This document discusses tuberculosis (TB) and its treatment. It begins by noting that TB is a treatable bacterial infection and discusses the global problem it poses. It then outlines first and second line anti-TB drugs, including their mechanisms of action and common adverse drug reactions. The standard treatment regimen for TB is described as a combination of rifampin, isoniazid, pyrazinamide, and ethambutol over 6 months. Key points about individual drug classes and drugs are summarized.

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2. TUBERCULOSIS:
 TB is a bacterial infection ,treatable by anti –TB drugs.
 global problem
 in 1993 increase in reported cases of TB in countries led the World Health
Organization (WHO) to declare TB a global emegency.
 additional concern has been increase in MDR-TB
 in 2006 , emergence of XDR-TB was first reported.
 adequate and effective treatment is essential , both clinically for patients and also to
control TB ,AS BCG VACCINE does not prevent infection.
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4. ANTI- TB DRUGS:
1 S T L I N E A G E N T S :
• isoniazid
 ethambutol
 pyrazinamide
 RIFAMYCINS e.g
 rifabutin
 rifampin/rifampicin
 rifapentine
2 N D L I N E D R U G S :
• aminoglycosides
• aminosalicylic acid
• capreomycin
• cycloserine
• fluoroquinolones
• macrolides
• ethionamide
• bedaquiline
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5. TREATMRNT:
 the recommended standard teatment regimen for respiratory and other forms of TB
in UK is:
o Rifampicin , isoniazid , pyrazinamide , and ethambutol for initial 2 months
(initial phase).
o a further 4 months of rifampicin and isoniazid (continuation phase).
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6. FIRST LINE AGENTS:
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7. 1. ISONIAZID:
 MOA:
 is a prodrug activated by KatG(mycobacterium catalase peroxidase).
 it targets enzymes acyl carrier protein reductase and beta ketoacyl -ACP
synthase and inhibit mycolic acid synthesis leads to disruption in bacterial
cell wall.
 ADR’ s:
• hepatitis
• fever
• skin rashes
• dose dependent peripheral neuropathy
• depletion of vitamin B6
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8. PATIENT COUNSELLING:
 liver function should be checked before treatment commences
with these drugs.
 liver function tests must be measured if fever , malaise , vomiting or
jaundice develop , and all drugs should be stopped.
 fever , skin rashes occur and pregnant women are at greater risk
and should receive pyridoxine supplementation .
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9. 2.RIFAMPIN:
 MOA:
• it blocks RNA transcription by interacting with the β-subunit of
mycobacterial DNA- dependent RNA polymerase.
 ADR’s:
• hepatitis , death due to liver failure.
• Greater doses cause flu-like syndrome , with fever , chills , myalgia
• acute renal failure
• hemolytic anemia
• shock
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10. DRUG INTERACTIONS:
 induce phase 1 &Phase 2 cytP450 enzymes .
 it can decrease half-lives of co-administered drugs that
are metabolized by these enzymes.
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11. PATIENT COUNSELLING:
• Don’t take it with medications like mathadone , protease inhibitors ,
non-nucleoside reverse transcriptase inhibitors due to adverse drug
reactions .
• git problems , fever and rash can occur.
• it cause orange-red urine with approx 4h of dose.
 women using the oral contraceptive pill should be advised to use
other non-hormonal methods of contraception for the duration of
rifampicin treatment and for 8 weeks afterwards as the effectiveness
of hormonal contraceptives is reduced by rifampicin.
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12. 3.RIFABUTIN:
• derivative of rifampin
• it is preferred for patient’s coinfected with HIV( human immuno
deficiency virus) and who are receiving protease inhibitors or
several of non- nucleoside reverse transcriptase inhibitors.
• less drug interactions.
 ADR’s:
• uveitis
• neutropenia
• skin hyperpigmentation
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13. 4.RIFAPENTINE:
• greater activity then rifampin.
• used in combination with isoniazid .
• rifapentine used in patient’s with LTBI and in select HIV –VE
PATIENT’S with minimal pulmonary TB.
