A PRESENTATION ON THE PHARMACOLOGY OF

FIRST LINE MEDICATIONS FOR TB MANAGEMENT

 INTRODUCTION
• TB is an infectious disease caused by Mycobacterium
• tuberculosis complex. It is therefore a multi-systemic
disease. It can also affect animals like cattle- Bovine
Tuberculosis

 Mycobacterium tuberculosis complex:

➢Mycobacterium tuberculosis; The main cause of TB

worldwide
➢Mycobacterium bovis
• Found mainly in animals, including cattle, camels, goats etc.
➢Mycobacterium africanum
• Found mainly in West Africa
GLOBAL BURDEN OF TB
 High Prevalence: An estimated 1.3 million people died from
TB in 2022, making it the second leading infectious killer after
COVID-19 [World Health Organization (WHO)].

 New Cases: In 2022, an alarming 10.6 million people fell ill

with TB worldwide. This translates to roughly 133 new cases
per 100,000 population [WHO].

 Unequal Impact: Low- and middle-income countries

disproportionately bear the burden. TB incidence (new cases) is
much higher in these regions compared to high-income
countries [WHO].
GLOBAL BURDEN OF TB
 Hidden Cases: A significant challenge is that many TB
cases go undiagnosed. WHO estimates around 30% of
people with TB are missed by healthcare systems, leading to
further spread [Centers for Disease Control and Prevention
(CDC)].

 Vulnerable Populations: Peoplewith compromised immune

systems, like those living with HIV, are at a higher risk of
developing active TB. Undernutrition, diabetes, and tobacco
use also increase the risk [WHO].

 Drug Resistance: Multidrug-resistant TB (MDR-TB) is a

growing concern. It arises when the TB bacteria develop
resistance to the standard TB drugs, making treatment
complex and expensive. Only a fraction of MDR-TB cases
receive proper treatment [WHO].
PATHOPHYSIOLOGY OF TB
• The pathophysiology of TB begins when the bacteria are inhaled
and reach the alveoli of the lungs.

• Here, they are phagocytosed by alveolar macrophages but often

evade destruction due to their thick, waxy cell wall.

• The bacteria can remain dormant or proliferate, leading to a

primary infection.

• The host's immune response involves T lymphocytes and the

formation of granulomas, which are clusters of immune cells
attempting to contain the infection.

• These granulomas are characterized by a central core of necrotic

tissue surrounded by macrophages, giant cells, and a fibrous
capsule.
PATHOPHYSIOLOGY OF TB
• If the immune system fails to contain the bacteria, the
granulomas can liquefy, creating cavities in the lungs and
leading to active TB.

• The bacteria can then disseminate via the bloodstream or

lymphatic system to other organs, causing extrapulmonary
TB.

• Symptoms of active TB include a persistent cough,

hemoptysis, fever, night sweats, and weight loss.

• Latent TB infection (LTBI) occurs when the bacteria remain

dormant within granulomas, without causing symptoms.
Individuals with LTBI are not infectious.
MODE OF TRANSMISSION
 The most important mechanism by which infectious droplets
are produced is coughing. Droplets produced by an average TB
patient through coughing are large (75,000 droplets) as they exit
the airway.

 However, any vigorous expiratory maneuver such as sneezing,

singing, talking or even quiet breathing, can also produce
infectious droplets.

 Less than 10 mycobacterial bacilli may initiate a pulmonary

infection. One person with smear positive PTB may
infect 10 persons/year

 Chemotherapy rapidly renders sputum non_x0002_infectious

within 2 weeks
LTBI VS TB DISEASE
LTBI TB Disease

Tubercle bacilli in the body

TST or QFT-Gold® result usually positive

Chest x-ray usually normal Chest x-ray usually abnormal

Sputum smears and cultures Symptoms smears and cultures

negative positive

No symptoms Symptomatic

Not infectious Often infectious before treatment

Not a case of TB Active case of TB

TYPES OF TB
• Pulmonary TB: This is the most common form, affecting the
lungs.

• Extrapulmonary TB: This occurs when TB bacteria spread

outside the lungs, affecting other organs. Types include:
• Lymphatic TB
• Pleural TB
• Skeletal TB
• Miliary TB
• Genitourinary TB
• Central Nervous System TB
SIGNS AND SYMPTOMS
PULMONARY TB EXTRA PULMONARY TB

Fatigue/tiredness Swollen neck glands

Weakness Pains in the bone, joint or spine

Disseminated throughout the

Weight loss
body

Fever and Drenching Breathlessness, chest pain, or

night sweat ankle swelling

Productive Cough that

Confusion, visual problems, or
may persist for more
persistent headache
than 3 weeks

