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1. TUBERCULOSIS
and
ANTI-
TUBERCULAR
DRUGS
G Vijay Narasimha Kumar
Asst. Professor,
Dept. of. Pharmacology
Sri Padmavathi School of Pharmacy

2. DEFINITION
•AchronicbacterialinfectioncausedbyMycobacterium
tuberculosis,usuallycharacterizedpathologicallybythe
formationofgranulomas.Themostcommonsiteof
infectionisthelung,butotherorganssuchasmaybe
involved.
•Othercommonnamesincluded“wastingdisease”andthe
“whiteplague.”
AETOLOGY
•TBiscausedbyMycobacteriumspeciesmainlyby
–Mycobacteriumtuberculiwhichisaerobicatypicalrodshaped
bacteria
•OtherstrainswhichcausesTBare
–M.avium
–M.bovis(Commonlycausedbyconsumptionof
unpasteurizedmilk)
–M.hominis

3. •Less common strains which causes TB are
–M.africanum
–M.microti
–Mpinnipeddi
–M.cannetti
•Less pathogenic strains are
–M.abscessus
–M.fortuitum
–M.chelonae
•Non pathogenic strains are M.smegmatis
•M.tuberculialso called as Koch’s bacilli or Acid Fast
bacilli

4. WHY TB IS A DREADFUL DISEASE ?
REASON FOR
DREADFUL DISEASE:
•Presence of Mycolic
acid (90’c’ atoms
arranged in a ring like
structure) in
Mycobacterium
species.
•Mycolicacids
Prevents ,resists
against hydrophilic
and lipophilic
antibiotics, loss of
water, transport
of various
substances
Helps in evading
from immune
system.

5. WHY IT CAN’T BE STAINED BY NORMAL STAINS?
•Due to presence of mycolicacids and cross linked fatty
acids and other lipids in the cell wall of organisms
,making it impermeable to usual stain.
M.tuberculiin Acid fast staining
Takes up satin by carbolfuschin.
Resists decolorisationby acids and alcohol.
Don’t acquire 2
0
stain methylene blue
These retain carbolfuschinhence they
appear red.

6. WHY TB AFFECTS ONLY LUNGS ?
M.tuberculi
Enters
Host cell
Utilizes
Cholesterolin cell membrane (Highly oxygenasesamount involved in
metabolism of cholesterol into)
e
-
•The concentrations of oxygenasesgreater in alveoli of
lungs .Hence Mycobacterium species majorly reside in
alveoli of lungs.
•And as it is strict aerobe strictly thrives best in tissues
with high Oxygen tension such as in the apex
of the lung
ATP

7. transmission
•TBisspreadthroughtheairfromonepersonto
anothervia
–Inhalation(coughdroplets)
–Ingestion(self-swallowingofinfected
sputum),
–Inoculation(organismsintotissuewhichmay
occurfrominfectedpostmortemtissue),
–Transplacentalroutes(Leadstocongenital
TB).
typesoftuberculosis
•Basedonanatomicalsite
–PULMONARY TB(lungs)
–MILIARYTB(Liver,kidneyspleenbrain)

8. •Basedonpresenceofsignsandsymptoms
–ActiveTB(onlyshowssignsandsymptoms).
–LatentTB(signsandsymptomsare
absent-DORMANT).
•Basedontypeoftissueresponseandage
–PrimaryTBorGhon’scomplexorchildhoodTB
(infectionofanindividualwhohasnotbeen
previouslyinfectedorimmunised)
–SecondaryTBorPost-primaryorReinfection,
orChronicTB(infectionofanindividualhas
beenpreviouslyinfectedorsensitized).

9. Pathogenesis
•When ever the Mycobacteriumtuberculienters body. As it is
strictly aerobic it resides in alveoli of lungs.
•In alveoli, they will be engulfed by alveolar macrophages and with in
macrophages they will be converted into phagosome
•Phagosomeshould convert into phagolysosomebut the M.tuberculiinhibits
the fusion of phagosomewith lysosome there by no formation of
phagolysosome.
•Thus the mycobacterium tuberculosis antigen becomes “Difficut to
undergo Degradation”.

