complete information of tuberculosis including OLD RNTCP and new RNTCP with the novel drug that is marketed; classification of tuberculosis (MDR XDR TDR). special population and tuberculosis treatment clinical presentation and diagnosis

1. 1

2. TUBERCULOSIS
PRESENTED BY:
SHARIQUE RAZA
M.PHARM 2nd SEM
JAMIA HAMDARD2

3. CONTENTS
• Introduction
• Clinical presentation
• Diagnosis
• Classification
• Goals of antitubercular drug
• Keypoints in the treatment
• Pharmacotherapy
• RNTCP
• MDR,XDR &TDR
• Special population
• Novel drugs
• References
3

4. INTRODUCTION
• Tuberculosis is a
communicable disease
which is caused by
bacteria
(mycobacterium
tuberculosis) that
most often affect the
lungs.
• Curable and
preventable
4

5. Biology of tubercular
infection
M. tuberculosis is an
aerobic organism.
In unfavorable conditions it
grows only intermittently
or remains dormant for
prolonged periods.
Several subpopulations of
bacilli, each with a
distinctive metabolic
state, could exist in an
infected patient.
5

6.  (a) Rapidly growing with high bacillary load :
• as in the wall of a cavitary lesion where oxygen tension is high
and pH is neutral. These bacilli are highly susceptible to H and
to a lesser extent to R, E and S.
 (b) Slow growing:
• located intracellularly (inside macrophages) and at inflamed
sites where pH is low. They are particularly vulnerable to Z,
while H, R and E are less active, and S is inactive.
6

7.  (c) Spurters:
• found mostly within caseous material where oxygen tension
is low but pH is neutral: the bacilli grow intermittently with
occasional spurts of active metabolism. R is most active on
this subpopulation.
 (d) Dormant :
• some bacilli remain totally inactive for prolonged periods.
No antitubercular drug is significantly active against them.
 However, there is continuous shifting of bacilli between these
subpopulations
7

8. Classification
Pulmonary TB Extra pulmonary
i) Lymph node TB
ii)Pleural TB
iii)TB of upper airways
iv)Skeletal TB
v)Genitourinary TB
vi)Miliary TB
vii)Pericardial TB
viii)Gastrointestinal TB
ix)Tuberculous Meningitis
x)Less common forms
8

9. Clinical presentation
 Signs and Symptoms
• Patients typically present with weight loss, fatigue, a
productive cough, fever, and night sweats.
• Frank hemoptysis.
 Physical Examination
• Dullness to chest percussion, rales, and increased vocal
fremitus are observed frequently on auscultation.
9

10.  Laboratory Tests
• Moderate elevations in the white blood cell (WBC) count with
a lymphocyte predominance.
 Chest Radiograph
• Patchy or nodular infiltrates in the apical areas of the upper
lobes or the superior segment of the lower lobes.
• Cavitation that may show air-fluid levels as the infection
progresses.
10

11. 11

12. Diagnostic test
• Sputum smear microscopy, using the Ziehl-Neelsen
staining technique.
• The Mantoux method of PPD (purified protein derivative)
administration consists of the intracutaneous injection of PPD
containing five tuberculin units. The test is read 48 to 72 hours
after injection by measuring the diameter of the zone of in
duration.
12

13. 13

14. Goals of antitubercular chemotherapy
 (a) Kill dividing bacilli :
• Drugs with early bactericidal action rapidly reduce bacillary
load in the patient and achieve quick sputum negativity so
that the patient is non-contagious to the community:
transmission of TB is interrupted. This also affords quick
symptom relief.
 (b) Kill persisting bacilli :
• To effect cure and prevent relapse. This depends on sterilizing
capacity of the drug.
 (c) Prevent emergence of resistance:
• So that the bacilli remain susceptible to the drugs.
14

15. Key points in the treatment
• The therapy must contain two or more drugs to avoid
development of resistance .
• Drugs must be taken regularly.
• Drug therapy must continue for a sufficient duration to
achieve adequate therapeutic results.
15

