Anuradha Nischal Deadly infectious disease caused by MYCOBACTERIUM TUBERCULOSIS Affects the lungs but can also affect other parts of the body It is currently estimated that 12 of the worlds population 35 billion is infected with Mycobacterium ID: 911692
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Slide1
Anti-tubercular drugs
Prof.
Anuradha
Nischal
Slide2Deadly infectious disease caused by MYCOBACTERIUM TUBERCULOSIS
Affects the
lungs but can also affect other parts of the body.
Slide3It is currently estimated that 1/2 of the world's population (3.5 billion) is infected with Mycobacterium
tuberculosis.
Epidemiology
Slide4Pulmonary
tuberculosis
Droplets
Patients with the active disease (bacilli) expel them into the air by:
coughing
sneezing
Transmission
Slide5Signs & symptoms
A bad
cough
that lasts 3 weeks or longer
Coughing up
blood or sputum (phlegm from deep inside the lungs)Fever
Weakness or fatigue
Weight lossAnorexiamailaisePain in the chest
Slide6Slide7Group 1/First line drugs include:
ISONIAZID RIFAMPICIN
PYRAZINAMIDE
ETHAMBUTOL
most potent and best tolerated oral drugs
HIGH EFFICACY AND LOW TOXICITY
Slide8Group 2/
Injectable
ATDs
Streptomycin
Kanamycin Amikacin Capreomycin
potent, bactericidal, but injectable drugs
Slide9Group 3/Flouroquinolones
Ofloxacin Levofloxacin Moxifloxacin
Ciprofloxacin(resistance) so removed
potent bactericidal well tolerated oral drugs.
MDR
Group 4/Second line oral drugs include:
ETHIONAMIDE PROTHIONAMIDE
CYCLOSERINE
TERIZODONE
p-AMINOSALICYLIC ACID
less effective, bacteriostatic, more toxic drugs for resistant tuberculosis
Slide11Group 5/Drugs with unclear efficacy
Thiacetazone Clarithromycin
Clofazimine
Linezolid Amoxicillin/clavulanate
Imipenem/
cilastin Drugs with uncertain efficacy, may be used for XDR
Slide12ISONIAZID[H]
Cheapest ATD
Mycobactericidal
Bactericidal for rapidly growing bacilli
Quiscent
ones are only inhibitedExtra and intracellular bacilli
Equally active in acidic & alkaline medium.
Slide13MOAInhibits
mycolic
acids synthesis (unique
component MBCW)
High
selectivity for mycobacteria
Slide14MOA of INH:
ISONIAZID
Kat G(
catalase
peroxidase
in mycobacteria)
Reactive metabolite
Inh
A &
Kas
A
Inh
DHFR
Inh
DNA
syn
Inhibits the synthesis of Mycolic Acid
Slide15Slide16Mechanism of Resistance
High level resistance is due to
mutation
in
catalase
peroxidase (Kat G) gene
Resistance may also develop due to
mutation in Kas
A & Inh A gene
Efflux Of INH
Loss of INH concentrating
ability of bacteria
Slide17Absorption:
completely absorbed
orally
Distribution:
penetrate all body tissue tubercular cavities, placenta & meninges
Metabolism:
in liver Excretion
: in urine
C/I
known hypersensitivity
acute hepatic disease
Peripheral Neuropathy
And neurological manifestations
Paresthesias
, numbness, mental disturbances most important dose dependent toxic effects.
Pyridoxine deficiency
Interference with activation of pyridoxine and its increased excretion in urine
Slide19Q- Why Vitamin B6 is given with INH
Pyridoxine deficiency
Interference with activation of pyridoxine and its increased excretion in urine
Slide20Pyridoxine given
prophylactically
(10mg/day) prevents neurotoxicity
INH
neurotoxicity
is treated by pyridoxine 100mg/day
Slide21WHOM
Must
: Diabetics, Chr. Alcoholics, malnourished, pregnant, lactating & HIV infected patients
Slide22Hepatitis
Common in older adults & alcoholics
Dose related damage to hepatic cells
reversible
Slide23RIFAMPICIN[R]
Semi synthetic derivative of
Rifamycin
B from
St.
meditarranei
Bactericidal: Bactericidal efficacy ≈ INH
Extra & intracellular bacteria Good sterilising property & resistance preventing action. All sub populations; best on spurters
Slide24MOA
Rifampicin
inhibits synthesis of R.N.A.
It binds to
β
subunit
of mycobacterial
DNA dependent RNA polymerase
& blocks its
polymerising
function
Resistance develop due to mutation in rpo B gene( codes for RNA polymerase);
X bind mammalian RNA polymerase (Basis for selectivity).
Slide25Other bacteria
Activity against other
gram positive and
gram negative
bacteriaStaph
N. meningitidisH. influenzae
E.coli
KleibseillaPsuedomonasProteusLegionella
Slide26M. leprae
is highly sensitive
MAC & other mycobacteria are moderately susceptible.
