Prepared basically for D.Pharm and B.Pharm Students

1. Antitubercular Drug
Mr.H.N.Singh(AssistantProfessor)
SchoolofPharmacy,ShardaUniversity
GreaterNoida(UP)

2. Introduction
• Tuberculosis - most important communicable
diseasein the world.
• Tuberculosis is an infectious disease caused
by “Mycobacterium tuberculosis”.
• The drugs which are used in the treatment of
tuberculosis are calledAntitubercular drugs.
• Symptoms: fever, sweating, cough and
headache appear slowly and are mild in
nature.

3. Introduction
• Combinations of two or moredrugs
– to overcome theseobstacles
– to prevent emergence of resistance duringthe
course of therapy
• Theresponse of mycobacterial infections to
chemotherapy is slow - treatment must be
administered for months to years,depending
on which drugs areused

4. Classification
• AntiTBdrugs canbe divided into 3groups
– First Line: high antitubercular efficacy aswell as
low toxicity – routinely used
• Isoniazid (H) ,Rifampin (R), Pyrazinamide(Z),
Ethambutol (E), Streptomycin (S) -HRZES
– Second Line: low antitubercular efficacy orhigh
toxicity
• ParaminosalicylicAcid, Cycloserine, Kanamycin,
Amikacin.

5. Classification
Newer Drugs: Ciprofloxacin, Olfloxacin,
Clarithromycin, Azithromycin

6. FirstLineDrug
Thesedrugshavehighantitubercularefficacyaswell
aslowtoxicity

7. ISONIAZID
• Isonicotinic acidhydrazide
• Most active drug for thetreatment
of tuberculosis
• freely soluble in water
• bactericidal for activelygrowing
tubercle bacilli
• penetrates into macrophages andis
active against both extracellular
andintracellular organisms.

8. Mechanism of Action&
Basis ofResistance
• inhibits synthesis of mycolic acids -essential
components of mycobacterial cellwalls.
• Higly selective for mycobacterium
• Resistance
– Its prodrug – activated by enzymecatalase-peroxidase
– No crossresistance occurs with otherantitubercular
drug
– Always given in combination

9. Properties
• It occurs as a white crystalline powder.
• It is odourless and has sweet taste.
• It is soluble in water.
• It is incompatible with aldehyde& ketone.
• Storage: It is affected by light hence it is
stored in tightly closed light resistant
containers.

10. Uses
• It is used in the treatment of pulmonary
tuberculosis.
• It is used in the treatment of meningitis&
genitourinalinfection.
• Preparations: Isoniazide tablet
Isoniazide elixir
Isoniazide & Ethambutol tablet
Isoniazide & Rifampicine tablet

11. Brand Name
• Isonex
• Isokin
• Zonazide
• Hycozid
• Isonicazide
• Isozide
• Tubizid

12. RIFAMPIN
• Semisynthetic derivative of rifamycin-produced
by Streptomycesmediterranei
• Active in vitro against gram-positiveand gram-
negative cocci, some enteric bacteria,
mycobacteria, and chlamydiae.
• Rapidly selected out if rifampin is used asasingle
drug – must be used in combination
• no cross-resistance to other classesof
antimicrobial drugs

13. Mechanism of Action &Resistance
• Binds to the bacterialDNA-dependent RNA
polymerase - inhibits RNAsynthesis
• Bactericidal for mycobacteria
• Readily penetrates most tissues and penetratesinto
phagocytic cells
• Cankill organisms that are poorly accessibletomany
other drugs
– Intracellular organisms
– sequestered in abscessesand lung cavities
• Resistance: mutations result in reduced bindingof
rifampin to RNApolymerase

14. Pharmacokinetics
• Well absorbed after oral administrationand
excreted mainly through the liver intobile
• Distributed widely in body fluids andtissues.
• Relatively highly protein bound
• Brand Names: Rifamycin, Riforal, Rifaprodin,
Rifolidine, Rimactan, Rifamicinum.

15. Uses
• Itisusuallythemosteffectivedrugforadministrationin
associationwithisoniazideintheprimarytreatmentof
pulmonarytuberculosis.
• Someatypical mycobacterial infections andin
Leprosy.

16. ETHAMBUTOL
• Synthetic, water-soluble, heat-stable
compound - dispensed asthe dihydrochloride
salt
• Bacteriostatic
• Additionally itslows the rate of sputum
conversion
• Development of resistance
• Givenin the combination withRHZ

17. Mechanism ofaction
• Inhibits mycobacterial arabinosyltransferases
- an essential component of themycobacterial
cell wall.
• Resistance– due to alteration in targetgene
• No crossresistance with other drug
• Reesistance to ethambutol emerges rapidly
when the drug is used alone - combination
with other antituberculousdrugs

18. PROPERTIES
• Itoccursasawhitecrystallinepowder.
• Itisodourless,bitterintasteandhygroscopicin
nature.
• Itissolubleinwaterandalcoholandinsolublein
chloroformandether.
• Asolutionofehtambutolinwaterisdextrorotatary.
• well absorbed from thegut

