Leprosy Tuberculosis TYB pharmacy Pharmacology semester VI notes Pharmacology VI semester Pharmacology notes Third year B pharmacy pharmacology notes Pharmacology unit 3 notes Pharmacology VI semester notes

1. Drugs used in the
treatment of TB
and Leprosy
Sapana Jain
M.Pharmacy (Quality assurance)

2. Tuberculosis
Tuberculosis (TB) is a chronic
granulomatous disease caused
by Mycobacterium
tuberculosis.
Tuberculosis is also an
enormous socioeconomic
burden to India with one-fifth
of global TB burden borne by
India alone, accounting for
~1000 deaths every day.
After the spread of AIDS, the
problem has become more
complex, as tuberculosis and
Mycobacterium avium complex
(MAC) infections are not only
more common but also rapidly
progress in these patients

3. Drugs used in Tuberculosis
First-line drugs
are superior in
efficacy to
second-line drugs.
Most patients
can be treated
successfully with
these drugs.
First line
drugs
Bactericidal Bacteriostatic
Isoniazid Ethambutol
Rifampicin
Pyrazinamide
Streptomycin
Second line
drugs
Levofloxacin Linezoid
Moxifloxacin Ethionamide
Bedaqualine Prothionamide
Delamanid cycloserine
Capreomycin Kanamycin
Amikacin Teridizone

4. Isoniazid (INH)
 It is the most effective and cheapest primary
antitubercular drug. It is effective both in acidic
and alkaline medium. INH is tuberculocidal for
rapidly multiplying bacilli but static for resting
bacilli. INH destroys:
i. Intracellular bacilli as it freely penetrates into the
cells, i.e. tubercle bacilli in macrophages, and
ii. Bacilli multiplying in the walls of the cavities. Thus
it is effective against both intra- and extracellular
organisms.
 If used alone, mycobacteria develop resistance to
it. Hence, it should be used in combination with
other drugs.

5. Mechanism of Action
 INH inhibits the synthesis of mycolic acids which are
important components of the mycobacterial cell
wall.
 The cell wall of mycobacteria differs from other
bacteria in having large amounts of mycolic acids
which form essential components of mycobacterial
cell wall.
 INH, a prodrug, freely enters the mycobacteria and
is converted to an active form by an enzyme
catalase-peroxidase (Kat G) present in the
mycobacteria.
 This active form covalently binds certain enzymes
and thereby inhibits mycolic acid synthesis.

6. Mycobacterium
INH
Enters mucobactria
Active form
Catalse peroxidase
Binds enzymes
Interacts with inhA gene
Mycolic acid synthesis
Weak cell wall
Tuberculocidal

7. Pharmacokinetics
INH is completely absorbed orally, penetrates all tissues
It is metabolised by acetylation.
Patients can be fast or slow acetylators depending on the
genetic inheritance-slow acetylators responding better.
Peripheral neuropathy is more common in slow
acetylators
Metabolites of INH are excreted in the urine

8. Adverse
Effects
 Peripheral neuritis due to
interference with utilization and
increased excretion of pyridoxine
can be avoided by giving
prophylactic pyridoxine (10-50
mg) with INH.
 Hepatitis is another major
adverse effect, more common in
alcoholics and in the elderly
 INH can cause hepatic necrosis
with anorexia, nausea, vomiting
and jaundice-can sometimes be
fatal.
 Other minor effects like
anorexia, gastrointestinal
discomfort, fever and allergic
reactions can occur.
 Hemolysis can occur in patients
with G6PD deficiency.

9. Rifampicin
 Rifampicin (rifampin) is a semisynthetic
derivative of rifamycin, an antibiotic
obtained from Streptomyces mediterranei.
 The other rifamycins are rifabutin and
rifapentine
 Rifampicin is bactericidal to M.
tuberculosis M. leprae and atypical
mycobacteria.
 It also inhibits most gram-positive and
gram negative bacteria like Staph. aureus,
N meningitidis, E. coli, Proteus,
Pseudomonas and Legionella.

10. Rifampicin
Binds to beta subunit of DNA dependent RNA
polymerase
Inhibits RNA synthesis
Cell death
Bactericidal


11. Antitubercular Action
 Rifampicin is highly effective, tuberculocidal
and is the only drug that acts on persisters;
 It acts on both intra- and extracellular
organisms and is effective against tubercle
bacilli resistant to other drugs-it is called a
'sterilizing agent'. If used alone resistance
develops.
 In therapeutic concentrations, rifampicin cannot
bind human RNA polymerase and it, therefore,
selectively destroys the bacteria.

