Module: Sem 2 /Respiratory

Plenary:4

ANTI-TUBERCULOSIS
DRUGS

Professor Dr Azizi Ayob (MD, PhD)

Pharmacology
Division of Pathology/School of Medicine
aziziayob@imu.edu.my (Extn: 2819)
LESSON OUTCOME
At the end of this session, students should be able to:
 Explain the use of multi-drug in the treatment of TB
 Discuss the basis for the two phases of anti TB treatment.
 Differentiate between 1st and 2nd phase treatment
 Describe the mechanism of action and adverse effect of each drug
 List the drugs used for atypical TB infection

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 Introduction: The Major Pathogens

 Mycobacteria are rod-shaped aerobic bacilli.

 It multiply slowly, every 18 to 24 hours in vitro.
 Mycobacterial infections classically result in the formation of slow-growing
and granulomatous lesions.
 The lesion can be in the lungs and other major organs.
 The diseases include:
 Mycobacterium tuberculosis causes the disease known as tuberculosis (TB):
 Pulmonary TB

 Extra-pulmonary TB

 Leprosy
 Non-Tuberculous Pathogenic Mycobacteria

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Introduction: The Major Pathogens

Mycobacterium
 Mycobacterium tuberculosis, (TB)
 Mycobacterium leprae, (leprosy)
 Mycobacterium bovis

Non-Tuberculous Pathogenic Mycobacteria

 M. avium-intracellulare complex (MAC, TB-like disease in AIDS)
 M. chimaera (Heater-cooler unit transmitted infection in cardiac surgery)
 M. marinum (swimming pool granuloma)
 M. scrofulaceum (cervical adenitis)
 M. chelonei & M. fortuitum (immunocompromised or prosthetic devices
implanted patients only)

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Introduction: Main Symptoms/Signs

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 The Principle of Therapy:
 Interrupt tuberculosis transmission
- To make the patient non-infectious
 To cure patient (curative) and eradicate the pathogens
- To reduce morbidity and death
 To prevent relapse and emergence of Multidrug-resistant TB
(MDR-TB)
 To achieve the therapeutic objectives
- Combination drug therapy is required
 - Two-Phase Multi-Drug treatment is mandatory

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 OVERVIEW:
ANTIMICROBIAL AGENTS

Drug Used in Drug Used in Drugs Used for

Tuberculosis Leprosy Atypical Mycobacteria

First Line Second Line Drugs For Drugs For Minor

Drugs Drugs Major Infections Infections

 Isoniazid, INH(H)  Aminoglycosides

 Rifampicin (R)  Capreomycin
 Pyrazinamide (Z)  Cycloserine
 Ethambutol (E)  PAS (Para-Amino
 Streptomycin (S) Salicylic acid)
(Malaysia and SEA)  Other
TB Treatment
 1st Line Drugs
 Refer to the main combination of drugs for TB therapy
 Isoniazid, INH (H), Rifampicin (R), Pyrazinamide (Z) , Ethambutol (E),
Streptomycin (S)

 2nd Line Drugs

 Typically less effective, more toxic, and less extensively studied
 Used for patients who cannot tolerate the 1st line drug or who are
infected with resistant TB
 TB Treatment
 Monotherapy with any single drug is unsatisfactory and
resistance develops.
 Multi-Drug Therapy must be followed (Combination).
 Long duration of treatment for cure – at least 6 months to 12-24
months

Drug combination is given by TWO PHASES

 Initial / Intensive Phase (Bactericidal)
 Continuation / Maintenance Phase (Sterilizing)

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Multi-Drugs & Two Phases of anti TB treatment

Maintenance/Continuation
Intensive Phase
Phase

Isoniazid

Rifampicin
Pyrazinamide

Ethambutol
Month 0 1 2 3 4 5 6
 TB Treatment: NEW CASES
 6-month regimen consisting of:
 2 months of EHRZ (2-EHRZ) followed by
 4 months of HR (4-HR) is recommended for newly-diagnosed
PTB.
 Pyridoxine 10-50 mg daily needs to be added if isoniazid is
prescribed.
 Daily treatment is the preferred regimen.

