PHARMACOLOGY OF ANTITUBERCULAR DRUGS [First Line]

India accounts for 1/5th of all TB incidence cases in the world

Global annual incidence = 9.4 million India annual incidence = 1.98 million

Non-HBCs 20%

India 20%

Other 13 HBCs 16%

China 14%

Philippines 3% Ethiopia 3% Pakistan 3%

Indonesia 6% Nigeria 5%

Bangladesh 4%

South Africa 5%

Source: WHO Global Report 2009

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis. Tuberculosis is the worlds second commonest cause of death from infectious disease, after AIDS. The mode of infection is mainly through inhalation of droplets of infected secretions. Tuberculosis is a difficult disease to treat.

Mycobacterium tuberculosis
Gram+ve bacilli

A.F.B => when stained by Carbol Fuschin by Z-N Stain they resist decolorisation by 25% H2S04 & Abs.alcohol Cell wall is lipid rich with mycolic acid which is essential & unique component

Diff. Subpopulation of M. Tb [Difficult to treat]

Rapid Growing

Spurters

Dormant

Slow growing

Difficult to treat:
1.

Most antibiotics are effective against rapidly growing organism in contrast to M.tb slow growing Mycobacterium Cell can be dormant, thus completely resistant to many antibiotics or killed very slowly by few drugs The lipid rich mycobacterium Cell wall is impermeable to many drugs. A substantial proportion are intracellular & chemotherapeutic agents penetrate poorly Mycobacterium develop resistance to any single drug Caseation & fibrosis block the b.v. supplying necrotic area thus penetration of antitubercular drug difficult

2 3 4 5 6

Difficult to treat:1

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

Difficult to treat:
1. Slow growing

2.Mycobacterium can be dormant, thus completely resistant to many antibiotics or killed very slowly by few drugs

Difficult to treat:
1.
2. Slow growing Dormant,

3.The lipid rich mycobacterium Cell wall is impermeable to many drugs.

Difficult to treat:
1.
2. 3. Slow growing Dormant, Impermeable

3 A substantial proportion are intracellular & chemotherapeutic agents penetrate poorly

Difficult to treat:
1.
2. 3. 4. Slow growing Dormant, Impermeable Intracellular

5.Mycobacterium develop resistance to any single drug

Difficult to treat:
1.
2. 3. 4. 5. 6. Slow growing Dormant, Impermeable Intracellular Resistance to any single drug Caseation & fibrosis block the b.v

6.

Caseation & fibrosis block the b.v. supplying necrotic area-penetration of antitubercular drug difficult

Classification of Antitubercular Drugs First line Drug (Essential AntiTB)

High Anti TB effect

Acceptable degree of toxicity

Used routinely. Lower cost

Used in DOTS regimen[RNTCP]

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

Second line drugs[MDR & XDR TB]

Thiacetazone Paraaminosalicylic acid Low anti-TB Ethionamide effect Cycloserine -High toxicity or both Kanamycin Used in special Amikacin circumstances Capreomycin only
-

Newer second line drugs [MDR&XDR] Ciprofloxacin Ofloxacin Clarithromycin Rifabutin & Rifapentin Linezolid

Rationale behind Combination Therapy To prevent emergence of resistant bacilli Drugs like H& R act synergistically Z is more active during the inflammatory states Duration of treatment is reduced To act simultaneously with all subpopulation of Mycobacterium tuberculosis

Isoniazid (Isonicotinic acid hydrazide, INH) [H]

It is bactericidal and acts well against rapidly multiplying organisms. Acts on both extracellular and intracellular organisms. Mechanism of action:

INH-MOA
INH
[Prodrug]

Catalase peroxidase
Gene inh A

Active metabolite

INHIBITS the synthesis of Mycolic acid

INH Resistance

1 in -Inherently resistant Mutation of Gene[inh A] responsible for the production of catalase peroxidase. Bacilli lose INH concentrating process.

