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Anti-Tubercular DrugsBy Dr.Naveen.

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AntiTubercular Drugs

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HISTORY OF TUBERCULOSIS

First Sighting (2400 BC): Egyptian MummiesFirst Sighting (2400 BC): Egyptian Mummies

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HISTORY OF TUBERCULOSIS

Robert Koch(1843-1910) Able to see TB!Able to see TB! In 1882

Robert Koch: Nobel Prize inmedicine in 1905

Streptomycin: 1st AMAadministered in 1944.

INH: 1954

Rifampin: early 1970s

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Tuberculosis-World wide

- 2.5 M deaths / year.

- 8 M new cases are reported each year

- Most common cause of death due toa single infectious agent.

- Up to 1/2 of the world's population isinfected with TB.

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Tuberculosis-World wide

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Tuberculosis

India- 0.5 M deaths / year.

2 M active cases / year.

Current concerns- AIDS & TB

MDRTB (Multi Drug Resistant TB)

Immigration Deteriorating health infrastructure.

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Anti-Tubercular agents

First Line Drugs-

High Efficacy Acceptable Toxicity.

1. ISONIAZID- H

2. RIFAMPIN- R 3. ETHAMBUTOL- E 4. STREPTOMYCIN- S 5. PYRAZINAMIDE- Z

2HRZE 4HR

2ND Line Drugs-

Low Efficacy High Toxicity

1.AMINOGLYCOCIDES-AMIKACIN / Kanamycin

2. Thiomides-Ethionamide/ Prothionamide3. Polypeptide- Capreomycin4. FQ- Cipro/ Oflox/ Spar/ Gati/

Moxi

5. PAS6. Macrolides- Azithro/ Clar.7. Cycloserine8. Rifabutin9. Linezolid10. IFN-

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1st Line Antitubercular Drug- INH

INH [H]

Isonicotinic acid hydrazide

Spectrum-

M.tuberculosis / M.

Kansasii.

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INH- MOA

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INH- MOA

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INHResistance-

y High level- mutations in kat G

y Low level- mutations in inh A

y Cross Resistance- Ethionamide

y Resistant bacilli are less virulent

y 1 in 106 R to INH

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INH Pk

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INH

ADR-1.Skin

H.S / DLE / Rashes

2.Peripheral Neuropathy Prevent & treat - vit B6

3.Hepatitis

4.Hematotoxicity

5.Arthritis

6.CNS- treat - vit B6(100mg/ day)

Drug interactions- 1. Al (OH)3 [Antacid]

2. INH is somalenzyme inhibitor

Phenytoin; CBZ; diazepam;

Warfarin

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Therapeutic Uses- INH

Tuberculosis Adults

INH dose

Children

INH dose

Prophylaxis 300mg / day X6- 9 months

10mg / kg/ dayX 6- 9 months

Treatment 5mg / kg / day( Max. of

300mg / day)

10- 20mg / kg/day.

Max. of 300mg

/ day)

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Mycobacterium tuberculosis

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1st Line Antitubercular DrugRifampicin, Rifampin [R]

y Rifamycin semi- syntheticderivatives-

Rifampin, Rifabutin,Rifapentine

y Streptomyces mediterranei

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Rifampin [R] - Spectrum

y Gram +ve- S.aureus y Gram-ve-

N.meningitides

H.i / E.coli / Pseudo / Proteus / Kleb. /Legionella

y Mycobact.- M.tuberculosis / M.kansasii / M.intracellulare /

M.avium / M.scrofulaceum.

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Rifampin [R]

MOA-1. Inhibit DNA dependent RNA Polymerases (B-

subunit)

2. Effective- `SPURTERS

3. Cidal- intra / extracellular.Resistance-

y Single Step Mutation (Rapid)

y Mutation in rpo B

y 1 in 107 to 108 bacilli

y Resistant are less virulent

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Pk ( Rifampin)

y Good oral absorb. &

Distribution [ BBB] y Orange red colored body

fluids

y Deacetylated metabolite

(Liver) yEnterohepatic circulation

y t = 2-5 hrs.

yRifampin is somal

enzyme inducer[+ CYP1A2 / 2C9 / 2C19 / 3A4]

Drug interactions-

enzyme induction

[ levels of Warfarin /

OCPs / SU /corticosteroids / Opioids /

PI / NNRTI, Digoxin /

Propranolol / Verapamil]

yPAS Rifampin absorb.