 Adopted from WHO. Treatment of Tuberculosis Guidelines (4th Ed.), 2010

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RECOMMENDED Treatment Plan – Category I

Daily 3 times / Week

2 months 4 months
mg/kg Max mg mg/kg Max mg
Isoniazid 5 (4-6) 300 10 (8-12) 900
Rifampicin 10 (8-12) 600 10 (8-12) 600
Pyrazinamide 25 (20-30) 2000 35(30-40)* 3000*

Ethambutol 15 (15-20) 1600 30 (25-35)* 2400*

Streptomycin 15 (12-18) 1000 15 (12-18)* 1500*

Pyridoxine 10 - 50 mg daily needs to be added if isoniazid is prescribed.

* Daily treatment is the preferred regimen.

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 Monitoring for Drug Toxicity

Investigations & Assessment:

 Baseline LFT, RFT, FBC
 H/o alcoholism, liver disease
 Uric acid if ‘Z’ is used
 Visual acuity if ‘E’ is used

Management
 Reassurance
 Stop drug if signs of liver dysfunction – Abdominal pain
 C/I: Thrombocytopenia, shock and renal failure, visual defect
to ‘E’, ototoxicity to ‘S’

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 Flow Chart for the Recommended Treatment of PTB

Follow Up 9 months 12 months 15 months

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15 OVERVIEW: Mechanisms of action of anti-TB drugs
 RIFAMPICIN (Rifampin)

Mechanism of Action:
 Bind to the beta subunit of DNA-dependent RNA polymerase
(rpoB) & blocks chain formation in RNA synthesis 
bactericidal (kills intracellular bacteria)
 Resistance occur at 1 in 107 bacilli due to changes in rpoB.

PK:
- Given oral, good distribution.
- Food decreases the rifampin CPmax by one-third; a high-fat meal
increases the AUC of rifapentine by 50%.
- Food has no effect on rifabutin absorption.
- Metabolized and excreted in bile, feces and urine.
- Crosses placenta (avoid in pregnancy)

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 RIFAMPICIN (Rifampin)

Therapeutic uses
 Tuberculosis, 600 mg o.d. 1hr before or 2hr after meal
 Leprosy (Mycobacterium leprae)
 Prophylaxis of meningococcal disease and H.influenzae
meningitis
 Eradication of the staphylococcal nasal carrier state in
patients with chronic furunculosis.
 Brucellosis (rifampin 900 mg daily combined with
doxycycline for 6 weeks)

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Adverse Effects and Drug Interactions of Rifampicin

Adverse Effects (4%)

 Skin Rash (0.8%), nausea & vomiting (1.5%), fever (0.5%)
 Hepatitis (cholestatic jaundice, liver failure, death)
 Allergy: haemolysis, flu-like (fever, myalgia)(at high dose),
renal damage (light-chain proteinuria, acute tubular necrosis)
 Imparts orange/red colour to urine, sweat, saliva and tear and contact
lenses
 ‘Red-man syndrome’ with overdose

Drug Interactions
 Induces liver CYP enzymes – increase metabolism of digoxin,
quinidine, warfarin, corticosteroids, oral contraceptives, oral anti-
diabetics etc.,

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 PYRAZINAMIDE (analog of nicotinamide)

 MOA:
 Activated inside Mycobacteria to pyrazinoic acid (POA− ) & POAH which acidify
extracellular milieu.
 Subsequent accumulation of POAH acidifies the intracellular milieu and inhibits
enzyme function and collapses the transmembrane proton motive force, thereby
killing the bacteria.
 Also inhibit cell membrane synthesis.
 PK:
 Well absorbed (F >0.9), wide distribution, concentrated in lung (20x),
 Excreted by the kidney.
 Adverse effects:
 Hepatitis (jaundice 2-3%, death),
 Hyperuricaemia (gout),
 Arthralgia,
 GI: Nausea, Vomiting, diarrhoea

