• Tuberculosis (TB) is an infectious disease usually caused by the bacterium Mycobacterium tuberculosis (MTB). • Tuberculosis generally affects the lungs, but can also affect other parts of the body. • Most infections do not have symptoms, in which case it is known as latent tuberculosis. About 10% of latent infections progress to active disease, which, if left untreated, kills about half of those infected. • The classic symptoms of active TB are a chronic cough with blood-containing sputum, fever, night sweats, and weight loss. • The historical term "consumption" came about due to the weight loss. Infection of other organs can cause a wide range of symptoms. • Tuberculosis is spread through the air when people who have active TB in their lungs cough, spit, speak, or sneeze. People with latent TB do not spread the disease. Active infection occurs more often in people with HIV/AIDS and in those who smoke.

1. TUBERCULOSIS
PHARMACOTHERAPY OF
BY
A.V.V.V. RAVI KIRAN
1ST M.PHARM
PHARMACOLOGY DEPT.

3. ‣ Tuberculosis (TB) is a communicable
infectious disease caused by Mycobacterium
tuberculosis, M.bovis, M.africanum etc.
‣ It can produce silent, latent infection, as well
as progressive, active disease.
‣ Globally, 2 billion people are infected and
roughly 2 million people die from TB each
year.
‣ The World Health Organization (WHO)
estimates that a third of the world’s
population is latently infected with M.
tuberculosis; around 1 in 10 of these will
develop clinical tuberculosis, falling to 1 in 3
if the individual is co-infected with HIV.
INTRODUCTION

4. TRANSMISSION
▸Mycobacterium tuberclosis is spread by small airborne droplets, called droplet
nuclei, generated by the coughing, sneezing, talking with a person with
pulmonary or laryngeal tuberculosis.
▸These minuscule droplets can remain air-borne for minutes to hours after
expectoration.
▸The number of bacilli in the droplets, the virulence of the bacilli, exposure of
the bacilli to UV light, degree of ventilation, and occasions for aerosolation all
influence transmission.
▸Introduction of M.tuberculosis into the lungs leads to infection of the
respiratory system; however, the organisms can spread to other organs, such
as the lymphatics, pleura, bones/joints, or meninges, and cause extra-
pulmonary tuberculosis.

5. PATHOPHYSIOLOGY
‣ Once inhaled, the infectious droplets settle throughout the air-ways. The
majority of the bacilli are trapped in the upper parts of the airways where
the mucus-secreting goblet cells exist.
‣ The mucus produced catches foreign substances, and the cilia on the
surface of the cells constantly beat the mucus and its entrapped particles
upward for removal.
‣ This system provides the body with an initial physical defense that
prevents infection in most persons exposed to tuberculosis.
‣ The subsequent phagocytosis by macrophages initiates a cascade of
events that results in either successful control of the infection, followed
by latent tuberculosis, or progression to active disease, called primary
progressive tuberculosis.
‣ After being ingested by macrophages, the mycobacteria continue to
multiply slowly,8
with bacterial cell division occurring every 25 to 32
hours

7. PATHOPHYSIOLOGY

8. SYMPTOMS
‣ Cough for 3 weeks
‣ Loss of appetite
‣ Fatigue
‣ Night sweats
‣ Fever
‣ Weight loss

9. DIAGNOSIS OF TUBERCULOSIS
Clinical examinations ( presenting symptoms , duration of symptoms ,
previous TB)
Diagnostic Imaging (X-rays , CT scans, MRI’s)
Bacteriology ( Smears , cultures )
Pathology of biopsy specimens
TB infection

10. PHARMACOTHERAPY
▸ Effective treatment requires multiple antibiotics for prolonged periods
of time, up to as long as 12 months and even longer for resistant
strains.
▸ There are now many resistant strains of TB, including Multi drug-
resistant tuberculosis (MDR-TB) and Extensively drug-resistant
tuberculosis(XDR-TB).
▸ The treatment of tuberculosis which is resistant to multiple drugs is
more difficult, and regimens have to be individualized according to
drug sensitivity.
▸ This therapy is completely combinational and not given alone.

