage

18. Inhibits synthesis of fatty acids
Pyrazinamide
Mechanism of action
Pyrazinamide
Prazinamidase in bacteria
Pyrazinoic acid
Inhibits synthesis of fatty acids
Adverse effects
Joint pain & hepatotoxicity

19. Second-line drugs for tuberculosis
Ethionamide
Similar to INH, acts by inhibition of Mycolic acid
Adverse effects include peripheral neuropathy & optic neuritis
Capreomycin
It acts by inhibition of protein synthesis
It is nephrotoxic & ototoxic

20. P-aminosalicylic acid
Chemically related to PABA, acts by inhibition of folate synthesis
Adverse effects include epigastric pain, liver damage & crystalluria
Cycloserine
Inhibits cell wall synthesis
Neurotoxic & hepatotoxic

21. Fluoroquinolones Macrolides
Examples: Moxifloxacin & levofloxacin
Can be used when there is resistance to first-line agents
Macrolides
Examples: Azithromycin & clarithromycin
Azithromycin is preferred for HIV-infected patients because it is least likely to interfere with the metabolism of antiretroviral drugs

22. Leprosy A chronic disease of the skin Caused by Mycobacterium leprae
The world health organization (WHO) recommends the triple drug regimen of dapsone, clofazimine & rifampicin for 6 to 24 months
ifampici

23. Dapsone Pharmacokinetics Well absorbed from the gastrointestinal tract
Distributed throughout the body, with high levels concentrated in the skin
Acetylated in liver
Excreted in urine

24. Mechanism of action
Chemically related to sulfonamides, acts by inhibition of folate synthesis via dihydrofolate synthase inhibition
Adverse effects
1- Hemolysis of RBCs, especially in patients with G6PD deficiency
2- Peripheral neuropathy

25. Clofazimine
Binds to DNA and prevents it from serving as a template for future DNA replication
Has some anti-inflammatory actions, so used in patients in whom dapsone causes inflammatory side effects