Anti Tubercular and anti leprotic agents.pdf

By Imtiyaz Bagban
M. Pharm. (Pharmacology)
Assistant Professor
Department of Pharmacology
Krishna School of Pharmacy & Research (KSP)
Drs. Kiran & Pallavi Patel Global University
(KPGU)
1
B. Pharm. Semester VI
Subject – Pharmacology
Subject Code- BP602T
UNIT 4
Antitubercular Agents

• Tuberculosis is a chronic granulomatous
disease
• In developing countries it is a major
health problem
• ≈ 30% of world population is infected
with Myc. Tuberculosis infection
• In India > 2 million people develop active
disease every year & half million die.

Tuberculosis
• It is an infection difficult to treat
• Typical growth characteristics
• Peculiar cell wall structure (waxy appearance ) due to
mycolic acid.
• Resistance to infection emerges quickly.
Mycobacterium tuberculosis

Antitubercular Drugs
Mycobacterium Infections
Common infection sites
• Lung (primary site) - Intestines
• Brain - Lymph nodes
• Bone
• Liver
• Kidney
• Aerobic bacillus
• Passed from infected:
– Humans
– Cows (bovine) and birds (avian)
• Much less common

Mycobacterium Infections
• Tubercle bacilli are conveyed by droplets
• Droplets are expelled by coughing or sneezing, then
gain entry into the body by inhalation
• Tubercle bacilli then spread to other body organs via
blood and lymphatic systems
• Tubercle bacilli may become dormant, or walled off by
calcified or fibrous tissue

Tuberculosis - Pathophysiology
• M. tuberculosis – gram-positive, acid-fast bacillus
• Spread from person to person via airborne droplets
– Coughing, sneezing, speaking – disperse organism and
can be inhaled
– Not highly infectious – requires close, frequent, and
prolonged exposure
– Cannot be spread by hands, books, glasses, dishes, or
other fomites

Tuberculosis – Clinical Manifestations
• Early stages – free of symptoms
– Many cases are found incidentally
• Systemic manifestations:
– Fatigue, malaise, anorexia, weight loss, low-grade fevers, night sweats
– Weight loss – occurs late
– Characteristic cough – frequent & produces mucoid or mucopurulent
sputum
– Dull or tight chest pain
• Some cases: acute high fever, chills, general flulike symptoms,
pleuritic pain, productive cough
• HIV Pt with TB: Fever, cough, weight loss –
– Pneumocystic carinii pneumonia (PCP)

Tuberculosis – Diagnostic Studies
• Tuberculin Skin Testing -- + reaction 2-12 weeks after the initial
infection
– PPD – Purified protein derivative – used to detect delayed
hypersensitivity response
• Two-step testing – health care workers
• 5mm > induration – Immunosuppressed patients
• 10 mm> “at risk” populations & health care workers
• 15 mm> Low risk people
– Chest X-ray -- used in conjunction with skin testing
• Multinodular lymph node involvement with cavitation in the
upper lobes of the lungs
• Calcification – within several years after infection
– Bacteriologic Studies –
• Sputum, gastric washings –early morning specimens for acid-
fast bacillus -- three consecutive cultures on different days
• CSF or pus from an abscess

M. tuberculosis: peculiar features
• Rapid growers: In the wall of cavitary lesion,
extracellular.
• Slow growers: intracellular, within the macrophages
at inflamed sites.
• Spurters: intermittent growth spurts.
• Dormant: Do not grow for long time, become active
at times of low host resistance.
Bacilli continuously shift from one to other subpopulation.

Chemotherapy in tuberculosis
• Goals of anti-tubercular chemotherapy
• Kill dividing bacilli: Patient is non-contagious :
transmission of TB is interrupted.
• Kill persisting bacilli: To effect cure and prevent
relapse.
• Prevent emergence of resistance: so that the bacilli
remain susceptible to the drugs.

• Now there is emergence of multidrug resistant ( MDR ) TB .
More than 0.4 million cases globally .
History
• First successful drug for treating TB was PAS (Para-
aminosalicylic acid) developed by Lehman in 1943.
• Dramatic success came when Waksman & Schutz discovered
Streptomycin which has made remarkable progress.
• Followed by Thiacetazone by Domagk in in 1946
• In 1952 Isoniazid came into being Pyrazinamide by Kushner &
colleagues in 1952 & later on Rifampicin in 1957 by S.
Margalith has totally changed the strategy in the
chemotherapy.
• Ethambutol came in 1961 by Lederle -laboratories
• Fluoroquinolones, newer macrolides & congener of Rifampicin
→Rifabutin are recent addition in antimycobacterial drugs

First line drugs:
Ionized ( H)
Rifampicin (R)
Ethambutol (E)
Pyrazinamide ( Z)
Streptomycin ( S) now reserved drug in
first line