10. However, a very few no.ofmacrophages/some cells can process the
mycobacterial tuberculosis
The APC containing expressed MTB antigen enters lymphatic system and
reaches lymphatic organs.
CLONAL SELECTION
Activation of TH
1cells(Cell mediated Immunity)
IL-1
INF-γ
TNF-α
Activation of INF-γon endothelial cells of blood vessels
TH
1
cell

11. ActivationofMonocyteAdherentProtein(MAP)onendotheliumandadherence
ofmonocytetoMAP
Squeezingofmonocytesfrombloodtositeofinjury.Thusmonocytes
enteredintositeofinjurybecomesMacrophagesandincreasesinnumber.
MacrophagesengulfMycobacteriumtuberculosisatsiteofinjury.Dueto
inhibitionofFusionofPhagolysosome,Macrophagesareunable todigest
Mycobacteriumtuberculosis

12. Granuloma(Agroupofclusterofepitheloidcellssurroundedbyrimof
lymphocytesaroundthem)
IN GRANULOMA
SomeofmacrophagesformMultinucleatedgiantcellsbyfusionofadjacent
cells(Langhanstype)
Surroundingtheepithelioidcellsandgiantcellsthereisazoneof
lymphocytes,plasmacells,andfibroblasts.Thislesionatthisstageiscalled
Hardtubercleduetoabsenceofcentralnecrosis.

13. Within10-14days,thecentreofthecellularmassundergoesinto
CASEATION NECROSIS(microscopicallynecrosisisstructurelessesinophilic
andgranularmaterialwithdebris).Thisstageiscalledsofttubercle.
WidespreadofSofttubercleovervariouspartsofalveoliandlungscauses
PULMONARY TB.
Thesesofttuberclewidespreadintovariouspartsofthebodylikekidney
spleen,liverandbonesetc.,.
InthosefreshlyinfectedpartsMycobacteriumtuberculidiffuseoutofSoft
tubercleandinfectswhichleadstoformationofnewgranulomas.
Newlyformedgranulomasdamagestissueanddegeneratestissuesurrounding
Extensivespreadanddamageofvariouspartsofbodyoccurs.Thisconditionis
calledMILIARYTUBERCULOSIS.

14. Wheninfectedpersoncoughsorsneezes,thegranulomasthatmaybepresent
insputumcomesincontactwithair.
Lymphocytes,fibroblastssurroundingtheclusterofepitheloidcellsbecome
inactivated.AndMycobacteriumtuberculigetsfreefromepitheloidcells
Comesincontactwithanotherperson
NewpersondevelopsTB

15. SIGNS AND SYMPTOMS OF TB

17. INVESTIGATIONS
•Chest X-ray
•Laboratory diagnosis
–Sputum examination for AFB
–Complete haemogram(lymphocytosis and raised ERR).
–Culture and drug sensitivity tests using BACTEC radiometric method (
this method used to detect live bacilli) .
–D.N.A probe technology
–Nucleic acid amplification test-PCR
–ELISA testing for IgGantibodies ( It denotes only past infection , but
not useful as diagnostic aid).
–Drug susceptibility testing to anti-TB drugs.
–Gene Xpert(to differentiate 1
0
/Multi drug resistant TB)
–Fine needle aspiration cytology of an enlarged peripherallymphnode is
quite helpful for confirmation of diagnosis
–INF-ɣTESTS
•T.SPOT
•Quantiferon TB gold intube
•Sputum collection
•Tuberculin test

