Chemotherapy of Tuberculosis

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Chemotherapy of Tuberculosis

• Medically important mycobacteria
• Mycobacterium Tuberculosis
• A typical Mycobacterium
• Mycobacterium Leprae

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Tuberculosis

• Common sites of infections
• Apical areas of lung
• Renal parenchyma
• Growing ends of bones
• Where oxygen tension is high

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Transmission

• Through air ( air borne transmission )
• Active tuberculosis kill about two of every
  three people if left untreated .

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Latent tuberculosis

• The inhaled bacilli are taken into alveolar
  macrophages and remain viable multiplying
  within the cells for extended period of time.
• The person is clinically asymptomatic
• Positive tuberculin test is the only indication
• Individuals with latent TB are not infectious
  can not transmit organisms.

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Active tuberculosis

• The goals for the treatment
• - Cure the individual patient
• - Minimize the transmission of TB to others
• -Kill the tubercle bacilli
• - Prevent drug resistance

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Treatment Of Tuberculosis

• Tuberculosis remains the primary cause of death
  due to infectious disease.
• Periods of treatment ( minimum 6 months)
• Drugs are divided into
• First line Second line
• Third line

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Antimycobacterial drugs

• First line of drugs
• Isoniazid (INH)
• Rifampin
• Ethambutol
• Streptomycin
• Pyrazinamide

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Never use a single drug therapy

• The standard short course treatment for TB is
  isoniazid , rifampin , pyrazinamide , and
  ethambutol for two months, then isoniazid and
  rifampin alone for a further four months .

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Continue

• For latent tuberculosis , the standard treatment
  is six to nine months of isoniazid alone.

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Isoniazid

• Bacteriostatic for resting bacilli.
• Bactericidal for rapidly dividing bacilli.
• Is effective against intracellular as well as
  extracellular bacilli

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Mechanism Of Action

• Is a prodrug, activated by mycobacterial catalase
  -peroxidase
• Cell wall synthesis inhibitor
• Inhibits synthesis of mycolic acids----
• Which are essential components of
• Mycobacterial cell walls.

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Pharmacokinetics

• Readily absorbed when given either orally or
  parenterally.
• Aluminum containing antacids interfere with
  absorption.

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Distribution

• Diffuse rapidly into all body fluids and cells.
• Highly concentrated in pleural fluids.
• Its concentration in CSF is significant in
  inflammed meninges.
• Penetrates well into caseous material.

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Metabolism Excretion

• Metabolized in the liver by acetylation .
• Excreted in urine mainly as metabolites.

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Clinical uses

• Mycobacterial infections (it is recommended to be
  given with pyridoxine to avoid neuropathy).
• Latent tuberculosis
• Prophylaxis against active TB in individuals who
  are in great risk as very young or
  immunocompromised individuals.

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Adverse effects

• Peripheral neuritis
• Optic neuritis atrophy.
• Allergic reactions ( fever,skin rash,systemic
  lupus erythematosus )
• Hepatitis

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Adverse effects (cont.)

• Hematological reactions
• Gastrointestinal upset
• Arthritic symptoms

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Adverse effects (cont.)

• CNS toxicity include
• Lack of mental concentration , memory loss.
• Excitability seizures
• Psychosis
• ( Respond to pyridoxine)

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Drug Interactions of INH

• Inhibits the hepatic microsomal enzymes,
  cytochrome P450 decrease metabolism of other
  drugs ( especially , Phenytoin )and increase
  their toxicity .

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Rifampin

• Bactericidal
• Inhibits RNA synthesis-by inhibiting bacterial
  DNA- dependent RNA polymerase enzyme.

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Site of Action

• Intracellular bacilli
• Extracellular bacilli
• Bacilli in caseous lesions

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Pharmacokinetics

• Well absorbed orally.
• Aminosalicylic acid delay the absorption of
  rifampin, (They should be given separately at an
  interval of 8-12 hour ).

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Metabolism Excretion

• Metabolized in liver by acetylation enters
  enterohepatic circulation.
• Half-life 1.5-5 hours increased in hepatic
  dysfunction.
• Eliminated in bile feces( 60-65 ) 30 in
  urine.

