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Chemotherapy of Tuberculosis

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Chemotherapy of Tuberculosis Medically important mycobacteria Mycobacterium Tuberculosis A typical Mycobacterium Mycobacterium Leprae – PowerPoint PPT presentation

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Title: Chemotherapy of Tuberculosis


1
Chemotherapy of Tuberculosis
  • Medically important mycobacteria
  • Mycobacterium Tuberculosis
  • A typical Mycobacterium
  • Mycobacterium Leprae

2
Tuberculosis
  • Common sites of infections
  • Apical areas of lung
  • Renal parenchyma
  • Growing ends of bones
  • Where oxygen tension is high

3
Transmission
  • Through air ( air borne transmission )
  • Active tuberculosis kill about two of every
    three people if left untreated .

4
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.

5
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

6
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

7
Antimycobacterial drugs
  • First line of drugs
  • Isoniazid (INH)
  • Rifampin
  • Ethambutol
  • Streptomycin
  • Pyrazinamide

8
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 .

9
Continue
  • For latent tuberculosis , the standard treatment
    is six to nine months of isoniazid alone.

10
Isoniazid
  • Bacteriostatic for resting bacilli.
  • Bactericidal for rapidly dividing bacilli.
  • Is effective against intracellular as well as
    extracellular bacilli

11
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.

12
Pharmacokinetics
  • Readily absorbed when given either orally or
    parenterally.
  • Aluminum containing antacids interfere with
    absorption.

13
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.

14
Metabolism Excretion
  • Metabolized in the liver by acetylation .
  • Excreted in urine mainly as metabolites.

15
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.

16
Adverse effects
  • Peripheral neuritis
  • Optic neuritis atrophy.
  • Allergic reactions ( fever,skin rash,systemic
    lupus erythematosus )
  • Hepatitis

17
Adverse effects (cont.)
  • Hematological reactions
  • Gastrointestinal upset
  • Arthritic symptoms

18
Adverse effects (cont.)
  • CNS toxicity include
  • Lack of mental concentration , memory loss.
  • Excitability seizures
  • Psychosis
  • ( Respond to pyridoxine)

19
Drug Interactions of INH
  • Inhibits the hepatic microsomal enzymes,
    cytochrome P450 decrease metabolism of other
    drugs ( especially , Phenytoin )and increase
    their toxicity .

20
Rifampin
  • Bactericidal
  • Inhibits RNA synthesis-by inhibiting bacterial
    DNA- dependent RNA polymerase enzyme.

21
Site of Action
  • Intracellular bacilli
  • Extracellular bacilli
  • Bacilli in caseous lesions

22
Pharmacokinetics
  • Well absorbed orally.
  • Aminosalicylic acid delay the absorption of
    rifampin, (They should be given separately at an
    interval of 8-12 hour ).

23
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.

24
Distribution
  • Distributed throughout the body organs fluids .
    Adequate CSF concentration is achieved in
    meningeal inflammation.

25
Clinical uses
  • Mycobacterial infections
  • Prophylaxis of active tuberculosis.
  • Treatment of deep seated staphylococcal
    infections .
  • Prophylactic agent following exposure to
    Neisseria meningitids H .influenzae

26
Adverse effects
  • Harmless red-orange discoloration of body
    secretions( urine, sweat, tears) contact lenses
    ( soft lenses may be permanently stained ).
  • Skin rash
  • Fever

27
Adverse Effects ( cont.)
  • Nausea vomiting
  • Hepatitis, cholestatic jaundice
  • Flu-like syndrome
  • Hemolytic anemia, thrombocytopenia acute
    tubular necrosis.

28
Drug Interactions
  • Potent inducer of hepatic microsomal enzymes (
    cytochrome P450)
  • Increase elimination of other drugs including
  • Anticoagulants
  • Anticonvulsants
  • Contraceptives

29
Ethambutol
  • Bacteriostatic
  • Inhibits mycobacterial arabinosyl transferase (
    inhibits polymerization of arabinoglycan an
    essential component of mycobacterial cell wall )

30
Site Of Action
  • Intracellular Extracellular bacilli

31
Phrmacokinetics
  • Well absorbed orally
  • Half-life 3-4 hours
  • 75 of the drug is excreted unchanged in the
    urine, 15 as metabolities.

