Antitubercular drugs

1. Antitubercular Drugs
Presented by:- Lingaraj .V. Anawal
M.Pharm
Department of Pharmacology
H.S.K College of Pharmacy B.G.K
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2. Tuberculosis (TB) is a disease caused by bacteria called Mycobacterium tuberculosis.
The bacteria usually attack the lungs, but they can also damage other parts of the
body.
TB spreads through the air when a person with TB of the lungs or throat coughs,
sneezes, or talks.
TUBERCULOSIS is an infectious disease caused by Mycobacteria; Mycobacterium
tuberculosis & Mycobacterium bovis.
MODE OF TRANSMISSION Inhalation of droplets, Ingestion-self swallowing of
infected sputum, or Ingestion of unpasteurized milk of infected cow, Inoculation – of
organism into skin may occur rarely from infected postmortem tissue.
Transplacental – i.e tuberculosis of fetus from mother.
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3. ANTI TB DRUGS
According to their clinical utility the anti-TB drugs can be divided into:
First line: These drugs have high antitubercular efficacy as well as
low toxicity; are used routinely.
Second line: These drugs have either low antitubercular efficacy or
higher toxicity or both; and are used as reserve drugs.
First line drugs 1. Isonized(H) 2.Ethambutol(E) 3.Rifampin(R)
4.Streptomycin(S) 5.Pyrazinamide(Z)
Second line drugs
a)Other oral drugs 1. Ethionamide(Eto) 2.Prothionamide(Pto)
3. Cycloserine(Cs) 4.Terizidone(Trd) 5. Para-aminosalicylic acid(PAS)
6. Rifabutin 7. Thiacetazone(Thz).
b)Fluoroquinolones 1.Ofloxacin(Ofx) 2.Levofloxacin(Lvx/Lfx)
3.Moxifloxacin(Mfx) 4.Ciprofloxacin(Cfx)
c) Injectable drugs 1.Kanamycin(Km) 2.Amikacin(Am) 3.Capreomycin
(Cm)
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4. Group I First line oral anti-
TB drugs
These are the most potent and
best tolerated oral drugs used
routinely.
Isonized (INH),
Rifampin,
Pyrazinamide,
Ethambutol
Group II Injectable anti-TB
drugs
These are potent and bactericidal,
but injectable drugs.
Streptomycin,
Kanamycin, Amikacin,
Capreomycin, Viomycin.
Group III Fluoroquinolones These includes fluoroquinolones
(FQs) which are well tolerated
bactericidal oral drugs; all patients
with drug resistant TB should
receive one FQ.
Ofloxacin, Levofloxacin,
Moxifloxacin(Mfx)
Ciprofloxacin
Group IV Second line oral
anti-TB drugs
These are less effective,
bacteriostatic/ more toxic oral
drugs for resistant TB
Ethionamide,
Prothionamide,
Cycloserine, Terizidone,
Para-aminosalicylic acid
Group V Drugs with
doubtful/unproven
/unclear efficacy
Theses are drugs with uncertain
efficacy; not recommended for
MDR-TB; may be used in
extensively resistant TB (XDR-TB).
Thiacetazone,
Clarithromycin,
Clofazimine, Linezolid,
Amoxicillin/clavulanate,
Imipenem/cilastatin
ALTERNATIVE GROUPING
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5. First line antitubercular drugs
They are cheap, more effective, and routinely used and less
toxic.
Isonized(Isonicoyinic acid hydrazide, INH)
 Isoniazid is a highly effective and the most widely used
antitubercular agent.
 It is orally effective, cheapest and has tuberculocidal
activity.
 It is active against both intracellular and extracellular bacilli.
 Most active drug for treatment of tuberculosis.
 Freely soluble in water.
 Penetrates into macrophages and is active against both
 Extracellular and intracellular organism.
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6. Isoniazid (MOA of First line antitubercular drug)
Isoniazid (prodrug)
Inside mycobacteria
Converted to active form
Inhibit the synthesis of mycolic acid
(component of mycobacterial cell wall)
Death of bacteria (Tuberculocidal)
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7. Metabolism and activation of isoniazid
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8. Pharmacokinetic
Readily absorbed from the GIT diffuses readily into all body fluids like
CSF and tissues.
Also crosses placental barrier.
It is metabolized by acetylation and the metabolite are excreted in
urine.
Adverse effects of drug interactions
Hepatotoxicity
Peripheral neuritis
Fever, skin rashes, anaemia, GI distribunace, psychosis, rarely
Convulsions.
