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Anti-tubercular drugs
Prof. Anuradha Nischal
• Deadly infectious disease caused
by MYCOBACTERIUM
TUBERCULOSIS
• Affects the lungs but can also
affect other parts of the body.
Epidemiology
It is currently estimated that 1/2
of the world's population (3.5
billion) is infected with
Mycobacterium tuberculosis.
Transmission
• Pulmonary tuberculosis
• Droplets
• Patients with the active disease
(bacilli) expel them into the air by:
– coughing
– sneezing
Signs &
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 loss
• Anorexia
• mailaise
• Pain in the chest
Group 1
• First line oral ATDs
Group 2
• Injectible ATDs
Group 3
• Flouroquinolones
Group 4
• Second line oral ATDs
Group 5
• Drugs with unclear
efficacy
Group 1/First line drugs include:
ISONIAZID
RIFAMPICIN
PYRAZINAMIDE
ETHAMBUTOL
most potent and best tolerated oral drugs
HIGH EFFICACY AND LOW TOXICITY
Group 2/Injectable ATDs
Streptomycin
Kanamycin
Amikacin
Capreomycin
potent, bactericidal, but injectable drugs
Group 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
Group 5/Drugs with unclear efficacy
Thiacetazone
Clarithromycin
Clofazimine
Linezolid
Amoxicillin/clavulanate
Imipenem/cilastin
Drugs with uncertain efficacy, may be used for XDR
ISONIAZID[H]
 Cheapest ATD
 Mycobactericidal
 Bactericidal for rapidly growing bacilli
Quiscent ones are only inhibited
 Extra and intracellular bacilli
 Equally active in acidic & alkaline
medium.
MOA
• Inhibits mycolic acids synthesis
(unique component MBCW)
• High selectivity for mycobacteria
MOA of INH:
ISONIAZID
Reactive metabolite
Kat G( catalase peroxidase
in mycobacteria)
Inh A & Kas A
Inh DHFR
Inhibits the synthesis of Mycolic Acid
Inh DNA syn
Mechanism 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
• Absorption: 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
• Q- Why Vitamin B6 is given with INH
Pyridoxine deficiency
Interference with activation of pyridoxine and its increased
excretion in urine
• Pyridoxine given prophylactically
(10mg/day) prevents neurotoxicity
• INH neurotoxicity is treated by pyridoxine
100mg/day
WHOM
Must: Diabetics, Chr. Alcoholics, malnourished,
pregnant, lactating & HIV infected patients
 Hepatitis
Common in older adults & alcoholics
Dose related damage to hepatic cells
reversible
RIFAMPICIN[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
MOA
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).
Other bacteria
Activity against other gram positive and gram
negative bacteria
• Staph
• N. meningitidis
• H. influenzae
• E.coli
• Kleibseilla
• Psuedomonas
• Proteus
• Legionella
• M. leprae is highly sensitive
• MAC & other mycobacteria are moderately
susceptible.
Pk
• 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
 T1/2 varies from 2-5 hrs
HEPATITIS a major
adverse effects:
effect
Adverse
Urine and secretions become orange-red in colour
• Cutaneous syndrome
• Flu syndrome
• Abdominal syndrome
SERIOUS BUT RARE
• Respiratory syndrome: breathlessness
• Purpura, haemolysis, shock and renal failure
INTERACTIONS
Rifampicin is a microsomal enzyme inducer
• It induces several CYP 450 iso enzymes
• Thus 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?
Other uses
Leprosy
Prophylaxis of meningococcal & H. influenzae
meningitis & carrier state
MRSA
Brucellosis.
PYRAZINAMIDE
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
• Its 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
MOA
Pyrazinamide
Mycobacterial Pyrazinamidase
Pyrazinoic Acid (gets accumulated in acidic
medium)
Inhibits Mycolic Acid Synthesis
+
• 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/dayAdverse effects:
Hepatotoxicity (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
ETHAMBUTOL[E]
Only Tuberculostatic drug among 1st line
drugs.
Added to RHZ hastens the rate of sputum
conversion and prevents the development of
resistance.
Primarily added for this reason.
MOA
E Inhibits Mycobact. Arabinosyl Transferase III

Arabinogalactan synthesis

Essential component of Myco. Cell wall;
disrupts the assembly of mycobacterial cell
wall.
PK
•
•
•
•
Absorption: Well absorbed from g.i.t.
Distribution : Widely distributed
T1/2 ~ 4hrs
Excretion: Glomerular filtration & tubular
secretion
Dose to be reduced in Renal failure
Side
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
• Contra-indication; In children <6yrs and
Creatinine clearance <50ml/min
• Hyperuricaemia
FQs
•
•
•
•
Ofloxacin
Levofloxacin
Ciprofloxacin
Moxifloxacin
New potent oral mycobactericidal drugs
• Primary 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
• Mfx is the most active FQ against M. TB
• Lvx is more active than Ofx & Cfx
Dose:
• Ofloxacin: 800mg OD
• Levofloxacin 750 mg OD
• Moxifloxacin 400mg OD
Goal of AT CTx
• Kill dividing bacilli
• Kill persisting bacilli
• Prevent emergence of resistance.