11. ▸ The treatment of pulmonary tuberculosis is summarized as

12. CLASSIFICATION OF TB DRUGS
TB DRUGS
FIRST LINE
SECOND LINE
Isoniazid
Rifampin
Ethambutol
Pyrazinamide
Thiacetazone
Para amino salicylic acid
Ethionamide
Cycloserine
NEWER DRUGS
Ciprofloxacin
Ofloxacin
Clarithromycin
Azithromycin
Amikacin*THIRD LINE DRUGS - FEW IN PHASE III
BEDAQUILINE
LINEZOLID
*PA-109

13. MECHANISM OF ACTION
Goodman & Gilman, 2012

14. DOT TREATMENT
‣ DOT is a component of case management that helps ensure patients
adhere to therapy. It is the method whereby a trained health-care
worker or another trained designated person watches a patient
swallow each dose of anti-TB drugs and documents it.
‣ DOT is the preferred core management strategy recommended by
CDC for treatment of TB disease and, if resources allow, for latent
tuberculosis infection (LTBI) treatment.
‣ DOT can reduce the development of drug resistance, treatment
failure, or relapse after the end of treatment. Good case management,
which includes establishing a relationship with the patient and
addressing barriers to adherence, facilitates successful DOT.
CDC- Centre for Disease Control and Prevention

15. LATENT TB INFECTION
▸ Latent TB occurs when a person has the TB bacteria within their body,
but the bacteria are present in very small numbers.
▸ People with latent TB do not feel sick and are not infectious. They
cannot pass the bacteria on to other people.
▸ It is often only known that someone has latent TB because they have
had a test , such as the TB skin test.

16. DRUG REGIMENS FOR TREATMENT OF LATENT TUBERCULOSIS INFECTION
DRUG
INTERVAL AND
DURATION
COMMENTS
Isoniazid
Daily for 6
months
Not indicated for HIV infected
persons, those with fibrotic
lesions on chest radiographs, or
children
Twice weekly for
6 months
Directly observed therapy must
be used with twice-weekly
dosing
Rifampin
Daily for 4
months
for persons who are contacts of
patients with isoniazid-resistant,
rifampin-susceptible TB who
cannot tolerate Pyrazinmide

17. ISONIAZID
▸ Most active drug which is structurally similar to pyridoxine.
▸ Bactericidal for fast growing bacteria
▸ Able to penetrate into phagocytic cells. Thus acting as both
intracellular and extracellular.
▸ Less active against atypical Mycobacterium.

18. Mechanism of Action:
▸ Isoniazid is a prodrug activated by
the mycobacterial enzyme katG.
▸ The activated compound reacts
with nicotinamide adenine
dinucleotide(NAD) to form an
INH-NAD complex.
▸ The INH-NAD complex inhibits
one of the final steps of mycelia
acid synthesis via the enzyme that
is abbreviated InhA.
▸ The net results are accumulation
of long-chain fatty acids,
decreased production of mycelia
acid, and cellular death.

19. Pharmacokinetics:
‣ readily absorbed by GIT.
‣ Peak plasma concentration of 3-5µg/ml within 1-2 hrs.
‣ Half life is about 1-3 hrs.
‣ Dosage :- 5mg/kg/day ; High dose is unto 15mg/kg/day
twice in a week.
Side effects:
‣ Hepatitis
‣ Peripheral neuropathy

20. RIFAMPIN
▸ Semi synthetic derivative of rifamycin, antibiotic produced
by Streptomyces mediterranei .
▸ Active against gram + & — , some enteric mycobacterium
and chlamydia.
▸ There is no cross resistance to other class of anti microbial
but there is a cross resistance with other rifamycin
derivatives

21. Mechanism of Action:
▸ Rifampin inhibits bacterial
RNA synthesis by binding
prokaryotic RNA
polymerase.
▸ It prevents Initiation of RNA
synthesis.
▸ It is bactericidal for
extracellular and
intracellular bacteria.
▸ Not commonly used as
SOLO agent for treatment of
established infections.