12. Pharmacokinetics
 Good tissue penetrability
 Appears in saliva ,tears, and sweat
 Metabolized in liver
 Excreted in bile

13. Adverse reactions
 Hepatotoxicity
 Gastrointestinal disturbances
 Flu like syndrome
 CNS symptoms
 Hypersensitivity reactions
 Staining of secretions

14. Drug
Interactions
 Aminosalicylic acid may delay the
absorption and reduce the
bioavailability of rifampicin.
 So when both are required, there
should be a gap of 8-12 hours.
 Rifampicin is a microsomal enzyme
inducer. So it hastens the metabolism
of anticoagulants, hormonal
contraceptives, corticosteroids,
ketoconazole, cyclosporine, some
anticonvulsants, anti- retroviral
protease inhibitors and NNRTIs.
 Oral contraceptive failures can be
expected-a preparation with higher
doses of oestrogen should be used or
alternative methods of contraception
followed.

15. Uses
 Tuberculosis and atypical mycobacterial infections:
Rifampicin is given in combination with other antitubercular
drugs-in both TB and atypical myobacterial infections. It can
also be used for the prophylaxis as an alternative to INH.
 Leprosy 600 mg once monthly supervised .
 Prophylaxis: H. influenzae and meningococcal meningitis in
close contacts particularly children-20 mg/kg/day for 4 days.
 Resistant staphylococcal infections: Rifampicin may be given
in combination with a beta lactam antibiotic or vancomycin.
 Brucellosis: Rifampicin 600-900 mg + doxycycline 200 mg
daily for 6 weeks- drug of choice.
 Pneumococcal meningitis: If pneumococci are resistant to
penicillin, they can be treated with rifampicin + ceftriaxone.
 To eradicate carrier state: Rifampicin eradicates the nasal
carrier state of N. meningitidis, H. influenzae and S. aureus-
600 mg BD for 2 days.

16. Rifabutin
 It is similar to rifampicin except that it causes milder
enzyme induction and is more active against atypical
mycobacteria.
 Rifabutin may be used in place of rifampicin in
tuberculosis patients with AIDS who are receiving
antiretroviral drugs, viz. protease inhibitors (PIs) and
NNRTIs.
 Adverse effects to rifabutin include myalgia and anterior
uveitis.
 Uses: Rifabutin can be used in tuberculosis and typical
mycobacterial infections for chemo-prophylaxis.
 Dose: 300 mg/day.

17.  Rifapentine is an analog of rifampicin and
is similar to it in mechanism of action,
actions, drug interactions and toxicity.
 Rifapentine 600 mg once weekly may be
used in tuberculosis in place of rifampicin.
It should, however, be avoided in AIDS
patients because of the risk of
development of resistance.

18. Pyrazinamide
 Pyrazinamide, an analog of nicotinamide, was
introduced in 1952.
 Mechanism of Action
 It is tuberculocidal. It requires an acidic pH (5.5)
for its tuberculocidal activity. This fact is
advantageous because tubercle bacilli reside in
the phagosomes of the macrophage where the pH
is acidic.
 Pyrazinamide converted to its active metabolite
pyrazinoic acid by an enzyme pyrazinamidase in
the mycobacteria. This metabolite may inhibit
the synthesis of mycolic acids by mycobacteria.
If used alone, resistance Develops.

19.  Pyrazinamide is well-absorbed and widely
distributed in the tissues (achieves goo
oncentration in the CSF).
 Hepatotoxicity is the most common
adverse effect
 It can result in jaundice and rarely
hepatic necrosis

20. Streptomycin
 Streptomycin is tuberculocidal, acts only
against extracellular organisms due to
poor penetrating power.
 It has to be given IM. When used alone
resistance develops.
 Because of these disadvantages and its
toxicity (oto- and nephrotoxicity),
streptomycin is the least preferred of the
first-line drugs.

21. Ethambutol
 Ethambutol is tuberculostatic and acts on fast
multiplying bacilli in the cavities. It is also
effective against atypical mycobacteria. It
inhibits the incorporation of mycolic acids into
the mycobacterial cell wall by inhibiting certain
enzymes (arabinosyltransferases) involved in it.
 Ethambutol is well absorbed on oral
administration (bioavailability ~80%). It crosses
the BBB in presence of meningeal inflammation.
Half the dose is excreted through the kidneys and
the dose should be reduced in renal failure.

