PHARMACEUTICAL CHEMISTRY: Lesson 5: Anti-tuberculosis and Anti-Leprosy Drugs

I. Anti-tuberculosis Drugs

1. Mechanism of Action of Pyrazinamide (PZA)

• Main Mechanism:

• Metabolized by pyrazinamidase (from bacteria) into pyrazinoic acid (POA).

• POA lowers the pH within macrophages, creating an unfavorable environment for bacteria.

• Most effective against intracellular tuberculosis bacilli (TB).

• Supplementary Mechanism:

• Inhibits the activity of FAS-I (fatty acid synthase I) in bacteria, preventing the synthesis of short-chain mycolic acids, essential for the TB cell wall.

2. Ftivazid:

• Ftivazid is a product of the reaction between INH (isoniazid) and vanillin.

• Forms a yellow precipitate.

3. Drug-Resistant TB States:

• Dormant state of TB.

4. Characteristics of Mycobacterium tuberculosis (TB):

• Strictly aerobic: can only survive in oxygenated environments.

• Slow-growing: the TB growth cycle is lengthy.

5. Drug Resistance Rates (from highest to lowest):

1. Streptomycin

2. INH (isoniazid)

3. Rifampicin

6. Forms of TB in the Body:

• Form 1: Living in tuberculous cavities (caverns), high oxygen levels, neutral pH.

• Form 2: Living in macrophages, acidic pH.

• Form 3: Living in caseous material (dead tissue), low oxygen levels.

7. Easiest Form of TB to Eliminate:

• Form 1: in tuberculous cavities due to rapid TB growth.

8. Form of TB that Causes Relapse:

• Forms 2 and 3.

9. Action of Each Drug:

• Streptomycin: treats TB in Form 1 (caverns).

• INH: treats TB in Forms 1 (caverns) and 2 (macrophages).

• Pyrazinamide: treats TB in Form 2 (macrophages).

• Rifampicin: effective against all 3 forms of TB.

10. Drugs with Bacteriostatic Action:

• Ethambutol and PAS (para-aminosalicylic acid)

11. Isoniazid (INH):

• Synthesized from:

• γ-picolin (Mayer-Maly)

• Citric acid

• Pyridine

• Possesses alkaloid-like properties due to: the presence of a nitrogen heterocycle with a tertiary amine.

12. Chemical Properties of INH:

• Alkaloid: reacts with Dragendorff’s reagent.

• Basic nature: forms precipitates with heavy metals.

• Hydrazide: possesses strong reducing properties, reduces Ag+, Cu2+.

• Reacts with Fehling’s reagent, PDAB, and vanillin: forms a yellow precipitate (Ftivazid).

13. INH Quantification:

• Iodine method, via hydrazine.

14. INH Distribution in the Body:

• Concentrates significantly in the brain, lungs, and diffuses well into caseous material.

15. INH Metabolism and Excretion:

• After passing through the liver, INH is acetylated, forming an inactive product.

• Primarily excreted via urine, in the form of:

• acetylated INH

• isonicotinic acid

• conjugated with glycine

16. Mechanism of Action of INH:

• Inhibits multiple enzymes of TB.

• Interrupts mycolic acid synthesis.

17. Cross-Resistance with INH:

• No cross-resistance between INH and other anti-tuberculosis drugs, except ethionamide.

18. Side Effects of INH:

• Promotes rapid scar formation.

• Stimulates appetite.

19. Toxicity of INH:

• Related to vitamin B6 deficiency.

20. Pyrazinamide:

• Primarily used for early stages of TB, with a role in preventing relapse.

• Rapidly develops resistance.

21. Ethambutol:

• Often combined with INH and pyrazinamide.

• Effective against INH-resistant strains.

22. Mechanism of Action of Ethambutol:

• Inhibits TB RNA synthesis.

23. Most Important Side Effect of Ethambutol:

• Affects the optic nerve, causing red-green color blindness, potentially leading to blindness.

24. Drug Interactions with Ethambutol:

• Caution is needed with aluminum-containing medications (such as antacids) as they form chelates with ethambutol, reducing drug absorption.

25. Rifampicin:

• Synthesized from rifamycin.

• Currently the best anti-tuberculosis drug.

• Important Note: Never use as monotherapy!

26. Mechanism of Rifampicin:

• Binds to TB RNA polymerase, inhibiting RNA synthesis.

27. Anti-tuberculosis and Anti-Leprosy Drugs:

• Rifampicin is effective against both tuberculosis and leprosy.

28. Common Side Effects of Anti-tuberculosis Drugs:

• Hepatotoxicity.

29. Anti-tuberculosis Drug that Causes Bone Marrow Toxicity:

• Rifampicin.

30. Drug Interactions with Rifampicin:

• Rifampicin increases the metabolism of INH and AZT in the liver.

• Rifampicin lowers the concentration of fluconazole, itraconazole, and ketoconazole by increasing their excretion.

31. Anti-tuberculosis Drug that Causes Serious Skin Reactions:

• Thiacetazon.

32. Anti-tuberculosis Drug that Causes Psychiatric Reactions in Alcohol Consumers, and Teratogenicity:

• Ethionamide.

II. Anti-Leprosy Drugs:

1. Groups of Anti-leprosy Drugs:

• Sulfon (Dapson)

• Iminophenazine (Clofazimine)

2. Mechanism of Action of Sulfon:

• Competes with PAB (para-aminobenzoic acid) in the synthesis of folic acid by bacteria (similar to sulfonamides).

3. Drugs that Cause Cyanosis:

• Sulfons due to their blue quinoline-like metabolites.

4. Chemical Structure of Dapson:

• Resembles the sulfanilamide group of antibiotics.

5. Clofazimine:

• Is a phenazine dye, with bactericidal and anti-inflammatory actions.

6. Mechanism of Action of Clofazimine:

• Binds to DNA and inhibits replication, at the Guanine base.

• Enhances macrophage activity.

• Anti-inflammatory action.

7. Drugs Quantified in Dry Media:

• Pyrazinamide, ethambutol, clofazimine.

8. DDS (Dapson) Derivatives:

• Do not show better efficacy than DDS.

Note:

• The information in this article is compiled from various sources and may not be completely accurate or exhaustive.

• Consult a qualified healthcare professional before using any medication.

• This article is for informational purposes only and does not substitute medical advice.