22. Pharmacokinetics:
‣ Is primarily metabolized by the liver and eliminated in the
bile.
‣ Potent inducers of a number of CYP enzymes.
‣ Dosage :- 10mg/kg/day ; High dose is unto 15mg/kg/day
twice in a week.
Side effects:
‣ Cholestatic jaundice and Hepatitis
‣ Orange red tint of secretions

23. ETHAMBUTOL
▸ It is Synthetic drug, soluble in water and heat stable
compound.
▸ It disrupts the formation of the tuberculous cell wall by
blocking arabinosyl transferases.
▸ These enzymes attach the arabinose residue to
arabinogalactan to mycelia acid.
▸ It is bacteriostatic ; suppresses the growth of TB but does
not kill TB.

24. Pharmacokinetics :
‣ It is cleared primarily by the
kidneys and doses need to be
adjusted downward in patients
with moderate to severe renal
dysfunction.
Side effects:
‣ Optic neuritis
‣ Peripheral neuropathy
‣ Rash
‣ Fever

25. PYRAZINAMIDE
▸ It is inactive at Neutral pH and gets active at pH 5.5.
▸ Drug act against intracellular organism.
▸ It is prodrug. It must first be converted to pyrazinoic acid.
by mycobacterial enzyme called Pyrazinamidase.
▸ Pyrazinamide is active only acidic environment.
▸ Never used as single drug; resistance develops very
quickly when it is used alone.

26. Mechanism of action :
‣ Pyrazinoic acid probably exerts its
antituberculous activity via
inhibition of an enzyme called
Fatty acid synthase I that is
involved in the cell wall synthesis.
Side effects :
‣ Hepatic Injury
‣ Arthalgia
‣ Increased uric acid
‣ Anorexia
‣ Nausea and vomiting

27. FLUOROQUINOLONES
▸ These antibiotics are well effective on the intracellular
organisms.
▸ Fluroquionolones bind to and inhibit DNA gyrase (in gram
—ve ) and topoisomerase IV (in gram +ve).
▸ Fluoroquinolones are absorbed very well from the gut.
▸ Most fluroquinolones are cleared renally, and dose
adjustment may be required in patients with renal
impairment.

28. ▸ Side effects :
Nausea
vomiting
diarrhea
Tendon ruptures

29. RECENT ADVANCES IN PHARMACOTHERAPY
▸ Bedaquiline ( formerly as TMC207) is the first new drug
from a new class to be treat TB to be approved by USFDA
in over 40 years.
▸ It is recommended in effective treatment regimen in MDR-
TB with second line drugs.
▸ TMC207 is a first in class diarylquinolone compound with
novel mechanism of action by blocking the proton pump
for ATP synthase of Mycobacterium leading to cell death.

30. ▸ Linezolid , is the first Oxazolidinone to be developed and
introduced in clinical use.
▸ Its anti-mycobacterial activity sharply increases the efficacy
of other second line therapies.
▸ The oxazolidinone are protein synthesis inhibitors i.e., they
stop the growth and reproduction of bacteria by disrupting
translation of mRNA into proteins in ribosome.
▸ Although its mechanism of action is not fully understood
linezolid appears to work on the first step of protein
synthesis, initiation, unlike most other protein synthesis
inhibitors, which inhibit elongation.

31. 2015

32. CONCLUSION
‣ Despite the increasing numbers of new
diagnosed cases of tuberculosis in
developed countries and the disease
still remaining one of the most frequent
reasons of deaths worldwide, clinical
and pre-clinical data indicate the
improvement of effectiveness of the
cure.
‣ Disturbing statistics of frequency of
newly recognized tuberculosis or multi-
drug resistant tuberculosis was a step
to counteract this disease and give
some perspectives in clinical trials.

33. REFERENCES
‣1. Applied Pharmacology, Stan Bardal , page no.258-263; 2011.
‣2. Fundamentals of Pharmacology, Shane Bullock, page no.947-952; 7th edition,2014.
‣3. Antimicrobial Chemotherapy, Peter Dave, page no. 326-337; 7th edition, 2015.
‣4. Goodman & Gilman’s The Pharmacological Basis of Therapeutics , page no.
1549-1570; 12th edition, 2011.
‣5. Organization, World Health (2008). Implementing the WHO Stop TB Strategy: a
handbook for national TB control programmes. Geneva: World Health Organization.
p. 179.
‣6. Recent Advances in the Development of Anti-tuberculosis Drugs Acting on
Multidrug-Resistant Strains: A review Amanuel Godebo , Abiy H/woldi , Alemayehu
Toma