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DRUG THERAPY OF

TUBERCULOSIS

Dr. Marlar Myint


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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

Drugs used for the treatment


of tuberculosis (Classification)
1.

First line drugs


Drugs with higher efficacy and relatively lesser toxicity
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol,
Streptomycin

2.

Second line drugs


Drugs which are reversed for the treatment of

drug-

resistant TB
Ciprofloxacin, Moxifloxacin, Ofloxacin

Kanamycin,

Amikacin, Ethionamide, Para-aminosalicylic acid (PAS),


Cycloserine,, Capreomycin, Linezolid

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
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Pharmacokinetics of INH

Readily absorbed orally ; penetrate cells to act on intracellular


mycobacteria (active against extra-cellular and intra-cellular bacteria)
Peak plasma concentration reaches at 1-2 hrs after ingestion
Widely distributed (pleural & ascitic fluid, CSF, macrophages, caseous
tuberculous lesion) and crosses the placenta
Metabolized in liver by acetylation and enzymatic hydrolysis; the rate of
acetylation is under genetic control
Half life of INH is 60 - 90mins fast, and 3 - 4 hrs in slow acetylators
75-95% excreted in urine within 24 hrs, mostly as metabolites
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Bimodal distribution of isoniazid half-lives caused by rapid and slow


acetylation of the drug

Therapeutic uses of INH


Treatment of all types of TB (as the main drug in anti-TB regimens
Chemoprophylaxis of TB (in contact, INH only)
Dose 5 mg/kg/day, maximum 300 mg

Adverse Effects of INH


Peripheral neuropathy due to pyridoxine deficiency (esp. in slow acetylators)
Hepatitis (esp. in elderly and fast acetylators as metabolites are more toxic to
the liver)
Drug hypersensitivity reactions - fever, arthritic symptoms, vasculitis and skin
eruptions
Haemolytic anaemia in G-6PD deficient patients

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Isoniazid potentiates the adverse effects of the antiepileptic drugs - phenytoin,


carbamazapine and ethosuximide by inhibiting the hepatic microsomal
enzymes
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Rifampin (Rifampicin)

Rifamycins - complex macrocyclic antibiotics.

Rifampin

- semisynthetic derivative of rifamycin B

Antimicrobial activity and spectrum


Bactericidal agent for both intracellular and extracellular
mycobacteria
Bactericidal most microorganisms such as E. coli, Proteus,
Pseudomonas, Klebsiella, Chlamydia and Pox virus
Also effective against Staph. Aureus, Nisseria meningitidis and H.
influenzae

Resistance may develop rapidly

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Mechanism of action of Rifampicin

Inhibits DNA-dependent RNA polymerase enzyme by


forming a stable drug-enzyme complex, leading to
suppression of initiation of chain formation in RNA synthesis
in susceptible bacteria
Human RNA is not affected (selective toxicity)
Bactericidal action

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Pharmacokinetics of Rifampicin
Well absorbed from GIT but impaired
by food

About 80% protein bound

Peak concentration reaches in 2-4 hrs

Widely distributed into tissue and body


body fluids including CSF

saliva, macrophages, nerves

Passes the BBB and placenta barrier

Metabolized in the liver and

eliminated in bile, faeces and urine


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Therapeutic uses of Rifampicin


Chemotherapy of tuberculosis (as a component of anti-TB regimens)
Prophylaxis in meningococcal and H. influenzae meningitis
Staphylococcal endocarditis together with beta lactam antibiotics
Osteomyelitis caused by staphylococcus tolerant to penicillin with other
antibiotics
To eradicate nasal staphylococcal infection
To treat meningococcal carriers
Chemotherapy for leprosy

Dose - 450-600 mg / day in adults, 10 mg / kg in children

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Adverse effects of Rifampicin

Orange coloration of urine, sweat, tears and


contact lens (side effect, not harmful)
Hepatitis

Flu-like syndrome with fever, chills and myalgia, rashes,


eosinophilia, interstitial nephritis, acute tubular necrosis,
thrombocytopenia, and even anaphylactic shock

Proteinuria, CNS disturbances

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Drug interactions with RFP


Induces drug metabolizing enzymes of digoxin, oral
contraceptives, oral anticoagulants, antidiabetic agents,
narcotic analgesics, quinidine, propranolol, clofibrate,
verapamil and theophylline
Other Rifamycins
Rifabutin equally effective, less resistance, less enzyme
inhibition
Rifabutin not absorbed from GI tract, used in travelers
diarrhoea

