Anti-tubercular drugs
Contents
Antitubercular drugs
• Classification
• Pharmacology
of individual drugs
At the
end of this lecture, the student will be able to:
• Describe
the mechanism of action and pharmacokinetics of First line and second line
anti-TB drugs
• Discuss
the adverse effects and drug interactions of anti-TB drugs
• Explain
the DOTS therapy based on WHO guidelines
Anti-tubercular Agents
• Tuberculosis
is a chronic granulomatous disease
• In
developing countries it is a major health problem
• 30%
of world population is infected with M. tuberculosis infection
• In
India > 2 million people develop active disease every year & half
million die.
• Anti-tubercular drugs used in
chemotherapy of tuberculosis, a disease caused by Mycobacterium tuberculosis
• Many drugs were developed to treat
tuberculosis and they are often used in combinations to reduce the emergence of
resistant strains of the mycobacterium
• Combination chemotherapy is also
used in the treatment of leprosy, caused by Mycobacterium leprae
Classification
First-line (High
efficacy, low toxicity)
– Isoniazid
– Rifampicin
– Ethambutol
– Pyrazinamide
– Streptomycin
Second-line (Low
efficacy, high toxicity)
– Clarithromycin
– Ciprofloxacin
– Capreomycin
– Cycloserine
– Kanamycin
– Amikasin
– Para
amino salicylic Acid
Isoniazid (Isonicotinic Acid Hydrazid)
• Isoniazid is an effective anti-tubercular drug
and is essential component of all anti tubercular regimens
• It
is more potent among the anti-tubercular drugs, but it is not used alone in
treatment of active tuberculosis
• It
acts on extracellular as well as on intercellular tubercule bacilli present
within macrophages
Mode of Action
• Acts
only on mycobacteria
• Interferes
with mycolic acid synthesis (unique to mycobacterial cell wall)
• Passes
freely to mammalian cell wall
• Effective
for intracellular organism
• Bacteriostatic
– to resting organism
• Bactericidal
– to multiplying organism
Pharmacokinetics
• Well
absorbed from GIT
• Fatty
food & aluminium-containing antacids may reduce absorption
• CSF
penetration: 20% of plasma concentration with non-inflamed meninges
• Penetrate
well into caseous material
• Excretion
– urine
• Plasma
half-life 3 hrs
Adverse Effects
• Hepatotoxicity
– Elderly,
slow acetylators more prone
• Polyneuropathy
– Prevented
by concurrent pyridoxine
• Rashes,
acne
• Heamatological
– haemolytic anaemia in G6PD deficiency
Drug Interactions
• Absorption
of Isoniazid is impaired if taken with food consisting carbohydrates or with
aluminium-containing antacids
• It
inhibits the metabolism of phenytoin, carbamazepine, diazepam and warfarin and
raised their blood levels
• Para
amino salicylic acid inhibits its metabolism and increases its metabolism
Rifampicin
• Rifampicin is semisynthetic
derivative of refamycin B, obtained from Streptomyces mediterannei
• It is one of the most active anti
tubercular drugs
• It is active against many other
Gram-positive and Gram-negative bacteria
Mechanism of Action
• Rifampicin acts by inhibiting DNA-
dependent RNA polymerase thus inhibiting RNA synthesis by suppressing the
initiation step in prokaryotic but not in eukaryotic cells
• It also enters phagocytic cells and
kill intercellular microorganism including tubercule bacilli
• It is the only drug which acts on
the persisters
Pharmacokinetics
• It is well absorbed orally and is
widely distributed in the tissues and body fluids
• It gives an orange tinge to saliva,
sputum, tears and sweat
• The drug is taken up by liver and
undergoes enterohepatic cycling
• The metabolite retains antibacterial
activity but less absorbed from the GIT tract
• Mainly Excreted in bile and also in
urine
Adverse
Effects
• Unwanted effects are infrequent and
include skin eruptions, fever and GIT disturbances
• The drug should be used carefully in
patients with hepatic failure as it may lead to jaundice
Drug
Interactions
• Rifampicin is an inducer of
cytochrome P-450 enzymes and decreases the half-life of drugs such as warfarin,
glucocorticoids, antidiabetic, oral-contraceptives leading to their failure
Anti-TB Therapy
• Multiple
drugs are used to reduce the emergence of resistance
• Given
as combination tablets
• Taken
30 min before the breakfast as absorption of rifampicin is influenced by food
• For
pulmonary TB – 6 months treatment
• For
renal, bone and CNS infection – longer treatment
Summary
• Isoniazid
– bactericidal to rapidly dividing bacteria
• Rifampicin
– kill intracellular bacteria
• Ethambutol
– bacteriostatic against multiplying bacteria
• Pyrazinamide
– kill dormant mycobacteria
• Adverse
effects:
ü INH-
Hepatotoxicity and Polyneuropathy
ü Rifampicin-
inducer of cytochrome P-450
enzymes and decreases the half-life of drugs such as warfarin, glucocorticoids,
antidiabetic, oral-contraceptives
ü Pyrazinamide- GI
disturbances, Hepatotoxicity, gout
ü Streptomycin- Ototoxicity,
vestibular toxicity, nephrotoxicity