Second line drugs:
Thiacetazone
Para aminosalicylic acid (PAS)
Ethionamide
Kanamycin
Cycloserine
Amikacin
Capreomycin

Newer Second Line drugs:
Ciprofloxacin
Ofloxacin
Levofloxacin
Clarithromycin
Azithromycin
Rifabutin

Drugs used in Tuberculosis
1st line drugs
high efficacy, low toxicity
• Isoniazid (INH)
• Rifampin
• Pyrazinamide
• Ethambutol
• Streptomycin
2nd line drugs
Low efficacy, high toxicity or both
• Ethionamide
• Para aminosalicylic acid
• Cycloserine
• Amikacin/ Capreomycin
• Fluoroquinolones
• Rifabutin

Isoniazid (Isonicotinic acid hydrazide,H):
Essential component of all anti TB regimen
(except intolerance to H or resistance)
-It is tuberculocidal , kills fast multiplying
organism & inhibit slow acting organism
-Acts both on intracellular ( present in
macrophages ) & extracellular bacilli
It is the cheapest AT Agent.

-Atypical mycobacteria are not inhibited by
INH.
Not active against any other micro-orgs.
Mechanism of Action :
Inhibit synthesis of mycolic acid ( unique
fatty acid component of mycobacterial cell
wall .)

• INH enters the bacilli by passive diffusion. It must be
activated to become toxic to bacilli. It became toxic by
Kat G (multifunctional Catalase - peroxidase , a bacterial
enzyme )
• Which catalyzes the product from INH an Isonicotinoyl
radical that subsequently inter-acts with mycobacterial
NAD & NADP to produce dozen of adducts.
• One of these a nicotinoyl NAD isomer which ↓ the
activity of enoyl acyl carrier protein reductase (Inh A)
& β- ketoacyl carrier protein synthase (Kas A)
• Inhibition of these enzymes↓ the synthesis of mycolic
acid an essential component of the mycobacterial cell
wall & causes cell death.

(another adduct , a nicotinoyl –NADP isomer potentially
mycobacterial dihydrofolate reductase → interfere with
nucleic acid synthesis. These adducts also produce H2O2 ,
NO radical & other free radicals which are toxic to bacilli )
- If INH is given alone , inherent resistant bacilli proliferate
selectively & after 2-3 months an apparently resistant
infection emerges .
(Mutation of the catalase –peroxidase gene in bacilli do not
generate the active metabolite of INH )
- Combination therapy with INH has good resistance preventing
action .
- There is no cross resistance .

Pharmacokinetics :
-Completely absorbed orally , penetrate all body tissues, tubercular
cavities , placenta & meninges .
- Metabolized in liver by acetylation & metabolites are excreted
in urine .
- Rate of acetylation shows genetic variation
( fast acetylators > 30% Indians - t½ -1 hr
Slow acetylators >60% Indians -t ½- 3 hrs)
(daily regimen is not affected but biweekly regimens are less
effective in fast acetylators )
Dose – 4-6 mg/ kg for >50 kg – 300 mg daily
- 600 mg bi-wkly

ADRs -
Well tolerated drug
1.Peripheral neuritis & other neurological manifestations-
parasthesia , numbness, mental disorientation & rarely
convulsion
( due to interference with utilization of pyridoxine & ↑
excretion in urine )
Due to this Pyridoxine given prophylactically
-10 mg/day which prevents neurotoxicities
(INH neurotoxicity treated with Pyridoxine-100 mg/ day )
2. Hepatitis – more common in older patients & alcohlics
3. Rashes , fever , acne & arthralgia .

D/I
• interactions : Aluminium hydroxide it inhibits INH
absorption.
• INH inhibits phenytoin, carbamazepine, diazepam and
warfarin metabolism: may raise their blood levels.
• PAS inhibits INH metabolism and prolongs its t1/2.

Rifampin ( Rifampicin , R ):
-Semisynthetic derivative of Rifamycin B from
Streptomyces mediterranei
-Bactericidal to M. Tuberculosis & others – S. aureus,
Klebsiella, N. meningitidis, Pseudomonas, H.
influenzae, Proteus, E. coli & Legionella.
- Best action on slowly or intermittently
dividing bacilli on extracellular as well as
intracellular organisms
-Also act on many atypical mycobacteria
-Have good resistance preventing action

Mechanism:
Inhibit DNA dependant RNA Synthesis
(by ↓ bact RNA polymerase , selective because does not
↓ mammalian RNA polymerase )
- TB patient usually do not get primary
Rifampicin resistance – If occurs is due to
mutation in the repo -B gene (β subunit of
RNA polymerase ).
- No cross resistance

PKT –
Well absorbed orally widely distributed in the
body , penetrate cavities , caseous mass,
placenta & meninges .
-Metabolized in liver
-Excreted mainly in bile & some in urine
-t½- 2-5 hrs

ADR’s
1. Hepatitis – mainly in pts having preexisting liver disease & is
dose related- Jaundice req. stoppage of drug
2. Respiratory syndrome –breathlessness, shock & collapse .
3. Purpura , hemolysis , shock , renal failure
4. Cutaneous syndrome – flushing , pruritis & rashes ( face &
scalp ), redness & watering of eyes.
5. Flue syndrome – Nausea , vomiting, abdominal cramps
6. Urine & secretions may become red – which are harmless &
Pt should be told about this effect.

