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TUBERCULOSIS
Objectives
1. Classify antituberculous/ antituberculosis drugs
2. Explain the meaning of the terms "first line" and "second line" drugs
3. Describe the mechanisms of actions, pharmacokinetics and adverse effects of the first line
antituberculosis drugs
4. List the second line antituberculosis drugs
6. State the objectives of antituberculosis chemotherapy and the rationale of giving combination
chemotherapy and long duration of therapy
7. State the guidelines for antituberculosis chemotherapy
8. Outline the standard treatment regimen of anti-tuberculosis therapy recommended by WHO
9. What is DOTS and describe the advantages of DOTS
Tuberculosis
Causal organism - Mycobacterium tuberculosis
(AFB)
Tuberculosis
2.
drug-
resistant TB
Ciprofloxacin, Moxifloxacin, Ofloxacin
Kanamycin,
Isoniazid (INH)
Isonicotinic Acid Hydrazide
Structural congener of pyridoxine (Vitamin B6)
Bacteriostatic for resting bacilli but bactericidal for rapidly
dividing microorganisms
Selective for mycobacteria but, only M. Kansasii is
susceptible among atypical mycobacteria
Mechanism of action
Inhibits the biosynthesis of mycolic acid, a characteristic
constituent of the mycobacterial cell wall
Interferes with cell wall formation
7
Pharmacokinetics of INH
10
Rifampin (Rifampicin)
Rifampin
12
13
Pharmacokinetics of Rifampicin
Well absorbed from GIT but impaired
by food
15
16
17
Ethambutol
Mechanism of action Bacteriostatic, inhibit arabinosyl transferase
involved in the synthesis of arabinogalactan, a component of mycobacterial
cell wall, effective against nearly all strains of mycobacteria
Pharmacokinetics
Well absorbed from GIT (80%); Peak concentration reaches in 2-4 hr
Widely distributed, can cross inflammed meninges and placenta
75% of drug is excreted unchanged in urine within 24 hrs
Clinical use Treatment of TB in combination with other anti-Tb drugs
Dose - 15-25 mg/kg/day
19
Hyperuricaemia, arthralgia
Peripheral neuritis
20
Pyrazinamide
Structurally related of nicotinamide
Mechanism of action
Bactericidal agent
Pro-drug, converted by pyrazinamidase into pyrazinoic acid and
inhibit FAS1 enzyme required for synthesis of fatty acid precursors
of mycolic acid , a component of mycobacteria cell wall
Resistance to PZA may be due to mutations in the pyrazinamidase
gene, resulting in inability to convert the prodrug into active form
Also effective for dormant mycobacteria often within the cells
21
Pyrazinamide
Pharmacokinetics
Well absorbed from GIT, penetrating into CSF and distributed
throughout the body
Hydrolysed to pyrazinoic acid (in liver) which inhibits renal tubular
secretion of uric acid and excreted by the kidneys
Adverse effects
Hepatotoxicity (low incidence with low dose and short course)
Hyperuricaemia may cause gouty arthritis
Arthralgia, GI upsets, anorexia, nausea, fever and malaise
22
Pyrazinamide and ethambutol may cause urate retention and gouty attacks
23
Streptomycin
First line drug in treatment of tuberculosis
Main action is on the extracellular organisms
Mechanism of action
Bactericidal, same as other aminoglycosides, irreversibly bind to 30S
ribosomal subunit of ribosomes and interfere protein synthesis of bacteria
Nephrotoxicity
Allergy
Neuromuscular blockade
25
Peripheral
Neuropathy
26
Objectives of anti-tuberculosis
therapy
To cure the patient of TB
To prevent death from active TB or its complications
To prevent TB relapse
To decrease TB transmission to others
27
28
+
29
31
2.
3.
No divided dosage
4.
5.
6.
Category I
:New case
smear positive
seriously ill smear negative or
extrapulmonary tuberculosis (severe)
Category II
:Relapse (treatment failure of
Cat: I & III) or retreatment of defaulters
Category III
:New case - smear negative
pulmonary TB, extrapulmonary TB
Category IV
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Standard treatment
regimen of WHO
CAT
Initial
Intensive
Phase
Continuation
Phase
Total
2 HRZE
(daily)
4 HR (daily)
6 Months
II
2 HRZES
(daily)
8 Months
III
2 HRZ (daily)
4 HR (daily)
6 Months
IV
For children
Initial phase
Continuation
phase
CAT I
2 HRZ
4 H3 R 3
CAT III
2 HR
2 H3 R 3
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In special circumstances
Initial Phase
Intolerance to H
Intolerance to Z
Pregnancy
Resistance to
HR
2RZE
2HRE
Continuation
Phase
7RE
7HR
2HRE
7HR
ZEOS or another injectable agent
throughout 12-18 mth
37
Definition of DOTS
Directly Observed Treatment, Short Course
The key to stop the TB epidemic.
Case detection through sputum microscopy is accurate,
simple and reliable.
Health workers and trained volunteers
Must watch the patient swallow of each dose
Monitor progress of the patient until cured
Supervision- must continue
everyday for the first 2 months
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Advantages of DOTS
DOTS doesnt require hospitalization or isolation.
Patients can remain in their homes and return to
work in a few weeks.
DOTS helps to prevent drug resistance which is
often fatal and up to 100 times more expensive to
treat.
DOTS can produce cure rates of up to 95%
Trained health workers and community volunteers
can administer treatment
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Drug-Resistant Tuberculosis
Mono-resistant: Resistance to a single drug
Poly-resistant: Resistance to more than one drug, but not
41
----- d. kanamycin
F
----- e. streptomycin
T
42
T
43
REFERENCES
Brunton LL, Chabner BA and Knollmann BC (2011). In: Goodman & Gilmans The
Pharmacological Basis of Therapeutics. 12th edition, The McGraw-Hill Companies Inc., USA.
Katzung BG (2007). In: Basic and Clinical Pharmacology. 10th edition, The McGraw-Hill
Companies Inc., Lange Medical publications, USA.
Laurence DR, Bennett PN and Brown MJ (2003). In: Clinical Pharmacology. 9th edition,
Churchill Livingstone, UK
Rang HP, Dale MM, Ritter JM and Moore PK (2007). In: Pharmacology. 6th edition, Churchill
Livingstone, USA.
Tripathi KD (2003). In: Essentials of Medical Pharmacology. 5th edition, Jaypee Brothers,
Medical publishers Ltd, New Dehli.
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