•Chest pain Skin lesions

•Haemoptysis
RISK FACTORS
1. HIV/AIDS
2. Chronic Diseases; Diabetes Mellitus, Lung disease,
Kidney disease
3. Close Contact with TB Patients
4. Malnutrition
5. Substance Abuse; Alcoho, smoking
6. Socioeconomic Factors
7. Age: Prevalence increases with age, Children below the
age of 5 years
8. Occupational Exposure
9. Pregnant women
INVESTIGATIONS

✓Ziehl-Nielsen (ZN) staining method for Acid-Fast Bacilli

❖Sputum Smear Microscopy

✓Available in most health facilities

(AFB)

✓Often include drug sensitivity testing (DST)

❖Mycobacterial culture and sensitivity - Gold Standard

✓Takes longer to get results

✓Identifies [Link] and resistance to Rifampicin

❖Gene Xpert - WHO preferred investigative tool.

✓Can be used directly on sputum, results in 100 mins

✓Widely available in most districts in Ghana now
INVESTIGATIONS
 Tuberculin Test (Mantoux Test)
 Not a good tool for diagnosis in Ghana in adults but useful in
non vaccinated children <6 years
 Used in measuring the prevalence of TB in a community

 Chest X-Ray
 Upper zone patchy or nodular shadows
 Cavitation(s) - micro or large and multiple
 Calcified shadows.

✓Laryngeal swabs
❖Other Tests for presence of bacilli

✓Gastric suction/aspiration/lavage/washing
✓Bronchoscopy, CSF
✓Pleural fluid and Pleural biopsy
TREATMENT OF TUBERCULOSIS
 Aims of Treatment
 To cure the patient with TB (with minimal interference with
his/her life)
 To prevent death from active disease or its complication➢To
prevent TB relapse
 To prevent TB transmission to others
 To prevent the development of resistant TB

 The DOTS / DOTS Plus Strategy

 The recommended WHO strategy for TB control
 An integrated approach to the management of TB (DOTS)
and MDR TB (Plus)
TB TREATMENT CATEGORIES
 Category 1:
 New cases – smear positive (NSP), smear negative (NSN),
extra-pulmonary TB (EP)

 Category 2 :
 Retreatment Regimen – for All previously treated TB, smear
negative or positive, or EP

 Category 3 :
Treatment for Children < 15yrs and/or < 30kg

 Category 4:
 All persons with MDR- TB (multi- drug resistance
tuberculosis) who failed previous treatment regimens
(Chronic case).
BASIS FOR TREATMENT
 Chemotherapy taken:
 In appropriate combination of drugs to prevent development
of resistance
 In correct dosage per pre-treatment weight
 Regularly by patient for long enough to prevent relapse of
disease after treatment.

 Intensive Phase - Minimum of 2 months

• 3 or more first line drugs
• Rapid elimination of TB bacilli
• Prevention of development of resistance

 Continuation Phase
• Ensures permanent cure
• Prevents relapse after completion of treatment
• Should be long enough to ensure success
Treatment Regimen
TREATMENT TB PATIENTS INTENSIVE CONTINUATIO
CATEGORY PHASE N PHASE

1. - New smear 2 HRZE = 56 4 HR = 112

positive and DOSES DOSES
negative PTB
- New Severe
EPTB

2. - Sputum smear 2 S + 3 HRZE = 5 HRE =

positive relapse 56 140 DOSES
- Treatment DOSES OF S +
failure 84
DOSES OF
HRZE

3. - New smear 2 HRZE = 56 4 HR = 112

negative DOSES DOSES
PTB
- EPTB (less
severe)
ISONIAZID 75MG ( Max 300mg)
 Class: Mycolic acid synthesis inhibitor
 A Pro-drug activated by KatG enzyme. It works by inhibiting
mycolic acid synthesis through the blocking of InhA & KasA
enzymes which interupts with the cell wall synthesis of the
bacteria.

 Pharmacokinetics:
• Rapid oral absorption
• Hepatic metabolism via acetylation
• Crosses the BBB which is useful in treating TB meningitis.
ISONIAZID 75 MG ( Max 300mg)

• Crosses BBB → treats TB meningitis

• Side effects: hepatotoxicity, peripheral
neuropathy due to pyrodoxine deficiency,
lupus-like syndrome
• Contraindications: acute liver disease,
severe hepatic impairment
– Interactions: phenytoin ↑, carbamazepine
↑; alcohol ↑ hepatotoxicity
– Addition of vitamin B6 (50 mg daily) to
the therapy
RIFAMPICIN 150MG ( Max
600mg)
 Class: Rifamycins
• Mechanism: Binds β-subunit of RNA polymerase
→ blocks mRNA synthesis. Bactericidal to
intracellular & extracellular TB