D/I
Rifampicin is microsomal enzyme inducer
-↑ several CYP 450 isoezymes
-↑ its own metabolism as well as of others
e.g.-Oral contraceptive Digoxin
Warfarin Theophylline
Steroids Metoprolol
Sulphonyl urea Fluconazole & Ketoconazole
etc.
(contraceptive failure can occur if given simultaneously in child
bearing age women taking oral contraceptive)

Other uses –
1. Atypical myc. Inf. (M. kansasii, marinum , avium &
intracellulare )
2. Leprosy
3. Prophylaxis of meningococcal & H. infl. meningitis
4. Diphtheroids & legionella inf.
5. Along with Doxycycline –first line therapy
in Brucellosis
Dose- 10 mg ( 8-12 mg / kg), for > 50 kg = 600 mg OD

3. Pyrazinamide ( Z)
Chemically≡ INH
-Weak tuberculocidal more active in acidic medium.
-More lethal to intracellular bacilli & to those at sites
showing an inflammatory response
( Therefore effective in first two months of therapy where
inflammatory changes are present )
-Good sterilizing activity
-It’s use enabled total duration of therapy to be shortened
& risk of relapse to be reduced.

- Mechanism ≡ INH - ↓ fatty acid synthesis but by
interacting with a different fatty acid synthesis
encoding gene.
- PZA is thought to enter M. tub. by passive diffusion
and converted to pyrazinoic acid (its active
metabolite) by bact. Pyrazinamidase enz.
- This metabolite inhibits mycobact. Fatty acid synthase
-I enz. and disrupts mycolic acid synthesis needed
for cell wall synthesis.
-Mutation in the gene (pnc A) that encodes
pyrazinamidase enzyme is responsible for drug
resistance ( minimized by using drug combination
therapy) .

PKT :
-Absorbed orally, widely distributed ,Good
penetration in CSF.
-Metabolized in liver & excreted in urine.
-t½ -6-10 hrs

ADRs :
- Hepatotoxic -dose related
- Hyper uricaemia is inhibition of uric acid secretion in
kidney
- flushing , rashes , fever & anaemia
- Loss of diabetic control
Dose – 20-30 mg /kg daily , 1500 mg if > 50 kg

Ethambutol ( E) :
-Tuberculostatic , clinically active as
Streptomycin
-Fast multiplying bact. are more sensitive
-Also act against atypical mycobacteria
-If added in triple regimen (RHZ) it is found
to hasten the rate of sputum conversion &
to prevent development of resist.

Mech. :Not well understood . Found to ↓arabinosyl
transferase III involved in arabino galactone synthesis &
also interfere with mycolic acid incorporation in
mycobacterial cell wall. this is encoded by emb AB genes
-Resistance develop slowly
- No cross resistance

PKT:
-3/4th of an oral dose of Ethm. is absorbed
-Distributed widely but penetrates in
meninges incompletely
-½ metabolized , excreted in urine
-caution is required in pts of renal disease
-Pts acceptability is good & side efffects are
low

ADRs:
-Loss of visual acquity / color vision due to optic neuritis
,which is most impt. dose & duration dependent toxicity.
(children can not report this complaint easily therefore not
given below 6 yrs of age)
-Early recognition –reversible
Others- Nausea , rashes & fever
-Neurological changes
-Hyper uricaemia is due to interference with urate excretion
Dose – 15-20 mg/kg , > 50kg -1000mg

Streptomycin (S):
-It was 1st clinically useful antibiotic drug
-It is protein synthesis inhibitor by combining
with 30S ribosome
-It is tuberculocidal , but less effective than
INH / Rifampicin
-Acts on extracellular bacilli only ( poor
penetration in the cells )

-It penetrates tubercular cavities but does not cross BBB
- Resistance when used alone (in average popul.1 in 10 to the
power 8 bacilli are resistant to streptomycin –they multiply
& cause relapse therefore stopped at the earliest .)
- Atypical mycobact.s are ineffective
- Popularity ↓ due to need of IM inj. & lower margin of safety (
because of ototox. & nephrotox.).
- Dose- 15 ( 12-18 ) mg/kg, >50 mg- 1000mg