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14. 5.ETHAMBUTOL:
 MOA:
• it inhibits Arabinosyl transferase and inhibit mycobacterial cell
wall.
• it is used in combination with pyrazinamide , rifampin and
isoniazid .
 ADR’s:
• optic neuritis(loss of optic acuity , and loss of ability to
discriminate between red and green.)
• the high risk in renal impaired patient’s.
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15. PATIENT COUNSELLING:
 visual acuity and color discrimination should be tested prior to
initiating therapy and periodically thereafter.
 uric acid excretion is decreased so caution should be exercised in
patient’s with gout.
 a baseline opthalmological assessment is important in children as
in adults and should be repeated after 1-2 months.
 if toxicity develops , drug must be stopped promptly.
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16. 6.PYRAZINAMIDE:
 MOA:
 precise mechanism of action is unclear.
 it must be enzymatically hydrolyzed by a pyrazinamidase to
pyrazinoic acid which is active form of drug.
 ADR’s:
• liver toxicity
• uric acid retention is common but rarely precipitated a gouty attack.
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17. PATIENT COUNSELLING:
• if patients have known pre- existing hepatic dysfunction ,the use of
pyrazinamide should be carefully considered.
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18. SECOND LINE AGENTS:
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19. 1-AMINOGLYCOSIDE (STREOTOMYCIN):
 MOA:
 they bind 30S ribosomal subunit , where they interfere with assembly
of functional ribosomal apparatus and hence mislead ganetic code.
 ADR’S:
• ototoxicity(vestibular and auditory)S
• deafness and affect developing featuses.
• vertigo
• nephrotoxicity
• neuromuscular paralysis
• allergic reactions.
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20. PATIENT COUNSELLING:
 it should not be used during pregnancy as cause deafness in
developing featus.
 it should not be concomitant use with loop diuretics and cisplatin.
 high doses or concurrent administration with neuromuscular
blockers cause neuromuscular paralysis.
 should not be used in patient’s with myasthenia gravis.
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21. 2-AMINOSALICYCLIC ACID
Aminosalicyclic acid is a folate synthesis antagonist that is active
exclusively against M.tuberculosis. It is structurally similar to p-
amino benzoic acid and to sulfonamides.
KINETICS :
It is readily absorbed from the gastrointestinal tract . It is widely
distributed in tissues and bodily fluids except the cerebrospinal
fluid . It is rapidly excreted in the urine .
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22. DRP’s :
1) Crystalluria
2) Gastrointestinal Symptoms
3) Hypersenstivity Reactions
4) Peptic ulceration and hemorrhage.
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23. 3- ETHIONAMIDE
It is chemically related to Isoniazid and similarly blocks the
synthesis of mycolic acid.
KINETICS :
It is poorly water soluble and available only in oral form. It is
metabolized by the liver,
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24. DRP’s :
1) Intense gastric irritation
2) Neurologic symptoms
3) Hepatotoxicity
4) Hypothyroidism
5) Alopecia
6) Impotence
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25. 4- CAPREOMYCIN
Capremycin is a peptide protein synthesis inhibitor antibiotic
obtained from Streptomyces capreolus .
for Multi-drug resistant TB.
Capreomycin is an important injectable agent for treatment of drug –
resistant Tuberculosis .
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26. ADRs:
1) Nephrotoxic
2) Ototoxic
3) Tinnitis , deafness and vestibular disturbances occur
4) Injection causes significant local pain , and sterile abscesses
may occur.
Point to remember:
*if ADRs are severe reduce dose to 1g 2-3 times weekly after initial
response is achieved.
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27. 5- CYCLOSERINE
Cycloserine is an orally effective tuberculostatic drug that disrupts
D-alanine incorporation into the bacterial cell wall .
PHARMACOKINETICS :
It distributes well throughout body fluids , including CSF .
Cycloserine is primarily excreted unchanged in urine.
