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Anti-tuberculosis therapy, isoniazid, Other important points of isoniazid:…
Anti-tuberculosis therapy
isoniazid
It is a prodrug activated by catalase-peroxidase coded by KatG.
Active metabolite inhibits the enzyme ketoenoylreductase coded by inhA required for mycolic acid synthesis,
an essential component of mycobacterial cell wall.
It acts by O2 dependent pathway such as catalase peroxidase reaction.
It is the single most important drug used in tuberculosis.
Mycobacterial strains are assumed to be susceptible to isoniazid, if the resistance is less than 4%.
It is bacteriostatic against resting and bactericidal against rapidly multiplying organism.it is effective against intra-as well as extracellular mycobacteria.
Other important points of isoniazid:
Action is most marked against rapidly multiplying bacilli but less effective against slow multipliers.
It is widely distributed in the body including CSF.
It is effective orally and metabolized by acetylation which is genetically controlled.
Fast acetylators requires high dose and slow acetylators are predisposed to toxicity particularly peripheral neuritis.
It is an essential component of multidrug therapy of tuberculosis and is a drug of choice used solely for prophylaxis of tuberculosis
and also for treatment of latent tuberculosis infections.
Rifampicin
It is a derivative of rifamycin(other derivatives are rifabutin and rifapentine).
It is bactericidal against both dividing and non-dividing mycobacterium
and acts by inhibiting DNA dependent RNA polymerase.
It undergoes enterohepatic circulation and is partly metabolized in the liver.
Metabolites are coloured and can cause orange discolouration of urine and secretions.
It is eliminated mainly in feces. And can be used safely in renal dysfunction.
Food interferes with absorption of rifampicin, therefore it must be given in empty stomach.
It penetrates all membranes including blood brain and placental barrier.
Rifampicin - An enzyme inducer!
Rifampicin is an inducer of drug metabolizing enzymes
and enhances the metabolism of many drugs like
anticonvulsants, oral contraceptives, oral anticoagulants, antiretroviral drugs.
The female on oral contraceptives should either increase the dose of the pill
or use an alternative method of contraception,
when using rifampicin as a component of anti-tubercular treatment.
Patient on warfarin therapy should be shifted to
unfractioned heparin or low molecular weight
heparin if rifampicin is being used for the treatment of tuberculosis.
The drugs for tuberculosis
It is caused by mycobacterium tuberculosis. The drugs for tuberculosis are
First line :
Essential : isoniazid H, rifampicin R, pyrazinamide Z and ethambutol E.
Supplementary: streptomycin S, rifabutin and rifapentine
Second line drugs: thiacetazone, paraaminosalicyclic acid, ethionamide, cycloserine, kanamycin, capreomycin, amikacin, ofloxacin, levofloxacin, moxifloxacin, linezolid and clarithromycin
ADRs of Isoniazid
It causes peripheral neuritis that can be prevented and treated by pyridoxine.
It is also hepatotoxic and can cause hemolysis in G6PD deficient patients.
Incidence of hepatotoxicity increases with age, daily alcohol consumption and in post partum 3 months period.
Isoniazid also inhibits MAO-A that can result in cheese reaction.
Rash, fever, anemia, optic atrophy, seizures, lupus like syndrome, psychosis and gynaecomastia has also been reported with this drug.
ADRs of Rifampicin
Rifampicin can cause light chain proteinuria and may impair antibody responses.
It is also hepatotoxic and may cause skin rash,
flu like syndrome(more prominent with intermittent regimen) and anemia.
Hepatotoxicity due to rifampicin is uncommon without pre-existing liver disease.
It presents as hyperbilirubinemia without SGPT elevations.
Important toxicity of ethambutol
Ethambutol causes dose dependent and reversible visual disturbances like optic neuritis presents as
reduced visual acuity, central scotoma and
loss of ability to see green, less commonly red.
It may be due to its effect on amacrine and bipolar cells of retina.
Because children are unable to report early visual impairment, the drug is contraindicated in children.
It also causes hyperuricemia and peripheral neuritis.
It requires dose adjustment in renal failure.
Pyrazinamide(Z)
this is a weakly bactericidal drug but more active against slowly replicating bacteria
than rapidly multiplying and in the acidic media(intracellular sites and at the sites of inflammation).
It is effective only against intracellular mycobacteria.
Its mechanism seems to be similar to isoniazid
but the exact site not known.
Half life of this is prolonged in hepatic as well as renal impairment.
Streptomycin:
this is tuberculocidal aminoglycoside.
it is not absorbed orally and must be administered by IM injection.
it is poorly plasma protein bound.
