Drugs Used to treat Tuberculosis

Dr ABID LAGHARI
 Mycobacteria
• Slow-growing bacillus  Dormant forms in
macrophages
 tuberculosis
• Kill 2 million people each year
• Increase incidence due to HIV associated Mycobacteria
• Prevalence of TB in Sri Lanka is 79 per 100 000 population
• 40 years ago drugs were developed
• Now Multi- Drug Resistance(MDR) strains are emerging
• 40 years ago drugs were developed

• Now multi- drug resistance strains are

emerging
 Anti-tubercular drugs
First-line Second-line
– Clarithromycin
– Isoniazid
– Ciprofloxacin
– Rifampicin – Capreomycin
– Ethambutol – Cycloserine
– Pyrazinamide – Kanamycin
– Amikasin
– Streptomycin – streptomycin
 Isoniazid (INH)

• Acts only on Mycobacteria

• Interferes with mycolic acid synthesis

(unique to mycobacterium cell wall)
Isoniazid cont:

• Passes freely to mammalian cell wall

• Effective for intracellular organism

• Bacteriostatic – to resting organism

• Bactericidal – to multiplying organism

Isoniazid cont:

Pharmacokinetics
• Well absorbed from GIT
• Fatty food & aluminum-containing antacids may reduce
absorption
• CSF penetration: 20% of plasma concentration with non-
inflamed meninges 
• Penetrate well into caseous material
• Excretion - urine
Isoniazid cont:

caseous material
Isoniazid cont:

Metabolism
• By acetylation – genetically determined

• Slow acetylation – better response

t ½ - 3h
• Fast acetylation – t ½ - 1h
 Isoniazid cont:

Adverse effect
• Hepatotoxicity
– Elderly, slow acetylators more prone
• Polyneuropathy
– Prevented by concurrent pyridoxine
• Rashes, acne
• Hematological – haemolytic anemia
Isoniazid cont

Acne
 Rifampicin
• Inhibits bacterial DNA-dependent RNA
polymerase

• Bactericidal

• Gram positive and negative

• kill intracellular organism

Rifampicin cont:

Resistance – chemical modification

of DNA-dependent RNA polymerase
 Rifampicin cont:

Pharmacokinetics
• Well absorbed from GIT
• CSF penetration: 10-40% of plasma
concentration with non-inflamed meninges
• Elimination hepatic, renal
Rifampicin cont:

Adverse effects
– Rashes, Hepatotoxicity,
thrombocytopenia

– Mild elevation of liver enzymes -

common
Rifampicin cont:

• Orange discoloration of
urine, sweat, tears

• Potent CYP-P450 inducer-

reduce the serum level of
drugs
• warfarin, estrogen
 Ethambutol

• Inhibits arabinosyl transferase involved in cell wall biosynthesis

• Bacteriostatic to M.tuberculosis

• Resistance develops rapidly if used alone

Ethambutol cont:

Pharmacokinetics

• Well absorbed from GIT

• bioavailability 80%

• CSF penetration poor

• Elimination renal
 Ethambutol cont:

Adverse effects

• Optic retro-bulbar neuritis

– Red-green color blindness → reduced visual acuity
– Dose-related
– Reversible
– May be unilateral Optic retro-bulbar neuritis
 Pyrazinamide
• Interferes with mycobacterial fatty acid synthesis

• Inactivate mycobacterium at acidic PH

• Effective against intracellular organism in macrophages – PH is low

 Pyrazinamide cont:

Pharmacokinetics

• Well absorbed from GIT

• CSF penetration: equal to plasma concentration

• Hepatic metabolism

• Excreation - kidney
Pyrazinamide cont:

Adverse effect

• GI disturbances

• Hepatotoxicity

• Hyperuricemia – gout

• Arthralgia
 Summary
• Isoniazid – bactericidal to rapidly dividing bacteria

• Rifampicin - kill intracellular bacteria

• Ethambutol – bacteriostatic against multiplying bacteria

• Pyrazinamide - kill dormant mycobacteria

 SIX MONTH REGIMEN
Name Doctors Name
Age PMDC Rg No.
Sex
Address
∆ Pulmonary Tuberculosis
Rx
Initial Phase 02 months

Tab. Isoniazed 300 mg as a single dose before breakfast

Tab. Rifampcin 600 mg as a single dose before breakfast
Tab. Pyrazinamide 25 mg / kg per day
Tab. Ethambutal 15 – 25 mg / kg per day
Tab. Pyridoxin 50 mg once daily
Tab. Paracetamol 500 mg 1x4 till fever subsides
Pholcodine cough syrup 02 tspx3

Continuation Phase 04 months

Tab. Isonized 300 mg as a single dose before breakfast

Tab. Rifampcin 600 mg as a single dose before breakfast
Tab. Pyridoxin 50 mg once daily
Signature
 SECOND-LINE DRUGS

– Clarithromycin
– Ciprofloxacin – Capreomycin
– Kanamycin – Cycloserine
– Amikasin
– Streptomycin
– Ethionamide
– Linezolid
– P-Amino salicylic Acid(PAS)
MDR MULTI-DRUG RESISTANCE

The treatment of multi-drug resistant

tuberculosis is specialized, complex and
expensive and should only be undertaken at
recognized centers with experience of
managing such patients
 Important risk factors for drug resistance

 Previous treatment for tuberculosis especially

if prolonged.
 Contact with another patient known to have
drug resistant disease.
 Immigration from an area with a high
incidence of drug resistance.
 HIV seropositivity.
 Substance abuse.
 Homelessness.
 The alternative drugs are usually
considered only
1. In case of resistance to first-line agents
2. In case of failure of clinical response to
conventional therapy.
3. In case of serious treatment-limiting
adverse reaction.
4. When expert guidance is available to
deal with the toxic effects.
 ETHIONAMIDE

Chemically related to Isoniazid and also

blocks the synthesis of mycolic acids.