 Pharmacokinetics:
• Potent CYP450 inducer (CYP3A4, 2C9)
• Widely distributed, enters macrophages
• Excreted mainly in bile
RIFAMPICIN 150mg ( Max
600mg)
Side effects: hepatotoxicity, orange
discoloration, flu-like syndrome,
thrombocytopenia

Contraindications: jaundice, concurrent protease

inhibitors

Interactions: strong CYP450 inducer—↓ OCPs,

warfarin, ART
Pyrazinamide 400mg ( Max
2000mg)
 Pro-drug converted to pyrazinoic acid (POA). It disrupts
membrane potential and ATP synthesis of the bacteria thus
causing a bacteriocidal effect. Works in acidic environments
(caseous lesions, macrophages)

 Pharmacokinetics:
• Excellent oral absorption
• Hepatic metabolism

 Side effects: hepatotoxicity, hyperuricemia, gout flares

 Contraindications: severe liver disease, acute gout
 Interactions: ↑ hepatotoxicity with rifampicin
ETHAMBUTOL 275MG (Max
1200mg)
 Class: Arabinosyl transferase inhibitor
 Mechanism: inhibits arabinosyl transferase by blocking
arabinogalactan which plays a factor in the thick cell wall
of the bacteria. This inhibition leads to weakened cell wall

 Pharmacokinetics:
• 50% renal excretion (dose adjust in renal failure)
• Widely distributed

 Side effects: optic neuritis (↓ red-green vision)

 Contraindications: optic neuritis, inability for visual
testing
 Interactions: minimal
RIFAPENTINE
 Class: Rifamycins

 Longer half-life than rifampicin → weekly dosing in 3HP

regimen

 Similar MOA to rifampicin

 Strong CYP450 induction

 Side Effects: Similar to rifampicin

Combination Pharmacology – Why
HRZE?
 INH: Strong activity against rapidly dividing bacilli

 RIF: Sterilizing activity against slow/semidormant bacilli

 PZA: Strongest action in acidic lesions → shortens

therapy

 EMB: Prevents resistance during intensive phase

 Combined therapy increases synergestic effect

prevents emergence of drug resistance
CONTRAINDICATIONS
➢Avoid Streptomycin in pregnancy due to ototoxicity in foetus

➢Avoid Ethambutol in visually impaired due to optic neuritis

worsening vision

➢Avoid Pyrazinamide in liver disease even though R and H also

affect liver

➢Avoid Ethambutol, Streptomycin and Rifampicin in renal

failure
Adult Dosing
INH 5 mg/kg (max 300 mg/day)
RIF 10 mg/kg (max 600 mg/day)
PZA 25 mg/kg
EMB 15 mg/kg

Pharmocokinetic Notes:
• Food delays absorption of rifampicin
• Pyridoxine supplementation prevents neuropathy
with INH
Pediatric Dosing
 Children metabolize rifampicin faster → higher mg/kg
needed

INH: 7–15 mg/kg

RIF: 10–20 mg/kg
PZA: 30–40 mg/kg
EMB: 15–25 mg/kg

 Pediatric Considerations:
• Good tolerance overall
• Assess vision only in children old enough to cooperate
Monitoring Requirements
• Baseline LFTs, HIV testing
• Visual acuity testing for EMB
• Sputum monitoring at months 2, 5 and
completion.
• Drug interactions with RIF
• Monitor for hepatotoxicity (INH, RIF, PZA)
RESISTANCE
❖Mono-resistance: resistance to only one of the 1st line
drugs
❖Poly-resistance: resistance to at least two drugs but not
to both Rifampicin and Isoniazid
❖Multi-drug resistance(MDR-TB): Resistance to atleast
Isoniazid and Rifampicin
❖Extensive-drug resistance(XDR-TB)

 Initial/Primary Resistance
✓Resistance in new cases of TB

✓Resistance among previously treated TB cases

❖Acquired Resistance

✓TB with bacilli resistant to one or more anti-TB drugs

❖Drug-Resistant TB
Take Home Message
" We can’t fight AIDS
unless we do much more
to fight TB as well "
Nelson Mandela
Bangkok, July 2004
REFERENCES
• World Health Organization. (2023). WHO
consolidated guidelines on tuberculosis: Module 4:
Treatment. WHO.
• Brunton, L. L., Hilal-Dandan, R., & Knollmann, B.
C. (Eds.). (2022). Goodman & Gilman's the
pharmacological basis of therapeutics (14th ed.).
McGraw-Hill.
• Centers for Disease Control and Prevention. (2023).
Treatment for TB disease. CDC.
• Nahid, P., Dorman, S. E., Alipanah, N., et al.
(2016). Official ATS/CDC/IDSA clinical practice.