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9. Second line antitubercular drugs
These are less effective and/or less well tolerated anti-TB drugs that are
used only in case the bacilli are resistant to one or more 1st line drugs or
when these are not tolerated/are Contraindicated
Fluoroquinolones (FQs)
 Fluoroquinolones (FQs) like ofloxacin (Ofx), levofloxacin (Lfx),
ciprofloxacin (Cfx) and moxifloxacin (Mfx) are relatively new potent oral
bactericidal drugs for TB, that have gained prominence as well tolerated
alternatives to 1st line anti-TB drugs.
 Mfx is the most active FQ against M.tuberculosis, while Lvx is more
active than Ofx and Cfx.
 On the other hand, Cfx is more active than Lfx against atypical
mycobacteria.
 The FQs penetrate cells and kill mycobacteria lodged inside
macrophages. 9

10. Para-amino salicylic acid (PAS)
 PAS is related to sulfonamides and acts probably by the same
mechanism, i.e. inhibition of folate synthase.
 Like sulphonamides, PAS also competitively inhibits folate
synthetase enzyme and prevents the formation of tetrahydrofolic
acid (THFA) necessary for growth and multiplication of bacteria.
 It is not active against other bacteria, and this selectivity may be
due to difference in the affinity for folate synthase of
M.tuberculosis compared to that of other bacteria.
 PAS is rapidly absorbed after oral administration and distributed
widely all over the body, but poorly penetrates the BBB.
 It is metabolized in liver by acetylation and excreated in urine.
Adverse effects are rashes, fever, malaise, hypokalaemia, goiter,
liver dysfunction and rarely blood dyscrasias.
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11. Drugs with MOA
Drugs Mechanism of Action Effects
Isoniazid Inhibits synthesis of mycolic acids, an
essential component of mycobacterial
cell walls
Bactericidal activity against
susceptible strains of M tuberculosis
Rifampin Inhibits DNA-dependent RNA
polymerase, thereby blocking
production of RNA
Bactericidal activity against
susceptible bacteria and
mycobacteria • resistance rapidly
emerges when used as a single drug
in the treatment of active infection
Pyrazinamide Not fully understood • pyrazinamide
is converted to the active pyrazinoic
acid under acidic conditions in
macrophage lysosomes
Bacteriostatic activity against
susceptible strains of M tuberculosis
• may be bactericidal against
actively dividing organisms
Ethambutol Inhibits mycobacterial arabinosyl
transferases, which are involved in
the polymerization reaction of
arabinoglycan, an essential
component of the mycobacterial cell
wall
Bacteriostatic activity against
susceptible mycobacteria
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12. Drugs with MOA
Drugs Mechanism of action Effects
Streptomycin Prevents bacterial protein
synthesis by binding to the
S12 ribosomal subunit.
Bactericidal activity against
susceptible mycobacteria
Ethionamide It blocks the synthesis of
mycolic acids
Bactericidal activity against
susceptible strains of
M.tuberculosis
Ciprofloxacin Inhibits DNA replication by
binding to DNA gyrase and
topoisomerase IV
Bactericidal activity against
susceptible bacteria
Macrolides Targets 23S ribosomal RNA,
inhibiting peptidyl
transferase
----
Para-amino salicylic acid
(PAS)
Inhibition of folate synthases Bactericidal activity against
susceptible strains of
M.tuberculosis
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13. MOA of experimental drugs
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Drug MOA Antibacterial activity Adverse effects
TMC-207(207910)
is a diarylquinone
Inhibit ATP synthase M.leprae,
M.bovis,
M.marinum,
M.kansasii,
M.ulcerans,
M.fortuitum,
M.szulgai,
M.abscessus.
nausea 26%,diarrhea
13%, arthralgia, pain
in extremities,
hyperuricemia.
(Full side effect
profile is unclear)
PA-824 is a
nitroimidazopyran
Inhibit mycolic acid and
protein biosynthesis;
It kills both
replicating and non
replicating
M.tuberculosis.
But lacks activity
against other
mycobacteria.

14. Mechanism of action of established and experimental drugs used
for the chemotherapy of mycobacterial infections.
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15. Mechanism of resistance of mycobacteria to different
chemotherapetic drugs.
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16. Treatment of tuberculsosis
WHO recommends the use of multidrug therapy(MDT) for
all cases of tuberculosis.
 To make the patient non-infectious as early as possible by rapidly
killing the dividing bacilli by using three to four bactericidal drugs.
 To prevent the development of drug-resistant bacilli.
 To reduce the total duration of effective therapy.