Its half life is prolonged in renal failure.
It is active only against extracellular bateria.
It is not hepatotoxic.
Other features are similar to aminoglycosides.
Rifabutin vs Rifampicin
Rifabutin is more effective than rifampicin against MAC.
It has longer t1/2 -45 hrs as compared to rifampicin 3-5 hours.
Clarithromycin and fluconazole inhibit its hepatic metabolism and increase t1/2.
it has less potential to induce microsomal enzymes
and thus preferred in patients on anti-HIV drugs(protease inhibitors or NNRIs mainly nevirapine.
Rifabutin commonly causes gastrointestinal adverse effects.
Rarely it can cause anterior uveitis, hepatitis,
clostridium difficle associated diarrhea, diffuse polymyalgia syndrome,
yellow skin discolouration(pseudo-jaundice) and
pancytopenia.
Unlike rifampicin it doesn’t require dose adjustment in liver disease.
Treatment for MDR-TB
BPaLM regimen – a novel treatment for Multi-
Drug-Resistant Tuberculosis (MDR-TB) under its
National TB Elimination Program (NTEP)
as a highly effective and shorter treatment option.
This regimen includes a new anti-TB drug namely
Pretomanid in combination with Bedaquiline &
Linezolid (with/without Moxifloxacin).
BPaLM regimen can cure the drug-resistant TB in just six months with high treatment success rate.
Treatment for Atypical mycobacterial infections:
Clarithromycin or azithromycin is recommended for prophylaxis of mycobacterium avium complex(MAC) in patients with CD4 count less than 50Ul.
Treatment of MAC requires REC regimen(rifabutin + ethambutol + clarithromycin/azithromycin).
Due to its long t1/2 azithromycin can be used once weekly dose in place of once daily dose of clarithromycin for prophylaxis of MAC.
Other drugs effective against atypical mycobacteria are quinolones like ciprofloxacin, levofloxacin, moxifloxacin and gatifloxacin and amikacin.
Dapsone:
it is a leprostatic drug related to sulfonamide with similar mechanism of action.
It is metabolized by acetylation and undergoes enterohepatic circulation.
It can cause GI irritation, fever, skin rash, methemoglobinemia and hemolysis in G-6-PD deficiency patients.
Hemolytic anemia is the most common adverse effect of dapsone.
It can also cause sulfone DDS syndrome that is called infectious mononucleosis like syndrome.
Dapsone is also an alternative drug for the treatment of pneumocystitis jiroveci infections in AIDS patient.
It is the drug of choice for dermatitis herpetiformis.
Mycobacterium
Mycobacterium causes tuberculosis and leprosy.
Several atypical mycobacteria may also cause infection in humans especially in the immunocompromised patients
Resistance of isoniazid
Resistance occurs due to mutation in Kat G(gene for catalase-peroxidase) or inhA.
Mutation in katG is responsible for high level resistance
whereas mutation in inhA confers cross resistance to ethionamide.
effective against intra- and extra cellular bacilli
It is equally effective against intra- and extra cellular bacilli.
It is the only bactericidal drug active against dormant bacteria in solid caseous lesions.
Other indications of Rifampicin
Apart from tuberculosis, it is also used in leprosy to delay resistance to dapsone.
It is the most effective and fastest acting drug in leprosy.
It can also be used as prophylactic drug for meningococcal and staphylococcal carrier states.
Rifabutin
Rifabutin has little chances of drug interactions and is equally effective
so it is used in the treatment of tuberculosis in AIDS patient getting antiretroviral drugs.
PAS and Rifampicin
PAS delays absorption, therefore concomitant administration should be avoided.
Rifampicin excretion
Rifampicin is secreted in bile so doesn’t require dose adjustment in renal failure.
Treatment and prophylaxis of meningococcal meningitis
While penicillin is DOC for treatment of meningococcal meningitis,
it is not indicated for prophylaxis where rifampicin or ceftriaxone is DOC
because only rifampicin and 3rd generation cephalosporins can eliminate nasal carriers
least toxic anti-tubercular drug
Rifampicin is the least toxic anti-tubercular drug and is also the safest drug in pregnancy.
Ethambutol
It is bacteriostatic agent for mycobacterium and
acts by inhibiting the synthesis of
arabinogalactan(a component of cell wall)
due to inhibition of arabinosyl transferase.
It is distributed through out the body except in the CSF.
ADRs of Pyrazinamide
In 40% of the patients it causes non-gouty athralgia.
Hyperuricemia also occurs commonly but is usually asymptomatic
and it should not be stopped if hyperuricemia develops.
