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Antimycobacterial drugs First line of drugs: Isoniazid (INH) Rifampicin Ethambutol Streptomycin Pyrazinamide Never use a single drug therapy –rifampicin combination administered for 9 months will cure 95-98% of cases . Addition of pyrazinamide for this combination for the first 2 months allows total duration to be reduced to 6 months. Isoniazid Isoniazid Bacteriostatic at low conc. & bacteriocidal at high conc. Especially against actively growing bacteria. Inhibits synthesis of mycolic acid is an essential components of mycobacterial cell wall. Pharmacokinetics Readily absorbed from GIT. Diffuse into all body fluids and tissues Penetrates caseous material and macrophages so it is effective against intra and extracellular organisms. Metabolized in liver by acetylation Excreted mainly in urine Clinical uses Mycobacterial infections (it is recommended to be given with pyridoxine to avoid neuropathy). Latent tuberculosis in patients with positive tuberculin skin test Prophylaxis against active TB in individuals who are in great risk as very young or immunocompromised individuals. Adverse effects Peripheral neuritis Optic neuritis. Allergic reactions ( fever,skin rash,systemic lupus erythematosus ) Hepatitis Gastric upset Haemolytic anaemia Enzyme inhibitor CNS toxicity. Rifampicin Bactericidal ,binds strongly to β subunit of bacterial DNA-dependent RNA polymerase leading to inhibition of RNA synthesis . Pharmacokinetics Well absorbed orall. Excreted mainly through liver into bile. Highly protein bind . Penetrates macrophages so affect extra and intracellular organisms. Adequate CSF conc. Only in meningeal inflammation. Clinical uses Mycobacterial infections Prophylaxis in contacts of children with Haemophilus influenzae type b disease. Treatment of serious staphylococcal infections as osteomyelitis and endocarditis. Meningitis by highly resistant penicillin pneumococci Adverse effects Harmless red-orange colour to urine,sweat,tears,contact lenses. Rashes Thrombocytopenia Nephritis Cholestatic jaundice,hepatitis Flu-like syndrome Induce cytochrome p-450 Ethambutol Inhibits mycobacterial cell wall synthesis by inhibiting arabinosyl transferase . Bacteriostatic Active against intra&extracellular bacilli . Well absorbed from gut. 20% excreted in feces and 50% in urine in unchanged form. Crosses BBB in meningitis Used only in mycobacterial infections. Adverse effects Retrobulbar (optic) neuritis causing loss of visual acuity and red-green colour blindness. It is relatively contraindicated in children. GIT .upset . Hyperuricemia Pyrazinamide It is converted to pyrazinoic acid ,the active form (prodrug) Mechanism is unknown. Bactericidal Acting on intracellular organisms. Well absorbed orally ,metabolized in liver ,excreted mainly through kidney . Clinical uses Mycobacterial infections (TB) mainly in multidrug resistance cases. It is important in short –course (6 months) regimens with isoniazid and rifampicin. Prophylaxis of TB in combination with ciprofloxacin. Adverse effects Hepatotoxic Hyperuricemia( provoke acute gouty arthritis ) Nausea & vomiting Drug fever & skin rash Streptomycin Life threating forms of TB ( meningitis, dissiminated disease). Resistant cases (Multidrug resistance tuberculosis at least to INH & rifampicin ) . Amikacin can be used as alternative to streptomycin. Both active mainly against extracellular bacilli. Indication of 2nd line treatment to the drugs of 1st line. Failure of clinical response Increase of risky effects. Patient is not tolerating the drugs first line drugs. Resistance Ethionamide As isoniazid blocks synthesis of mycolic acid . Available only in oral form. Metabolized by the liver ,excreted by kidney. It is poorly tolerated because of : -intense gastric irritation -neurologic symptoms -hepatotoxicity Used in TB & leprosy. Capreomycin It is an important injectable agent for treatment of drug-resistant tuberculosis. It is nephrotoxic and ototoxic. Local pain & sterile abscesses may occur. Cycloserine Inhibitor of cell wall synthesis Cleared renally The most serious side effects are peripheral neuropathy and CNS dysfunction, including depression & psychotic reaction. Pyridoxine should be given. Contraindicated in epileptic patients. Amikacin Used as alternative to streptomycin. Used in multidrug- resistance tuberculosis. No cross resistance between streptomycin and amikacin. Ciprofloxacin & levofloxacin Effective against typical and atypical mycobacteria. Used against resistant strains. Used in combination with other drugs. Rifapentine As rifampicin , it is RNA polymerase inhibitor. Cross resistance with rifampicin. Potent inducer of cytochrome p450. Effective against typical and atypical mycobacteria. Aminosalicylic Acid (PAS). Similar in structure to sulfonamide and p-aminobenzoic acid. Folate synthesis inhibitor. Well absorbed from GIT. Widely distributed in tissues except CSF. Excreted in urine as active and as metabolic products. Causes crystalluria,anorexia,nausea,diarrhea,epigastric pain. Peptic ulcer and haemorrhage can occur. Hypersensitivity reactions. Drugs used in leprosy Dapsone Inhibits folate synthesis. Well absorbed orally,widely distributed . Half-life 1-2 days,tends to be retained in skin,muscle,liver and kidney. Excreted into bile and reabsorbed in the intestine. Excreted in urine as acetylated. It is well tolerated. Clinical uses Tuberculoid leprosy. Lepromatous leprosy in combination with rifampin & clofazimine. To prevent & treat Pneumocystis pneumonia in AIDS caused by Pneumocystis jiroveci ( Pneumocystis carinii). Adverse effects Haemolytic anaemia Methemoglobinemia Gastrointestinal intolerance Fever,pruritus,rashes. Erythema nodosum leprosum Clofazimine It is a phenazine dye. Unknown mechanism of action ,may be DNA binding. Antiinflammatory effect. Absorption from the gut is variable. Given orally , once daily. Excreted mainly in feces. Stored mainly in reticuloendothelial tissues and skin. Half-life 2 months. Delayed onset of action (6 weeks). Clinical uses Multidrug resistance TB. Lepromatous leprosy Tuberculoid leprosy in : patients intolerant to sulfones dapsone-resistant bacilli. Chronic skin ulcers caused by M.ulcerans. Adverse effects Skin discoloration ranging from red-brown to black. Gastrointestinal intolerance. Red colour urine. Eosinophilic enteritis Treatment of TB in pregnant women INH ( pyridoxine should be given ), Rifampicin , ethambutol Pyrazinamide is given only if : Resistant to other drugs is documented Streptomycin is contraindicated. Breast feeding is not contraindication to receive drugs , but caution should be observed.