18. •Apresumptivediagnosisiscommonlybasedon
thefindingofAFBonmicroscopicexamination
ofaclinicalsample(e.g.,sputum/pus).
•Whenthisisnotpossible,aprobablediagnosis
maybemadeusingimaging(X-ray/scans)and/or
atuberculinskintest(Mantouxtest).
•Tuberculinskintest,whichyieldsadelayed
hypersensitivitytyperesponse(asmall,raised,
blanchedwheal)toanextractmadefromM.
tuberculosis(purifiedproteinderivative;PPD).
•TUBERCULIN SKINTEST:Purifiedprotein
derivative(PPD),0.1mlIntradermally,conc.
0.002mg/ml.Ifaraisedbumpofmorethan5
mm(0.2in)appearsatthesite48hourslater,
thetestmaybepositive.

19. •Thistestcanoftenindicatediseasewhenthereis
none(falsepositive).Also,itcanshownodisease
whenyoumayinfacthaveTB(falsenegative).
Interpretation
•0–4mmNegative
•5–9mmDoubtful(maybeduetoatypica
mycobacteria)
•10mmormorePositive
•InHIVinfectedindividuals,5mmisconsidered
positive.
•Tuberculinnegativepatientsshouldbe
vaccinatedwithBCG.
•False-negativetuberculintests(i.e.negativeskin
testsoccurringinpatientswithtuberculosis).

20. 20
Fig: Tuberculin test
Fig: Chest X-ray radiography
Showing cavity
Wheal

21. Complications

22. Prevention of TB
22
•Prevention strategies include BCG vaccination
and treatment of persons with latent
tuberculosis infection who are at high risk of
developing active disease.
•BCG was derived from an attenuated strain of M.
bovis.
•Efficacy is between 0-80%.
•BCG vaccine is recommended for routine use at
birth in countries with high tuberculosis
prevalence.
•Bacillus Calmette-Guérin(BCG)

23. ANTITUBERCULA
R DRUGS
FIRST LINE AGENTS
ISONIAZID(H)
RIFAMPICIN®
PYRAZINAMIDE
ETHAMBUTOL(E)
STREPTOMYCIN(S)
SECOND LINE
AGENTS
THIOCETAZONE(T)
PARAAMINOSALICYLIC
ACID(PAS)
ETHIONAMIDE(ET)
CYCLOSERINE(C)
AMIKACIN(A)
KANAMYCIN AND
CAPREOMYCIN (K)
NEWER DRUGS
(FLUOROQUINOLON
E MACROLIDE
ANTIBIOTICS,LINE
ZOLID,RIFAPENTIN,
RIFABUTIN)

25. ISONIAZID
Isonicotinicacidhydrazide
Catalaseperoxidase(enzymeof
mycobacterium)activates
Aductswith
NAD NADP
InHa Kasa dihydrofolate
reductase
Inhibition of Inhibition of
Mycolicacid DNA synthesis
Bactericidal action
•Resistance :
–Mycobacteria may develops
resistance towards H due to
change in genes coding for
catalase peroxidase.
–Alteration in Kasa and Inha
and in structure of efflux
pumps of bacteria.
•Pharmacokinetics:
–Orally well absorbed
–Well distributed
–Metabolized in Liver by
–Based on acylation
•Slow acetylators(Half
life-3h)
•Fast acetylators( Half
life-1h)
–Excreted through urine
•Adverse effects:
–GI disturbances,
–Hepatotoxicity
–Peripheral Neuritis
–Hypersensitivity reactions

26. Mechanism of action
Rifampicin
Binds with Beta subunit of
DNA dependent RNA
polymerase
Inhibition of m.R.N.A
synthesis
Tuberculocidal effect
•PHARMACOKINETICS:
–Orally well absorbed
–High protein bound
–Distributed to all parts
–Metabolized in liver into desacetyl
rifampicin which undergoes entero-
hepatic circulation.
–Excreted largely in feces and small in
urine.
–Enzyme inducer for
•HIV protease inhibitors
•NNRTI’s
•Azole antifungals,Sulphonyl
ureas,Phenytoin, Warfarin,
Theophylline Carbamazepine.
•ADVERSE EFFECTS:
–Patients with hepatic disease are prone
to hepatitis
–Allergic reactions-Pruritis
–GI disturbances
–Flulike symptoms
RIFAMPICIN