22. Second line drugs
Used only if organism is resistant to first line drugs
1)Bedaquiline:
MOA:It binds to and inhibits mycobacterial ATP
synthase .it's tuberculocidal
2)Delamanid: It's nitroimidazole recently approved
for TB.it acts by inhibiting synthesis of mycolic
acid which is important component of
mycobacterial cell wall.
3)Thiacetazone:It is tuberculostatic with low
efficacy ,delays development of resistance.
4)Ethionamide: these tuberculostatic drugs are
effective against intra and extra cellular
organisms. also effective in atypical mycobacteria.

23. 4)PAS : it's related to sulfonamides ,it's
tuberculostatic.
5)Amikacin ,kanamycin and capreomycin :
have good antitubercular activity
6)Cycloserine is antibiotic that inhibits cell
wall synthesis, is tuberculostatic and also
effective against some gram positive

24. ?combination of drugs
 A combination of drugs is used in
tuberculosis for:
1. Delay the development of resistance
2. Reduce toxicity
3. Shorten the course of treatment.
 Majority of cases are sensitive to first-line
drugs. Good patient compliance and cost
of therapy should also be considered.

25.  Chemotherapy is given in two phases:
1. Intensive phase is the first phase of 1-3
months duration aimed at killing as many
bacilli as possible.
2. Continuation phase is second phase to
des- troy the dormant or persisters-duration
4-9 months.

26. Directly Observed Treatment, Short
Course (DOTS) Chemotherapy
 Directly Observed Treatment, Short Course
(DOTS) chemotherapy is a strategy found
to be effective and recommended
throughout the world.
 It involves providing most effective
medicine and confirming that it is taken-a
DOTS provider ensures that the drug is
taken by the patient in his presence

27. Resistant Tuberculosis
 If sputum remains positive even after 6 months of
treatment, organisms are likely to-be resistant.
Such patients should be treated with 4-5 drugs, of
which 3 are first-line drugs and treatment is
continued for at least 1 year after the sputum
becomes negative.
 Resistance may be to one or multiple drugs. As
per WHO, a multidrug-resistant ADR) strain is one
that is at least resistant - isoniazid and
rifampicin.
 Extensively drug-resistant tuberculosis (XDR-TB) is
resistant to almost all second-line drugs like
fluroquinolones, amikacin, capreomycin and
kanamycin.

28. Drugs for Mycobacterium avium
Complex (MAC)
 Infection with MAC is more common in HIV
patients and is more severe in them.
 In non- HIV patients, MAC infection causes
milder disease with chronic productive cough.
 The drugs effective are:
 Rifabutin, clarithromycin
 Azithromycin, fluoroquinolones
 Ethambutol, clofazimine
 Amikacin, ethionamide.

29. Drug Antitubercular action Serious toxicity
Isoniazid Tuberculocidal,
acts on intra and extracellular
organisms
Peripheral
neuritis,hepatitis,seizures,psych
osis
Rifampicin Tuberculocidal, acts on intra
and extracellular organisms
Hepatotoxicity,flu-like
syndrome,urine and secretions
are colored orange red
Pyrazinamide Tuberculocidal, kills
intracellular organisms, more
active in acidic pH
Hepatotoxicity,
arthralgia
Streptomycin Tuberculocidal acts on
extracellular organisms
Ototoxicity, nephrotoxicity
Ethambutol Tuberculostatic,
inhibits tubercle bacilli in
walls of cavities
Optic neuritis with reduced
visual acuity
Bedaquiline Tuberculocidal,
inhibits mycobacterial ATP
synthase and interferes with
generation of energy
QTc prologation, hepatotoxicity,
arthralgia

30. DRUGS
USED IN
THE
TREATMENT
OF LEPROSY
 Leprosy caused by
Mycobacterium leprae is a
chronic infectious disease
affecting skin, mucous
membranes and nerves
 Hansen discovered lepra
bacillus in 1873. As lepra
bacillus does not grow on
artificial media and cannot be
transmitted to all animals, it
is difficult to culture this
organism and study the effect
of drugs.
 In India, leprosy is a major
public health problem
affecting millions of people.

