antituberculosis drugs

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Antituberculosis Drugs:

Antituberculosis Drugs Dr.S.P.Dhanya

Introduction:

Introduction chronic granulomatous disease Drugs-First Line H - ISONIAZID R-RIFAMPIN/RIFAMPICIN Z-PYRAZINAMIDE E-ETHAMBUTOL S-STREPTOMYCIN

Second Line :

Second Line Tzn-Thiacetazone PAS- Paraaminosalicyclic acid Etm-Ethionamide Cys-Cycloserine Kmc-Kanamycin Am- Amikacin Cpr-Capreomycin

Second line newer drugs:

Second line newer drugs Ciprofloxacin Ofloxacin Clarithromycin Azithromycin Rifabutin

Isoniazid:

Isoniazid Essential component of ATT Primarily tuberculocidal Fast multiplying organisms are killed , quiescent ones are inhibited Act on extracellular and intracellular Tuberculosis bacilli Cheapest antituberculosis drug

PowerPoint Presentation:

Highly selective mycobacteria Concentrate INH Catalase peroxidase convert INH into active metabolite inh A gene -codes-fatty acid synthase enzyme- enoyl ACP reductase Inhibition of synthesis of mycolic acids-unique fatty acid component of mycobacterial cell wall Lipid content of mycobacteria is reduced

Resistance:

Resistance Inherent resistance-Primary Mutation of catalase peroxidase gene Mutation of inh A gene Lose of active INH concentarting process

Pharmacokinetics:

Pharmacokinetics Completely absorbed and penetrates all body tissues, tubercular cavities, placenta and meninges Extensively metabolized in liver- acetylation Fast acetylators (30-40%)- t ½=1 hr Slow acetylators (60-70%)-t ½ =3hr

Interactions:

Interactions AlOH inhibits INH absorption INH inhibits phenytoin,carbamazepine,diazepam and warfarin metabolism PAS inhibits INH metabolism

Dose:

Dose Daily 5mg/kg 300 mg 3 x per week dose 10mg/kg 600mg

Adverse Effects:

Adverse Effects Peripheral neuritis ---slow acetylators --- paresthesia , numbness , mental disturbances, convulsions Interference with utilisation of pyridoxine and increased excretion in urine Pyridoxine 10mg/day- prophylatic 100mg/day-for toxicity

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Hepatitis-older and alcoholics-dose related damage to liver cells ----reversible on stopping the drug Rash Fever Acne Arthralgia

Rifampicin:

Rifampicin Semisynthetic derivative of rifamycin B Source- Streptomyces mediterranei Bactericidal As efficacious as INH

PowerPoint Presentation:

On all subpopulation Slowly/intermittently dividing, spurters as well as atypical mycobacteria Both extra and intracellular organisms are affected Good sterilizing and resistance preventing actions

Spectrum:

Spectrum M.tuberculosis M.kasasi M.scrofulaceum M avium intracellularae M.fortuitum , Staph aureus N.meningitidis H.influenzae E.coli Klebsiella Pseudomonas Proteus Legionella Brucella

Mechanism of action :

Mechanism of action Target-----repo B gene Inhibits DNA dependent RNA polymerase Suppress initiation of chain formation in RNA synthesis Mammalian RNA polymerase doesnot avidly bind rifampin

Resistance:

Resistance Rapid but unusual Mutation of repoB gene

Pharmacokinetics :

Pharmacokinetics Well absorbed orally Wide distribution- cavities,placenta,meninges Deacetylated in liver Excreted in bile Undergoes enterohepatic circulation t ½ -2-5hrs

Interactions:

Interactions Microsomal enzyme inducer Increases CYP3A4,CYP2D6,CYP1A2 and CYP2C Enhances its own as well as Warfarin, OCP, corticosteroids , sulfonylurea,digitoxin,steroids,PI,NNRTIs

Adverse effects:

Adverse effects Hepatitis Respiratory syndrome Purpura, hemolysis, shock, renal failure Cutaneous syndrome - flushing, pruritus,rash,redness,watering of eyes Flu syndrome chills,fever,headache,malaise,bone pain Abdominal syndrome - nausea,vomiting,cramps,diarrhoaea

Uses:

Uses Treatment of TB-10mg/kg 600mg Prevention of H.influenza /meningococcal disease and carrier Staphylococcal endocarditis on natural/prosthetic valves 2 nd /3 rd line for MRSA, diphetheroids , Legionella

PowerPoint Presentation:

First line for brucellosis along with doxycycline Leprosy Eradication of Staph nasal carrier state in furunculosis Atypical mycobacteria infection

Pyrazinamide:

Pyrazinamide Weakly tuberculocidal Lethal to intracellularly located bacilli-slow Highly effective –inflammation Kills and sterilizes Helps shorten regimen and decreases relapse

Mechanism of cation:

