1st Line Anti-Tubercular Drugs

download 1st Line Anti-Tubercular Drugs

of 58

Transcript of 1st Line Anti-Tubercular Drugs

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    1/58

    1stt -ine Anti-ine Antiubercular Drugsubercular DrugsSaurabh Biswas

    PGT,Dept. Of Chest MedicineCNMCH

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    2/58

    History

    MycobacteriumTuberculosis

    Drugs(1st line)

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    3/58

    H isto ry

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    4/58

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    5/58

    1961-discovery of ethambutol

    1962-discovery of rifampicin

    1974-concept of SCC daily regimen includingRZ

    1980- six-month fully intermittent effectiveSCC evolved.

    2001-possibility of 4-month ultra short-course

    effective regimen containing quinolones isexplored

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    6/58

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    7/58

    Slow growing aerobic rod-shaped organism 2-4microm in length and 0.2 -0.8 microm inbreadth.

    Weakly Gram positive and Acid-fast.

    Infects humans,monkeys,cows,buffaloes,pigs,dogs and occ. Parrots.

    Under experimental conditions virulent toguinea pigs and mice.

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    8/58

    Best method to inactivate heat- death time at60 degree is 15 mins.

    More resistant to chemical agents than otherbacteria-80% ethanol kills it in 2-10 mins,sorecommended for disinfection of skin &rubber gloves.

    Daylight has lethal effect on it.

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    9/58

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    10/58

    A-rapidly multiplying found in caseous debris in pulcavity,B-slowly multiplying due to acidic cond.,C-

    multiplying sporadically

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    11/58

    Elimination of population A and B results innegative sputum cultures typically after 2months of rx.

    Population C is a potential source of relapsesalong with Dormant bacilli-the persisters.

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    12/58

    line)

    Isoniazid(H)

    Rifampicin(R)

    Pyrazinamide(Z)Ethambutol(E)

    Streptomycin(S)

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    13/58

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    14/58

    minimal inhibitory concentrations (MICs) ofisoniazid for wild-type (untreated) strains ofM. tuberculosis are

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    15/58

    Pharmacokinetics

    Completely absorbed orally

    Penetrates all body tissues,tubercularcavities,placenta and meninges.

    metabolized in the liver via acetylation andhydrolysis

    metabolites are excreted into the urine.

    The rate of acetylation is genetically controlled-fast & slow acetylators.

    T1/2-1hr in fast and 3 hrs in slow

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    16/58

    30-40% Indians fast acetylators 60-70% areslow.

    The standard adult daily oral dose of 300 mgproduces peak serum levels of 35 microg/mL

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    17/58

    Dosage:

    The usual dose is 5mg/kg daily maximum upto

    300mg or 10mg/kg thrice weekly upto amaximum of 600mg.

    15mg/kg if given twice weekly-less effective infast acetylators.

    does not require dosage adjustment in patientswith renal insufficiency or with end-stage renaldisease requiring chronic hemodialysis.

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    18/58

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    19/58

    Contraindications:

    Known hypersensitivity

    Active hepatic disease

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    20/58

    UNTOWARD EFFECTS

    occur in ~5%

    rash (2%), fever (1.2%), jaundice (0.6%), andperipheral neuritis (0.2%)-Preventable withpyridoxine

    Risk factors for peripheral neuropathy-slowacetylators, elderly, pregnant women, human

    immunodeficiency virus [HIV]-infected subjects,diabetics, alcoholics, and uremics

    Isoniazid hypersensitivity may result in fever,

    rashes, and hepatitis

    Hematological reactions-agranulocytosis,eosinophilia, thrombocytopenia, and anemia

    Vasculitis associated with antinuclear antibodies

    convulsions, usually in patients with known seizure

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    21/58

    Optic neuritis ,muscle twitching, dizziness,ataxia, paresthesias, stupor, and potentiallyfatal encephalopathy

    euphoria, transient memory impairment, loss ofself-control, and psychosis.

    Hepatic injury

    Severe hepatic injury leading to death-presenting 48 weeks after initiation

    Drug continuation after hepatic dysfunction-worsen the damage.

