anti tubercular drugs.pptx

anti Tubercular drugs

1. GRACE COLLEGE OF PHARMACY,PALAKKAD APPROVED BY PCI,GOVERNMENT OF KERALA AFFLIATED TO KERALA UNIVERSITY OF HEALTH SCIENCES ANTI-TUBERCULAR DRUGS Prepared by: Mr. GOKUL J SIDDHARTH RESEARCH SCHOLAR [email protected]

2. ANTI-TUBERCULAR DRUGS Tuberculosis is a chronic granulomatous disease. Infected with mycobacterium tuberculosis. Infection is due to inhalation of infected droplet nuclei and lung is the major organ affected. Symptoms: Low grade fever (99°F) in evening. Night sweat. Malaise. Fatigue. Weight loss. Blood streaked productive cough.

3. Treatment: Anti-TB drugs can be divided into: First line drugs: Drugs have high anti-tubercular efficacy as well as low toxicity; used routinely. Second line drugs: •Low anti-tubercular efficacy or higher toxicity or both . •Used special circumstances . •Therapy must contain two or more drugs to avoid resistance(multi drug therapy). •The drugs must be taken regularly. •Drugs must continue for sufficient duration to achieve adequate therapeutic results.

4. Newer drugs Ciprofloxacin •Ofloxacin •Clarithromycin •Azithromycin •Rifabutin First line drugs Thiacetazone Para-aminosalicyclic acid(PAS) Ethionamide Cycloserine Kanamycin Amikacin Capreomycin Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin Second line drugs

5. Isoniazid(isonicotinic acid hydrazide,H) It is the primary drug for the chemotherapy of TB. It is tuberculocidal. Fast multipyling organism are rapidly killed ,bacteriostatic for resting bacilli. Act on extracellular and intracellular T.B. Active in acidic and alkaline medium. Mode of action: INH inhibit synthesis of mycolic acid. Mycolic acid is an essential component of mycobacterial cell wall. A gene labelled inhA which encode fatty acid synthase enzyme it is the target of INH action. INH is a prodrug. It is activated by kat G(Catalase-peroxidase enzyme in to active metabolites)

6. The active metabolites interact with inhA gene by forming a covalent bond with acyl carrier protein and beta ketoacyl carrier protein synthase . Which block mycolic acid synthesis and kill the cell. Resistance : Resistance to the drugs produced by reduced penetration into the bacterium. Cross resistance with other anti-TB drugs does not occur. The common mechanism of INH is the mutation of kat Ggene responsible for the activation if INH. Mutation of the target gene inhA involved in mycolic acid biosynthesis. ADME: Orally absorbed and also parentrally. Aluminium containing antacid interfere absorption of INH Widely distributed-saliva,milk,CSF,meninges,placenta.

7. Metabolized in liver-by acetylation(N-acetyltransferase) Excreted through urine. Interaction : INH × Aluminum hydroxide= INH absorption. I N H × Phe n y t oi n / c arbama z epin e /dia z ep a m/theop h yllin e / w ar f arin/ = inhibit the metabolism. INH × PAS = Inhibit INH metabolism Adverse Drug Reaction : Peripheral neuritis ,paresthesias,numbness,mental disturbances, rarely convolutions. Rashes, Fever, Jaundice .Anemia, Thrombocytopenia, Agranulocytosis, Hepatotoxicity Dose : INH Tab I N H S yr u p 300mg/d or 900mg twice weekly. 50-100mg/ml

8. INH Inj. 100mg/ml RIFAMPIN(RIFAMPICIN) It is a semi synthetic derivative of rifamycin. It is an antibiotic produced by streptomyces -mediterranei. Bactericidl to mycobacterium tuberculosis mycobacterium leprea, gram +ve, gram-ve bacteria. Act both extra and intracellular organism. Good sterilizing and resistance preventing action. Mode Of Action: Ri f ampin bin d β - subuni t RNApolyme r ase and inhibit DNA dependent RNA polymerase enzyme of mycobacteria. Suppression of initiation of chain formation in RNA synthesis Produce bactericidal effects.