16. PHARMACOTHERAPY
FIRST LINE DRUGS
• High antitubercular efficacy
as well as low toxicity.
• Used routinely.
• Isoniazid (H)
• Rifampin (R)
• Pyrazinamide (Z)
• Ethambutol (E)
• Streptomycin(S)
SECOND LINE DRUGS
• Low antitubercular efficacy
or higher toxicity or both
• Used as reserve drugs.
• Ethionamide (Eto)
• Prothionamide (Pto)
• Cycloserine (Cs)
• Terizidone (Trd)
• Para-amino salicylic acid
(PAS)
• Rifabutin
16

17. Second line drugs continue….
FLUOROQUINOLONES
• Ofloxacin (Ofx)
• Levofloxacin (Lvx)
• Moxifloxacin (Mfx)
• Ciprofloxacin (Cfx)
INJECTABLE DRUGS
• Kanamycin (Km)
• Amikacin (Am)
• Capreomycin (Cm)
17

18. ISONIAZID(H)
• It is primarily tuberculocidal.
• Fast multiplying organisms are rapidly killed, but quiescent
ones are only inhibited.
• It acts on extracellular as well as on intracellular TB (bacilli
present within macrophages), and is equally active in acidic or
alkaline medium.
• It is one of the cheapest antitubercular drugs.
• Essential component of all antitubercular regimens, unless the
patient is not able to tolerate it or bacilli are resistant.
18

19. MOA:
• inhibition of synthesis of mycolic acids which are unique
fatty acid components of mycobacterial cell wall.
 PHARMACOKINETICS:
• completely absorbed orally and penetrates all body tissues,
tubercular cavities, placenta and meninges.
• It is extensively metabolized in liver; most important pathway
being N-acetylation by NAT2.
• The acetylated metabolite is excreted in urine.
19

20. INTERACTION:
• Aluminium hydroxide inhibits absorption.
• retards phenytoin, carbamazepine, diazepam, theophylline
and warfarin metabolism by inhibiting CYP2C19 and CYP3A4,
and may raise their blood levels.
• rifampin is an enzyme inducer, its concurrent use counteracts
the inhibitory effect of INH.
• PAS inhibits metabolism and prolong its t1/2.
20

21. Side effect:
• Lethargy, rashes, fever, acne & anthralgia
 ADVERSE EFFECT:
• Peripheral neuritis , numbness , mental disturbances,
convulsion(rarely).
21

22. Rifampin
• semisynthetic derivative of rifamycin B obtained from
Streptomyces mediterranei.
• Rifampin is bactericidal to M. tuberculosis.
• It is as efficacious as INH and better than all other drugs.
• Both extra- and intracellular organisms are affected.
• It has good sterilizing and resistance preventing actions.
Mechanism of action:
• interrupts RNA synthesis by binding to β subunit of
mycobacterial DNA-dependent RNA polymerase (encoded by
rpoB gene and blocking its polymerizing function).
22

23. Pharmacokinetics:
• well absorbed orally,(bioavailability is ~ 70%),
• food decreases absorption; rifampin is to be taken in empty
stomach.
• It is widely distributed in the body: penetrates intracellularly,
enters tubercular cavities, caseous masses and placenta.
crosses meninges, pumped out from CNS by P-glycoprotein.
• metabolized in liver to an active deacetylated metabolite
which is excreted mainly in bile, some in urine also.
• undergo enterohepatic circulation.
• The t½ of rifampin is variable (2–5 hours).
23

24. INTERACTIONS:
• Rifampin is a microsomal enzyme inducer—increases several
CYP450 isoenzymes, including CYP3A4, CYP2D6,CYP1A2 and
CYP2C subfamily.
• It thus enhances its own metabolism as well as that of many
drugs including:-
• warfarin, oral contraceptives, corticosteroids
• sulfonylureas, steroids, HIV protease inhibitors,
• Nonnucleoside reverse transcriptase inhibitors (NNRTIs),
• theophylline, metoprolol, fluconazole,ketoconazole,
• clarithromycin, phenytoin.
24