MOA of 1st line drugs
Mycolic Acid
Arabinogalactan
Peptidoglycan
Cell membrane
R
I
B
O
S
O
M
e
Protein
Isoniazid
-
Pyrazinamide
- Mitochondria
(ATP)
- Rifampin
-
Ethambutol
-
Streptomycin
- Cytoplasm

Thiacetazone (TZN) :
-First AT drug tested but weak
-Discarded due to hepatotoxicity
-In India revived in 1960s for oral use along with INH as a substitute
to PAS
- Tuberculostatic , does not add to the therapeutic effect of H,S, R, E
ADRs -
Hepatotoxic, Exfoliative dermatitis, Stevenson Johnson’s syndrome
Can cause bone marrow depression
Others- Nausea , anorexia , Abd. Discomfort, loose motions, Mild
anemia, Pruritis
Dose- 150 mg OD (2-5 mg/ kg ) ,used in combined tablet with
INH

Relative activity of first line Drugs
• INH: potent bactericidal
• Rifampin: potent bactericidal
• Pyrazinamide: Weak bactericidal, active against
intracellular bacilli.
• Ethamutol: bacterisostatic, prevents resistance
development.
• Streptomycin: bactericidal, active against
extracellular rapid growers.
Never use a single drug for chemotherapy
in tuberculosis, a combination of two or
more drugs must be used.
Combination is synergistic

PAS – Paraaminosalicylic acid:
-Related to sulfonamides chemically as well as in mech.
of action.
-Tuberculostatic , not add to therapeutic value , only
delay resistance
-Interfere with absorption of Rifampicin
S/E - Acceptability is poor due to frequent anorexia ,
nausea & epigastric pain
Other use- Goiter, Liver dysfunction & Blood dyscrasias
Dose- 10- 12 gm ( 200 mg/ kg) / day
Rarely used now

Ethionamide :
-Tuberculostatic , having moderate efficacy
-Acts both on extra as well as intracellular bacteria.
Mechanism:
Ethionamide is a prodrug which is activated by the enzyme ethA,
a mono-oxygenase in Mycobacterium tuberculosis, and then
binds NAD+ to form an adduct which inhibits InhA in the
same way as isoniazid. The mechanism of action is thought to
be through disruption of mycolic acid.
-Resistance develop readily & some cross resistance to TZN
-Absorbed orally ,distributed all over including CSF
S/E- Anorexia, Nausea & vomiting, Rashes, Hepatitis, Peripheral/
Optic neuritis
Dose- 1 gm / day, but more than 0.5 gm not tolerated.
- seldom used now , only used in resistance cases .

Cycloserine (Cycs):
- Obtained from S. orchidaceus & is a chemical analogue of D- alanine
- Cyclic analogue of D-alanine, cycloserine acts against two crucial enzymes important in
the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D-
alanine ligase (Ddl).
- The first enzyme which converts the L-alanine to the D-alanine form.
- The second enzyme is involved in joining two of these D-alanine residues together by
catalyzing the formation of the ATP-dependent D-alanine-D-alanine dipeptide
bond between the resulting D-alanine molecules.
- If both of these enzymes are inhibited, then D-alanine residues cannot form and
previously formed D-alanine molecules cannot be joined together.
- This effectively leads to inhibition of peptidoglycan synthesis
-Tuberculostatic & ↓ other G +ve organisms ( E. coli , Chlamydia)
-Resistance develop slowly , no cross resist.
CNS toxicity is high , sleepiness , headache, tremor , psychosis & convulsions
-Rarely used (only in resistance cases)
Dose – 250 mg BD
Kanamycin , Amikacin & Capreomycin:
Used as reserved drug in severe cases not responding to usual therapy

Newer drugs :
Ciprofloxacin
Ofloxacin
Levofloxacin
( all are used in TB & MAC )
Clarithromycin
Azithromycin
( used in MAC )
Rifabutin - > in MAC < in TB

Antitubercular Therapy
Treatment of Tuberculosis :
Remarkable change, conventional 1-1½yr Tt – is replaced by more
effective & less toxic 6 month-8 month therapy
a) Rapidly growing with higher bacillary load e.g. wall of the
cavity region- highly suscep. to INH & lesser extent to R,E,S
b) Slow growing – intracellular & at inflamed sites – vulnerable
to Z while H,R,E are lesser active
c) Spurturs - with in caseous material (where O2 tension is less)
the bacilli grow intermittently. R- is most active in this sub
population
d) Dormant –bacilli remain totally inactive for prolonged periods-
No ATT is effective

Goals-
1. Killing of dividing bacilli- drugs with bactericidal activity
rapidly reduce the bact. load in the Pt & achieve quick
sputum clearance – Pt become non con-tageous to the
community - Transmission is interrupted
2. Killing of persistent bacilli for effective cure &
prevention of relapse
3. Prevent emergence of resistance (Drug combination are
selected to maximize the above action together with
consideration of cost & convenience )
H & R are most efficacious drugs ,their combination is
synergistic