Slide27Pk
Absorption
Well absorbed from
g.i
tract
Food also interferes with abs; empty stomach
Distribution
widely distributed. Penetration
intracellularly & enters • tubercular cavities
•
Caseous
masses
• Placenta
Metabolism
Chiefly
in liver to an active
deacetylated
metabolite. Which is excreted mainly in bile some in urine also. (30-70%). R and its metabolite undergoes enterohepatic circulation
T
1/2
varies from 2-5 hrs
Slide28Adverse effects:
HEPATITIS a major adverse effect
Urine
and secretions become
orange-red
in colourCutaneous syndromeFlu syndrome
Abdominal syndrome
SERIOUS BUT RARERespiratory syndrome: breathlessnessPurpura, haemolysis, shock and renal failure
Slide29INTERACTIONS
Rifampicin is a
microsomal
enzyme inducer
It induces several CYP 450
iso enzymesThus enhances its own metabolism as well as of other drugs including:
Warfarin, OCPs, Corticosteroids, Anti-fungal drugs, Digitoxin, Protease inhibitors, NRTIs, etc.Increase dose; alternative method
Why should Rifampicin not given with OCP?
Slide31Other uses
Leprosy
Prophylaxis of meningococcal & H.
influenzae
meningitis & carrier state
MRSA
Brucellosis.
Slide32PYRAZINAMIDE
Weakly
tuberculocidal
More active in
acidic
medium
More lethal to intracellular bacteria
& bacteria at the site of
inflammation Highly effective during 1st 2 months
By killing the residual intracellular bacteria it has good sterilizing activity
Slide33Its inclusion has enabled duration of treatment to be
shortened
& reduced risk of relapse
One third reduction in the duration of anti-TB therapy & a two third reduction in TB relapse
This led to reduction in duration of therapy to 6
mths
, producing the short course
ctx
Slide34MOA
Pyrazinamide
Mycobacterial Pyrazinamidase
Pyrazinoic
Acid (gets accumulated in acidic medium)
Inhibits Mycolic Acid Synthesis
Slide35+
Pyrazinoic
acid also disrupts mycobacterial cell membrane and its transport function
Resistance develops rapidly if used alone &
is due to mutation of gene
pncA
Absorption
: Well absorbed orally
Distribution
: good penetration to all body
tissue & CSF
Metabolism
: extensively in liver
Excreted in urine
T1/2
6-10hrs
Dose: 25-30mg/kg/
day
Adverse
effects:
Slide37Hepatotoxicity (dose dependent); occurs at 40mg/kg/day; hepatic disease in 15%. Regimens employed currently 15-30 mg/kg/day are much safer.
Hyperuricemia
;
inhibits excretion of
urates
. In nearly all patients. May ppt acute episodes of gout.
Arthralgia
, nausea, vomiting, dysuria, malaise and fever, loss of diabetes control
Slide38ETHAMBUTOL[E]
Only
Tuberculostatic
drug among 1
st
line drugs.
Added to RHZ hastens the rate of sputum conversion and prevents the development of resistance.
Primarily added for this reason.
Slide39MOA
E
Inhibits
Mycobact
. Arabinosyl Transferase
III
Arabinogalactan
synthesis
Essential component of
Myco
. Cell wall;
disrupts the assembly of mycobacterial cell wall.
Slide40PK
Absorption: Well absorbed from g.i.t.
Distribution : Widely distributedT
1/2
~
4hrsExcretion: Glomerular filtration & tubular secretion
Dose to be reduced in Renal failure
Slide41Side effects:
Loss of visual acuity
(reversible)
loss of color vision
Field Defect due to optic neuritis
Dose & duration dependent toxicity.
Pt should be instructed to stop the drug at first indication of visual impairment. Visual toxicity: reversible
Slide42Contra-indication; In children <6yrs and Creatinine clearance <50ml/min
Hyperuricaemia
Slide43FQs
Ofloxacin
LevofloxacinCiprofloxacin
Moxifloxacin
New potent oral
mycobactericidal drugs
Slide44Primary indication Drug resistant TB
key component of all regimens for MDR TB
Alternative to first line Substitution of
Ethambutol
with Mfx
has been found to enhance rate of bacterial killing & cause faster sputum conversion Possibility of decreasing the duration of treatment to
less than 6 months
Slide45Mfx is the most active FQ against M. TBLvx
is more active than
Ofx & Cfx
Dose
:
Ofloxacin: 800mg ODLevofloxacin 750 mg ODMoxifloxacin 400mg OD
Slide46Goal of AT CTx
Kill dividing bacilli
Kill persisting bacilliPrevent emergence of resistance.
Slide47Goal of AT CTx
Kill dividing bacilli
Reduce bacillary loadAchieve quick sputum negativity
Patient non-contagious
Transmission interupted
Quick symptomatic reliefKill persisting bacilliEffect cure & prevent relapse
Slide48Goal of AT CTx
Prevent emergence of resistance
.So that bacteria remain susceptible to the drugs
Slide49Short Course Chemotherapy
Who has introduced 6-8 months multidrug “short course” regimens under DOTS
programme
.