25. Pyrazinamide
• Weakly tuberculocidal and more active in acidic medium.
• highly effective during the first 2 months of therapy.
• Mechanism of action:
• converted inside the mycobacterial cell into an active
metabolite pyrazinoic acid by an enzyme (pyrazinamidase)
encoded by the pncA gene.
• This metabolite gets accumulated in acidic medium and
probably inhibits mycolic acid synthesis.
25

26. Pharmacokinetics:
• absorbed orally,
• Widely distributed, has good penetration in CSF, because of
which it is highly useful in meningeal TB
• extensively metabolized in liver and excreted in urine; plasma
t½ is 6–10 hours.
 ADVERSE EFFECT:
• Hepatotoxicity, hyperuricaemia,abdominal stress, anthralgia,
flushing, rashes, fever, loss of diabetes control(warned in
diabetic patients).
• Contraindicated in pregnancy
26

27. Ethambutol
• selectively tuberculostatic.
• Added to the triple drug regimen of RHZ it has been found to
hasten the rate of sputum conversion and to prevent
development of resistance.
MECHANISM OF ACTION:
• inhibit arabinosyl transferases (encoded by embAB genes)
involved in arabinogalactan synthesis thereby interfering
with mycolic acid incorporation in mycobacterial cell wall.
27

28. Pharmacokinetics:
• 3/4 of an oral dose of is absorbed.
• It is distributed widely, penetrates meninges incompletely and is
temporarily stored in RBCs.
• Less than ½ is metabolized.
• It is excreted in urine by glomerular filtration and tubular secretion;
plasma t½ is ~4 hrs.
• Caution is required in its use in patients with renal disease.
Adverse effect:
• Loss of visual acuity.
• Hyperuricemia.
28

29. Streptomycin
• tuberculocidal
• but less effective than INH or rifampin;
• acts only on extracellular bacilli (because of poor penetration
into cells).
• It penetrates tubercular cavities, but does not cross to the
CSF, and has poor action in acidic medium.
• lower margin of safety (ototoxicity and nephrotoxicity,
especially in the elderly and in those with impaired renal
function) used only as an alternative to or in addition to other
1st line anti- TB drugs
29

30. Kanamycin (Km), Amikacin (Am)
• Tuberculocidal aminoglycoside antibiotics.
• Many S resistant and MDR strains of M.tuberculosis remain
sensitive to them.
• One of these is mostly included in the regimen for MDR-TB
during the intensive phase.
• produce less vestibular toxicity than hearing loss, but both are
nephrotoxic.
• Patients should be instructed to report vertigo and tinnitus.
• Audiometry and monitoring of renal function is
recommended.
30

31. Ethionamide (Eto)
• acts on both extra- and intracellular bacilli.
• MOA: converted by mycobacteria into an active
intermediate which interferes with mycolic acid synthesis.
• PHARMACOKINETICS: completely absorbed orally, distributed
all over and crosses into CSF.
• It is completely metabolized in liver and has a short t½ of 2–3
hours.
• Adverse effects are anorexia, nausea, vomiting, salivation,
metallic taste, epigastric discomfort, sulfurous belching and
hepatitis. It also causes aches peripheral neuritis, impotence,
menstrual disturbances and goiter on prolonged use.
31

32. cycloserine
• tuberculostatic
• MOA: it inhibits bacterial cell well synthesis by inactivating
the enzymes which racemize L-alanine and link two D-alanine
residues.
• Oral absorption of Cs is good; it diffuses all over the body
• CSF concentration is equal to that in plasma.
• About 1/3 of a dose is metabolized; the rest is excreted
unchanged in urine; plasma t½ is 9 hours.
• Adverse effects of Cs are primarily neurological;
neuropsychiatric symptoms neurotoxicity and prevent
convulsions.
• Cs is contraindicated in patients with a history of mental
illness or seizures
32