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Distribution

• Distributed throughout the body organs fluids .
  Adequate CSF concentration is achieved in
  meningeal inflammation.

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Clinical uses

• Mycobacterial infections
• Prophylaxis of active tuberculosis.
• Treatment of deep seated staphylococcal
  infections .
• Prophylactic agent following exposure to
  Neisseria meningitids H .influenzae

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Adverse effects

• Harmless red-orange discoloration of body
  secretions( urine, sweat, tears) contact lenses
  ( soft lenses may be permanently stained ).
• Skin rash
• Fever

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Adverse Effects ( cont.)

• Nausea vomiting
• Hepatitis, cholestatic jaundice
• Flu-like syndrome
• Hemolytic anemia, thrombocytopenia acute
  tubular necrosis.

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Drug Interactions

• Potent inducer of hepatic microsomal enzymes (
  cytochrome P450)
• Increase elimination of other drugs including
• Anticoagulants
• Anticonvulsants
• Contraceptives

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Ethambutol

• Bacteriostatic
• Inhibits mycobacterial arabinosyl transferase (
  inhibits polymerization of arabinoglycan an
  essential component of mycobacterial cell wall )

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Site Of Action

• Intracellular Extracellular bacilli

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Phrmacokinetics

• Well absorbed orally
• Half-life 3-4 hours
• 75 of the drug is excreted unchanged in the
  urine, 15 as metabolities.

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Clinical uses

• In combination therapy for
• Ttreatment of tuberculosis
• Mycobactrium avium complex
• in patients with or without
  HIV

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Adverse effects

• Retrobulbar (optic) neuritis causing loss of
  visual acuity and red-green color blindness.
• Relatively contraindicated in children( under 5
  years).
• GIT .upset .
• Hyperuricemia

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Pyrazinamide

• Prodrug( converted to pyrazinoic acid ,the active
  form .
• Bacteriostatic
• Mechanism unknown
• May act through inhibition of mycobacterial
  fatty acid synthase I gene

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Site Of Action

• More active at an acidic pH ( within
  macrophages ) and active against Intracellular
  Bacilli

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Phrmacokinetics

• Well absorbed from GIT
• Widely distributed including CSF
• Half-life 9-10 hours
• Excreted primarily by renal route.

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Clinical uses

• Mycobacterial infections mainly in multidrug
  resistance cases.
• It is important in short course (6 months)
  regimens with isoniazid and rifampin.
• Prophylaxis of TB in combination with
  ciprofloxacin.

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Adverse effects

• Hepatotoxicity
• Hyperuricemia( provoke acute gouty arthritis )
• Nausea vomiting
• Drug fever skin rash

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Streptomycin Amikacin

• Bactericidal
• Inhibitors of protein synthesis by biding to 30 S
  ribosomal subunits.
• Active mainly on extracellular bacilli

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Clinical uses

• Severe , life-threating form of T.B. as
  meningitis, disseminated disease, infections
  resistant to other drugs( Multidrug resistance
  tuberculosis).
• In aerobic gram ve bacterial infections.

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Adverse Effects

• Ototoxicity
• Nephrotoxicity
• Neuromuscular block

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Contraindications

• Myasthenia gravis
• Pregnancy

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Indication of 2nd line treatment

• Resistance to the drugs of 1st line.
• Failure of clinical response
• There is contraindication for first line drugs.
• Patient is not tolerating the drugs first line
  drugs.

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Ethionamide

• Blocks synthesis of mycolic acid .
• Prodrug
• Is converted to active form (sulfoxide ).

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Pharmacokinetics

• Absorbed from GIT, Given only orally
• Rapidly widely distributed
• Half-life 2 hours
• Metabolized in liver, less than 1 is excreted in
  active form in urine
• Inhibits the acetylation of INH

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Clinical uses

• Is a secondary agent , to be used concurrently
  with other drugs when therapy with primary agents
  is ineffective or contraindicated.

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Adverse Effects

• Anorexia, nausea, vomiting, intense gastric
  irritation.
• Poorly tolerated (About 50 of patients are
  unable to tolerate a single dose more than 500 mg
  ).