27. PYRAZINAMIDE
MECHANISM OF ACTION
PYRAZINAMIDE
PYRAZINOIC ACID
mycolicacid synthesis Disrupts
inhibition cell
membrane
integrity
Tuberculocidal effect
•Pyrazinoicacid Highly effective in
acid environment and inflammatory
conditions
•PHARMACOKINETICS:
–Rapidly absorbed from GI tract
–It is widely distributed in the
body and achieves a concentration
in the CSF equal to the plasma
levels.
–Deaminatedin theliver.
–Degradation products and he free
drug are eliminated in urine
•ADVERSE EFFECTS:
–Hyperuricemia(precipitating
gout)
–Metallic state
–Sulfurous eructation's
–Toxic hepatitis (Not dose related)
–Arthralgia,nausea,vomiting,anorex
ia,malaise,
–Rarely photosensitivity reaction
•Used in both Extrapulmonary and
pulmonary TB

28. ETHAMBUTOL
MECHANISM OF ACTION
Ethambutol
Inhibits Arabinosyltransferase
Inhibits Synthesis of ARABINO
GLYCANS
Inhibits cell wall synthesis
•Only tuberculostatic among all first line
Anti tubercular agents.
•Suppress the emergence of resistance
•Hastens sputum conversion
•PHARMACOKINETICS:
–70% is absorbed
–Penetrates into erythrocytes, gets
deposited, and released into
circulation
–50% of oral dose excreted
unchanged in urine with in 24h
–15% excreted in the form of two
metabolites
–Accumulates in presence of renal
damage
•ADVERSE EFFECTS:
–Retrobulbular optic neuritis on
prolonged therapy which results in
decrease visual acuity.
–Others are
Nausea,headache,anorexia,allergic
reactions,andconfusion
•If any visual disturbances are seen in
the patient,Ethambutolshould be
removed from patient’s regimen

29. STREPTOMYCIN
MECHANISM OF ACTION
STREPTOMYCIN
Binds to 30S subuintof
ribosomes
Which results in production
Abnormal proteins
Accumulates in
mycobacterium
Destruction of
mycobacterium
•PHARMACOKINETICS:
–Not absorbed orally and must be
given in IM. Well absorbed when
instilled in intrapleurally
–It doesn’t cross BBB. However,
high concentrations are seen in
CSF during meningeal
inflammation.
–It is mainly concentrated in
kidneys, liver, and skeletal
tissues.
–It crosses Placental barrier,
–Excreted unchanged by GFR. And
approximately 50-60% of drug is
eliminated in urine in active form
within 24h.
•ADVERSE EFFECTS:
–Pain at the site of injection
–8
th
cranial nerve damage
–Neuromuscular blockade
–Nephrotoxicityand ototoxicity
–Super infections with
Staphylococcus aureusand
candida

30. THIACETAZONE
•Because of its low cost and
efficacy combination with H it
was once used in 1
st
line drugs
for TB.
•It is orally active , rapidly
diffuses into various body
tissues ,Partly metabolized in
liver and about 40% excreted
unchanged in urine with t
1/212h.
•Itisnolongerusednowbecause
ofitsExfoliativedermatitis
Stevens-Jhonson syndrome
ototoxicityandlife-threatening
hypersensitivity reactions
(Hepatitis, neutropenia,
thrombocytopenia).
PARA-AMINO SALICYLIC ACID(PAS)
•Itischemicallyaswellasin
mechanismofactionrelatedto
Sulfonamides.Itisnotactiveagainst
otherbacteriaandthereasonmaybe
duetothedifferenceintheaffinity
offolatesynthetaseofTBandother
bacteria.
•Absorbedcompletelybyoralroute
anddistributedalloverthebody
exceptCSF,about50%PASis
aceylatedandcompetes with
acetylationofH-Prolongsits
t
1/2.ExcretedrapidlybyGlomerular
filtrationandtubularsecretion.
•Patientacceptibilityispoorbecause
offrequentanorexia,nauseaand
epigastricpainandotheradverse
effectsareblooddyscrasias,fever
rash,etc.,.
SECOND LINE AGENTS
These alternative drugs that are useful in cases of resistance to 1
st
line drugs