33. Terizidone
• Same as cyloserine
• less neurotoxic ; reported incidence of adverse effects is
lower.
• It is used as a substitute of Cs, especially in genitourinary TB,
because it attains higher and longer lasting concentration in
urine.
33

34. Para-amino salicylic acid
• Tuberculostatic
• MOA: inhibition of folate synthase.
• Pharmacokinetics: absorbed completely by the oral route and
distributed all over except in CSF.
• It is excreted rapidly by glomerular filtration and tubular
secretion;
• t½ is short, ~1 hour.
• Patient acceptability of PAS is poor because of frequent
anorexia, nausea and epigastric pain.
• adverse effects are rashes, fever, malaise, hypokalaemia,
goiter, liver dysfunction and rarely blood dyscrasias
34

35. Rifabutin
• It is related to rifampin in structure and mechanism of action.
• used as a substitute for R to minimise drug interactions due to
strong enzyme inducing property of R.
• Rifabutin is a much weaker inducer of CYP enzymes than R.
• This is especially needed in HIV coinfected patients of TB who
receive a protease inhibitor (PI) and/or a non-nucleoside
reverse transcriptase inhibitor (NNRTI) whose metabolism is
markedly induced by R rendering them ineffective
• Oral bioavailability of rifabutin is low (~20%), but t½ is much
longer (>30 hours).
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36. 36

37. 37

38. RNTCP
• Revised National Tuberculosis Control Program is the state-
run tuberculosis (TB) control initiative of the Government of India.
• As per the National Strategic Plan 2012–17, the program has a
vision of achieving a "TB free India", and aims to achieve Universal
Access to TB control services.
• The program provides:
various free of cost,
quality tuberculosis diagnosis and treatment services
across the country through the government health system.
• It seeks to employ the WHO recommended tuberculosis control
strategy, DOTS (Directly Observed Treatment, Short Course), to the
Indian scenario.
38

39.  DOTS has five main components:
• Government commitment (including political will at all
levels, and establishment of a centralized and prioritized
system of TB monitoring, recording and training)
• Case detection by sputum smear microscopy
• Standardized treatment regimen directly of six to nine
months observed by a healthcare worker or community
health worker for at least the first two months
• A drug supply
• A standardized recording and reporting system that allows
assessment of treatment results
39

40. Difference
old NTP
• NTP : Less successful
• Inadequate funding
• Interrupted supply of drugs
• Low treatment compliance
• Over reliance on CXR for
diagnosis
RNTCP
• RNTCP : Moresuccessful
• Adequate funding
• Regular supply of quality
assured drugs
• High treatment compliance
due to the introduction of the
DOTS regimen with directly
monitered treatment.
• Reliance on sputum
examination ,CXR,CBNAAT etc
for diagnosis
40

41. 41

42. Mutiple drug resistant
• MDR-TB is defined as resistance to both H and R, and may be
any number of other (1st line) drug(s).
• The general principles of treatment of MDR-TB are:
• The regimen should have at least 4 drugs certain to be
effective. Often 5–6 drugs are included, since efficacy of some
may be uncertain.
• Reliance about efficacy may be placed on survey of similar
patients who have been treated, DST results (applicable to H,
R, Km, Am, Cm, FQs), and the anti-TB drugs used previously in
that individual.
• Avoid combining cross resistance drugs, e.g. two FQs, Km
with Am or Eto with Pto, or Cs with terizidone
42

43. Include drugs from group I to
group IV .
Group I drugs (except H and R)
can be included,
add one injectable drug (group
II),
One FQ (group III) and one or
two group IV drugs
43

44. 44

45. XDR
• These are MDR-TB cases that are also resistant to FQs as well
as one of the injectable 2nd line drugs and may be any
number of other drugs.
• The bacilli thus are resistant to at least 4 most effective cidal
drugs, viz. H,R,FQ and one of Km/Am/Cm
45