It can also hepatic dysfunction, porphyria and photosensitivity.
Other aminoglycosides used for the treatment of tuberculosis
Other aminoglycosides used for the treatment of tuberculosis are amikacin, kanamycin and capreomycin.
Streptomycin is contraindicated in pregnancy.
Ethambutol and streptomycin
Ethambutol and streptomycin are not hepatotoxic.
Thiacetazone
is a tuberculostatic drug.
Major adverse effects include hepatitis, bone
marrow suppression and steven johnson
syndrome(not used in HIV positive patients due to risk of severe hypersensitivity reactions including exofoliative dermatitis).
It is not used in intermittent regimen.
MOA: thought to interefere with mycolic acid synthesis.
Paraaminosalicylic acid(PAS)
Paraaminosalicylic acid(PAS) is related to sulphonamides, acts by similar mechanism and is bacteriostatic.
It can cause liver, kidney and thyroid dysfunction.
Ethionamide
Ethionamide is another tuberculostatic drug that can cause hepatitis, optic neuritis and hypothyroidism.
It can also be used in leprosy.
It has mechanism similar to INH and bacteria resistant to INH are cross resistant to ethionamide also.
Cycloserine
Cycloserine is a cell wall synthesis inhibiting drug and can cause neuropsyschiatric adverse effects.
Kanamycin and amikacin
Kanamycin and amikacin are injectable aminoglycosides which can be used in the treatment of MDR tuberculosis
Capreomycin
Capreomycin is an injectable polypeptide.
It an cause ototoxicity, nephrotoxicity, hypokalemia and hypomagnesemia.
Fluoroquinolones in TB
Fluoroquinolones used for this indication include ofloxacin, moxifloxacin and levofloxacin.
These are also effective against mycobacterium avium complex in AIDS patient.
Rifapentine
Rifapentine is similar to rifampicin but is more lipophilic and longer acting.
It is not approved for administration to patients with HIV disease because of higher rates of relapse.
Its absorption increases with meals.
Bedaquiline
Bedaquiline is an inhibitor of mycobacterial ATP synthase.
It is indicated as part of MDT in adults with pulmonary MDR-TB.
It can cause QT prolongation.
Rifaximin
Rifaximin is a rifampicin derivative indicated for travellers diarrhea E.coli and hepatic encephalopathy.
CNS penetration
H and Z have maximum CNS penetration whereas E and S donot cross BBB.
R has moderate CNS entry.
Definition of MDR and XDR Tuberculosis
MDR tuberculosis is defined as resistance to minimum H and R,
whereas XDR tuberculosis is defined as resistance to H and R, all fluoroquinolones and atleast one injectable agent.
Treatment for TB
New case or old case:
IP: 2HRZE – 7days/week
CP: 4HRE- 7 days/ week
Duration – 6 months
Treatment regimen for XDR TB
New treatment regimen for XDR TB BPaL regimen:
Bedaquiline, pretomanid, linezolid
just for 6 months(drastic reduction from 18-24 months old treatment plan)
Treatment for leprosy
The drugs used for the treatment of leprosy include rifampicin, dapsone, clofazimine, ethionamide, ofloxacin, minocycline and clarithromycin.
Clofazimine:
it is a dye with leprostatic and anti-inflammatory activity.
It interferes with template function of DNA.
It can cause gastrointestinal irritation, icthyosis of skin and discolouration of skin and secretions.
Due to its anti-inflammatory action it can be used for lepra reaction.
Rifampicin in Leprosy
it is the bactericidal drug and most effective drug used in leprosy.
It prevents the development of resistance to dapsone.
Other drugs used in Leprosy
ethionamide has antileprotic action but causes hepatotoxicity in 10 percent patient.
Ofloxacin, pefloxacin and sparfloxacin are effective but not ciprofloxacin.
Minocycline and clarithromycin can also be used in leprosy.
Treatment regimen for multibacillary leprosy
For the treatment of multibacillary:
Rifampicin 600mg once monthly supervised
Clofazimine 300 mg once monthly supervised.
Dapsone 100mg OD X 12 months
Clofazimine 50mg OD X 12 months
Treatment regimen for Paucibacillary leprosy
For the treatment of paucibacillary:
Rifampicin 600mg once monthly supervised
Clofazimine 300 mg once monthly supervised.
Dapsone 100mg OD X 6 months
Clofazimine 50mg OD X 6 months
Treatment for lepra reaction
DOC for type 1 and type 2 lepra reaction is corticosteroids
Other drugs used in type 2 lepra reaction
Clofazimine
Thalidomide
Chloroquine
Colchicine
Other drugs used in tuberculosis