1 st

Line Anti -
tubercular Drugs
Saurabh Biswas
PGT,Dept . Of Chest Medicine
CNMCH
History
Mycobacterium
Tuberculosis
Drugs(1st line)
H isto ry
Tuberculosis known to mankind since time
immemorial- one of the deadliest diseases in
the world today.
No effective treatment before the last 60
years.
1946- first clinical use of streptomycin-but
monotherapy led to resistance
1952-INH introduced to make a two drug
regimen.
1958-data from India showed the effectiveness
of supervised treatment(now DOT)
1961-discovery of ethambutol
1962-discovery of rifampicin
1974-concept of SCC daily regimen including
RZ
1980- six-month fully intermittent effective
SCC evolved.
2001-possibility of 4-month ultra short-course
effective regimen containing quinolones is
explored
Mycobacterium
tuberculosis- the bacillus
Slow growing aerobic rod-shaped organism 2-4
microm in length and 0.2 -0.8 microm in
breadth.
Weakly Gram positive and Acid-fast.
Infects humans,monkeys,cows,buffaloes,pigs,
dogs and occ. Parrots.
Under experimental conditions virulent to
guinea pigs and mice.
Best method to inactivate –heat- death time at
60 degree is 15 mins.
More resistant to chemical agents than other
bacteria-80% ethanol kills it in 2-10 mins,so
recommended for disinfection of skin &
rubber gloves.
Daylight has lethal effect on it.
Three populations of tubercular bacilli
-postulated to be present in a tuberculosis
cavity based on their anatomic and metabolic
characteeristics.
A-rapidly multiplying found in caseous debris in pul
cavity,B-slowly multiplying due to acidic cond.,C-
multiplying sporadically
Elimination of population “A” and “B” results in
negative sputum cultures typically after 2
months of rx.
Population “C” is a potential source of relapses
along with Dormant bacilli-the persisters.
Anti-tubercular Drugs(1
line)

Isoniazid(H)
Rifampicin(R)
Pyrazinamide(Z)
Ethambutol(E)
Streptomycin(S)
Isonicitinic acid hydrazide
Isoniazid
bactericidal effect and low cost - the most
important drug used for the treatment of TB.
acts by inhibiting mycolic acid synthesis by
mycobacteria
activated by a catalase-peroxidase enzyme
within mycobacteria
bacteriostatic against resting bacilli and
bactericidal against rapidly multiplying
organisms, both extracellularly and
intracellularly


minimal inhibitory concentrations (MICs) of
isoniazid for wild-type (untreated) strains of
M. tuberculosis are <0.1 microg/mL
The MICs of this drug for NTM are often higher.
Pharmacokinetics


Completely absorbed orally

Penetrates all body tissues,tubercular
cavities,placenta and meninges.
metabolized in the liver via acetylation and
hydrolysis
metabolites are excreted into the urine.
The rate of acetylation is genetically controlled-
fast & slow acetylators.
T1/2-1hr in fast and 3 hrs in slow



30-40% Indians fast acetylators 60-70% are
slow.
The standard adult daily oral dose of 300 mg
produces peak serum levels of 3–5 microg/mL


Dosage:


The usual dose is 5mg/kg daily maximum upto

300mg or 10mg/kg thrice weekly upto a
maximum of 600mg.
15mg/kg if given twice weekly-less effective in
fast acetylators.
does not require dosage adjustment in patients
with renal insufficiency or with end-stage renal
disease requiring chronic hemodialysis.


Drug interaction:


Al hydroxide inhibits its absorption

INH inhibits phenytoin,carbamazepine,
diazepam and warfarin metabolism-may raise
their blood levels.
PAS inhibits INH metabolism & prolongs its t1/2

Contraindications:


Known hypersensitivity
Active hepatic disease
UNTOWARD EFFECTS


occur in ~5%
rash (2%), fever (1.2%), jaundice (0.6%), and
peripheral neuritis (0.2%)-Preventable with
pyridoxine
Risk factors for peripheral neuropathy-slow
acetylators, elderly, pregnant women, human
immunodeficiency virus [HIV]-infected subjects,
diabetics, alcoholics, and uremics

Isoniazid hypersensitivity may result in fever,
rashes, and hepatitis
Hematological reactions-agranulocytosis,
eosinophilia, thrombocytopenia, and anemia
Vasculitis associated with antinuclear antibodies
convulsions, usually in patients with known seizure
Optic neuritis ,muscle twitching, dizziness,
ataxia, paresthesias, stupor, and potentially
fatal encephalopathy
euphoria, transient memory impairment, loss of
self-control, and psychosis.
Hepatic injury

Severe hepatic injury leading to death-

presenting 4–8 weeks after initiation
Drug continuation after hepatic dysfunction-
worsen the damage.