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    22/58

    Risk factors-Alcoholic hepatitis,Age(mostimportant),excessive alcohol intake, history

    of liver diseasechronic carriers of the hepatitis B virus tolerate

    isoniazid

    Up to 12% of patients may have elevated

    serum transaminase levelsDrug to be discontinued if ALT>5-fold of

    normal without any signs and symptoms or ifALT>3 times normal plus signs and

    symptoms of hepatitis

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    23/58

    Rifampicinsemisynthetic derivative ofStreptomycesmediterranei

    most important and potent antituberculous

    agent

    also active against a wide spectrum of otherorganisms, including some gram-positive andgram-negative bacteria, Legionella spp., M.

    kansasii, and M. marinum

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    24/58

    Susceptible strains ofM. tuberculosis as well asM. kansasii and M. marinum are inhibited by 1

    microg/mL.Bactericidal-both intracellularly and

    extracellulararly.

    Inhibits DNA dependent RNA polymerase,

    leading to suppression of initiation of chainformation (but not chain elongation) in RNAsynthesis

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    25/58

    Pharmacokinetics:

    absorbed readily after either PO or IV

    administrationSerum levels of 1020 microg/mL follow a

    standard adult oral dose of 600 mg

    eliminated rapidly in the bile, and an

    enterohepatic circulation ensues.drug is progressively deacetylated by hepatic

    CYPS

    after 6 hours, nearly all drug in the bile is in the

    deacetylated form, which retains antibacterialactivity

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    26/58

    Intestinal reabsorption is reduced bydeacetylation and by food-metabolism

    facilitates drug eliminationt1/2 is progressively shortened (~40%) during

    the first 14 days of treatment due to inductionof hepatic CYPs.

    t1/2 is variable-2 to 5 hrs.Dosage adjustment is not necessary in patients

    with renal insufficiency

    Penetrates cavities,caseous masses,placenta

    and meninges.

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    27/58

    Dosage:

    10 mg/kg daily,2 or 3 times daily upto amaximum of 600 mg.

    given either 1 hour before or 2 hours after ameal

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    28/58

    Drug interaction:

    potent inducer of hepatic CYPs- decreases thet1/2 of many drugs

    HIV protease and nonnucleoside reversetranscriptase inhibitors, digoxin, quinidine,mexiletine, tocainide, ketoconazole,propranolol, metoprolol, clofibrate, verapamil,

    cyclosporine, glucocorticoids, oralanticoagulants, theophylline, barbiturates,oral contraceptives,fluconazole, and thesulfonylureas

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    29/58

    Interaction with oral anticoagulants-impairanticoagulation

    Decrease effectiveness of oral contraceptives

    and induce adrenal insufficiency in patientswith marginal adrenal reserve

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    30/58

    Contraindications:

    Known hypersensitivity

    Active hepatic disease

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    31/58

    Untoward effects:

    Significant effects in

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    32/58

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    33/58

    Other uses:

    Leprosy

    prophylaxis of meningococcal disease andHaemophilus influenzae meningitis

    Combined with a b-lactam antibiotic orvancomycin-selected cases of staphylococcalendocarditis or osteomyelitis

    Doxycycline + R-first line therapy forbrucellosis.

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    34/58

    Ethambutolderivative of ethylenediamine, ethambutol is awater-soluble compound -active only againstmycobacteria

    Active against M. tuberculosis, M. marinum, M.kansasii, and MAC organisms

    Among first-line drugs, ethambutol is the leastpotent against M. tuberculosis

    Tuberculostatic

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    35/58

    Used in combination with other ATDs toprevent or delay emergence of resistantstrain.

    Growth inhibition by ethambutol requires 24hours-inhibition of arabinosyl transferasesinvolved in cell wall biosynthesis

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    36/58

    Pharmacokinetics:

    About 80% of an oral dose of ethambutol isabsorbed from the GI tract.