9. Resistance : Resistance produce rapidly. It is due to mutation of repoB gene (β-subunit of RNA Polymerase). No cross resistance ADME: Well absorbed orally. Widely distributed in the body. Metabolized in liver by deacetylation. Excreted mainly in bile and less in urine. metabolism of Interactions: Rifampin × warfarin/oral contraceptives/ steroids/theophylline/metaprolol/fluconazole = precipitant drugs.

10. Adverse Drug Reaction: Hepatitis, jaundice,breathlessness,hemolysis,shock,renal failure,flushing,Pruritus rash, redness and watering of eyes. Flu syndrome: with chills, fever ,headache, malaise and bone pain. Abdominal syndrome: nausea, vomiting, abdominal cramps with or without diarrhoea. Urine and secretion may become orange-red-but this is harmless. Use : Leprosy Meningococcal and H.influenza. Brucellosis (Doxycycline+Rifampin)

11. PRAZINAMIDE: It is a weak tuberculocidal drugs. More active in acidic medium. Good sterilizing action. Mode Of Action: Same as INH Inhibit mycolic acid synthesis. Resistance: If it is used alone, resistance produce rapidly. ADME Absorbed orally Widely distributed Good penetration CSF Metabolized in liver Excreted in urine t1/2:6-10hr

12. Adverse Drug Reaction: Hepatotoxicity Hyperuricaemia Flushing,rashes,fever C.T with liver disease patients. ETHAMBUTOL Tuberculostatic drugs Mode Of Action: Ethambutol Inhibit arabinosyl transferace. Bacteriostatic effect It also involved in cell wall synthesis

13. Resistance: Resistance emerge rapidly, when it is used alone ADME: Nausea Vomiting Rashes Fever hyperuricemia

14. STREPTOMYCIN: It is a tuberculocidal drugs Less effective than INH Act only on extracellular bacilli(poor penetration) Does not cross CSF Poor action in acidic medium Given as i.m inj. Mode Of Action: • Streptomycin Bind with 30S Subunit of ribosomal protein Inhibit bacterial protein synthesis

15. Resistance: Produced rapidly( when it is alone) Adverse Drug Reaction: Ototoxicity Nephrotoxicity THIACETAZONE Tuberculostatic,low efficacy drug Used in combination with INH Orally active Excreted in urine t1/2-12hr Adverse Drug Reaction: Exfoliative dermatitis Steven- johnson syndrome, bone marrow depression . Anorexia loose motion abdominal discomfort.

16. PARA-AMINO SALICYCLIC ACID (PAS) It is a bacteriostatic drug. Least active drug Related to sulfonamides. Delay development of resistance Used as Na⁺ salt/Ca⁺ salt.

17. Mode of action:

18. ADME: Absorbed orally Distributed overall except CSF Metabolized in liver by acetylation. Excreted in urine. Adverse Drug Reaction: Anorexia Nausea Vomiting epigastric pain Rashes fever liver dysfunction

19. ET H IONAMIDE Similar to INH Tuberculostatic drugs Moderate efficacy Act as both intra and extracellular organisms Resistance produce rapidly Cross resistance with thiacetazone ADME: Absorbed orally Widely distributed includes CSF Metabolized in liver Excretion by urine Adverse Drug Reaction: Anorexia,nausea,vomiting Abdominal upset,aches,pains,hepatitis

20. Mode Of Action Inhibit mycolic acid synthesis CYCLOSERINE Analogue of D-Alanine Inhibit bacterial cell wall synthesis Mode Of Action: Cycloserine Inactivating the enzyme Racemize L-Alanine and link two D-Alanine residues. It is a tuberculostatic drugs. Inhibit gram+ve bacteria Resistance develops slowly No cross resistance

21. ADME: Absorbed orally Distributed all over the body ⅓rd of the dose is metabolized by liver Rest dose eliminated in urine Adverse Drug Reaction: Sleepiness Head ache Tremors Psychosis convulsion

22. KANAMYCIN,AMIKACIN,CAPREOMYCIN Toxic antibiotic. Used as reverse drugs in rare cases not responding to usual therapy. Resistance not developed. Adverse Drug Reaction: Ototoxicity, nephrotoxicity Electrolyte abnormality ADME: Absorbed orally Penetrate meninges Excreted by kidney Mode Of Action: Kanamycin: inhibitprotein synthesis by binding to the four nucleotides of 16srRNA and single amino acid of protein s12 Amikacin :inbihit protein synthesis by binding to 30s ribosomal subunit.