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17. Short course chemotherapy
Intensive phase:- The patient receive intensive treatment with four
tuberculocidal drugs daily or thrice weekly for a period of 2 months.
The main objective of this phase is to render the patient non-
contagious.
Continuation phase:- The patient receive two drugs, usually INH and
rifampicin daily or thrice weekly for the period of 4 months.
This phase helps to eliminate the remaining bacilli and prevents
relapse.
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18. The goals of antitubercular chemotherapy are:-
1)Kill dividing bacilli Drugs with early bactericidal action rapidly
reduce bacillary load in the patient and achieve quick sputum
negativity so that the patient is non-contagious to the
community: transmission of TB is interrupted. This also affords
quick symptom relief.
2)Kill persisting bacilli To effect cure and prevent relapse. This
depends on sterilizing capacity of the drug.
3)Prevent emergence of resistance So that the bacilli remain
susceptible to the drugs. The relative activity of the first line drugs
in achieving these goals differs, e.g. H and R are the most potent
bactericidal drugs active against all populations of TB bacilli, while
Z acts best on intracellular bacilli and those at inflamed sites.
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19. Category wise treatment regimens for tuberculosis (adopted from
WHO guidelines 2010)
Intensive phase Continuation
phase
Duration
(months)
comment
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, and no HIV
coinfection or its risk
2 HRZES daily
+
1 HRZE daily
5 HRE daily 8 For patient with
low/medium risk of
MDR-TB
(failure, default, etc)
Empirical
(standardized)
MDR- regimen
Empirical
(standardized)
MDR-regimen
18-24
Or
till DST result
For patient with high
risk of MDR-TB
(failure,2nd default,
contact of MDR-TB
etc)
Category
1
New patient
2
Previously
treated
patients
pending DST
result
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20. Multidrug-resistant(MDR) TB
Multidrug-resistant (MDR) TB MDR-TB is defined as resistance to both H
and R, and may be any number of other (1st line) drug(s).
MDR-TB has a more rapid course with worse outcomes.
Its treatment requires complex multiple 2nd line drug regimens which are
longer, more expensive and more toxic.
As per WHO, India has the highest number of MDR-TB cases in South-East
asia.
The general principles of treatment of MDR-TB are:
The regimen should have at least 4 drugs certain to be effective.
Often 5–6 drugs are included, since efficacy of some may be uncertain.
Avoid combining cross resistance drugs, e.g. two FQs, Km with Am or Eto
with Pto, or Cs with terizidone.
Include drugs from group I to group IV (alternative classification) in a
hierarchical order.
Group I drugs (except H and R) can be included, add one injectable drug
(group II), One FQ (group III) and one or two group IV drugs.
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21. Tuberculosis in pregnant women
 The WHO and British Thoracic Society consider H,R, E and Z to be
safe to the fetus and recommend the standard 6 month (2HRZE +
4HR) regimen for pregnant women with TB.
 Streptomycin S is contraindicated because it is ototoxic to the
fetus.
 However, Z is not recommended in the USA (due to lack of
adequate teratogenicity data).
 In India, it is advised to avoid Z, and to treat pregnant TB patients
with 2 HRE + 7HR (total 9 months).
 Treatment of TB should not be withheld or delayed because of
pregnancy.
 All pregnant women being treated with INH should receive
pyridoxine 10–25 mg/day.
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22. Management of anti-TB drugs induced adverse drug
reaction(WHO guidelines)
Anorexia, nausea administer the drugs with small meals.
Skin rash stop anti all TB drugs promptly
drowsiness—give drugs before bed time;
flu syndrome due to intermittent dosing of R—change to daily dosing
of R(Rifampin)
Z(Pyrazinamide) induced arthralgia can be treated by analgesic
NSAIDs;
Peripheral neuritis due to H(Isoniazid) can be mitigated by pyridoxine.
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23. Reference:-
 Essential of medical pharmacology 8th edition by K.D Tripathi page
no;815.
 Essential of medical pharmacology 7th edition by K.D Tripathi page
no;765
 Basic & Clinical Pharmacology 12th edition by Bertram G. Katzung,
Susan B. Masters, Anthony J. Trevor. Chapter no;47
Antimycobacterial drugs by Daniel H. Deck,PharmD, & Lisa G.
Winston, MD page no;839.
 Goodman & Gilman’s The pharmacological basis of therapeutics
page no;1549.
 Modern pharmacology with clinical application 5th edition by
Charles R. Craig & Robert E. Stitzel page no;557.
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24. THANK U
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