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ADR- ( Rifampin)

1. Hepatitis

2. Flu-like syndrome

3. GIT

4. Skin

5. Hemat.

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Therapeutic Uses- Rifampin 1. Tuberculosis

Prophylaxis- R + Z x 2 mth; R x 4 mth

Treatment-Adults (600mg/d)

2. Chemoprophylaxis of Meningitis

3. Staph. Infections- Endocardidtis /

Osteomyelitis 4. Brucellosis 5. Chronic Furunculosis

6. Leprosy 7. Legionnaires disease 8. Diphtheroids.

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1st Line Antitubercular Drug

Pyrazinamide [Z]

Chemically INH

Spectrum- M.tuberculosisonly

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Pyrazinamide [Z]

Cidal

Active in acidic environment

Good activity againstintracellularbacilli

Resistance-

Gene mutation

Rapid

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Pyrazinamide [Z]

Pk-

Good oral absorb. &

Distribution ( BBB) t = 10 hrs

Liver metab.

kidney elimination

ADR-

1. Hepatotoxicity

2. Hyperuricemia

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Pyrazinamide [Z]-Therapeutic Uses

Treatment of TB-

Adults & child- 15-30 mg/kg/dayOD doses.

(Not to exceed 2gm/day)

Shortened regimen to 6 months

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1s Line Antitubercular DrugEthambutol [E]

Spectrum-

M.tuberculosis, M.kansasii,MAC

MOA

Inhibit Arabinosyl transferas

Static

Resistance

Mutations in emb A gene Slow

No cross Resistance

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Ethambutol [E]

Pk-

Good oral absorb. &Distribution.

Renal elimination

t

ADR- Optic Neuritis

Minor rash,

arthalgia, uric acid,fever

Contraindication-children < 5 years.

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Ethambutol [E]- ADR

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Ethambutol [E]- Therapeutic Use-

Treatment of T.B- Adult dose- 15 mg/kg/day

Child. Dose- 10-15 mg/kg/day

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1st Line Antitubercular Drug

Streptomycin [S] AminoglycosideStreptomyces griseus

1st clinically available

drug for TBSpectrum-

Gram negative bacilli

M.tuberculosis,M.kansasii

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Streptomycin [S]

MOA- Protein synthesis

inhibitor

Cidal

Poor intracellular killing

Not effective in acidic

environment

Resistance- Mutations

Rapid

1 in 10

8

to 1 in 106

longer therapy single

drug- Resistance

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Streptomycin [S]

ADR-

1. Ototoxicity

2. Nephrotoxicity

Therapeutic Uses

Treatment of TB- in serious TB Adult dose- 15-mg/kg/day IM-

BD doses X 2-3 mths

Child. Dose- 20-40mg/kg/day IM- BD doses X 2-3 mths

Not to exceed 1 gm / day

C/I- PREGNANCY

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2nd Line Anti-Tubercular agents

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2nd Line Anti-Tubercular agents

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2nd Line Anti-Tubercular agentsCapreomycin

S.capreolus

Cyclic peptide

IM inj.

Cross Resistance with Kanamycin /

Neomycin

ADR- Nephrotoxic / ototoxic.

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MCQ

Q. 30 yr. Old pregnant lady develops TB.

Which of the drug should not be used?(A.I-2004)

1. H

2. R3. S

4. E

Ans: 3. S

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MCQQ. All the following are true about Antitubercular

treatment Except- (AIIMS 04)a. Flu-like syndrome in patients taking R on daily

basis.

b. E- accumulates in Renal failure

c. Hyperuricemia-ADR ofZ

d. Red-Green color impairment is an early sign ofE induced optic neuritis

Ans: a. Flu-like syndrome in patients taking R ondaily basis.

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MCQ

Q. Least Toxic AntiTubercular drug is-

(AIIMS 90)a. R

b. Cycloserine

c. Thiacetazone

d. E

Ans: d. E

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MCQ

Q. One of the following is not a Hepatotoxic

AntiTubercular drug-a. R

b. Z

c. H

d. S

Ans: d. Streptomycin