 It is poorly water soluble and available

only in oral form.
 ETHIONAMIDE
 KINETICS:
 Administered at a dose of 250mg OD
 Which is increased to 250 mg
 Increments to the recommended dose of 1
g/day ( or 15 mg/kg/D).
 SIDE EFFECTS:
 Intense gastric irritation,
 Neurologic symptoms which can be alleviated
by pyridoxine.
 Is also Hepatotopxic.
 Capreomycin (injectable)Aminoglycosides
Capreomycin is a peptide protein
synthesis inhibitor antibiotic obtained
from streptomyces capreolus.

 It is given 1gm daily i/m which results in blood

levels of 10 mcg/ml.
 Which is sufficient to inhibit for many
mycobacteria including MDR strains of M.
tuberculosis.
 Capreomycin (injectable)
SIDE EFFECTS:

 Nephrotoxic

 Ototoxic leading to tinnitus deafness and vestibular

disturbance.

 Local pain, and abscess formation.

 Cyclocerine (Cell wall synthesis inhibitor)

 It is produced by strptomyces orchidaceus.

 it is water soluble and unstable at acid pH.
Inhibits many gm +ve and gm –ve
bacteria

But is exclusively to treat TB

caused by strains of M. tuberculosis
resistant to first line agents.
 Cyclocerine (Cell wall synthesis inhibitor)

MECH OF ACTION:
Cycloserine is structural analog of D-
alanines
Inhibits the incorporation of D- alanine into peptidoglycan
pentapeptide

By inhibiting alanine racemase

Which converts L- alanine to D- alanine ligase.

 Cyclocerine (Cell wall synthesis inhibitor)

KINETICS:

 The drug is widely distributed in tissues.

 After ingestion of 0.25 g of cyclocerine blood levels

reach 20-30mcg/ml

 Which is sufficient to inhibit many strains of

mycobacteria and gm –ve bacteria
 Cyclocerine (Cell wall synthesis inhibitor)

SIDE EFFECTS

 Serious dose related side effects are seen

 CNS toxicity with headaches, tremors and

acute convulsions and psychosis.

 If oral dosages are maintained below

0.75g/day such effects can usually be avoided.
 LINEZOLID (synthetic antimicrobials)

 It is considered to be the drug of last resort for

the infections caused by M. tuberculosis.

 Linezolid is the member of the Oxazolidinones,

a new class of synthetic antimicrobials

 LINEZOLID (synthetic antimicrobials)

MECH OF ACTION
 Linezolid inhibits protien synthesis

 Preventing formation of the ribosome complex

that initiates protien synthesis

 Its unique binding site, located on 23S ribosomal

RNA of the 50S subunit

 Resistance is caused by mutation of the linezolid

binding site on 23S ribosomal RNA.
 LINEZOLID (synthetic antimicrobials)

KINETICS
 It achieves good intracellular cons of 4-
8mcg/ml. it is 100% bioavailability after oral
 Administration. and has a half life of 4-6 hours.
 Metabolized by oxidative metabolism, yielding
inactive metabolites
 Neither an inducer nor an inhibitor of CYP450
enzyme
 LINEZOLID (synthetic antimicrobials)

USES
 Used in combination with second line drugs to treat
MDR TB

SIDE EFFECTS
 Bone marrow suppression
 Irreversible peripheral and optic neuropathy.
 The most common and reversible side effect is
Thtombocytppenia.
 Neutropenia may also occur
 Para-AMINO-SALICYLIC ACID(PAS)
Is a folate synthesis antagonist
Active exclusively against
M.Tuberculosis.
It is structurally related to
Paramino Benzoic Acid(PABA)
&
sulphonamides.
 Para AMIN-OSALICYLIC ACID(PAS)

KINETICS
Readilly absorbed from GIT
The dosage is 8-12g/daily for adults and
300mg/kg/d for children.
Widely dustribuer in tissues, and body
fluids except CCF
Metabolized in liver & excreted through
kidneys.
 Para AMINOSALICYLIC ACID(PAS)
SIDE EFFECTS
 Very high cons reach in urine which can result in
crystalluria

 GI symptoms r common may be reduced by giving

the drug with meals

 Hypersensitivity reaction manifested by fever, joint

pain, skin rashes hepatosplenomegaly

 Hepatitis and granulocytopenia seen after 3-8 wks of

therapy.
 THANKS
FOR
YOUR ATTENTION !