19. Use
• Ethambutol hydrochloride is used in
treatment of pulmonary tuberculosis.
• Brand Names:
• Dadibutol,
• Sural,
• Tibutol,
• Etambol,
• Myambutol

20. PYRAZINAMIDE
• Relative of nicotinamide
• Stable and slightly soluble
in water but weekdrug
• Inactive at neutral pH, but
at pH5.5 it inhibitstubercle
bacilli
• Takenup by macrophages
and exerts its activity
• Highly effective duringthe
first 2 month oftherapy

21. Mechanism ofAction
• Pyrazinamide is converted to pyrazinoicacid
(active form) - by mycobacterial
pyrazinamidase.
• Disrupts mycobacterial cell membrane
metabolism and transport functions
• Resistance
– impaired uptake of pyrazinamide
– mutations of enzyme causing conversionof
pyrazinamide to its activeform

22. Properties
• It occurs as a white crystalline powder.
• It is odourless and has slightly bitter taste.
• It is sparingly soluble in water but soluble
in ether and chloroform.
Stability: It is stored in a tightly closed light
resistant container.

23. Clinical Use
• Usedasfront line drug for tuberculosiswith
rifampin andisoniazid
• Normal Dose: 40–50 mg/kg thrice weeklyor
twice-weekly treatment regimens for 6
months.
• Brand Names: Addinamide, Eprazin,
Pyrafat, Pirilene, Tebrazid, Zinamide.

24. Streptomycin
• Part of aminoglycosidesantibiotic
• First clinically useful antitubercular drug,but
lesseffective than INHor rifampin
• Acts only on extracellular bacilli –poor
penetration into cells
• Doesn’t crossthe BBB,but penetrates
tubercular cavities

25. Mechanism of action
• Irreversible inhibitors of proteinsynthesis,
• Bactericidal
• Inside the cell, aminoglycosides bind tospecific
30S-subunit ribosomal proteins and inhibits
protein synthesis
• Resistance
– Inactivation by adenylylation, acetylation,or
phosphorylation
– impaired entry into thecell
– receptor protein on the 30Sribosomal subunit-
deleted or altered asaresult of amutation

26. Pharmacokinetics
• absorbed very poorly from theintact
gastrointestinal tract
• intramuscular injection or usually
administered intravenously asa30- to 60-
minute infusion
• Normal half-life - 2–3 hours, but inrenal
failure patient itreduces to 24-48 hrs

27. Clinical Use
• Treatment of infections resistant to other drugs
• Adults: 20–40 mg/kg/d daily forseveral weeks
– Followed by 1–1.5 gtwo or three times weeklyfor
severalmonths
• Other drugs are alwaysgiven in combinationto
prevent emergence of resistance
• Nontuberculosis speciesof mycobacteriaother
than Mycobacterium avium complex (MAC)
and Mycobacterium kansasii areresistant
• Doseis reduced to half in hemodialysispatient

28. Second LineDrugs

29. Second LineDrugs
• Thisdrugs are considered only when
– resistance to first-lineagents
– failure of clinical response toconventional therapy;
– Serious treatment-limiting adverse drugreactions
Expertguidanceto dealwith the toxiceffectsis required
• Ex:ParaminosalicylicAcid (PAS)
• Ethionamide, Cycloserine both are Static
• Capriomycine,Kanamycin,Amikacin- Cidal
• Newer Drugs: Ciprofloxacin, Ofloxacine,
Clarithromycin,Azithromycin, Rifobutin

30. Para-aminosalicyclic Acid
–structural analogue of paminobenzoic acid(PABA)
–highly specific for M. tuberculosis - not effective
against other mycobacterium species
–Combined with isoniazid - an alternative substrate
and block hepatic acetylation of isoniazid- increasing
free isoniazid levels.
–limited to the treatment of MDR tuberculosis
–Discouraged its use : primary resistance,poor
compliance due to GIintolerance, and lupus like
reactions

31. Ethionamide
• Chemically related to isoniazid
• Blocksthe synthesis of mycolicacids
• Poorly water soluble and available only inoral
form.
• Dosageof 15 mg/kg/d- initial dose of 250 mg
once daily, which is increased in 250-mg
increments to the recommendeddosage
• Intense gastric irritation andneurologic
symptoms aswell ashepatotoxic

32. The drug occurs as a yellow, crystalline substance,
m.p.164-166.
Brand Names: Amidazine, Ethioniamide, Nistotin,
Trecator, Trescatyl, Aetina, Ethimide,Iridocin,Tiomid.

33. Cycloserine
• inhibitor of cell wallsynthesis
• D-4-Amino-3- isozolidinone
• Cleared renally - Doseis reduced to halfin
caseof renal dysfunction
• White to pale yellow hygroscopic, crystalline
material that is soluble in water.
• Pyridoxine, 150 mg/d given in addition toit

34. Brand Names
1. Closina
2. Orientomycin
3. Farmiserina
4. Micoserina
5. Oxamycin
6. Seromycin
7. D-Cycloserine
8. Cycloserinum

35. References
• Pharmaceutical Chemistry II- V.N.Raje
• Taxt book of pharmaceutical organic
chemistry- Mohammed ali
• Essential of medical pharmacology - K.D.Tripathi
6th edition