46. TDR
• Totally drug-resistant tuberculosis (TDR-TB) is a generic term
for tuberculosis strains that are resistant to a wider range of
drugs than strains classified as extensively drug-resistant
tuberculosis.
• TDR-TB has been identified in three countries;
India, Iran, and Italy.
46

47. SPECIAL POPULATION
• Treatment of breastfeeding women:
• All anti-TB drugs are compatible with breastfeeding; full
course should be given to the mother, but the baby should be
watched.
• The infant should receive BCG vaccination and 6 month
isoniazid preventive treatment after ruling out active TB.
47

48. • Pregnancy :
• Isoniazid or ethambutol are relatively safe for use in pregnant
women.
• Rifampin is associated rarely with birth defects, including limb
reduction and CNS lesions.
• Streptomycin use may lead to hearing loss in the newborn,
including complete deafness
• Ethionamide may cause premature delivery and congenital
deformities when used during pregnancy
48

49. Renal failure
• Isoniazid and rifampin do not require dose modification in
renal failure, however the frequency of isoniazid dosing may
be reduced.
• Pyrazinamide and ethambutol typically require a reduction in
dosing frequency from daily to three times weekly
• Renally cleared TB drugs include the aminoglycosides (Am,
km, and s), capreomycin, ethambutol, cycloserine, and
levofloxacin. Dosing intervals need to be extended for these
drugs .
• The metabolites of isoniazid, pyrazinamide, and p -
aminosalicylic acid are cleared primarily by the kidneys.
• Serum concentration monitoring must be performed for
cycloserine to avoid dose-related toxicities in renal failure
patients.
49

50. 50

51. AIDS PATIENT
• The metabolism of nucleoside reverse transcriptase
inhibitors (NRTIs, zidovudine, etc.) is not induced by
rifampin, and no dose adjustment is needed.
• An alternative regimen of 3 NRTIs (zidovudine +
• lamivudine + abacavir) has been advocated for patients
who are to be treated by rifampin.
• If 2 NRTI + NNRTI is to be used, efavirenz should be
selected as the NNRTI because its metabolism is induced
to a lesser extent.
• MDR-TB in HIV-AIDS patients should be treated in the
same way as that in non-HIV infected patient for a total
of 18–24 months.
51

52. NOVEL DRUGS
Nix-TB
• The Nix-TB trial is the first TB clinical trial to test a new drug
combination which has the possibility of being a shorter, all oral,
and affordable treatment for XDR-TB.
• This combination does not require injections and has far fewer
pills.
• The Nix-TB drug combination is:
• Pretomanid(inhibition of cell wall mycolic acid biosynthesis)
• bedaquiline( blocks the proton pump for ATP synthase of
mycobacteria)
• and linezolid (disrupts bacterial growth by inhibiting the initiation
process of protein synthesis)
• This drug combination is predicted to be able to cure XDR-TB in six
to nine months.
52

53. • In February 2017 the results became available for the first 72
people to be treated in the study. Thirty one people have
completed treatment and 6 months of post treatment follow
up. Of these 31 people, 29 people cleared XDR-TB. This
means that TB bacteria could no longer be cultured from their
sputum. Twenty people stopped taking the drug after six
months of follow up and only one relapsed.
53

54. AZD5847
AZD5847 is a potential new TB drug being developed by
AstraZeneca. In December 2012 it was announced that the
first patient had been enrolled in a Phase 2a trial of the drug
in South Africa, to assess the effectiveness of the drug for
patients with TB, including patients with HIV and
TB coinfection. The study is sponsored by the National
Institute of Allergy and Infectious Diseases (NIAID), which is
part of the U.S. National Institutes of Health.
54

55. Nitroimidazoles
• derivatives of this class of drugs, OPC-67683 (now
also known as delamanid) and PA-824 are under
development as potential TB drugs.
55

56. REFERENCE
• https://www.tbfacts.org/new-tb-drugs/
• K.D.TRIPATHI essential of medical pharmacology 7th edition.
• Joseph T. Dipiro Pharmacotherapy A pathological approach 8th
edition.
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57. THANK YOU
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