Duration of therapy shortened from 12 to 9 months.
Addition of Z for initial 2 months further reduces duration of
treatment to 6 months
DOTs –Directly observed treatment short course ,was
recommended by the WHO in 1995
Short course chemotherapy- Regimen of 6-9 months treatment
In 1997 WHO framed clear cut guidelines for different category
of TB treatment .
All regimen have initial intensive phase - 2-3 months to rapidly
kill the TB bacilli & bring sputum conversion & afford
symptomatic relief
followed by continuation phase last 4-6 months for elementary
remaining bacilli

Categories:
Category I
–New ( untreated ) smear +ve pulmonary TB
-New smear –ve pulmonaryTB with extensive parenchymal involvement
-New cases of severe forms of extra- pulmonary TB e.g.- meningitis , miliary TB ,
pericarditis
-Bilateral or extensive pleural effusion, intestinal or genitourinary TB
(Revised National Tub. Control programme In India in 1997— DOTs –follow thrice
wkly regimen to ↓ cost & it is more practical )
WHO :
- 2 HRZE(S) (initial phase)-daily
- 4 HR or 6 HE (continuation phase) daily total duration 6-8 months
RNTCP :
2 H3R3Z3E3 + 4 H3R3 -total duration- 6month

Category II
-Smear +ve failure , relapse & interrupted Tt cases
-Relapse- cured TB Patient again become sputum +ve
-Tt after interruption –interrupted Tt x 2month →return to
sputum + ve case
WHO: Initial phase –daily 2 HRZES +1 HRZE
Continuation phase –5 HRE - total 8 month
RNTCP:
Initial phase – 2 H3R3Z3E3S3 +1 H3R3Z3E3
Continuation phase -5 H3R3E3 –total 8 months

Category III
New cases of smear –ve pulmonary TB with limited parenchymal involvement
or severe form of extra pulmonary TB .
e.g.-Lymph node TB
Unilateral pleural effusion
Bone (excluding spine )
Peripheral joint & skin TB
WHO : Initial phase -2HRZ (daily)
Continuation phase - 4HR or 6HE (daily)
Total duration-6-8 months
RNTCP :
Initial phase -2 H3R3Z3 ( daily )
Continuation phase -4 H3R3 ( daily )
Total duration- 6 months

CATEGORY-WISE TREATMENT
(WHO1997 & RNTCP1997)
TB
Category
Initial Phase
(daily /3xper week)
Continuation
Phase
(daily/3xper week)
Total
Duration
i. 2 HRZE(S)/
2H3R3Z3E3
4 HR/ 4H3R3 or 6HE 6
8
ii. 2 HRZES+
1HRZE /
2H3R3Z3E3S3+1H3R3Z3E
3
5 HRE or 5H3R3E3 8
8
iii. 2 HRZ/
2H3R3Z3
4 HR/4 H3R3 or 6 HE 6
8

DOTS PLUS:
Refers to DOTS programme which includes
component for multidrug resistance (MDR)
tuberculosis , its diagnosis , management &
treatment.
(It began in 2000 by WHO & implemented in India in 2010
& thus category IV is created) .

Cat IV –
Chronic cases who have remained or become smear +ve after
completing fully supervised Tt / close contact of most likely
MDR cases
MDR –TB –Resistant to both H & R & many other anti -TB
drugs
(Tt difficult because –one or more 2nd line drugs are to be given
for 12-24 months & they are less efficacious , less convenient
& more toxic & expensive )
Chronic – presence of association of AIDS /Diabetes /
Leukemia /Silicosis
-If sensitivity of drugs known then resistant drugs are excluded
-For H resistance – RZE X 12 months
- For H+ R resistance- ZE+ S / Kanamycin / Capreomycin/ +
Ciprofloxacin or Ofloxacin ± Ethionamide could be used

Extremely drug resistant (XDR) TB :
Term applied to bacilli that are resistant to at least 4 most effective
cidal drugs i.e. H ,R
Ofloxacin , one of Kanamycin / Amikacin/ Capreomycin.
Global survey –reveals 20% TB isolates are MDR out of which 2%
are XDR .

 TB in pregnant women :
WHO – H,R,Z –safe
(Recommended - – 2 HRZ + 6 HR regimen -8 month, -E can be added late,
-S is C/I
In India Z is avoided -(2 HRE + 7 HR total 9 month regimen )
 Breast feeding mother:
All ATT drugs are compatible ,baby should be watched ,the infant should receive
BCG vaccination & INH prophylaxis
 Indication of Glucocorticoids in TB:
-In TB Pts, glucocorticoids if at all used are always used with AT drugs,
they are considered in –
- Miliary TB
- Tuberculous Meningitis
- Rapidly filling Pleural effusion &
- Renal TB ( to reduce exudation & stricture formation)
( Its administration should be withdrawn gradually when the G.C. of Pts
improved).

