ANTITUBERCULOSIS DRUGS

First – line Drugs

(more effective & less toxic)
→ Isoniazid
→ Rifampin (OR Rifabutin , Rifapentine)
→ Ethambutol(Myambutol)
(OR Streptomycin)
→Pyrazinamide
 SECOND – LINE DRUGS

(less effective & more toxic)

• Amikacin
• Aminosalicylic acid
• Bedaquilline
• Capreomycin
• Ciprofloxacin
• Clofazimine
• Cycloserine
 SECOND – LINE DRUGS

• Ethionamide
• Levofloxacin
• Moxifloxacin
• Rifabutin
• Rifapentine
 Why use multiple drugs?
• Mycobacteria are by nature resistant to most antibiotics
• Mycobacterium can also be dormant and thus completely
resistant to many drugs or killed only very slowly.
• Lipid rich mycobacterial cell wall is impermeable to many
agents
• Mycobacterial species are Intracellular pathogens and
organisms residing within macrophages are inaccessible to
drugs that penetrate these cells poorly
• Finally mycrobacteria are notorious for their ability to develop
resistance
• Combination of two or more drugs is required to overcome
these obstacles
 THERAPEUTIC GOALS

• Prevention or prophylaxis
• Cure of clinical disease
• Prolonged therapy
• Combined therapy
• Compliance
• Development of drug resistance
• Cures, Ideally, 95 – 100%
 RECOMMENDED DURATION OF
THERAPY FOR TUBERCULOSIS

Regimen Duration Months

• INH. RIF. PYRA 6

• INH. RIF. 9

• RIF. ETH.PYRA 6

• RIF. ETH. 12

18
• INH.ETH
• All others 24 or more than 24
 ISONIAZID (INH)
• INH is most active drug for treatment of TB
caused by susceptible strains
• INH is bactericidal for actively growing tubercle
bacilli
• Small molecular weight (137) & freely soluble in
water
• INH is structurally similar to Pyridoxine (B6)
• INH penetrate into macrophages & is active
against both extracellular & intracellular organisms
 MECHANISMS OF ACTION

ISONIAZID (INH  Isonicotinic acid

hydrazide) is Prodrug  activated by
mycobacterial catalase-peroxidase (KatG).

It target enzymes acyl carrier protein

reductase (InhA) and Beta-ketoacyle-ACP
synthase (KasA).
 MECHANISMS OF ACTION

• Activated drug covalently binds to and

inhibits these enzymes  essential for
the synthesis of mycolic acid.

• INH inhibit synthesis of mycolic acid

which are essential components of
mycobacterial cell wall.
 Resistance

• Mutation or deletion of Kat G gene.

• Over expression of inhA through mutation
which encodes NADPH dependant acyl
carrier protein reductase
• Over production of ahpC gene which
protects cell from oxidative stress
• Cross resistance to Ethionamide also occur.
 Pharmacokinetics
• INH is readily absorbed from GIT
• Absorption is impaired if INH is taken with food (carbohydrate) or
antacids
• Drug diffuses into all body fluids & tissues
• Penetrate meninges CSF
• The liver metabolism of INH is by acetylation & is under genetic
control
• Patients may be slow or fast acetylators
• Halflife fast
acetylators 1 hour
Slow acetylators 3 hours
INH metabolites & small amount unchanged drug is excreted mainly in
urine
 Clinical Uses
• Mycobacterium tuberculosis infection along with
rifampin, ethambutal, and pyrazinamide.
• Dose:
5-10mg/kg body weight or
300mg X O.D
● Also indicated for Latent TB as a single agent
Dose 300mg/d or 900mg twice weekly for 9
months
• Vit B6 supplement is also given with ATT for
prevention of Neuropathy.
 ADVERSE REACTION
• S.E are related to dosage & duration of
administration.
• ImmunologicReactions
Fever ,skin rashes, Drug induced SLE
• Hepatotoxicity (Age dependent jaundice)
• Peripheral neuropathy -> pyridoxine deficiency
(numbness, tingling, or burning in the hands and
feet)
• G.I.T discomfort (Loss of appetite, vomiting,
diarrhea, stomach pain)
• Convulsion in patient of prone to seizure
• Psychosis ,memory loss
 RIFAMPIN