Inhibition of synthesis of mycolic acids-unique fatty acid component of mycobacterial cell wall pncA gene-enzyme-activates pyrazinamide - pyrazinoic acid Lipid content of mycobacteria is reduced Interacts with a different fatty acid synthase encoding gene Mechanism of cation

Resistance:

Resistance Mutation of pncA gene Impaired uptake

Pharmacokinetics:

Pharmacokinetics Absorbed orally Wide distribution Metabolised in liver Excreted in urine t ½=6-10h

Adverse effects:

Adverse effects Hepatotoxicity Hyperuricemia,gout Arthralgia , flushing, rashes, fever, loss of diabetes control

Dose:

Dose Daily 25mg/kg 1500 mg 3 x per week dose 35mg/kg 2000mg

Ethambutol:

Ethambutol Tuberculostatic Fast multiplying organisms are affected Atypical mycobacteria Hasten sputum conversion and prevent development of resistance

Mechanism of action:

Mechanism of action emb operon-arabinosyl transferase Arabinogalactan synthesis inhibited Incorporation of mycolic acid interfered Lipid content of mycobacteria is reduced

Resistance:

Resistance Mutation of emb gene No cross resistance

Pharmacokinetics:

Pharmacokinetics 75-80% absorbed from GIT Wide distribution,penetrate meninges incompletely Temporairly stored in RBC < ½ metabolized Excreted by GF and TS t ½ =4h

Adverse effects:

Adverse effects Dose related and duration dependent Loss of visual acuity/red green colour vision Optic neuritis-field defects Should not be used in children less than 6y Nausea , rashes , fever , hyperuricemia , neurological changes-headache, dizziness, mental confusion, hallucination, numbness, tingling of fingers

Dose:

Dose Daily 15mg/kg 1000 mg 3 x per week dose 30mg/kg 1600mg

Streptomycin:

Streptomycin First clinically useful antitb drug Tuberculocidal Acts only on extracellular bacilli Penetrate TB cavities, do not cross CSF Resistance has increased-bacilli selectively multiply and stage a comeback after initial control

Mechanism of action:

Mechanism of action Binds to 30s Freeze initiation of protein synthesis Prevent polysome formation Promote disaggregation to monosome Cause misreading of codon Resistance-----mutation of traget -----inactivating enzymes

ADR:

ADR Ototoxicity Vertigo Rash Nephrotoxicity Fever

Use:

Use Life threatening TB Resistant TB In MAC and M.kansasi infection Dose-15mg/kg 1000 mg

Second line drugs:

Second line drugs

Thiacetazone:

Thiacetazone Tuberculostatic Low efficacy Low cost-----prevent resistance As a substitute of PAS along with INH Hepatitis, Exfoliative dermatitis, SJS, BM depression Contraindicated in HIV patients

PAS:

PAS Tuberculostatic PABA analogue MOA= folate synthase inhibition Delays development of resistance -directly inhibit episomal resistance transfer Ca/Na salts Metabolism by acetylation Anorexia, nausea, epigastric pain, rash, fever,malaise , goitre , liver dysfn , bld dyscrasias

Ethionamide:

Ethionamide Tuberculostatic Inhibit mycolic cell wall Both extra and intracellular Rapid resistance Anorexia,nausea,vomiting , aches,pain,rash , optic neuritis

Cycloserine:

Cycloserine Source- S.orchidaceus Tuberculostatic MOA-analogue of d- alanine L alanine racemase inhibits cell wall synthesis by inactivating enzyme which racemizes L alanine d alanyly d alanine ligase link 2 d- alanine residues

PowerPoint Presentation:

Sleepiness,headache,tremor,psychosis Convulsions---pyridoxine for treatment

Kanamycin,Amikacin,Capreomycin:

Kanamycin,Amikacin,Capreomycin Reserve in rare cases------toxic Any one used at a time in combination Not combined among themselves/with S Act by inhibiting…………….synthesis Route------------------? None penetrate meninges Excreted unchanged by kidney Dose-0.75-1g/day Capreomycin -----e abnormalities

Newer drugs:

Newer drugs Quinolones-Ciprofloxacin,Moxifloxacin,Ofloxacin,Gatifloxacin , Sparfloxacin M.tuberculosis,MAC,M.fortuitum Penetrate cell and kill mycobacteria lodged in macrophages Good tolerability MDR TB,MAC ,supplement ES

Macrolides:

Macrolides Clarithromycin,Azithromycin nonTB mycobacteria MAC,M.fortuitum,M.kansasi,M.marinum Clarithro -low MIC value-500mgBD Azithro -better tissue and intracellular levels-500mg OD

Rifabutin:

Rifabutin More active against MAC MAC prophylaxis-300mg/day Treatment-along with E+Clarithro / azithro GI intolerance,rash,granulocytopenia,myalgia,uveitis Weak enzyme inducer Substituted for Rifampin in HIV patients

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