31. CYCLOSERINE
•MECHANISM OFACTION:Itis
D-alanineanalogueandhenceit
replacesalaninewhichisessential
forcellwallsynthesis.
•PHARMACOKINETICS :Rapidly
absorbedfromgut,distributed
throughoutthebody(csfand
plasmaconcentrationsareequalin
meningitiscondition).50%oforally
administereddosegetsexcreted
inurineinunchangedformand
65%isexcretedbykidneyswithin
72h.
•Broadspectrumantibioticanditis
tuberculostatic.
•Itiseffectiveagainsttubercle
bacilliresistanttoHorSand
againstatypicalmycobacterium.
•ADVERSEEFFECTS:
–Peripheralneuropathy,
–Ataxia
–Delusions,Nervousnessetc.,.
ethionamide
•MECHANISM OFACTION:
Blocksthesynthesisof
mycolicacidsanditisa
tuberculostaticdrug.
•PHARMACOKINETICS :
ABSORPTION issimilartoH,
Metabolizedinliverandonly
1%excretedunchangedin
urine
•BecauseofitsIntensegastric
irritationandneurological
toxicity(opticandperipheral
neuritis)andhepatotoxicity,it
israrelyused,asin
recommendeddoseof1mg/kg.
•ADVERSEEFFECTS:
•Purpura,
•GIdisturbances
•Toxichepatitis
•Miscellaneous:
Gynecomastia,
Mennorhagiaetc.,.

32. Fluoroquinolones(CIPROFLOXACIN
and OFLOXACIN):
•Thefluoroquinolonesareuseful
newadditiontotheanti
tubercular drugs.
Ciprofloxacin,Ofloxacinand
sparfloxacinareactiveagainst
M.tuberculosisaswellas
M.aviumcomplex.
•Theypenetratecellsandkill
mycobacteria lodged in
macrophagesalso.
•Because oftheirgood
tolerability,theyarebeing
increasingly included
combinationregimensagainst
MDRTBandMACinfection
HIVpatients.
•Thegenerallyemployeddoses
areciprofloxacin1500mg/day
andofloxacin800mg/dayin2
divideddoses.Sparfloxacinis
more active against
mycobacteriainvitro,buthas
beenusedclinicallytoalesser
extent.
Macrolideantibiotics
(CLARITHROMYCIN AND
AZITHROMYCN:
•These newermacrolide
antibioticsaremostactive
against nontubercular
mycobacteriaincludingMAC,
M.fortuitum,M.Kansasii
andM.marinum.
•Clarithromycinhasbeen
usedtoagreaterextent
becauseitsMICvaluesare
lower,butazithromycinmay
beequallyefficaciousdueto
itshighertissueand
intracellularlevels.
•combinationwithother
drugs.InAIDSpatients,
life-long therapy is
required-may cause
ototoxicity
NEWER DRUGS

33. MANAGEMENT OF TB
•Aims:
1.Tokillthedividingbacteriainthelunglesions.
2.Tokillthepersisterssoastoavoidrelapseandensuretotalcure
3.Topreventemergenceofdrugresistance
Andbasedon
treatmentisgiven
PATIENT
NEWLY
AFFECTED
PATIENTS
ACTIVE TB LATENT TB
PREVIOUSLY TREATED
PATIENTS AND BASED ON
DRUG SENSITIVITY TEST
LESS SENSITIVE
MORE
SENSITIVE