RECENT DRUGS
Three novel drugs currently under clinical
development which are active against MDR-TB-
1. Linezolid
2. OPC-67683, a nitroimidazole
3. TMC207, a diarylquinoline ( Bedaquiline)

Newer Antitubercular Drugs in
Clinical Trials
1.LINEZOLID (Also known as 3rd line agent)
• Linezolid is an oxazolidinone used primarily for the
treatment of drug-resistant gram-positive infections.
• Also active against M. tuberculosis
• Mechanism of action is disruption of protein synthesis by
binding to the 50S bacterial ribosome.
• Linezolid has nearly 100% oral bioavailability, with good
penetration into tissues and fluids, including CSF.
• Adverse effects may include optic and peripheral
neuropathy, pancytopenia, and lactic acidosis .

Clinical Trials
2.TMC207 (R207910 ) by Andries etal in 2005 :
• TMC207 is a new diarylquinoline with a novel mechanism of
action: inhibition of the mycobacterial ATP synthetase proton
pump.
• TMC207 is bactericidal for drug-susceptible and MDR strains
of M. tuberculosis.
• Resistance has been reported and is due to point mutations in
the gene coding for the ATP synthetase proton pump.
• A phase 2 randomized controlled clinical trial demonstrated
substantial improvement in rates of 2-month culture
conversion, with improved clearance of mycobacterial
cultures, for MDR-TB patients.

Clinical Trials
• This drug is metabolized by the hepatic cytochrome
CYP3A4.
• Rifampin lowers TMC207 levels by 50%, and
protease inhibitors also interact significantly with
this drug.
• The dosage is 400 mg/d for the first 2 weeks and
then 200 mg thrice weekly.
• Adverse effects are reported to be minimal, with
nausea and slight prolongation of the QTc interval.

Clinical Trials
3. OPC-67683 AND PA 824 :
• The prodrugs OPC-67683 and PA 824 are
novel nitro- dihydro- imidazoxazole
derivatives.
• Antimycobacterial activity is due to inhibition
of mycolic acid biosynthesis.
• Early clinical trials of these compounds are
ongoing.

CHANGES IN RNTCP
GUIDELINES IN
2010-11

Changes in RNTCP
Guidelines
• Discontinuation of Cat III Regimen under
RNTCP
• The programme has now revised its
categorization of patients from the earlier 3
categories (Cat I, Cat II and Cat III) to 2
categories (New and Previously treated cases)

NEW (CAT I)
New Sputum smear-positive
New Sputum smear-negative
New Extra-pulmonary
New Others
PREVIOUSLY TREATED (CAT II)
Smear-positive relapse
Smear-positive failure
Smear-positive treatment after default
Others

TREATMENT
Category Initial Phase Continuation Phase
• New (Cat I) 2 H3R3Z3E3 4 H3R3
• Previously 2 H3R3Z3E3S3/ 5 H3R3E3
Treated 1 H3R3Z3E3
(Cat II)

Anti- Leprotic agents
• Also known as Hansen’s disease
• It is a chronic granulomatous infection caused by Mycobacterium
leprae
• These bacteria grow very slowly and it may take up to 20 years to
develop signs of the infection.
• The disease can affect the nerves, skin, eyes, and lining of the
nose (nasal mucosa). The bacteria attack the nerves, which can
become swollen under the skin.
• This can cause the affected areas to lose the ability to sense
touch and pain, which can lead to injuries, like cuts and burns.
• Usually, the affected skin changes color and either becomes:
lighter or darker, often dry or flaky, with loss of feeling, or reddish
due to inflammation of the skin.

• If left untreated, the nerve damage can result in paralysis of hands
and feet.
• In very advanced cases, the person may have multiple injuries due to
lack of sensation
• Eventually the body may reabsorb the affected digits over time,
resulting in the apparent loss of toes and fingers.

• Corneal ulcers and blindness can also occur if facial nerves are
affected.
• Other signs of advanced Hansen’s disease may include loss of
eyebrows and saddle-nose deformity resulting from damage to
the nasal septum.
• Disease is still considered as social stigma but it needs a change
in the attitude of public to consider it just like any other disease .
• Important is early diagnosis & Tt. Which makes it non infectious
& prevents complcations.

Treatment of Leprosy
Classification:
1. Tuberculoid
2. Borderline
3. Lepromatous

Tuberculoid:
- Well defined skin lesion
- Anesthetic patches
- Organism may or may not be found in skin lesions.
-Lepromine test is positpive.
- Prolonged remission occurs
Lepromatous:
- Skin is thickened & glossy
- Disease progresses – large nerve trunks get involved – anesthetic patches
- Atrophy of skin & muscles & absorption of small bones e.g. phalanges of
extremities,
- Ulceration & spontaneous amputation occurs.
- Lepromine test is –ve
- Smear is +ve for organism .