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28. TOXIC EFFECTS :
1) Peripheral neuropathy
2) CNS dysfunction ( depression , psychotic reactions , lethargy ,
anxiety , suicidal tendency . )
3) Seizures .
Points to remember:
* reduce dose in renally compromised patients if creatinine clearance
is less than 50ml/min.
*monitor serum conc.
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29. 6- FLUOROQUINOLONES
The fluoroquinolones have an important place in the treatment of
multi-drug resistant tuberculosis .
Ciprofloxacin , Levofloxacin , Gatifloxacin , and Moxifloxacin
inhibits strains of M.tuberculosis at concentrations less than 2
mcgMl.
They are also active against atypical mycobacteria.
RATE OF ACTIVITY :
Moxifloxacin > Gatifloxacin > Levofloxacin > Ciprofloxacin
FluoroQuinolones are an important addition to the drugs available
for tuberculosis , especially for strains that are resistant to first –
line agents .
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30. MOA :
Fluoroquinolones enter bacteria through porin channels and
exhibit antimicrobial effects on DNA gyrase ( topoisomerase 2 ) and
topoisomerase 4 .
Inhibition of DNA gyrase results in relaxation of supercoiled DNA
, promoting DNA strand breakage . Inhibition of topoisomerase 4
impacts chromosomal stabilization during cell division thus
interfering with the separation of newly replicated DNA .
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31. ADVERSE REACTIONS :
common side effects are nausea , vomiting , diarrhea . Headache
and dizziness may occur . Peripheral neuropathy and glucose
dysregulation have also been noted . Fluoroquinolones can cause
phototoxicity ,
Points to remember:
patients taking these agents should be advised to use sunscreen
and avoid excess exposure to sunlight . If phototoxicity occurs ,
discontinuation of the drug is advisable.
antacids not given because divalent and trivalent cations prevent
absorption.if given then 2-4 hours before or after taking.
Dose adjustment in renally compromised pat. . * moxifloxacin not given to
hepatic failure patient.
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32. 7- MACROLIDES
The macrolides are a group of antibiotics with a macrocyclic
lactone structure to which one or more deoxy sugars are attached
.
Azithromycin and Clarithromycin are included in regimens for
several NTM infections .
MOA :
These bind irreversibly to a site on the 50S subunit of the
bacterial ribosome thus inhibiting translocation steps of protein
synthesis .
They may also interfere with the step of transpeptidation.
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33. ADVERSE EFFECTS :
1) Gastric distress
2) Cholestatic jaundice
3) Ototoxicity
4) Contraindications :
a) Patients with hepatic dysfunction should be treated
cautiously because these drugs accumulate in the liver
b) These drugs may prolong QT interval so should be
used cautiously in patients with proarythmatic conditions .
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34. Points to remember: 1- hpur before or 2 hour after meal.
Erythromycin: destroyed by gastric acid so administered in enteric coated.
Inhibit cytp450 , increase serum conc. Of theophylline, cyclosporine,
warfarin, oral digoxin.
Clathiromycin: reduce dose in pat, with creatinine clearance 30ml/min.
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35. 8- BEDAQUILINE
It is an ATPase synthase inhibitor , approved for the treatment of MDR
– TB .
PHARMACOKINETICS :
It is administered orally and it is active against many types of
mycobacteria .
ADRs: hepatotoxicity and QT prolongation, dose monitoring.
Used for patients that are resistant to isoniazid and rifampicin.
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36. Points to remember:
It is a CYP3A4 substrate and administration with strong CYP3A4
inducers such as rifampin should be avoided .
Must be taken with fatty meal which increase their absorption upto two
folds.
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37. REFERENCES :
1) CLINICAL PHARMACY and THERAPEUTICS by ROGER WALKER
and CATE WHITTLESEA.
2) BASIC and CLINICAL PHARMACOLOGY by BETRAM G. KATZUNG
and ANTHONY J. TREVOR
3) PHARMACOLOGY LIPPINCOTT ILLUSTRATED REVIEWS by KAREN
WHALEN
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