Download Tuberculosis Chemotherapy

• TUBERCULOSIS is an infectious disease caused by Mycobacteria;
Mycobacterium tuberculosis & Mycobacterium bovis.
MODE OF TRANSMISSION
Inhalation of droplets
Ingestion --self swallowing of infected sputum/ or ingestion of
unpasteurised milk of infected cow
Inoculation – of organism in to skin may occur rarely from infected
postmortem tissue.
Transplacental – ie tuberculosis of foetus from mother.
• Major portion of tubercle bacilli become intracellular(i.e
reside in macrophage),so it is inaccessible for majority of
antibiotics as they cannot penetrate easily in to the
macrophage.
• It was once considered to be an incurable disease but now
it is curable by a number of chemotherapeutic agents.
Macrophage
with tubercle
bacilli
Classification of anti TB drugs
1st Line Essential
drugs
EgRIFAMPICIN
ISONIAZID
PYRIZINAMIDE
ETHAMBUTOL
(RIPE)
1st Line
supplemental
drugs
EgRifabutin
Rifapentin
streptomycin
2nd Line drugs
EgFluroquinolones
Amikacin
Capreomycin
Ethionamide
p-Aminosalicylic
acid
Cycloserine
(FACEPaC)
• 1st line essential drugs– most effective & basic components of anti
tubercular treatment.
• 1st linesupplemental drugs– are quite effective & posseses an
acceptable limit of toxicity. These are kept as reserved drugs & used in
special settings.
• 2nd line drugs—these drugs are used if there is resistance to 1st line
drugs or if 1st line drugs are contraindicated for some reason. These
drugs are less effective & slightly more toxic than Ist line drugs(except
Fluoroquinolones)
•
Individual drugs.
Isonicotinic acid hydrazide
• INH is a pro drug & is converted into active form by bacterial enzyme
catalase peroxidase.
• SITE OF ACTION– Both intracellular & extracellular ; also in casseous
lesions.
MECHANISM OF ACTION
INH is converted to active form by catalase
peroxidase (produced by mycobacterium) .
The active form inhibits mycolic acid in outer layer
of cell wall.
Also inhibits DNA, RNA & various oxidative
enzymes.
It is equally active in acidic & alkaline medium
Mycobaterium cell wall has the following layers viz. – mycosides,
mycolic acid, arabinoglycan, peptidoglycan.INH inhibits mycolic acid synthesis while
INH
ethambutol inhibit
arabinoglycan layer
MYCOLIC
ACID
SYNTHESIS
INHIBITED
(PRODRUG)
ARABINOGLYCAN
PEPTIDOGLYCAN
CELL MEMBRANE
Catalase peroxidase
INH
(ACTIVE)
MECHANISM OF RESISTANCE
• Resistance to INH is due to mutation in CATALASE – PEROXIDASE
GENE which is responsible for activation of INH.
ADR
• Allergic reactions: Fever,Skin rashes.
• Hepatotoxicity : Increase level of serum enzymes.
RIFAMPICIN is a semisynthetic derivative of macrocyclic antibiotic
Rifamycin.
Mechanism of action of Rifampicin
Rifampicin inhibits bacterial DNA DEPENDENT RNA POLYMERASE.
Mammalian RNA polymerase is not inhibited , so RNA synthesis of host
cells is not affected
MECHANISM OF RESISTANCE
Resistance develops mutation in rpo B gene which prevents binding of
rifampicin to RNA polymerase.
Hence if used alone resistance develops rapidly. It is a potent enzyme
inducer
Pharmacokinetics
Absorption--well absorbed after oral administration
Distribution – it penetrates in all tissues , tubercular cavities, placenta.
Adequate CSF levels are reached if meninges are inflammed.
It is significantly protein bound.
• Excretion – drug is excreted via bile & undergoes entero
hepatic circulation.
ADVERSE EFFECTS
• HEPATITIS is major side effect. It is dose dependent &
reversible. It is common in patients with underlying liver
disease. Risk of hepatitis increses when used in combination
with INH.