35. FOR NEWLY INFECTED PATIENTS
FORPREVIOUSLY TREATED PATIENTS WITH LOW
RESISTANCE TO DRUGS
INTENSIVEPHASE
(2months)
H,R,Z,E+VitB
6
CONTINUOUS
PHASE
(4months)
H,R+VIT B
6
INTENSIVE PHASE
(3months)
HRZES HRZE
+
Pyridoxine 100mg/day
CONTINUOUS PHASE
(5months)
HRZ + Pyridoxine
100mg/day

36. MULTI DRUG RESISTANT OR HIGHLY
RESISTANT
INTENSIVE PHASE
(6months)
Z
E
AMIKACIN/KANAMYCI
N
OFLOXACIN/LEVOFLO
XACIN
CYCLOSERINE
ETHIONAMIDE+
PYRIDOXINE
CONTINUOUS PHASE
(12-18months)
E
OFLOXACIN/LEVOFLOXA
CIN
CYCLOSERINE
ETHIONAMIDE+
PYRIDOXINE
For H resistance: R+Z+E for 12Months
For R resistance: H+Z+E for 12Months
For both H+R resistance: Z+E+S(Et)+CIROFLOXACIN(OR OFLOXACIB
OR LEVOFLOXACIN),for 12-18 Months

37. DOT’s REGIMEN OF RNTCP(REVISED NATIONAL TUBERCULOSIS
CONTROL PROGRAMME) -1997

38. TB in special population
•TUBERCULOSISINPREGNANTWOMEN:
•H,RandZtobesafetothefoetusand
recommendthestandard6month(2HRZ
+4HR)regimenforpregnantwomenwith
TB.Ecanbeaddedduringlatebutnot
earlypregnancy.Siscontraindicated.
•India,itisadvisedtoavoidZ,andto
treatpregnantTBpatientswith2HRE+
7HR(total9months).TreatmentofTB
shouldnotbewithheldordelayed
becauseofpregnancy.
•TREATMENTOFBREASTFEEDINGWOMEN:
•AllantiTBdrugsarecompatiblewith
breastfeeding;fullcourseshouldbe
giventothemother,butthebaby
shouldbewatched.Theinfantshould
receiveBCGvaccinationandisoniazid
prophylaxis.
•IncaseofM.tuberculosisinfection,drugsusedarethesameasinnon-HIVcases,
butthedurationislongerandatleast4drugsareused.
•Initialtherapywith2monthHRZEisstartedimmediatelyonthediagnosisofTB,
andisfollowedbyacontinuationphaseofHRfor7months(total9months).
•Alternatively,3drugs(HRE)aregivenfor4monthsinthecontinuationphase.
Pyridoxine25-50mg/dayisroutinelygivenalongwithHtocounteractits
neurologicalsideeffects,whicharemorelikelyinAIDSpatients.
•MDR-TBinHIV-AIDSpatientsshouldbetreatedforatotalof18-24
monthsorfor12monthsaftersputumsmearnegativity.
Tb in hiv

39. Treatment of TB in MAC
•Mycobacteriumaviumcomplex(MAC)infectioniscommonin
HIV-AIDSpatients,particularlywhentheCD4countdropsto<
100cells/J.IL
•Clarithromycin/azithromycinarethemostactivedrugsagainst
MAC.Afavouredregimenconsistsofanintensivephaseofat
least4drugsclarithromycin/azithromycin+ethambutol
rifabutin+oneFQ/clofazimine/ethionamidegivenfor2-6
months(durationisresponsebased).
•Followedby2drugmaintenancephasewithclarithromycin/
azithromycin+ethambutol/oneFQ/rifabutinforatleast12
monthsoreYenlifelong.
•However,anyadditionalbenefitoftheinitial4drugintensive
phaseisunproven.Clarithromycininhibitsthemetabolismof
rifabutin.