Diagnosis of Leprosy:
Diagnosed with any of the following-
- Skin lesions ( hypopigmented patches )
- Impaired or loss of sensation
- Acid fast bacilli in skin smears
- Nerve thickening
- Lepromin skin test

Anti- Leprotic drugs :
Classification-
-Sulfone- Dapsone (DDS)
-Phenazine derivatives- Clofazimine
-Antitubercular drugs- Rifampicin
Ethionamide
-Other Antibiotics -
Ofloxacin , Minocycline & Clarithromycin

Sulfones -
Derivative of 4-4’ diamino diphenyl sulfone (DDS)
Dapsone:
-Bacteriostatic
-High risk of resistance if used alone
Mechanism:
 Similar to sulfonamide i.e. ↓ of dihydrofolate synthase
enzyme.
 Anti-inflammatory effect occurs via ↓ of migration of
neutrophils to the inflammatory sites.

ADRs:
-Nausea , vomiting , anorexia
-Allergic reaction
-Hemolysis in pts with G6PD deficiency
-Methemoglobinaemia
-Neurotoxicity & Psychosis
Sulphone Syndrome:
After 5/6 wks of Tt. in malnourished patients there may
be characterized by fever, malaise , exfoliative
dermatitis , lymph node enlargement, Jaundice etc.

Clofazimine :
• It is a dye , weak bactericidal by ↓ the function of DNA.
• Also having anti- inflammatory activity so prevents
Lepra reaction.
-used for common skin ulcers & MAC
S/E- Skin- Red discolouration of skin
GI- Enteritis with intermittent loose stools, nausea,
abdominal pain, anorexia and weight loss can occur,
particularly when higher doses used to control lepra
reaction.

Rifampicin :
- Important antiTb drug also bactericidal to M. Leprae.
- Rapidly make leprosy Pts noncontagious
- However not satisfactory if used alone-
some bacilli persist after prolonged Tt –can cause resistance .
Ethionamide - Has significant antileprotic activity but is
hepatotoxic .
It can be used as an alternative to Clofazimine but other
substitutes are preferred.

Other Antibiotics:
-Fluoroquinolones : Ofloxacin , Pefloxacin, Gatifloxacin are
highly active against M. leprae ( but not Ciprofloxacin )
-Minocycline: due to high lipophilicity, it is active against M.
leprae. , antibacterial activity is less than Rifampicin but more
than that of Clarithromycin .
Clarithromycin :
Only macrolide antibiotic having significant activity against M.
leprae . It is being included in alternative MDT regimens.

• Leprosy primarily affect skin , mucous membranes & nerves
• Prevalent in poors ( low socioeconomic strata ) .
• National Leprosy Control Programme launched in 1955
• It was changed to National Leprosy Eradication Programme
( NLEP) in 1982
• India achieved elimination of Leprosy as a public health
problem . Incidence is less than 1 case/ 10,000 population

-For treatment purpose –leprosy is classified
as-
Single lesion paucibacillary –single dose
ROM- Rifampicin-600 mg + Ofloxacin - 400mg +
Minocycline-100 mg
Paucibacillary : ( small no. of organism)-
It includes indeterminate & tuberculoid
Tt- Rifampicin – 600 mg / month supervised
Dapsone – 100 mg / day self administration
X minimum for 6 months-repeat if relapse

Multibacillary - It includes lepromatous, borderline
cases with +ve skin smear test
Tt- Rifampicin - 600 mg / month supervised
Dapsone-100 mg / day self administration
Clofazimine – 300 mg/ month supervised
+ 50 mg/ day self administration
X 2 years- relapse – repeat

MDT was introduced by the WHO in 1981 & was implemented under the
NLEP ( National Leprosy Eradication Programme).
It includes Dapsone , Rifampicin & Clofazimine .
The WHO in 1994 recommended a fixed duration therapy( FDT) of 2 years for
MBL & 6 months for PBL.
WHO expert committee On Leprosy in 1995 recommended shortening of
MDT in MBL to 12 months & this was implemented in our country since
1999 .
The purpose of this is to render the Pts noncontiguous & therefore cut down
transmission

Alternative regimens :
Incorporating newer antileprotic drugs , but these are
used only in case of Rifampicin resistance or when MDT is
not advisable e.g.-
Clofazimine + any two of Ofloxacin / Minocycline/ Clarithromycin
for 6 months followed by Clofazimine + any one of Ofloxacin /
Minocycline x additional 18 months .