Risk factors-Alcoholic hepatitis, Age(most
important),excessive alcohol intake, history
of liver disease
chronic carriers of the hepatitis B virus tolerate
isoniazid
Up to 12% of patients may have elevated
serum transaminase levels
Drug to be discontinued if ALT>5-fold of
normal without any signs and symptoms or if
ALT>3 times normal plus signs and
symptoms of hepatitis



Rifampicin
semisynthetic derivative of Streptomyces
mediterranei
most important and potent antituberculous
agent
also active against a wide spectrum of other
organisms, including some gram-positive and
gram-negative bacteria, Legionella spp., M.
kansasii, and M. marinum
Susceptible strains of M. tuberculosis as well as
M. kansasii and M. marinum are inhibited by 1
microg/mL.
Bactericidal-both intracellularly and
extracellulararly.
Inhibits DNA dependent RNA polymerase,
leading to suppression of initiation of chain
formation (but not chain elongation) in RNA
synthesis


Pharmacokinetics:


absorbed readily after either PO or IV

administration
Serum levels of 10–20 microg/mL follow a
standard adult oral dose of 600 mg
eliminated rapidly in the bile, and an
enterohepatic circulation ensues.
drug is progressively deacetylated by hepatic
CYPS
after 6 hours, nearly all drug in the bile is in the
deacetylated form, which retains antibacterial
activity

Intestinal reabsorption is reduced by
deacetylation and by food-metabolism
facilitates drug elimination
t1/2 is progressively shortened (~40%) during
the first 14 days of treatment due to induction
of hepatic CYPs.
t1/2 is variable-2 to 5 hrs.
Dosage adjustment is not necessary in patients
with renal insufficiency
Penetrates cavities,caseous masses,placenta
and meninges.



Dosage:


10 mg/kg daily,2 or 3 times daily upto a

maximum of 600 mg.
given either 1 hour before or 2 hours after a
meal

Drug interaction:


potent inducer of hepatic CYPs- decreases the

t1/2 of many drugs
HIV protease and nonnucleoside reverse
transcriptase inhibitors, digoxin, quinidine,
mexiletine, tocainide, ketoconazole,
propranolol, metoprolol, clofibrate, verapamil,
cyclosporine, glucocorticoids, oral
anticoagulants, theophylline, barbiturates,
oral contraceptives,fluconazole, and the
sulfonylureas

Interaction with oral anticoagulants-impair
anticoagulation
Decrease effectiveness of oral contraceptives
and induce adrenal insufficiency in patients
with marginal adrenal reserve



Contraindications:


Known hypersensitivity
Active hepatic disease

Untoward effects:


Significant effects in <4% of patients

most commonly rash (0.8%), fever (0.5%), and
nausea and vomiting (1.5%)
Rarely, hepatitis and deaths due to liver
failure-Chronic liver disease, alcoholism, and
old age increase the risk
should not be administered less than twice
weekly and/or in daily doses of 1.2 g or
greater-flu-like syndrome with fever, chills,
and myalgias develops in 20% of patients so
treated



Exfoliative dermatitis-more frequent in HIV
positives.
Temporary oliguria,dyspnea, hemolytic
anemia,thrombocytopenia- these usually
subside if intermittent regimen changed to
daily regimen.

Other uses:


Leprosy
prophylaxis of meningococcal disease and
Haemophilus influenzae meningitis
Combined with a b-lactam antibiotic or
vancomycin-selected cases of staphylococcal
endocarditis or osteomyelitis
Doxycycline + R-first line therapy for
brucellosis.


Ethambutol
derivative of ethylenediamine, ethambutol is a
water-soluble compound -active only against
mycobacteria
Active against M. tuberculosis, M. marinum, M.
kansasii, and MAC organisms
Among first-line drugs, ethambutol is the least
potent against M. tuberculosis
Tuberculostatic

Used in combination with other ATDs to
prevent or delay emergence of resistant
strain.
Growth inhibition by ethambutol requires 24
hours-inhibition of arabinosyl transferases
involved in cell wall biosynthesis



Pharmacokinetics:


About 80% of an oral dose of ethambutol is

absorbed from the GI tract.
Concentrations in plasma peak 2–4 hours after
the drug is taken-Peak serum levels of 2–4
microg/mL
t1/2 of 3–4 hours.
Within 24 hours, 75% of an ingested dose of
ethambutol is excreted unchanged in the
urine
up to 15% is excreted in the form of aldehyde
and dicarboxylic acid derivatives.