Slide504 drugs
Slide51Multidrug therapy
Slide524 drugs/Multidrug therapy
Slide53Why?????Use of single drug in tuberculosis results in the emergence of resistant organisms and relapse in almost 3/4
th
of patients. Combination:H & R
most potent bactericidal
Combination synergistic
Duration of therapy shortened from >12 months to 9 months
Slide54Z acts on intracellular bacteria
It has very good sterilizing activity
Addition of Pyrizinamide further reduces duration from 9 to 6 months
E
is bacteriostatic mainly serves to prevent resistance and may hasten sputum conversion
Single daily doseAKT-4
Slide55Cost
Convenience
FeasibilityDecreased resistance
Slide56TREATMENT CATEGORIES
Slide57Category I
New case
Sputum positive for Mycobacterium TB
Slide58Category II
Smear positive TB patients
Exposed to ATT in the pastDid not complete the courseOr took irregular medication
Or
relapsed after responding
Failed to respond; failuresHigher risk of harbouring
DR bacilli
Slide59Slide60Intensive phase
4-5 drugs
2-3 monthsRapidly kill the bacilli
Bring about sputum conversion
Afford symptomatic relief
Continuation phase
2-3 drugs
4-5 months Remaining (few) bacilli eliminated So that relapse does not occur
Slide61Category
Intensive phase
Continuous phase
Duration
(months)
Comment
I
2 HRZE daily4 HR daily6Optimal
2 HRZE daily4 HR thrice weekly
6Acceptable if DOT ensured
2 HRZE thrice weekly
4 HR thrice weekly
6
Acceptable if DOT ensured
II
2 HRZE
S
daily
+
1
HRZE daily
5
HR
E
daily
8
For patient with low/medium
risk of MDR-TB.Emperical (Standardized) MDR regimenEmperical(Standardized)MDR regimen18-24Till DSTFor patient with high risk of MDR-TB.Failures, 2nd default, contact of MDRTt
of TB Guidelines, 4th edition (2010), WHO , Geneva.
Slide62Category twoThrice weekly option not available for retreatment categories
Assess risk of MDR-TB (DST)
Slide63Recommended doses
Drug
Daily dose
mg/kg maximum
3 times per week dose
mg/kg maximum
Isoniazid
5(4-6)
300 mg10(8-12) 900 mgRifamin
10(8-12) 600 mg10(8-12) 600mg
Pyrazinamide
25(20-30)
35(30-40)
Ethambutol
15(15-20)
30(25-35)
Streptomycin
15(12-18)
15(12-18) 1000mg
Tt
of TB Guidelines, 4
th
edition (2010), WHO , Geneva.
Slide64Multiple Drug Resistance(MDR)
Defined as Resistance to both
Isoniazid and
Rifampin
(compulsorily) and number of other(1st
line drugs)Rapid course
With worse outcomes
Slide652.8% of all new cases12-17% of retreatment cases
Treatment is
difficult as second line drugs are less
efficacious, less convenient,
more expensive and toxic for longer duration
Slide66General principles
MDR Regimen
At least 4 drugsInclude drugs from group I to group IV Gp
I drugs (except H;R) 2
+ one injectable
; Gp II 1 One FQ; Gp
III 1
One/two Gp IV drugs 2
Slide67General principles
Slide68Standardized RNTCP regimen for MDR-TB
Intensive phase
6 drugs; 6-9 months;
Kanamycin
Ofloxacin
Ethionamide
Cycloserine
PyrazinamideEthambutol Continuous Phase
4 drugs; 18 monthsOfloxacinEthionamide
CycloserineEthambutol
+ Pyridoxine 100 mg/day
RNTCP DOT plus guidelines;2010.
Slide69Extensively Drug Resistant(XDR)
This term is applied to bacilli that are
resistant to at least four most effective
cidal
drugs
, i.e. Cases resistant to INH
Rifampicin
Flouroquinolone and one of Kanamycin/Amikacin/Capreomycin
Virtually untreatableMortality is very high, particularly among HIV positive patients.
Slide70detected or diagnosedStandardized MDR regimen must be
stopped
immediatelyExpert panel may decide on instituting treatment with group v drugs
Uncertain efficacy
Expensive
Slide71Chemoprophylaxis
INH
: 300mg daily X 6 months Children : 10 mg /Kg
INH resistance
H(5 mg/kg)+R(10 mg/kg; max: 600 mg)X 3 months
If INH cannot be used : R X 4 months
Slide72Whom
Contacts of open cases
Children with Mx positive & TB pt in the family
Neonate of TB mother
Pt of leukemia
DiabetesSilicosisHIV positiveC. steroid therapy; who show +ve
Montoux
Slide73Pregnancy
S contraindicated
;
ototoxicity
USA
Z not recommendedINDIA
Avoid Z
2HRE+7HR
Slide74Treatment should not be withheld or delayed
because of pregnancy
All pregnant women being treated with INH should receive pyridoxine 10-25 mg/day
Slide75Lactation
All ATDs compatible with breast feeding
Full course should be given to mother
Infant
: BCG vaccination
6 month INH prophylaxis after ruling out active TB.
Slide76Thanks for your attention