• Occasional side effects include FLU-LIKE SYNDROME
characterised by fever chills , myalgias & thrombocytopenia,
• Rifampicin imparts RED ORANGE COLOR TO URINE.
Ethambutol is a synthetic tuberculostatic drug
M.tuberculosis, M.kamsasii & M.avium intracellulare.
active
against
MECHNISM OF ACTION
ETHAMBUTOL inhibits polymerisation of arabinoglycans of cell wall by
inhibiting arabinosyl transferase
MYCOLIC ACIDS
ARABINOGLYCAN
PEPTIDOGLYCAN
CELL MEMBRANE
MECHANISM OF RESISTANCE
Resistance develops due to point mutations in emb B gene that encodes
arabinosyl transferases enzyme involved in mycobacterial cell wall
synthesis.
Pharmacokinetics
Bioavailability– 80%
Distribution– widely distributed in all body fluids including CSF
• Ethambutol should be avoided in in children
below 5 years where it is difficult to asses visual
activity & red – green color discrimination.
• Ethambutol decreases renal excretion of urates &
may precipitate gouty arthritis.
• Mild GIT intolerance , rashes, fever & dizziness
are also possible.
Streptomycin
• It is the first antitubercular drug.
• It is bactericidal but because of poor penetration it acts only on
extracellular tubercular bacilli.
• It is also active against M.kansasii & M.avium intracellulare.
• It is less effective than INH or Rifampicin
Pharmacokinetics
Route of administration– I.M , cant be given orally as it is highly polar
• Distribution – poorly distributed , do not penetrate most cellular
compartments.
• Metabolism -- as they do not penetrate most cellular compartments ,
they do not undergo significant metabolism.
• Excretion- nearly all of the drug is cleared by kidneys as they do not
undergo significant metabolism.
• Plasma half life– 1.5 – 3 hrs(24-48 hrs in renal insufficiency)
Mechanism of action
1.The mechanism of action of streptomycin is inhibition of protein
synthesis of mycobacteria in the ribosome.
2. Interfere with complex peptide formation.
3. Incorporation of incorrect amino acid into Peptide Resulting in Non
functional toxic Protein.
Adverse effects– nephrotoxicity & ototoxicity.
Amikacin
• It is an aminoglycoside antibiotic.
• It is 2nd choice after streptomycin & for multi drug resistant
tuberculosis.
• Most M.tuberculosis strains are that are resistant to streptomycin are
sensitive to amikacin.
• MOA- Bind to 30 s ribosomal subunit and bacterial ribosome block
protein synthesis. Responsible for growth inhibition.
• ADR- Neurotoxicity, Nephrotoxicity, Ototoxicity, Cross resistance
usually occur between Km and Am is very common.
MOA: Mechanism of Action:
Inhibition of topoisomerase (DNA gyrase) enzymes, which Resposible for
Nikking of DNA Stand and promotes breakage of double stranded DNA.
ADR: headache, insomnia, dizziness; hallucinations, depression.
Chemotherapy of Leprosy
• Leprosy is an infectious disease that causes severe, disfiguring skin
sores and nerve damage in the arms and legs
• Leprosy is caused by a slow-growing type of bacteria called
Mycobacterium leprae (M. leprae). Leprosy is also known as Hansen's
disease, after the scientist who discovered M. leprae in 1873.
• Skin Lesions that are lighter than your normal skin
color
• Lesions have decreased sensation to touch, heat,
or pain
• Lesions do not heal after several weeks to
months
• Muscle weakness
• Numbness or lack of feeling in the hands, arms,
feet, and legs
cLASSIFICATION
• Sulfone: Dapsone
• Phenazine Derivatives: Clofazimine
• Anti tubercular drugs: Rifampin
• Anti biotics : Minocycline (Tertracycline antibiotics)
Moa of DAPSONE
ADR
• Hemolytic anemia
• Gastric intolerance
• Headache, Mental symptoms
• Monotherapy cause Resistance in 1-3 yrs.
• Dapsone Resistant Respond to Clofazimine.
• ADR
• Reddish Black Discoloration
• Dryness of Skin
• Nausea, Vomiting, Abdominal pain.