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Adverse Effects (cont.)

• Neurological adverse effects relieved by
• pyridoxine ( vit.B6 ) .
• Hypotension
• Alopecia
• Metallic taste

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Capreomycin

• Aminoglycosides
• It is an important injectable agent for treatment
  of drug-resistant tuberculosis.
• It is nephrotoxic and ototoxic.
• Local pain sterile abscesses may occur.

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Cycloserine

• Inhibitor of cell wall synthesis
• Cleared renally
• The most serious side effects are peripheral
  neuropathy and CNS side effects.
• Pyridoxine should be given.
• Contraindicated in epileptic patients.

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Amikacin

• Used as alternative to streptomycin.
• Used in multidrug- resistance tuberculosis.
• No cross resistance between streptomycin and
  amikacin.

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Ciprofloxacin levofloxacin

• Effective against typical and atypical
  mycobacteria.
• Used against multidrug- resistant tuberculosis.
• Used in combination with other drugs.

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Rifabutin

• As rifampin , it is RNA polymerase inhibitor.
• Cross resistance with rifampin
• Enzyme inducer of cytochrome p450.
• Effective against typical and atypical
  mycobacteria.

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Phrmacokinetics

• Absorbed from GIT
• Excreted in urine bile
• Adjustment of dosage is not necessary in patients
  with impaired renal function.

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Clinical uses

• Treatment of T.B. in HIV- infected patients (
  received concurrent antiretroviral therapy)
• Prevention of tuberculosis
• Prevention treatment of disseminated atypical
  mycobacterial infections in AIDS patients

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Adverse Effects

• Skin rash
• GIT intolerance
• Neutropenia
• Orange-red discoloration ( skin, urine, -----as
  rifampin ).

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Drug Interactions

• Enzyme inducer of cytochrome P450 enzymes (Less
  potent than rifampin ).

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Aminosalicylic Acid (PAS).

• Similar in structure to sulfonamide and
  p-aminobenzoic acid.
• Bacteriostatic
• Folate synthesis inhibitor.

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Pharmacokinetics

• Well absorbed from GIT
• Best given after meals
• High concentration in pleural fluid caseous
  tissues.
• Excreted mainly in urine as metabolites.

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Clinical uses

• Treatment of pulmonary other forms of
  tuberculosis.

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Adverse effects

• GIT upset
• Hypersensitivity reactions
• Hematological troubles
• Crystalluria

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Third line

• Arginine
• Vitamin D
• Thioridazine
• Macrolides as clarithromycin
• Corticosteroids is proven for TB meningitis and
  pericarditis

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TB Pregnancy

• Untreated TB represents a far greater risk to a
  pregnant woman and her fetus than treatment.
• Rifampin makes hormonal contraception less
  effective , so additional precautions to be
  taken for birth control .
• Streptomycin is used as a last alternative

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TB Breast Feeding

• It is not a contraindication to receive drugs ,
  but caution is recommended

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Leprosy ( Hansen, s disease)

• Deforming disease caused by Mycobactrium leprae.
• Affect cooler areas of the body in humans ( skin
  , nerve segments near to skin , mucous membranes
  of the upper respiratory tract )

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Transmission

• Respiratory route

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Drugs used in leprosyDapsone

• 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.

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Clinical uses

• Tuberculoid leprosy.
• Lepromatous leprosy in combination with rifampin
  clofazimine.
• To prevent treat Pneumocystis jiroveci
  pneumonia in AIDS .

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Adverse effects

• Haemolytic anaemia
• Methemoglobinemia
• Gastrointestinal intolerance
• Fever,pruritus,rashes.
• Erythema nodosum leprosum
• Peripheral neuropathy

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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).

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Clinical uses

• Multidrug resistance TB.
• Lepromatous leprosy
• Tuberculoid leprosy in
• patients intolerant to sulfones
• dapsone-resistant bacilli.
• Chronic skin ulcers caused by M.ulcerans.

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Adverse effects

• Skin discoloration ranging from red-brown to
  black.
• Gastrointestinal intolerance.
• Red colour urine.
• Eosinophilic enteritis