6 10

PHARMACOKINETICS:INH

Well absorbed orally and widely distributed. Metabolized in the liver by acetylation [N-acetyl transferase]. Rate of acetylation shows Genetic variation. Enzyme inhibitor

PHARMACOKINETICS:INH Rate of acetylation shows Genetic variation.

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]

Adverse effects Peripheral neuritis and neurological manifestations. For prophylaxis and treatment Pyridoxine. Hepatitis Rashes, fever and arthralgia.

PERIPHERAL NEUROPATHY 1.INH + Pyridoxal = Hydrazone EXCRETED 2. INH + Pyridoxal Po4 INTERFERES WITH CO-ENZYME FUNCTION Prophylaxis:10mg once daily
Tt of established neuropathy:100-200mg/once daily

Drug interactions
Aluminium hydroxide inhibits INH absorption. INH inhibits metabolism phenytoin, carbamazepine and diazepam. [Enzyme inhibitor] PAS inhibits INH metabolism.

Rifampicin (Rifampin,R)
Isolated from Streptomyces mediteranei. Bactericidal and acts on both intracellular and extracellular bacilli. It is the only drug acting against persisters.

Rifampicin (Rifampin,R) Mechanism of action: It binds to subunit of DNA dependent RNA polymerase Inhibits RNA synthesis of bacteria.

Resistance:Rifampicin

Mutation in the rpo gene on RNA polymerase, thereby preventing the binding of the drug to RNA polymerase.

Pharmacokinetics[R]
Well absorbed orally and widely distributed [Empty stomach]. Metabolized in liver to an active deacetylated metabolite. Rifampicin and metabolite undergoes enterohepatic circulation. Enzyme inducer

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 OF URINE & SECRETIONS.[Precaution]

Drug interactions: [R]

Enhances
Enzyme inducer.

Itself, Warfarin, Oral contraceptives, Corticosteroids, Protease inhibitors, Digitoxin

the metabolism of

Other uses of [R]

Leprosy Prophylaxis of Meningococcal and H.influenzae meningitis and carrier state. MRSA Legionella Brucellosis Atypical mycobacteriae

ETHAMBUTOL ( E ) It is tuberculostatic and also effective against atypical mycobacteria. Good action against rapidly multiplying bacilli.

ETHAMBUTOL ( E ): Mechanism of action: Inhibits the enzyme Arabinosyl transferase Prevents polymerization of Arabinoglycans, Arabinoglycans, Essential component of mycobacterial cell wall.

( E ): Resistance:

Mutations take place in the emb B gene that encodes the arabinosyl transferase enzyme.

( E ) Pharmacokinetics:

Well absorbed from the gut and widely distributed. Penetrates meninges incompletely. Stored temporarily in Erythrocytes. About 50% of the drug is eliminated unchanged in the urine..

( E ): Adverse effects:
Impairment of visual acuity, field of vision and colour vision due to retro bulbar neuritis. Difficult to detect in children May precipitate gouty arthritis.[decreased urate excretion] Nausea, rashes & fever.

Pyrazinamide ( Z )
Weak tuberculocidal. Highly effective against - Intracellular bacilli. -Bacilli at inflammatory sites. [pH is acidic at these sites]

MOA OF Z
Pyrazinamide

Mycobacterial

Pyrazinamidase

Pyrazinoic Acid
Inhibits fatty acid synthase I enzyme

Inhibits Mycolic Acid Synthesis

Pharmacokinetics Well absorbed orally and widely distributed. Good penetration in CSF.

Resistance: Mutation in gene pcn A that encodes pyrazinamidase enzyme.

Adverse effects

Hepatotoxicity Hyperuricemia Nausea,Vomiting,Anorexia, Arthralgia, loss of diabetes control.

[Related to nicotinamide]

Streptomycin ( S ):
It is bactericidal and effective against extracellular bacilli only. Does not cross to the CSF and poor action in acidic medium. Indicated in CAT II[Previously treated]