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Chemotherapy of Tuberculosis
Medically important mycobacteriaMycobacterium TuberculosisA typical MycobacteriumMycobacterium Leprae
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Treatment Of Tuberculosis
Tuberculosis remains the primary cause of death due to infectious disease.
Organs involved --------- primarily lungsDrugs are divided into two groups:First lineSecond line
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Antimycobacterial drugs
First line of drugs:Isoniazid (INH)RifampicinEthambutolStreptomycinPyrazinamide
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Never use a single drug therapy
Isoniazid –rifampicin combination administered for 9 months will cure 95-98% of cases .
Addition of pyrazinamide for this combination for the first 2 months allows total duration to be reduced to 6 months.
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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 prodrugCell wall synthesis inhibitorInhibits 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.
Detected in significant concentrations in pleural & ascitic fluids.
Its concentration in CSF is significant in inflammed meninges.
Penetrates well into caseous material.
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Metabolism & Excretion
75% to 95% of a dose of INH is excreted in urine within 24 hours.
Mostly as metabolities.The main excretory products in
human result from enzymatic acetylation.
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Clinical usesMycobacterial infections (it is recommended
to be given with pyridoxine to avoid neuropathy).Latent tuberculosis in patients with
positive tuberculin skin test Prophylaxis against active TB in individuals
who are in great risk as very young or immunocompromised individuals.
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Adverse effects
Peripheral neuritisOptic neuritis &atrophy.Allergic reactions ( fever,skin
rash,systemic lupus erythematosus )Hepatitis
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Adverse effects (cont.)
Hematological reactionsVasculitisArthritic symptoms
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Adverse effects (cont.)
CNS toxicity include ;Lack of mental concentration , memory
loss.Excitability & seizuresPsychosis( 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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Rifampicin
BactericidalInhibits RNA synthesis----- by binding to
the beta –subunit of bacterial DNA dependent RNA polymerase.
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Site of Action
Intracellular bacilliExtracellular bacilliBacilli in caseous lesions
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Pharmacokinetics
Well absorbed orally.Aminosalicylic acid delay the absorption
of rifampicin, (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 including CSF in effective concentration.
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Clinical uses
Mycobacterial infectionsProphylaxis of active tuberculosis.Treatment of serious staphylococcal
infections as osteomyelitis and endocarditis.
Meningitis by highly resistant penicillin pneumococci
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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 rashFever
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Adverse Effects ( cont.)
Nausea & vomiting Hepatotoxicity ( Hepatitis, cholestatic jaundice) If administered less than twice weekly causes a
flu-like syndrome( fever , chills, myalgias, 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 :
AnticoagulantsAnticonvulsantsContraceptives
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Ethambutol
BacteriostaticInhibits mycobacterial arabinosyl
transferase ( inhibits polymerization reaction 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 orallyHalf-life 3-4 hours75% of the drug is excreted unchanged in
the urine, 15% as metabolities.
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Clinical uses
Treatment of tuberculosis in combination with other drugs.
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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 .
BactericidalActing on mycobacterial fatty acid
synthase I gene involved in mycolic acid biosynthesis.
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Site Of Action
Intracellular Bacilli
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Phrmacokinetics
Well absorbed from GITWidely distributed including CSFHalf-life 9-10 hoursExcreted primarily by renal route.
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Clinical uses
Mycobacterial infections (TB) mainly in multidrug resistance cases.
It is important in short –course (6 months) regimens with isoniazid and rifampicin.
Prophylaxis of TB in combination with ciprofloxacin.
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Adverse effects
HepatotoxicHyperuricemia( provoke acute gouty
arthritis )Nausea & vomitingDrug fever & skin rash
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Streptomycin & Amikacin
BactericidalInhibitors of protein synthesis by biding to
30 S ribosomal subunits.Acting 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
OtotoxicityNephrotoxicityNeuromuscular block
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Contraindications
Myasthenia gravisPregnancy
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Indication of 2nd line treatment
Resistance to the drugs of 1st line.Failure of clinical responseThere 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 .