32
Clinical uses
  • In combination therapy for
  • Ttreatment of tuberculosis
  • Mycobactrium avium complex
  • in patients with or without
    HIV

33
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

34
Pyrazinamide
  • Prodrug( converted to pyrazinoic acid ,the active
    form .
  • Bacteriostatic
  • Mechanism unknown
  • May act through inhibition of mycobacterial
    fatty acid synthase I gene

35
Site Of Action
  • More active at an acidic pH ( within
    macrophages ) and active against Intracellular
    Bacilli

36
Phrmacokinetics
  • Well absorbed from GIT
  • Widely distributed including CSF
  • Half-life 9-10 hours
  • Excreted primarily by renal route.

37
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.

38
Adverse effects
  • Hepatotoxicity
  • Hyperuricemia( provoke acute gouty arthritis )
  • Nausea vomiting
  • Drug fever skin rash

39
Streptomycin Amikacin
  • Bactericidal
  • Inhibitors of protein synthesis by biding to 30 S
    ribosomal subunits.
  • Active mainly on extracellular bacilli

40
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.

41
Adverse Effects
  • Ototoxicity
  • Nephrotoxicity
  • Neuromuscular block

42
Contraindications
  • Myasthenia gravis
  • Pregnancy

43
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.

44
Ethionamide
  • Blocks synthesis of mycolic acid .
  • Prodrug
  • Is converted to active form (sulfoxide ).

45
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

46
Clinical uses
  • Is a secondary agent , to be used concurrently
    with other drugs when therapy with primary agents
    is ineffective or contraindicated.

47
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
    ).

48
Adverse Effects (cont.)
  • Neurological adverse effects relieved by
  • pyridoxine ( vit.B6 ) .
  • Hypotension
  • Alopecia
  • Metallic taste

49
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.

50
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.

51
Amikacin
  • Used as alternative to streptomycin.
  • Used in multidrug- resistance tuberculosis.
  • No cross resistance between streptomycin and
    amikacin.

52
Ciprofloxacin levofloxacin
  • Effective against typical and atypical
    mycobacteria.
  • Used against multidrug- resistant tuberculosis.
  • Used in combination with other drugs.

53
Rifabutin
  • As rifampin , it is RNA polymerase inhibitor.
  • Cross resistance with rifampin
  • Enzyme inducer of cytochrome p450.
  • Effective against typical and atypical
    mycobacteria.

54
Phrmacokinetics
  • Absorbed from GIT
  • Excreted in urine bile
  • Adjustment of dosage is not necessary in patients
    with impaired renal function.

55
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

56
Adverse Effects
  • Skin rash
  • GIT intolerance
  • Neutropenia
  • Orange-red discoloration ( skin, urine, -----as
    rifampin ).

57
Drug Interactions
  • Enzyme inducer of cytochrome P450 enzymes (Less
    potent than rifampin ).

58
Aminosalicylic Acid (PAS).
  • Similar in structure to sulfonamide and
    p-aminobenzoic acid.
  • Bacteriostatic
  • Folate synthesis inhibitor.

59
Pharmacokinetics
  • Well absorbed from GIT
  • Best given after meals
  • High concentration in pleural fluid caseous
    tissues.
  • Excreted mainly in urine as metabolites.

60
Clinical uses
  • Treatment of pulmonary other forms of
    tuberculosis.

61
Adverse effects
  • GIT upset
  • Hypersensitivity reactions
  • Hematological troubles
  • Crystalluria

62
Third line
  • Arginine
  • Vitamin D
  • Thioridazine
  • Macrolides as clarithromycin
  • Corticosteroids is proven for TB meningitis and
    pericarditis

63
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

64
TB Breast Feeding
  • It is not a contraindication to receive drugs ,
    but caution is recommended

65
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 )

66
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67
Transmission
  • Respiratory route

68
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.

69
Clinical uses
  • Tuberculoid leprosy.
  • Lepromatous leprosy in combination with rifampin
    clofazimine.
  • To prevent treat Pneumocystis jiroveci
    pneumonia in AIDS .

70
Adverse effects
  • Haemolytic anaemia
  • Methemoglobinemia
  • Gastrointestinal intolerance
  • Fever,pruritus,rashes.
  • Erythema nodosum leprosum
  • Peripheral neuropathy

71
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).

72
Clinical uses
  • Multidrug resistance TB.
  • Lepromatous leprosy
  • Tuberculoid leprosy in
  • patients intolerant to sulfones
  • dapsone-resistant bacilli.
  • Chronic skin ulcers caused by M.ulcerans.

73
Adverse effects
  • Skin discoloration ranging from red-brown to
    black.
  • Gastrointestinal intolerance.
  • Red colour urine.
  • Eosinophilic enteritis
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