Anti-tubercular agents (Mycobacterium tuberculosis)

Tuberculosis is a chronic granulomatous disease and a major health problem in developing countries.
About 1/3rd of the world’s population is infected with Mycobacterium tuberculosis.

1. Anti-Tubercular Agents Mr. S Maheen Abdul Rahman, M. Pharm. Assistant Professor Department of Pharmaceutical Chemistry PA College of Pharmacy (PACP) Mangalore, Karnataka.

2. Tuberculosis is a chronic granulomatous disease and a major health problem in developing countries. About 1/3 rd of the world’s population is infected with Mycobacterium tuberculosis. As per WHO statistics for 2010, there were 9.4 million active TB cases globally, to which India was the highest contributor with 2.3 million cases. India is being the highest TB burden country for the past many years. Tuberculosis

3. The main symptoms are cough, tachycardia, cyanosis, and respiratory failure. Depending upon the site of infection, the disease can be categorized as follows: • Pulmonary tuberculosis (respiratory tract). • Genito-urinary tuberculosis (genitourinary tract). • Tuberculous meningitis (nervous system). • Miliary tuberculosis (a widespread infection).

4. First line: These drugs have high antitubercular efficacy as well as low toxicity; are used routinely Second line: These drugs have either low antitubercular efficacy or higher toxicity or both; and are used as reserve drugs . General MOA : Antitubercular agents work by stopping the growth of the bacteria that causes TB (Mycobacterium tuberculosis).

5. Group I: are the most potent and best tolerated oral drugs used routinely. Group II: are potent and bactericidal, but injectable drugs . Group III: includes fluoroquinolones (FQs) which are well tolerated bactericidal oral drugs; all patients with drug resistant TB should receive one FQ.

6. Group IV: are less effective, bacteriostatic/more toxic oral drugs for resistant TB. Group V: are drugs with uncertain efficacy; not recommended for MDR-TB; may be used in extensively resistant TB (XDR-TB)

7. Isoniazid (INH) is primarily metabolized in the liver by the enzyme N-acetyltransferase-2 (NAT2). The main active metabolite of isoniazid is N- acetylisoniazid ( AcINH ). This metabolite can further undergo hydrolysis to form isonicotinic acid (INA) and acetyl hydrazine. Isoniazid: Highly effective and the most widely used anti-tubercular agent. It is active against both intracellular and extracellular bacilli.

8. Isoniazid (INH) Active metabolite Formation of covalent complex between ACP reductase and b -ketoacyl-ACP synthase Inhibits the bacterial cell wall mycolic acid, thereby making M. tuberculosis susceptible to reactive oxygen radicals (ROS) Inhibition of mycolic acid synthesis Mycobacterial catalase peroxidase ( KatG )

9. ADR Hepatotoxicity: Patients receiving INH should be monitored for symptoms like anorexia, nausea, vomiting, jaundice, etc. Peripheral neuritis: It is a dose-related toxicity. INH is structurally similar to pyridoxine; hence, INH competitively interferes with utilization of pyridoxine. It also promotes the excretion of pyridoxine. So, Pyridoxine 10 mg/day is routinely given along with INH to reduce the risk of peripheral neuritis. It is also used for the treatment of INH induced peripheral neuritis. Other side effects are fever, skin rashes, arthralgia, anaemia, GI disturbances, psychosis and rarely convulsions .

10. 2.   Rifampin ( Ripampicin ) Derivative of rifamycin. K ills intracellular and extracellular bacilli including spurters (those residing in caseous lesion). It is the only agent that can act on all types of bacillary subpopulations ; hence rifampin is called sterilizing agent . Adverse effects 1. Leprosy 2. Hepatitis 3. Flu-like syndrome with fever, chills, headache, muscle and joint pain. 4. GI disturbances such as nausea, vomiting and abdominal discomfort.

11. Multidrug-resistant (MDR): TB MDR-TB is defined as resistance to both H and R, and may be any number of other (1st line) drug(s). MDR-TB has a more rapid course with worse outcomes. Its treatment requires complex multiple 2nd line drug regimens which are longer, more expensive and more toxic. As per WHO, India has the highest number of MDR-TB cases in South-East Asia. Multidrug-resistant (MDR)

12. DOTs (Directly Observed Treatment, Short-Course) The RNTCP (Revised National TB-Control Program) initiated the DOTS-plus program in the year 2000 to cover the diagnosis and treatment of MDR-TB.

13. Mycobacterium avium complex (MAC) infection: MAC is an opportunistic pathogen which causes disseminated and multifocal disease in immunocompromised (HIV-AIDS) patients. The disease develops when cell mediated immunity is markedly depressed, i.e. when CD4 count drops to <50 cells/μL, HIV-RNA load is high and other opportunistic infections (P. jirovecii , etc.) are also present. The newer macrolide antibiotics are particularly active drugs against MAC. Mycobacterium avium complex (MAC)

14. SYNTHESIS 1. Isoniazid ( Isonicotinic acid hydrazide) IUPAC name: Pyridine-4-carbohydrazide It is used as an antituberculosis drug.

15. Para-amino-salicylic acid p-Amino salicylic acid exerts its bacteriostatic activity against Mycobacterium tuberculosis by competing with PABA for enzymes involved in folate synthesis Hence, there will be a suppressing growth M. tuberculosis, eventually leading to cell death.

16. 2. Para-amino-salicylic acid 4-Amino-2-hydroxy benzoic acid

17. Rifabutin

18. cycloserine

19. Reference Book: An Introduction to Medicinal Chemistry by GRAHAM L. PATRICK Text book of medicinal chemistry by K. Ilango and Valentina