31. Drugs used in Leprosy
• Sulfones: Dapsone
• Rifampicin
• Clofazimine
• Ethionamide and protionamide.

32. Dapsone
 Dapsone is diaminodiphenylsulfone (DDS) and is
related to sulfonamides.
 Mechanism of Action
 Like sulfonamides, dapsone inhibits the incorporation
of para-amino benzoic acid (PABA) into folic acid.
 The lepra bacillus develops resistance to dapsone on
prolonged use.
 Hence, it should be used with other drugs in leprosy.
 Pharmacokinetics
 Dapsone is completely absorbed on oral
administration and reaches high concentrations in
the skin. It attains higher levels in the skin infected
with lepra bacillus than the normal skin. It is
metabolised in the liver and excreted in the bile.

33. Adverse Effects
 Dapsone is well-tolerated-anorexia,
nausea and vomiting are common.
 Fever, pruritus, rashes and dermatitis can
occur.
 Haemolytic anaemia is the most important
dose-related toxicity (more common in
patients with G6PD deficiency).
 Iron preparations should be given to
prevent anemia.

34. Uses
1. Leprosy: Dapsone is the primary drug in leprosy
used for both treatment and chemoprophylaxis.
2. P. jiroveci: Dapsone is used along with
trimethoprim as an alternative in P. jiroveci
infections in patients with AIDS-both for the
prevention and treatment.
Dose: Dapsone 100 mg + Trimethoprim 15-20
mg/kg/day for 3 weeks. Prophylaxis: Dapsone 100
mg/daily.

35.  Rifampicin is rapidly to M. leprae and is highly
effective-a single dose of 1500 mg can kill 99% of
the lepra bacilli. It can be conveniently given once
monthly. Used in combination with dapsone, it
shortens the duration of treatment
 Clofazimine imparts a reddish-black discolouration
to the skin specially on the exposed parts which
remains for several months. It can also cause
dryness of skin, itching and phototoxicity. It can
rarely cause gastrointestinal disturbances.
 Ethionamide is bactericidal to lepra bacilli but is
more expensive and more toxic than dapsone. It
can cause gastric irritation, peripheral neuritis and
hepatotoxicity. Ethionamide can be used in
multidrug regimen in patients who cannot tolerate
clofazimine. Prothionamide is similar to
ethionamide.

36. Lepra Reactions
 Lepra reactions are immunologically
mediated acute inflammatory reactions
that occur in leprosy.
 They are acute exacerbations triggered
by acute infections, stress, anxiety and
treatment with dapsone.
 Lepra reactions need to be suppressed
promptly because they can result in
permanent neurological changes. Early
detection and prompt treatment are
essential.

37. Type I
reactions
 Type I reactions (reversal reactions)
seen in tuberculoid leprosy are cell-
mediated, delayed hypersensitivity
reactions to the antigens of M. leprae.
 Cutaneous ulcerations occur and
existing lesions show more erythema;
nerves may be painful and tender.
 If untreated, there could be permanent
damage to the nerves. It should be
differentiated from relapse.
 They are treated with glucocorticoids or
clofazimine while in mild cases aspirin
suffices.
 Dose: Prednisolone 40-60 mg daily for 2
weeks and gradually tapered over next
8-10 weeks by reducing 10 mg every 2
weeks.

38. Type II
reactions
 Type II reactions are seen in lepromatous
leprosy (are known as erythema nodosum
leprosum or ENL). New lesions appear and
the existing lesions become worse.
 Fever, lymphadenitis, myositis and neuralgia
may occur.
 The severity varies; it is a hyper- sensitivity
reaction to the antigens of M. leprae an
arthus type reaction.
 Mild ENL is treated with aspirin or
clofazimine which is effective due to its
anti-inflammatory properties but has weak
and slow effects-may require several weeks.
Chloroquine, corticosteroids and
thalidomide are also effective.
 All severe ENL cases are treated with
prednisolone. Dapsone should be continued
throughout.

39. Multidrug regimen for leprosy
drugs Multibacillary leprosy
(24 months
Paucibacillary
leprosy (for 6
months)
Rifampicin 600mg once monthly
supervised
600mg once
monthly supervised
Dapsone 100mg daily self
administered
100mg daily self
administered
Clofazimine 600mg once monthly
supervised
-
50 mg daily salf
administered
-