Dosage:


Adults:15mg/kg daily,30mg/kg 3 times weekly

or 45mg/kg twice weekly.
Children:15mg/kg daily
Dose to be reduced in impaired renal function
Contraindications:


Known hypersensitivity
Pre-existing optic neuritis from any cause
Creatinine clearance <50ml/min
Children <6 yrs
Untoward effects:


optic neuritis, resulting in decreased visual

acuity and red–green color blindness-<1% in
patients
Intensity of the visual difficulty - related to the
duration of therapy after visual impairment
first becomes apparent - unilateral or bilateral.
Recovery usually occurs when ethambutol is
withdrawn.
rash, drug fever, pruritus, joint pain
GI upset, malaise,
headache, dizziness, confusion, disorientation,
and hallucinations.


Numbness and tingling of the fingers owing to
peripheral neuritis –infrequent
Anaphylaxis and leukopenia are rare.
increased urate concentration in the blood in
~50% of patients, owing to decreased renal
excretion of uric acid.



Pyrazinamide
Synthetic pyrazine analogue of nicitinamide
Weakly tuberculocidal
Highly active in acidic medium(it is active only
at a pH of <6.0)-itracellularly and at sites
showing inflammatory response
Highly effective during 1st 2 months of therapy
when inflammatory changes are present.
prodrug -converted by the tubercle bacillus to
the active form pyrazinoic acid

target for this compound is thought to be a
fatty acid synthase gene (fasI) involved in
mycolic acid biosynthesis
Susceptible strains of M. tuberculosis are
inhibited by 20 microg/mL

Pharmacokinetics:


well absorbed after oral administration, with a

plasma concentration range of 20–60
microg/mL 1–2 h after oral ingestion
well distributed throughout the body
Levels in CSF are excellent-reaching 50–100%
of levels in serum
The serum half-life is 9–11 h
metabolized by at least two major pathways
and one minor pathway in the liver
metabolites include pyrazinoic acid, 5-
hydroxypyrazinamide, and 5
hydroxypyrazinoic acid
not available in a parenteral formulation
Dosage:


For 1st 2 or 3 months-25mg/kg daily,35mg/kg 3

times weekly ,50mg/kg 2 times weekly

Contraindications:


Known hypersensitivity
Severe hepatic impairment

UNTOWARD EFFECTS:


Hepatic injury is the most serious side effect

At the currently recommended dosages, the
frequency of hepatotoxicity is no higher than
that for concomitant isoniazid and rifampin
therapy
Hyperuricemia is a common adverse effect-
reduced by concurrent rifampin therapy
Polyarthralgias encountered fairly commonly-
not related to the hyperuricemia



Rash,fever , loss of diabetes control
Streptomycin
An aminoglycoside isolated from Streptomyces
griseus
active against untreated strains of M.
tuberculosis, M. kansasii, and M. marinum
and against some strains of MAC organisms
Also active against some Gram negative
organisms
Tuberculocidal

Acts only in extracellular bacilli-poor
penetration into cells
Doesn’t cross CSF and poor action in acidic
media.
Binds to bacterial 30s ribosome-inhibits
protein synthesis.
Serum levels of streptomycin peak at 25–40
microg/mL after a 1.0-g dose
Pharmacokinetics:


Highly ionized
Neither absorbed nor destroyed in GIT
Absorption from injection site-rapid
Distributed extracellularly only
Low concentrations in serous fluid like synovial
and pleural and also in CSF.
Not metabolized-excreted unchanged in urine
T1/2 is 2-4 hrs-but persists longer in tissues

Dosage:


15mg/kg daily,2 or 3 times weekly by deep IM

injection
dosage must be lowered and the frequency of
administration reduced (to only two or three
times per week) in most patients >50 years
of age and in any patient with renal
impairment
Contraindications:


Known hypersensitivity
Auditory nerve impairment
Myasthenia gravis
Pregnancy

UNTOWARD EFFECTS:


Adverse reactions to streptomycin therapy

occur in 10–20%
Ototoxicity and renal toxicity are the most
common and the most serious
Renal toxicity, usually manifested as nonoliguric
renal failure
Ototoxicity involves both hearing loss and
vestibular dysfunction-latter is more common
and includes loss of balance, vertigo, and
tinnitus

perioral paresthesia, eosinophilia, rash,
and drug fever
Drug interaction:


Avoid use with other ototoxic drugs like higgh

ceiling diuretics,minocycline
Avoid concurrent use of other nephrotoxic
drugs
Cautious use with muscle relaxant-it may add
to the action of other muscle relaxant
Do not mix with any other drug in same
syringe/infusion

Other uses:


SABE –along with penicillin

Plague
Tularemia-drug of choice
THANK YOU