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PHARMACOLOGYOF

ANTITUBERCULAR

DRUGS

[First Line]

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India accounts for 1/5India accounts for 1/5thth of all TBof all TBincidence cases in the worldincidence cases in the world

Non-HBCs

20%

Pakistan

3%

Ethiopia

3%

Philippines

3%

South Africa

5%Bangladesh

4%

Nigeria

5%

Indonesia

6%

China

14%

India

20%

Other 13 HBCs

16%

Source: WHO Global Report 2009

Global annual incidence = 9.4 million

India annual incidence = 1.98 million

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Tuberculosis is a chronic infectious disease causedby Mycobacterium tuberculosis.

Tuberculosis is the worlds second commonest

cause of death from infectious disease, afterAIDS.

The mode of infection is mainly through inhalation

of droplets of infected secretions.Tuberculosis is a difficult disease to treat.

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Mycobacterium tuberculosisGram+ve bacilli

A.F.B => when stained by Carbol Fuschin by

Z-N Stain they resist decolorisation by 25%H2S04 & Abs.alcoholCell wall is lipid rich with mycolic acid which isessential & unique component

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Diff. Subpopulation ofM. Tb

[Difficult to treat]

Rapid GrowingRapid Growing

Slow growingSlow growing

SpurtersSpurters Dormant Dormant

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Difficult to treat:

1. Most antibiotics are effective against rapidly growingorganism in contrast to M.tb slow growing

2 Mycobacterium Cell can be dormant, thus completelyresistant to many antibiotics or killed very slowly byfew drugs

3 The lipid rich mycobacterium Cell wall isimpermeable to many drugs.

4 A substantial proportion are intracellular &chemotherapeutic agents penetrate poorly

5 Mycobacterium develop resistance to any single drug

6 Caseation & fibrosis block the b.v. supplyingnecrotic area thus penetration of antituberculardrug difficult

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Difficult to treat:1

Most antibioticsare effective

against rapidlygrowing organism incontrast to M.tb

slow growing

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Difficult to treat:

1. Slow growing

2.Mycobacterium can

be dormant, thuscompletely resistant

to many antibioticsor killed very slowlyby few drugs

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Difficult to treat:1. Slow growing

2. Dormant,

3.The lipid rich

mycobacteriumCell wall is

impermeable tomany drugs.

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Difficult to treat:

1. Slow growing

2. Dormant,3. Impermeable

3A substantial

proportion areintracellular &

chemotherapeuticagents penetratepoorly

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Difficult to treat:

1. Slow growing

2. Dormant,3. Impermeable

4. Intracellular

5.Mycobacteriumdevelop resistance

to any single drug

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Difficult to treat:

1. Slow growing

2. Dormant,3. Impermeable

4. Intracellular

5. Resistance to any single drug

6. Caseation & fibrosis block the b.v

6. Caseation & fibrosis block

the b.v. supplying necroticarea-penetration ofantitubercular drug

difficult

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Classification of Antitubercular

Drugs

First line Drug (Essential AntiTB)High Anti TB effect

Acceptable degree of toxicityUsed routinely.Lower cost

Used in DOTS regimen[RNTCP]

- ISONIAZID (H)- RIFAMPICIN (R)- PYRAZINAMIDE (Z)- ETHAMBUTOL (E)- Streptomycin(S)

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Second line drugs[MDR & XDR TB]

Thiacetazone

Paraaminosalicylic acid

Ethionamide

Cycloserine Kanamycin

Amikacin Capreomycin

Low anti-TBeffect

-High toxicityor both

Used in specialcircumstancesonly

-

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Newer second line drugs

[MDR&XDR] Ciprofloxacin

Ofloxacin

Clarithromycin

Rifabutin & Rifapentin

Linezolid

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Rationale behind Combination

Therapy

To prevent emergence of resistantbacilli

Drugs like H& R act synergistically

Z is more active during theinflammatory states

Duration of treatment is reduced

To act simultaneously with allsubpopulation of Mycobacterium

tuberculosis

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Isoniazid

(Isonicotinic acid hydrazide, INH)

[H] It is bactericidal and acts wellagainst rapidly multiplying

organisms.

Acts on both extracellular andintracellular organisms.

Mechanism of action:

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INH-MOA

INH[Prodrug]

Active

metaboliteCatalase peroxidase

INHIBITS the synthesis of Mycolic acid

Gene inh A

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INH Resistance

1 in 106

-InherentlyresistantMutation of Gene[inh A]

responsible for theproduction of catalase

peroxidase.Bacilli lose INH

concentrating process.

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PHARMACOKINETICS:INH

Well absorbed orally and widelydistributed.

