1st Line Anti-Tubercular Drugs
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Transcript of 1st Line Anti-Tubercular Drugs
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1stt -ine Anti-ine Antiubercular Drugsubercular DrugsSaurabh Biswas
PGT,Dept. Of Chest MedicineCNMCH
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History
MycobacteriumTuberculosis
Drugs(1st line)
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H isto ry
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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
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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.
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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.
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A-rapidly multiplying found in caseous debris in pulcavity,B-slowly multiplying due to acidic cond.,C-
multiplying sporadically
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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.
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line)
Isoniazid(H)
Rifampicin(R)
Pyrazinamide(Z)Ethambutol(E)
Streptomycin(S)
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minimal inhibitory concentrations (MICs) ofisoniazid for wild-type (untreated) strains ofM. tuberculosis are
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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
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30-40% Indians fast acetylators 60-70% areslow.
The standard adult daily oral dose of 300 mgproduces peak serum levels of 35 microg/mL
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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.
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Contraindications:
Known hypersensitivity
Active hepatic disease
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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
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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.
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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
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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
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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
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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
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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.
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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
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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
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Interaction with oral anticoagulants-impairanticoagulation
Decrease effectiveness of oral contraceptives
and induce adrenal insufficiency in patientswith marginal adrenal reserve
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Contraindications:
Known hypersensitivity
Active hepatic disease
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Untoward effects:
Significant effects in
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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.
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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
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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
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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.
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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
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Contraindications:
Known hypersensitivity
Pre-existing optic neuritis from any cause
Creatinine clearance
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Untoward effects:
optic neuritis, resulting in decreased visual
acuity and redgreen color blindness-
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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.
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PyrazinamideSynthetic pyrazineanalogue of nicitinamideWeakly tuberculocidal
Highly active in acidic medium(it is active onlyat a pH of
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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
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metabolites include pyrazinoic acid, 5-hydroxypyrazinamide, and 5hydroxypyrazinoic acid
not available in a parenteral formulation
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Dosage:
For 1st 2 or 3 months-25mg/kg daily,35mg/kg 3times weekly ,50mg/kg 2 times weekly
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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
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Rash,fever , loss of diabetes control
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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
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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
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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
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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
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Contraindications:
Known hypersensitivity
Auditory nerve impairment
Myasthenia gravis
Pregnancy
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perioral paresthesia, eosinophilia, rash,and drug fever
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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
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Other uses:
SABE along with penicillin
Plague
Tularemia-drug of choice
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