Anti-TB Agents

Question 1

What kind of bacilli is Mycobacterium tuberculosis?

Answer 1

Obligate aerobe, acid-fast bacilli

Question 2

When is the highest risk of progression to active TB?

Answer 2

In the first 2 years after initial infection

Question 3

Which population is most susceptible to progression to active TB?

Answer 3

Immunocompromised patients, elderly, HIV positive patients

Question 4

What is STEP and their strategies to control TB?

Answer 4

Singapore Tuberculosis Elimination Programme (STEP)
1. Direct Observation Therapy (DOT)
2. Monitoring
3. Contact investigation

Question 5

First line Anti-TB agents

Answer 5

Rifampicin, Isoniazid, Pyrazinamide, Ethambutol, Streptomycin

Question 6

Why is monotherapy of active TB avoided and why must it be prolonged treatment?

Answer 6

Reduce transmission

Ensure killing of slow growing semi-dormant organisms that can cause relapse

Question 7

Clinical diagnosis that prompts treatment initiation

Answer 7

Sputum obtained from Ziehl Neelsen stain for acid fast bacilli is positive (Red)

Question 8

What to check before initiating TB treatment?

Answer 8

1. Baseline liver enzymes
2. Visual acuity & color vision (for ethambutol)
3. Weight loss and dose adjustments

Question 9

Standard TB Regimen duration and phases? What is the endpoint at each phase

Answer 9

6 Month Regimen

• 2 month Intensive Phase (RIPE) daily
  »> Majority elimination
• 4 month Continuous Phase (RI) 3x/wk to daily
  »> Cure

Question 10

Cutaneous reactions (Pruritus and rash) are adverse effects present in ________

Answer 10

All first-line TB drugs

Question 11

Gastrointestinal symptoms (Nausea, anorexia, abdominal discomfort) are adverse effects of _____________ and you should administer _____________

Answer 11

Rifampicin, Isoniazid, Pyrazinamide

after light meals or before bedtime

Question 12

Rifampicin: Administration? MOA?

Answer 12

Oral

Bactericidal effect on metabolically active bacilli / bacilli in stationary phase

Inhibition of DNA-dependent RNA polymerase and thus halting gene transcription (mRNA synthesis) and protein synthesis

Question 13

Rifampicin Resistance mechanism

Answer 13

Mutation in gene coding for RNA polymerase beta chain

Question 14

Rifampicin clinical indications

Answer 14

Active and latent TB; Leprosy (Mycobacterium leprae)

Question 15

Rifampicin is cleared by?

Answer 15

Hepatic metabolism and Biliary excretion

Question 16

Rifampicin should be used with caution in which patients?

Answer 16

Pregnancy - Cat C but not teratogenic
Breastfeeding - Monitor for jaundice
Liver failure - Monitor LFT

Question 17

For pregnant women, what else should be administered with Rifampicin and why?

Answer 17

Vitamin K - To avoid postpartum hemorrhage (ADR: Thrombocytopenia)

Question 18

How does rifampicin affect CYP450 enzymes? Which drugs have DDI with rifampicin?

Answer 18

Inducer of CYP450 to increase metabolism
- Warfarin, corticosteroids, contraceptives, HIV protease inhibitors

Hepatotoxicity potential increased
- Isoniazid

Question 19

5 ADRs of Rifampicin

Answer 19

1. Cutaneous Syndrome (Flush, pruritus)
2. Hepatitis
3. Flu-like Syndrome (Fever, chills)
4. Respiratory Syndrome (SOB)
5. Immune reactions (Thrombocytopenia)

Question 20

Patient counselling point for rifampicin ADR

Answer 20

Orange discoloration of body fluids (tears, sweat, urine)

Question 21

Isoniazid: Administration? MOA?

Answer 21

Oral Prodrug

Bactericidal effect mainly on rapid growing bacilli

Catalase-peroxidase enzyme produced by Mycobacterium Tuberculosis activates isoniazid to form oxidative-derived free radicals that can inhibit mycolic acid formation in bacterial cell wall and DNA damage

Question 22

Isoniazid Resistance mechanism

Answer 22

Mutations in (regulatory) genes coding for:
1. Mycolic acid synthesis
2. Catalase-oxidase enzyme

Question 23

Isoniazid is clinically indicated in ________

Answer 23

Active/Latent TB and Prophylaxis

Question 24

Isoniazid is cleared by _______ and how does genetic polymorphism affect it?

Answer 24

Hepatic metabolism by N-acetyltransferase 2 that converts isoniazid to acetylhydrazine by NAT2 pathway. Hydrazine, a reactive metabolite, can also be formed through amidase pathway.

Different people - Slow acetylators vs Rapid acetylator phenotype affect acetylation rate

Question 25

Isoniazid should be used with caution in _______________________ and why?