Goal of AT CTx
Kill dividing bacilli
• Reduce bacillary load
• Achieve quick sputum negativity
• Patient non-contagious
• Transmission interupted
• Quick symptomatic relief
Kill persisting bacilli
• Effect cure & prevent relapse
Goal of AT CTx
Prevent emergence of resistance.
• So that bacteria remain susceptible to the
drugs
Short Course Chemotherapy
Who has introduced 6-8 months multidrug “short course”
regimens under DOTS programme.
•4 drugs
Multidrug therapy
H
R
Z
E
4 drugs/Multidrug therapy
Why?????
• Use of single drug in tuberculosis results in the
emergence of resistant organisms and relapse
in almost 3/4th of patients.
• Combination:
• H & R most potent bactericidal
Combination synergistic
Duration of therapy shortened from >12
months to 9 months
• Z 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 dose
• AKT-4
•
•
•
•
Cost
Convenience
Feasibility
Decreased resistance
TREATMENT CATEGORIES
CATEGORY-I
CATEGORY-II
New cases
Previously
treated
patient.
Category I
• New case
• Sputum positive for Mycobacterium TB
Category II
•
•
•
•
•
•
Smear positive TB patients
Exposed to ATT in the past
Did not complete the course
Or took irregular medication
Or relapsed after responding
Failed to respond; failures
Higher risk of harbouring DR bacilli
Intensive
phase
Two phases
Continuation
phase
Intensive phase
• 4-5 drugs
• 2-3 months
• Rapidly 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
Category
Intensive phase
Continuous
phase
Duration
(months)
Comment
I
2 HRZE daily
4 HR daily
6
Optimal
2 HRZE daily
4 HR thrice
weekly
6
Acceptable if
DOT ensured
2 HRZE thrice
weekly
4 HR thrice
weekly
6
Acceptable if
DOT ensured
2 HRZES daily
+
1 HRZE daily
5 HRE daily
8
For patient with
low/medium risk
of MDR-TB.
Emperical
(Standardized)
MDR regimen
Emperical
(Standardized)
MDR regimen
18-24
Till DST
II
For patient with
high risk of MDRTB.
Failures, 2nd
default, contact
of MDR
th
Tt of TB Guidelines, 4 edition (2010), WHO , Geneva.
Category two
• Thrice weekly option not available for
retreatment categories
• Assess risk of MDR-TB (DST)
Recommended doses
Drug
Daily dose
3 times per week dose
mg/kg
maximum
mg/kg
maximum
Isoniazid
5(4-6)
300 mg
10(8-12)
900 mg
Rifamin
10(8-12)
600 mg
10(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, 4th edition (2010), WHO , Geneva.
Multiple Drug Resistance(MDR)
• Defined as Resistance to both Isoniazid and
Rifampin (compulsorily) and number of other(1st
line drugs)
• Rapid course
With worse outcomes
• 2.8% of all new cases
• 12-17% of retreatment cases
• Treatment is difficult as second line drugs
are less efficacious, less convenient, more
expensive and toxic for longer duration
General principles
MDR Regimen
• At least 4 drugs
• Include 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
General principles
Gp I drugs
2;
(except
H;R)
Gp II
one
injectable
1
Gp III
One FQ
1
One/two
Gp IV drugs
2
Standardized RNTCP regimen for MDR-TB
Intensive phase
6 drugs; 6-9 months;
Continuous Phase
4 drugs; 18 months
•
•
•
•
•
•
•
•
•
•
Kanamycin
Ofloxacin
Ethionamide
Cycloserine
Pyrazinamide
Ethambutol
Ofloxacin
Ethionamide
Cycloserine
Ethambutol
+ Pyridoxine 100 mg/day
RNTCP DOT plus guidelines;2010.
Extensively 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 untreatable
• Mortality is very high, particularly among HIV positive
patients.
detected or diagnosed
• Standardized MDR regimen must be stopped
immediately
• Expert panel may decide on instituting
treatment with group v drugs
• Uncertain efficacy
• Expensive
Chemoprophylaxis
• 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
Whom
•
•
•
•
Contacts of open cases
Children with Mx positive & TB pt in the family
Neonate of TB mother
Pt of leukemia
– Diabetes
– Silicosis
– HIV positive
– C. steroid therapy; who show +ve Montoux
Pregnancy
• S contraindicated; ototoxicity
USA
• Z not recommended
INDIA
• Avoid Z
• 2HRE+7HR
• Treatment should not be withheld or delayed
because of pregnancy
• All pregnant women being treated with INH
should receive pyridoxine 10-25 mg/day
Lactation
• 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.
Thanks for your attention