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ISONIAZID, INH (isonicotinic acid hydrazide)

 Antibacterial effect limited to mycobacteria

 Bacteriostatic on resting and bactericidal on growing bacteria
 MOA:
 Activated inside bacillus by KatG to an isonicotinoyl radical,
 Eventually inhibits synthesis of mycolic acid, essential component in cell wall,
leading to cell death.
 PK:
 F=1, rapid absorption
 Enters CNS and casseous focus, metabolized by NAT2,
 Excreted in urine within 24 hr.
 The prevalence of drug-resistant mutants is about 1 in 106 bacilli.

KatG = multifunctional catalase-peroxidase

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Adverse Effects & Drug Interactions of INH
Adverse Effects:
 Hepatitis (0.1%, increased risk in slow metabolizers and rifampin,
3%). Most cases of hepatitis occur after 4–8 weeks.
 Peripheral neuritis (give prophylactic pyridoxine to patient with DM,
alcoholism, malnutrition, CRF)
 CNS: convulsion, optic neuritis, dizziness
 Allergy: vasculitis, arthritis, skin rashes, SLE

Drug Interactions:
 Inhibit CYP2C19, CYP3A, CYP2D6 and
 Increase toxicity of carbamazepine, diazepam, theophylline,
phenytoin and warfarin

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 ETHAMBUTOL
 MOA:
 Ethambutol inhibits arabinosyl transferase III, thereby disrupts the
assembly of mycobacterial cell wall.
 No activity against other genus.
 PK:
 Bioavailability ~80% after oral administration
 Widely distributed, not metabolized
 >80% excreted unchanged in urine.
 Adverse Effects:
 Optic neuritis (decreased visual acuity and inability to differentiate red/green),
1% - 15%, depends on dose/duration & reversible.

 Rash, drug fever, GI upset, peripheral neuritis, hyperuricemia, headache,

confusion, pruritus and joint pain.

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Second Line Anti-TB Drugs

Aminoglycosides: Amikacin, Kanamycin

 MOA:
 Inhibits protein synthesis by binding with 30S ribosomal subunit and
causing misreading of the genetic code during translation.
 PK:
 Water soluble, highly polar (ionized), poor GI absorption.
 Need to be given parenterally. Low passage across cell membranes.
 Excreted in urine
 Adverse Effects:
 Ototoxic - vertigo, deafness,
 Nephrotoxic - renal damage
 CI: Pregnancy (deafness in infant)

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Second Line Anti-TB Drugs
Capreomycin
 Peptide protein synthesis inhibitor, given by injection.
 ADR: nephrotoxic and ototoxic

Cycloserine
 Inhibits cell wall synthesis
 ADR: peripheral neuropathy, depression, psychosis.
Pyridoxine should be given.

PAS (Para-Amino Salicylic acid)

 Folate synthesis antagonist, similar structure to PABA & sulfonamides.
Bacteriostatic.
Active exclusively against M. tuberculosis.
 Good absorption and rapid excretion in urine
 Toxicity: GI upset (give with meals or antacid),
Allergy-fever, joint pain, skin rash, hepatitis, jaundice

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Second Line Anti-TB Drugs
Quinolones: moxifloxacin, levofloxacin, gatifloxacin
 Both more active against M. tuberculosis than ciprofloxacin (which is
more active against atypical mycobacteria) (bactericidal)
 Inhibit DNA synthesis and supercoiling by binding with
topoisomerase

Linezolid
 Good intracellular concentration. Used for MDR TB. Limited by bone
marrow suppression, irreversible peripheral & optic neuropathy.