    Concentrations in plasma peak 24 hours afterthe drug is taken-Peak serum levels of 24microg/mL

    t1/2 of 34 hours.Within 24 hours, 75% of an ingested dose of

    ethambutol is excreted unchanged in theurine

    up to 15% is excreted in the form of aldehydeand dicarboxylic acid derivatives.

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    37/58

    Dosage:

    Adults:15mg/kg daily,30mg/kg 3 times weeklyor 45mg/kg twice weekly.

    Children:15mg/kg daily

    Dose to be reduced in impaired renal function

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    38/58

    Contraindications:

    Known hypersensitivity

    Pre-existing optic neuritis from any cause

    Creatinine clearance

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    39/58

    Untoward effects:

    optic neuritis, resulting in decreased visual

    acuity and redgreen color blindness-

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    40/58

    Numbness and tingling of the fingers owing toperipheral neuritis infrequent

    Anaphylaxis and leukopenia are rare.

    increased urate concentration in the blood in~50% of patients, owing to decreased renalexcretion of uric acid.

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    41/58

    PyrazinamideSynthetic pyrazineanalogue of nicitinamideWeakly tuberculocidal

    Highly active in acidic medium(it is active onlyat a pH of

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    42/58

    target for this compound is thought to be afatty acid synthase gene (fasI) involved inmycolic acid biosynthesis

    Susceptible strains ofM. tuberculosis areinhibited by 20 microg/mL

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    43/58

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    44/58

    metabolites include pyrazinoic acid, 5-hydroxypyrazinamide, and 5hydroxypyrazinoic acid

    not available in a parenteral formulation

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    45/58

    Dosage:

    For 1st 2 or 3 months-25mg/kg daily,35mg/kg 3times weekly ,50mg/kg 2 times weekly

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    46/58

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    47/58

    UNTOWARD EFFECTS:

    Hepatic injury is the most serious side effect

    At the currently recommended dosages, the

    frequency of hepatotoxicity is no higher thanthat for concomitant isoniazid and rifampintherapy

    Hyperuricemia is a common adverse effect-reduced by concurrent rifampin therapy

    Polyarthralgias encountered fairly commonly-not related to the hyperuricemia

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    48/58

    Rash,fever , loss of diabetes control

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    49/58

    StreptomycinAn aminoglycoside isolated from Streptomycesgriseus

    active against untreated strains ofM.

    tuberculosis, M. kansasii, and M. marinumand against some strains of MAC organisms

    Also active against some Gram negativeorganisms

    Tuberculocidal

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    50/58

    Acts only in extracellular bacilli-poorpenetration into cells

    Doesnt cross CSF and poor action in acidic

    media.Binds to bacterial 30s ribosome-inhibits

    protein synthesis.

    Serum levels of streptomycin peak at 2540microg/mL after a 1.0-g dose

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    51/58

    Pharmacokinetics:

    Highly ionized

    Neither absorbed nor destroyed in GITAbsorption from injection site-rapid

    Distributed extracellularly only

    Low concentrations in serous fluid like synovial

    and pleural and also in CSF.Not metabolized-excreted unchanged in urine

    T1/2 is 2-4 hrs-but persists longer in tissues

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    52/58

    Dosage:

    15mg/kg daily,2 or 3 times weekly by deep IMinjection

    dosage must be lowered and the frequency ofadministration reduced (to only two or threetimes per week) in most patients >50 yearsof age and in any patient with renal

    impairment

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    53/58

    Contraindications:

    Known hypersensitivity

    Auditory nerve impairment

    Myasthenia gravis

    Pregnancy

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    54/58

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    55/58

    perioral paresthesia, eosinophilia, rash,and drug fever

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    56/58

    Drug interaction:

    Avoid use with other ototoxic drugs like higghceiling diuretics,minocycline

    Avoid concurrent use of other nephrotoxicdrugs

    Cautious use with muscle relaxant-it may addto the action of other muscle relaxant

    Do not mix with any other drug in samesyringe/infusion

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    57/58

    Other uses:

    SABE along with penicillin

    Plague

    Tularemia-drug of choice

  • 8/14/2019 1st Line Anti-Tubercular Drugs

    58/58