Answer 25

Pregnancy - Peripheral neuropathy ADR risk Breastfeeding - Monitor jaundice Liver failure - Monitor LFT

Question 26

What should be given with isoniazid and why?

Answer 26

Pyridoxine; Avoid vitamin B6 deficiency leading to peripheral neuropathy

Question 27

How does isoniazid cause vitamin B6 deficiency?

Answer 27

Competitive interference with pyridoxine metabolism results in the inhibition of active vitamin B6 formation

Question 28

How is pyridoxine used by the body?

Answer 28

Pyridoxine is converted to pyridoxal phosphate cofactor (active form) involved in many metabolic processes

Question 29

Isoniazid food interactions?

Answer 29

Carbohydrates decrease absorption Tyramine and histamine rich food (MAO and histaminase inhibition by isoniazid) Antacids increase pH, reduce absorption

Question 30

Isoniazid affects CYP450 by acting as a ________

Answer 30

Inhibitor that increases phenytoin anticonvulsant and anticoagulant concentrations

Question 31

Isoniazid ADRs?

Answer 31

1. Hypersensitivity (Rare) - Lupus-like syndrome, psychosis, hematologic reactions 2. Hepatitis 3. Peripheral Neuropathy

Question 32

What is responsible for bacteriological relapse? Which drug can solve this problem?

Answer 32

Persistent bacilli; Pyrazinamide

Question 33

Comment on Pyrazinamide molecular structure and derivative

Answer 33

Similar to isoniazid; Nicotinic acid derivative But no cross-resistance to isoniazid

Question 34

Comment on the effect of pyrazinamide action on bacteria and macrophages

Answer 34

1. Bactericidal 2. Potent sterilizing effect 3. In acid medium within macrophages and at site of acute inflammation

Question 35

Pyrazinamide: Administration? MOA?

Answer 35

Oral Prodrug Converted to active form by pyrazinamidase upon entering bacteria into pyrazinoic acid which reduces the pH level in the bacterial cell, inactivating critical pathways needed for bacterial survival

Question 36

Pyrazinamide Resistance Mechanism?

Answer 36

Mutation in gene coding for pyrazinamidase

Question 37

Pyrazinamide is clinically indicated for ________

Answer 37

Active TB

Question 38

Can TB drugs penetrate CSF fluid?

Answer 38

Rifampicin - 10-20% of serum concentration found in CNS & increases with meningitis Pyrazinamide - Same concentration in CNS as in plasma and crosses BBB Ethambutol - Does not cross unless meningitis where therapeutic concentration is achieved

Question 39

Are all TB drugs safe in pregnancy? What category?

Answer 39

Cat C Rifampicin - Give with Vitamin K (Hemorrhage) Isoniazid - Give with Pyridoxine (Peripheral Neuropathy) Pyrazinamide - Safe Ethambutol - Not teratogenic

Question 40

Pyrazinamide cautions in which patients?

Answer 40

Pregnancy Breastfeeding - Monitor jaundice Liver failure - Hepatotoxicity of drug should warrant avoidance in liver diseases Kidney failure - Dose adjustment

Question 41

Pyrazinamide DDI with _________

Answer 41

Probenecid, Rifampicin, Isoniazid

Question 42

Pyrazinamide ADR

Answer 42

1. GI effect N/V 2. Hepatotoxicity 3. Photosensitivity 4. Hyperuricemia & Arthralgia (Gout-like symptoms) 5. Exanthema (Rash) & Pruritus

Question 43

How does pyrazinamide cause gout-like symptoms?

Answer 43

Pyrazinoic acid inhibits renal tubular secretion of uric acid

Question 44

Ethambutol effect on bacilli and what bacilli?

Answer 44

Bacteriostatic, Rapid growing bacilli

Question 45

Ethambutol Administration, MOA?

Answer 45

Oral Inhibits arabinosyltransferase from polymerising the arabinose into arabinogalactan (principal polysaccharide of mycobacterial cell wall) This affects the cell wall integrity and facilitate lipophilic abx entry (rifampicin & levofloxacin)

Question 46

Ethambutol Resistance Mechanism

Answer 46

Mutation in embB gene encoding arabinosyltransferase

Question 47

Ethambutol is cleared by?

Answer 47

Urine excreted unchanged (50%) Liver metabolism (25%) Feces unchanged (25%)

Question 48

Ethambutol ADRs?

Answer 48

1. Visual toxicity (Acuity, color, blurring) 2. Hyperuricemia/Gout (Less than pyrazinamide)

Question 49

Who has greater risk of visual toxicity taking ethambutol?

Answer 49

Kidney failure, elderly, prolonged treatment (> 2 months) Caution in young children

Question 50

What drug can replace ethambutol in the intensive phase?

Answer 50

Streptomycin