Metabolized in the liver by acetylation[N-acetyl transferase].Rate of acetylation shows Geneticvariation.

Enzyme inhibitor

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PHARMACOKINETICS:INH

Rate of acetylation shows Geneticvariation.

Rapid acetylators 30 to 40% of Indians-t - 1 hour

[Frequency of administration]

Slow acetylators 60 to 70% of Indians t - 3 hours

[Peripheral neuritis more common]

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Adverse effects

Peripheral neuritis and neurologicalmanifestations.

For prophylaxis and treatment Pyridoxine.

Hepatitis

Rashes, fever and arthralgia.

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PERIPHERAL NEUROPATHY

1.INH + Pyridoxal = Hydrazone EXCRETED

2. INH + Pyridoxal Po4

INTERFERES WITH CO-ENZYMEFUNCTION

Prophylaxis:10mg once daily

Tt of established neuropathy:100-200mg/once

daily

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Drug interactions

Aluminium hydroxide inhibitsINH absorption.

INH inhibits metabolismphenytoin, carbamazepine and

diazepam. [Enzyme inhibitor]

PAS inhibits INH metabolism.

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Rifampicin (Rifampin,R)

Isolated from Streptomycesmediteranei.

Bactericidal and acts on bothintracellular and extracellularbacilli.

It is the only drug acting

against persisters.

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Rifampicin (Rifampin,R)

Mechanism of action: It binds to subunit of

DNA dependent RNApolymerase Inhibits RNA synthesis of

bacteria.

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Resistance:Rifampicin

Mutation in the rpo gene on RNApolymerase, thereby preventing the

binding of the drug to RNApolymerase.

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Pharmacokinetics[R]Well absorbed orally and widelydistributed [Empty stomach].

Metabolized in liver to an active

deacetylated metabolite.Rifampicin and metaboliteundergoes enterohepatic

circulation.Enzyme inducer

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Adverse effects:[R]

Hepatitis

Respiratory syndrome[Breathlessness]

Cutaneous syndrome[Pruritus, flushing] Flu syndrome[Chills, fever]

Abdominal syndrome[Nausea, diarrhoea, colic]

Enzyme inducer-[PI in HIV] ORANGE RED DISCOLORATION OFURINE & SECRETIONS.[Precaution]

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Drug interactions: [R]

Enzyme inducer. Enhances the metabolism of Itself,

Warfarin, Oral contraceptives, Corticosteroids, Protease inhibitors,

Digitoxin

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Other uses of [R]

Leprosy Prophylaxis ofMeningococcal and

H.influenzae meningitis andcarrier state.

MRSA

Legionella Brucellosis

Atypical mycobacteriae

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ETHAMBUTOL ( E )

It is tuberculostatic andalso effective againstatypical mycobacteria.

Good action againstrapidly multiplying bacilli.

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ETHAMBUTOL ( E ):

Mechanism of action:

Inhibits the enzyme Arabinosyl

transferase Prevents polymerization of

Arabinoglycans, Arabinoglycans, Essentialcomponent of mycobacterial cell

wall.

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( E ): Resistance:

Mutations take place in the emb B gene

that encodes the arabinosyl transferaseenzyme.

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(E ) Pharmacokinetics:

Well absorbed from the gut andwidely distributed.

Penetrates meninges incompletely.

Stored temporarily in

Erythrocytes.About 50% of the drug iseliminated unchanged in the urine..

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( E ): Adverse effects:

Impairment of visual acuity,field of vision and colour visiondue to retro bulbar neuritis.

Difficult to detect in children

May precipitate gouty

arthritis.[decreased urateexcretion]

Nausea, rashes & fever.

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Pyrazinamide ( Z )

Weak tuberculocidal. Highly effective against

- Intracellular bacilli.

-Bacilli at inflammatory sites.

[pH is acidic at these sites]

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MOA OF Z

Pyrazinamide

Mycobacterial Pyrazinamidase

Pyrazinoic Acid

Inhibits Mycolic Acid SynthesisInhibits fatty acid synthase I enzyme

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PharmacokineticsWell absorbed orally andwidely distributed.

Good penetration in CSF.

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Resistance:Mutation in gene pcn A that

encodes pyrazinamidase enzyme.

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Adverse effects

Hepatotoxicity [Related to nicotinamide]

Hyperuricemia Nausea,Vomiting,Anorexia,

Arthralgia, loss of diabetescontrol.

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Streptomycin ( S ):

It is bactericidal and effectiveagainst extracellular bacilli only.

Does not cross to the CSF and

poor action in acidic medium. Indicated in CAT II[Previouslytreated]