Two types of reactional state may occur
with therapy
1. Type I : Lepra reaction (reversal reaction)
In borderline leprosy due to increased in host
immunity- skin lesion & nerves become swollen
& tender without systemic manifestation –
Tt. –
Prednisolone (Thalidomide not effective)

Type II :Lepra reaction ( erythema nodosum
leprosum) –observed in lepromatous leprosy – there is
skin & nerve manifestation with fever & systemic
involvement.
Tt.- by analgesic /antipyretic for mild cases, in severe cases-
Prednisolone or Thalidomide.
-Chloroquine & cytotoxic drugs are also effective.
-Clofazimine require 3-4 wks so not suitable for acute cases, but
useful in chronic cases & prevention of this reaction .
- No need to stop the antileprotic drugs .

MCQs
1. A middle aged man with chronic renal failure is diagnosed to have sputum +ve
Pulmonary tuberculosis. His creatinine clearance is 25 mg/ min. All of the following
Drugs need modification in doses EXCEPT :
a) Isoniazid
b) Streptomycin
c) Rifampicin
d) Ethambutol
( Ans- c ,Ref : Katzung 11/e p826)
2. A 30 year old pregnant women develops Tuberculosis. Which of the following
antitubercular drug should not be given ?
a) Rifampicin
b) INH
c) Streptomycin
d) Ethambutol
( Ans- b ,Ref : KDT 6/e p748)

MCQs
3. A patient suffering from AIDS is on Zidovudine ,Lamivudine and Indinavir therapy.
He develops Pulmonary tuberculosis for which treatment is started. Which of the
Following should be avoided in him ?
a) INH
b) Ethambutol
c) Pyrazinamide
d) Rifampicin ( Ans- d ,Ref : KDT 6/e p741)
4. A patient of multidrug resistant Tuberculosis is on antitubercular drugs. After a few Months he
develops an inability to distinguish between red & green color. Most likely drug causing these
symptoms is :
a) Rifampicin
b) Ethambutol
c) Cycloserine
d) Ethionamide ( Ans -b ,Ref : KDT 6/e p742)
5. In multidrug resistant strains of M. tuberculosis which of the following drugs is likely
to be effective, including those resistant to Streptomycin?
a) Amikacin
b) Gentamicin
c) Spectinomycin
d) Clarithromycin ( Ans- a ,Ref: Katzung 11/e p825)

MCQs
6. In atypical mycobacterial infection which of the following drug is active?
a) Ethionamide
b) Streptomycin
c) INH
d) Clarithromycin ( Ans- d , Ref: KDT 6/e p750)
7. Which of the following antitubercular drug DOES NOT cross blood brain barrier?
a) Isoniazid
b) Pyrazinamide
c) Rifampicin
d) Streptomycin ( Ans- d , Ref: KDT 6/e p743 )
8. Which of the following anti-tubercular drug is implicated in the causation of transient
memory loss?
a) Ethambutol
b) Ethionamide
c) Pyrazinamide
d) Isoniazid ( Ans –d , Ref : Goodman & Gilman 10/e p1277 )

MCQs
9. Most effective drug for extracellular mycobacteria is:
a) Ethambutol
b) Rifampicin
c) Isoniazid
d) Pyrazinamide
( Ans –c , Ref : Goodman & Gilman 11/e p1205 ,1208,1211 )
10. In severe liver disease which of the following combination of antitubercular drug can
be used ?
a) Isoniazid + Streptomycin
b) Rifampicin + Isoniazid
c) Rifampicin + Ethambutol
d) Streptomycin + Ethambutol
( Ans -d , Ref: KDT 6/e p 742-743 )
11. In Leprosy , the best bactericidal agent is :
a) Rifampicin
b) Clofazimine
c) Dapsone
d) Ethionamide
( Ans-a ,Ref : KDT 6/e p753)

MCQs
12. What is the side effect of Dapsone apart from hemolytic anaemia ?
a) Infective mononucleosis like syndrome
b) Flu like syndrome
c) Lichenoid eruptions
d) G-6-PD deficiency
( Ans -a , Ref: KDT 6/e p752 )
13. Dapsone is used in all EXCEPT :
a) Dermatitis herpitiformis
b) Leprosy
c) Pneumocystis jiroveci pneumonia
d) Tuberculosis
( Ans -d , Ref: KDT 6/e p752 )
14. In Lepra reaction , the drug useful is :
a) Penicillins
b) Clofazimine
c) Dapsone
d) Rifampicin
( Ans -a , Ref: KDT 6/e p752 )

MCQs
15. Treatment of Lepromatous leprosy is :
a) Rifampicin + Dapsone
b) Rifampicin + Clofazimine
c) Rifampicin + Dapsone + Clofazimine
d) Rifampicin + Ofloxacin + Minocycline
( Ans -c , Ref: KDT 6/e p755 )

Bibliography
1.Goodman & Gilman’s ,The Pharmacological Basis of
Therapeutics (12th Edition).
2. A complete Textbook of Medical Pharmacology by
S. K. Srivastava ( Latest Edition )
3.. Essentials of Medical Pharmacology by K. D. Tripathi
(7th edition)

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