23. Capreomycin: peptide protein synthesis inhibitors obtained from streptomyces capreolous Resistance due to rrs mutation Newer Drugs: CIPROFLOXACIN,OFLOXACIN,MOXIFLOXACIN These are fluroquinolone and as anti-T.B • Bind to A Subunit of DNA gyrase enzymes. • Prevent binding of substrate to the active site of DNA gyrase Absence of formation of E-S Complex

24. Blockade of unwinding of double stranded DNA with a single stranded structure Prevent synthesis of mRNA Inhibit bacterial protein synthesis Antibacterial activity CLARITHROMYCIN,AZITHROMYCIN Newer macrolide antibiotic Most active against non-tubercular mycobacteria Mode Of Action: macrolide bind to 50S subunit ribosomal subunit.

25. Inhibit polypeptide chain elongation and protein synthesis inhibition Inhibit growth and multiplication of bacteria Bacteriostatic effect Adverse Drug Reaction: Ototoxicity RIFABUTIN Related to rifampin structure and mechanism of action Less active against M.Tuberculosis More active against M.Avium complex Partial cross resistance occur Adverse Drug Reaction GI intolerance, rashes, granulocytopenia,myalgia,uvetis

26. THE WHO GUIDELINES FOR THE TREATMENT OF TUBERCULOSIS. The regimen recommended for each patient depend category for each patient. The revised national tuberculosis control programme(RNTCP) was launched in India in1997. under this programme.DOTS( directly observed treatment short course) chemotherapy is being implemented. Out of the WHO recommended regimens, the thrice weekly regimens is followed in DOTS, in DOTS, patients is administrated drugs under the supervision of the health workers or other trained person to ensure that drugs are actually consumed. The therapy must be supervised and monitored by bacteriological examination dots is the backbone of RNTCP. It is aimed at ensuring patient compliance thus preventing the emergence of drugs-resistant tuberculosis. MULTIDRUG-RESISTANT TUBERCULOSIS (MDR-TB) It is defined as Resistance to both isoniazide and rifampicin with or without resistance to any other anti-TB drugs.

27. TYPE OF PATIENT TB TREATMENT REGIMEN S GNOSTIC TEGORY INTENSIVE PHASE CONTINUATION PHASE TOTAL DURATION (MONTHS) egory 1 New sputum +ve Seriously ill sputum Negative , seriously ill extra pulmonary Daily 2 H R Z E Thrice weekly 2(HRTZE)ȝ 4HR 4(HR)ȝ 6 6 egory 2 sputum +ve relapse sputum +ve failure sputum +ve treatment after default Daily 2 H R Z E S 1HRZE thrice weekly 2(HRZES)ȝ 1(HRZE)ȝ 5HRE 5(HRE)ȝ 8 8 egory 3 Sputum negative not seriously ill, Extra pulmonary not seriously ill Daily 2 H RZ thrice weekly 2(HRZ)ȝ 4HR 4(HR)ȝ 6 6 egory 4 chronic or suspected MDR-TB cases Specially des regimens igned standardi zed or individua

28. TR E A TM E N T : MDRT-TB can be treated by either specially designed standardized regimens . Drugs susceptibility testing is recommended for the cases if facilities are available. MDR-TB is treated with 5-6 drugs including 2-3 anti-TB drugs which the patients has not received in the past. Treatment should be given daily and observed directly .treatment should be continued for at least 24 months. To address the problems of MDR-TB,WHO is implementing a strategy DOTS plus . DOTS plus is designed to treat MDR-TB using second line anti-TB it is recommended in area where DOTS is fully in place. TB TREATMENT IN HIV PATIENTS The diagnostic categories for patient are the same irrespective of HIV status generally,TB treatment is the same for HIV infected as for non- HIV infected TB patients Short-course chemotherapy must be stared immediately once TB is diagnosed .Rifabutin is preferred over Rifampicin in HIV patients on antiretroviral drugs as it does not interact with Pls .

29. TUBERCULOSIS IN PREGNANCY INH, Rifampicin and ethambutol are considered safe in pregnancy

30. REFERANCE KD Tripathi Essential of Medical Pharmacology 7 th Edition Page no:765-779 ©2013,KD Tripathi