It is active against
• Gram +ve cocci Gram -ve cocci
• Meningococci haemophilis influenzae
• Mycobacterium TB Mycobacterium laprae
• It readily penetrates most tissues and into
phagocytic cells
• It can kill organisms that are poorly accessible to
many other drugs such as intracellular organism
and those sequestered in abscesses and lung
cavities
 MECHANISM OF ACTION

• Rifampin binds to β sub unit of bacterial

DNA – dependent RNA polymerase and
there by INHIBIT RNA SYNTHESIS
 Pharmacokinetics

• Well absorbed orally (Dose 600mg/d)

• Distrubution to all body fluid & organs
• Adequate level attained in CSF in meningeal
inflamation
• Metabolism by liver
• Induce the hepatic mixed function oxidase
enzyme system (P450)
• Excreation of drugs & metabolites via bile,
faces & urine
 ADVERSE REACTIONS

• GIT disturbances (e.g.; Nausea vomiting epigastric pain)

• Hypersensitivity reaction like rash
• Orange coloration of urine, sweat, tears and contact
lenses
• Hepatitis (Most notable problem) more in alcoholic &
elderly persons
• flue like syndrome
(fever ,chills, myalgia ,anemia and thrombocytopenia)
Some time associated with acute tubular necrosis
• Induces CYP450 enzymes
 Rifabutin , Rifapentine
• Rifabutin derivative of rifampin preferred
for TB patients co infected with HIV
• Rifapentine has greater activity than
rifampin
• May be used in combination with isoniazid
in LTBI
 ETHAMBUTOL (MYAMBUTOL)
• Synthetic drug.
• Water soluble.
• Heat stable.
• Accumulates in renal failure.( Must adjust
dose if impaired renal function)
• Cross BBB during inflammation
 ETHAMBUTOL
• Ethambutol is bacteriostatic & specific for
mycobacterium TB & other mycobacteria
• Suppresses growth (static) of organisms
resistant to streptomycin and Isoniazid
i.e. no cross resistance.
• Resistance to ethambutol develops slowly
• One of four main drugs for treatment of
tuberculosis
• Always used in combination
 MECHANISM OF ACTION

• Inhibits microsomal arybinosyl transferase

which is involved in polymerization
reaction of arybinoglycans which is also
essential component of cell wall of
mycobacteria.
 ADVERSE EFFECTS
• Hypersensitivity reaction rare
• Retrobulbar neuritis(most common & serious S.E)
• Retrobulbar neuritis results in loss of visual acuity
and red-green colour blindness
• Occurs in 15% of patients receiving 50 mg/kg per
day and less than 1% of those receiving 25mg/kg
per day
• Relatively contraindicated in children
• Uric acid excretion is dec: by ethambutol
 PYRAZINAMIDE
• Bactericidal antitubercular agent
• It is bactericidal to actively dividing organism
• Pyrazinamide must be enzymatically
hydrolyzed by pyrazinamidase to
pyrazinoic acid which is the active form of
the drug
MOA→ Pyrazinoic acid disturbs mycobacterial
cell membrane metabolism and transport
functions
 Clinical Uses
• It is active against tubercle bacilli in the
acid environment of lysosomes as well as
in macrophages
 ADVERSE EFFECTS
liver injury most common and serious
side effect

• Major side effects include

Hepatotoxicity (1-5% Pt)
Nausea, vomiting, drug fever & hyperuricemia
 PEOPLE WHO HAVE CERTAIN MEDICAL
CONDITIONS MAY HAVE PROBLEMS IF THEY ARE
USES ANTITUBERCULOSIS DRUGS

For example
• Cycloserine or Isoniazid may increase the risk of
seizures (convulsions) in people with a history of
seizures
• The dosage of Cycloserine may need to be
adjusted for people with kidney disease
• Ethambutol or Pyrazinamide may cause or
worsen attacks of gout in patient with gout
• Ethambutol may cause or worsen eye damage
PEOPLE WHO HAVE CERTAIN MEDICAL CONDITIONS MAY
HAVE PROBLEMS IF THEY ARE USES ANTITUBERCULOSIS
DRUGS

• People with liver disease or a history of

alcohol abuse may be more likely to have
side effects that effect the liver when
taking Rifampin