Drugs Used In Tuberculosis

First-line agents     

Isoniazid(INH) Rifampicin Pyrazinamide Ethambutol Streptomycin

Isoniazid(INH)    

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Most active drug for tuberculosis MOA: Inhibits synthesis of mycolic acid Prodrug-activated by KatG, mycobacterial catalase-peroxidase. Activated form, forms covalent complex with AcpM & KasA.

Resistance to INH 

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Mutation from overexpression of inhA(low resistance). Mutation or deletion of katG gene(high resistance) Overexpression of ahpc Mutation in KasA. PK: Clinical uses:

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Adverse Reactions: Immunological reactions Direct toxicity: Hepatitis Peripheral neuropathy Pyridoxine deficiency Anemia, tinitis, GI discomfort.

RIFAMPICIN  

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Antimicrobial activity: Binds to ß-subunit of bacterial DNA dependent RNA polymerase & inhibits RNA synthesis. Bacteriocidal for mycobacteria. It will kill intracellular organisms & those sequestered in abscesses & lung cavities.

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Resistance: Mutation in rpoB, the gene for ßsubunit of RNA polymerase. Mutations--Result in reduced binding of rifampin to RNA polymerase. PK: Absobed after oral adm. Excerted –through liver into bile. Distributed widely in body tissue & fluids. Highly protein bound, adequate CSF conc. –meningeal inflammation.

RIFAMPICIN    

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Clinical uses: Mycobacterial infections- 600mg orally. Atypical Mycobacterial infect.& in leprosy. Prophylaxis ( only in pts with INHresistance). OTHERS: Meningococcal carriers. Prophylaxis--H.influenzae type B Staphylococcal carriage. Staph. Infect. As osteomyelitis, prostatic valve endocarditis.

RIFAMPICIN 

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Harmless orange color to urine, sweat, tears, contact lenses. Rashes, thrombocytopenia & nephritis. Choleststic jaundice, light chain proteinuria. Flu-like syndrome, fever, chills, myalgia, anemia, thrombocytopenia, acute tubular necrosis. Strongly induces most cytochrome P450 isoforms.(inc. elimination of methadone, anticoagulants, cyclosporine, anticonvulsants, PI, NNRTI, contraceptives). Lower serum level of the above drugs.

Ethambutol  

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MOA: Inhibits mycobacterial arabinosyl transferase.(coded by embCAB operon) Responsible for polymerisation reaction of arabinoglycan--- component of mycobacterial cell wall. Resistance: mutation of emb gene. S/E: Hypersensitivity Loss of visual acuity– red-green color blindness. CI; in children -- red-green color blindness.

Pyrazinamide   

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Related to nicotinamide. MOA: Taken up by macrophages & active against mycobacteria residing in the acidic environment of lysosomes. Converted to pyrazinoic acid ( active form of drug) by mycobacterial pyrazinamidase—enceded by pncA Resistance: Impaired uptake. mutation of pncA. S/E Hepatotoxic Nausea, vomiting, drug fever. Hyperurecemia--- gouty arthritis.

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Streptomycin

Penetrates into the cell poorly & is active against extracellular tubercle bacilli.  Crosses b/b barrier & active therappeutic conc. in inflammed meningies.  Clinical uses:  Inj. indicated for life threatening form of TB e.g meningitis, disseminated diseases, inf. Resistant to other drugs,  S/E;  Ototoxic & nephrotoxic.  Vertigo & hearing loss--- may be permanent ( red by therapy no more than 6 months). 

TREATMENT OF MDRTUBERCULOSIS DR.SAMIA

TB IN SPUTUM

First-line agents     

Isoniazid(INH) Rifampicin Pyrazinamide Ethambutol Streptomycin

Second-line drugs   

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In case of resistance to first-line failure of clinical response to conventional therapy Serious treatment limiting adverse drug reactions Expert guidance is available to deal with toxic effects.

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Drug resistant tuberculosis is transmitted in the same way as regular TB. Primary resistance: occurs in persons who are infected with a resistant strain of TB. Secondary resistance: inadequate treatment, not taking the prescribed regimen appropriately, or using low quality medication. Multi-drug resistant TB (MDR-TB) is defined as resistance to the two most effective first line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB (XDR-TB) is also resistant to three or more of the six classes of second-line drugs.

ALTERNATIVE SECOND-LINE DRUGS         

Ethionamide Capreomycin Cycloserine Aminosalicylic acid Kanamycin & Amikacin Fluoroquinolones Linezolides Rifabutin Rifapentine

Ethionamide      

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Chemically related to INH. Blocks synthesis of mycolic acids. Available in oral form S/E: gastric irritation ( 1g/d) neurological symptoms( Rxpyridoxine) hepatotoxicity Resistance- single agent.

Capreomycin       

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Protein synthesis inhibitor 1g-i/m- MDR strains Inj. treatment for MDR-TB Resistance- due to rrs mutation. S/E: nephrotoxic Ototoxic- tinnitus, deafness, vestibular disturbance. Inj. site- local pain, sterile abscesses.

Cycloserine  

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Inhibitor of cell wall synthesis. Cleared – renaly (dose is red. to ½ if creatinine clearance is less than 50ml/min). S/E: Peripheral neuropathy. CNS dysfunction-Psychosis, depression.

Aminosalicylic acid  

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Folate synthesis antagonist. Structurally similar to PABA & sulfonamides. Widely distributed in fluids & body tissue except CSF. S/E: Peptic ulcers, hemorrhages(give with meals) Hypersensitivity reactions- fever, joint pain, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, granulocytopenia,

Kanamycin & Amikacin    

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Inc. used due to MDR. For streptomycin resistant or MDR. Combination with two or three drugs. MOA: Protein synthesis inhibitor by binding to specific 30S-subunit ribosomal protein. S/E: ototoxic & nephrotoxic.

Fluoroquinolones 

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Ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin. For resistant strains against first-line drugs. Resistance: Mutations in gyrase A subunit ( if used as single agent)

Linezolides  

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Achieves good intracellular conc. In combination with other second-line drugs. MOA: inhibit protein synthesis by preventing formation of ribosome complex that initiate protein synthesis. S/E: Bone marrow suppression Irreversible peripheral & optic neuropathy. Drug of last resort.

Rifabutin    

Derived from rifamycin. Resistance: rpo B mutation. Less potent inducer(P450 enzymes) is indicated in place of rifampin for HIV-infected patients.

Rifapentine    

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Analog of rifampin Both M tuberculosis & M avium. Potent inducer of P450 enzymes. Cross-resistance b/w rifampin & rifapentine is complete. Should not be used in HIV-infected pts –high relapse rate with rifampinresistant organisms.

Rifapentine is & microbiological active metabolite (25desacetylrifapentine has elimination ½ life of 13 hrs.  Once weekly in rifampin-susceptible strains during continuation phase. ( after first two months therapy). 