ProdrugIs converted to active form (sulfoxide ).
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Pharmacokinetics
Absorbed from GIT, Given only orallyRapidly & widely distributed Half-life 2 hoursMetabolized in liver, less than 1% is
excreted in active form in urineInhibits 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, gastric irritation.
About 50% of patients are unable to tolerate a single dose more than 500mg.
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Adverse Effects (cont.)
CNS symptoms include :Mental depressionDrowsinessConvulsions & peripheral neuropathyHeadache( Pyridoxine relieves the neurologic
symptoms)
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Adverse Effects(cont.)
Severe hypotensionAllergic skin reactionsHepatitisAlopeciaMetallic taste
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Capreomycin
AminoglycosidesIt 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 dysfunction, including depression & psychotic reaction.
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 rifampicin , it is RNA polymerase inhibitor.
Cross resistance with rifampicin but not to all microorganisms.
Enzyme inducer of cytochrome p450.Effective against typical and atypical
mycobacteria.
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Phrmacokinetics
Absorbed from GITLipophilic drug Excreted in urine & bileAdjustment 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 ( replaced rifampicin, because it is less potent enzyme inducer)
Prevention of tuberculosisPrevention & treatment of disseminated
atypical mycobacterial infections in AIDS patients
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Adverse Effects
Skin rash(4%)GIT intolerance (3%)Neutropenia (2%)ArthralgiaOrange-red discoloration ( skin,urine, -----
as rifampicin ).
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Drug Interactions
Enzyme inducer of cytochrome P450 enzymes.
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Aminosalicylic Acid (PAS).
Similar in structure to sulfonamide and p-aminobenzoic acid.
BacteriostaticFolate synthesis inhibitor.
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Pharmacokinetics Well absorbed from GIT Best given after meals Distributed throughout the total body water &
reaches high concentration in pleural fluid & caseous tissues.
CSF levels are low Half-life one hour 80% of the drug is excreted in urine as
metabolities.
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Clinical uses
AS a second line agent is used in the treatment of pulmonary & other forms of tuberculosis.
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Adverse effects
GIT upset ( anorexia, nausea, epigastric pain , diarrhea ).
Hypersensitivity reactionsHematological troubles ( leukopenia,
agranulocytosis, eosinophilia)Crystalluria
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Clofazimine
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Drug Regimens
6 months durationA) First 2 months:INH+ Rifampin + Pyrazinamide +
Ethambutol or StreptomycinB) Last 4 monthsINH + Rifampin
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2- Drug Regimens
2- 9 months duration:A) First 2 months:INH + Rifampicin + Ethambutol
B) Last 7 months:INH + Rifampicin
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Drug Regimens(cont.)
If there is possibility of drug resistance, Ethambutol or Streptomycin or even second line drugs is added
Depending on :Type of resistanceSensitivity of microorganisms
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Drug Regimens (cont.)
We give drug combination to :1- Avoid the emergence of resistance2- Increase therapeutic efficacy3- Decrease : Dose, Frequency of dose
administration, adverse effects
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Treatment Of Tuberculosis In Pregnant Women
AS previously mentioned , but streptomycin is contraindicated because it can cause congenital ototoxicity
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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 pneumonia in
AIDS caused by Pneumocystis jiroveci ( Pneumocystis carinii).
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Adverse effects
Haemolytic anaemia Methemoglobinemia Gastrointestinal intolerance Fever,pruritus,rashes. Erythema nodosum leprosum
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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 effectsSkin discoloration ranging from red-brown to black.Gastrointestinal intolerance.Red colour urine.Eosinophilic enteritis
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Treatment of TB in pregnant women
INH ( pyridoxine should be given ), Rifampicin , ethambutol Pyrazinamide is given only if : Resistant to other drugs is documented Streptomycin is contraindicated. Breast feeding is not contraindication to receive
drugs , but caution should be observed.