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Rifampin induces cytochrome P450, which can decrease the half-lives of


coadministered drugs that are metabolized by this system
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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
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Adverse effects of Ethambutol

Visual toxicity due to optic neuritis is common esp. in children resulting


in decreased visual acuity, color blindness, retinal damage

Dose related, reversible if drug is withdrawn or reduction in dose

Children under 5 years are contraindicated

Allergic reactions - drug fever, rashes

GI upsets, headache, confusion

Hyperuricaemia, arthralgia

Peripheral neuritis
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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
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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
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Pyrazinamide and ethambutol may cause urate retention and gouty attacks
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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

Uses - for treatment of:


Tuberculosis, Tularaemia, Plague
Brucellosis (combined with tetracyclines), Bacterial endocarditis
Dose - adult - 0.75-1 g IM, child - 30 mg/kg IM
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Adverse effects of Streptomycin:


Ototoxicity - 8th cranial nerve toxicity leading to dysfunction of
labyrinth, inability to maintain equilibrium; early signs of vestibular
toxicity include motion related headache, dizziness or nausea
(with streptomycin vestibular toxicity is more common)

Nephrotoxicity
Allergy
Neuromuscular blockade

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Some common adverse/ side


effects of anti-TB drugs
H

Peripheral
Neuropathy

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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

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Rationale of combination chemotherapy in the


treatment of TB
1. To prevent microbial resistance
2. To achieve antimicrobial synergism (to reduce the bacterial
population as rapidly as possible)
3. To reduce the adverse effects by reducing the dose of each drug

Rationale of giving prolong duration of treatment


1. For complete eradication of infection as organisms grow slowly
2. To prevent microbial resistance
3. To prevent relapse
4. To prevent transmission

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+
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One of several recommended multidrug schedules for the treatment of


tuberculosis
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Major challenging factors


M. tuberculosis is an intracellular organism
Organism grows very slowly, consequently
infections are chronic & prolonged therapy may
require
Resistance to drugs develops rapidly

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Guidelines for anti-TB


chemotherapy
1.

Consideration for history of prior anti-TB therapy

2.

No single drug therapy

3.

No divided dosage

4.

To add at least 2 new drugs at a time, if not respond to


previous regimen

5.

To give adequate dosage regimen

6.

To give adequate duration of treatment according to


the disease condition (category)
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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

:Chronic case (failure after Cat II)


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H = isoniazid (300 mg)


Z = pyrazinamide (1.5-2 G)
S = streptomycin (0.75-1 G)
R = rifampicin (450-600 mg)
E = ethambutol (0.8-1.2 G)

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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)

1 HRZE & then


5 HRE
(daily)

8 Months

III

2 HRZ (daily)

4 HR (daily)

6 Months

IV

To be treated in specialized centers


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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

Resistance to all injectable agent + 3 of these 4:


Ethionamide, Ofloxacin first line
anti-TB agents
Cycloserine and PAS throughout
24 month

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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

the combination of isoniazid and rifampicin


Multidrug-resistant (MDR): Resistance to at least

isoniazid and rifampicin


Extensively drug-resistant (XDR): MDR plus resistance

to fluoroquinolones and at least 1 of the 3 injectable drugs


(amikacin, kanamycin, capreomycin)
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TB and HIV Mortality


HIV/AIDS is the number
one infectious killer in the
world
TB is number two
TB is the number one
cause of death in people
with HIV worldwide

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First line anti-tuberculous drugs include:


----T a. pyrazinamide
----F b. ofloxacin
----- c. ethambutol
T

----- d. kanamycin
F

----- e. streptomycin
T

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Regarding antituberculous agents,


----F a. streptomycin acts mainly on
intracellular organisms
----- b. rifampincin causes orange

coloration of body fluids


----- c. INH is excreted unchanged in urine

----- d. ethambutol cause visual toxicity

----- e. pyrazinamide is useful for TB menigitis

T
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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.

Finkel R, Cubeddu LX and Clark MA (2009). In: Lippincotts Iillustrated Reviews


Pharmacology. 4th edition, Lippincott Williams and Wilkins, New York.

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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