Clofazimine
 MOA: Possibly membrane disruption, inhibition of phospholipase A2,
K+ transport, electron transport chain, or efflux pump; generation of
hydrogen peroxide.
ADR: GI disturgance ~50%, skin and body secretion discoloration

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 TB Treatment: COMPLIANCE

Lack of Adherence to Treatment or

Non-compliance  Multi-Drug Resistant TB

Patient and Disease-related

Factors

Provider-related Factors

Drug-related Factors

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COMPLIANCE:
Poor Tx outcome due to Patient/Drug related Factors

Patient: inadequate drug intake or Drugs: inadequate supply

treatment response or quality
 Lack of belief, information  Poor quality medicines
 Lack of means to adhere to treatment  Unavailability of certain
medicines (stock-outs or
(transport, food, social barriers) delivery disruptions)
 Severity of TB – MDR, XDR TB  Poor storage conditions
 Poverty (Jobless/homeless/nutrition)  Wrong dose or
combination
 Substance abuse/dependence  Poor regulation of
 Adverse effects / complications medicines
 Co-morbidity: Diabetes, HIV

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 COMPLIANCE:
Poor Tx Outcome due to Provider-related Factors: inappropriate
treatment
 Inconvenient clinic hours
 Inappropriate guidelines
 Non-compliance with
guidelines
 Absence of guidelines
 Poor training
 Financial disincentives
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• Poor patient education
• No monitoring of treatment
• Poor management of adverse
drug reactions
• Poor treatment support
• Poorly organised or funded TB
control programmes
 Non-compliance due to Drug-related Factors

 Not using FDC (fixed dose combination)

 Adverse drug reactions:
Hepatitis (alcohol abuse, h/o hepatitis C)(HRZ), hyperuricemia (Z)
 Optic neuritis (E)
 Autoimmune thrombocytopenia (R)
 Allergy: Skin eruptions, pruritus, rash

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FDC (Fixed Dose Combination) in Ministry of Health Malaysia

• 4-Drug combination:
• Isoniazid 75 mg, rifampicin 150 mg, pyrazinamide 400 mg &
ethambutol 275 mg tablet
• 3-Drug combination:
• Isoniazid 75 mg, rifampicin 150 mg & pyrazinamide 400 mg tablet

OTHER TYPES - FIXED-DOSE COMBINATION (FDC) IN MALAYSIA

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Mechanisms of Drug Resistance in TB
A Drug-resistant TB regimen consists of two phases
(a) First/intensive phase is the period in which the injectable agent is
used
(b) Second/maintenance phase is after the injectable agent has been
stopped.

Medicines Recommended:
A. Fluoroquinolones – levofloxacin, moxifloxacin, gantifloxaxin
B. Second-line injectable agents – amikacin, capreomycin, kanamycin
C. Other core second-line agents – ethionamide, prothionamide,
cycloserine, terizidone, linezolid, clofazimine
D. Add-on agents (not core regimen) – Z, E, Hh, bedaquiline,
delamanid, PAS, meropenem, amoxicillin-clavulanate

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 WHO Categorization of Second-line Anti-TB Drugs
for Rifampicin-resistant & MDR TB

Group A: Group B: Second- Group C: Other core second-line

Fluoroquinolones line injectable agents agents
• Levofloxacin • Amikacin • Ethionamide or Prothionamide
• Moxifloxacin • Capreomycin • Cycloserine or terizidone
• Gatifloxacin • Kanamycin • Linezolid
• Streptomycin • Clofazimine
Group D: Add-on agents (not part of the core multidrug-resistant tuberculosis
regimen)
Group D1: Group D2: Group D3:
• Pyrazinamide • Bedaquline • Para-aminosalicylic acid
• Ethambutol • Delamanid • Imipenem or Meropenem plus
• High-dose INH cilastatin
• Amoxicillin plus clavulanate
• Thioacetazone
Atypical Mycobacteria
 M.avium complex infection observed in immunocompromised
patient.
 Treatment is triple drug therapy with:
 Clarithromycin or azithromycin (SE: cholestatic hepatitis), rifampin
and ethambutol.
 Three times a week and continued 12 months after the negative
culture.
 In cavitatory disease, inj. amikacin or streptomycin can be added
as a 4th drug.
 Resistance is a problem and outcome may not be successful.

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THANK YOU