Anti- Tuberculosis Agents

Question 1

What is TB caused by?

Answer 1

Mycobacterium tuberculosis
(Obligate aerobic, slow-growing, acid-fast bacilli)

Question 2

Name 3 Singapore Tuberculosis Elimination Programme (STEP) strategies

Answer 2

1. Promotion of directly observed therapy (DOT) for TB pt
2. Implementation of a National Treatment Surveillance Registry to monitor trx progress and outcome for all TB pts
3. Contact investigations to identify recently infected close contacts of infectious TB cases, and offer preventive therapy to reduce risk of progression to active TB

Question 3

Name 4 principles of TB trx

Answer 3

1. Different rates of metabolic activity for each subpopulation of tb for active TB pt
2. Prolonged trx to reduce transmission and ensure killing of these slow growing/ semi-dormant organisms to prevent relapse
3. No monotherapy in active TB
4. If suspected MDR, adequate number of drugd to be taken based on AST

Question 4

Clinicial diagnosis of TB

Answer 4

Hx, RF, CLinical presentation, physical exam findings, chest x-rays,
Positive for sputum obtained for Ziehl-Neelsen strain for acid-fast bacilli

Question 5

Baseline for monitoring

Answer 5

1. LFT
2. vision acuity and colour
3. Weight at each visit

Question 6

First line drugs for TB

Answer 6

2 months of daily
1. Rifampicin
2. Isoniazid
3. Pyrazinamide
4. Ethambutol
+ streptomycin

Then 4 months of daily or 3x/week of RI

Question 7

How is rifampicin cleared?

Answer 7

Hepatic metabolism, CYP450 inducer

Question 8

Can pregnant women take rifampicin?

Answer 8

Yes, taken with vit K to prevent postpartum haemorrhage from thrombocytopenia

Question 9

ADR for rifampicin

Answer 9

Orange discolouration of bodily fluids
(Tears stain contact lenses, sweat and urine)
Flushing, redness, pruritus, flu-like Sx, SOB, shock, hepatitis

Question 10

MOA of rifampicin

Answer 10

Inhibits gene transcription of mycobacteria by blocking DNA-dependent RNA polymerase, preventing mRNA and protein synthesis, causing cell death

Question 11

Resistance to rifampicin occurs when…

Answer 11

Mutation in gene encoding for RNA polymerase beta chains

Question 12

Isoniazid MOA

Answer 12

Prodrug; activated by catalase-peroxidase enzyme of mycobacteria tb, producing oxygen-derived free radicals and blocking mycolic acid synthesis, which is an essential component of cell wall, thus causing DNA damage and death

Question 13

Mechanism to resistance for isoniazid

Answer 13

Mutations to catalase-peroxidase enzymes and regulatory genes involved in mycolic acid synthesis

Question 14

Isoniazid ADME

Answer 14

A: oral absorption best on empty stomach
M: metabolised by N-acetyltransferase (genetic polymorphism)
E: renal as inactive metabolites

T1/2: ave 1, 2-5h

Question 15

Can isoniazid be taken by pregnant women?

Answer 15

Yes, with pyridoxine to prevent B6 def for ppl at risk of peripheral neuropathy

Question 16

FDI/DDI with isoniazid

Answer 16

Food:
- carbs decrease A by half
- food rich in tyrosine and histamine (tuna, cheese, red wine) –> flushing, headache by inhibiting MAO and histaminase

DDI:
- Antacids delays A, separate by 2h
- CYP450 inhibitor

Question 17

ADR for Isoniazid

Answer 17

1. Peripheral neuropathy (HIV, DM, uraemic or malnourished and alc users)
2. Hepatitis
3. Psychosis, convulsions, haematologic rxns

Question 18

Pyrazinamide MOA

Answer 18

Nicotinic acid derivative to be converted to active form, pyrazinoic acid by microbial enz, pyrazinamidase

Accumulation of acid decreases pH and inactivate crucial pathways

Question 19

ADR of pyrazinamide

Answer 19

1. GI Sx (NV)
2. Photosensitivity
3. Hepatotoxicity: dose adj
4. Hyperuricemia and arthralgia: pyrazinoic acid inhibit renal tubular secretion of uric acid, resulting in gout like Sx
5. Exanthema(widespread rashes) and pruritus

Question 20

Ethambutol MOA

Answer 20

Inhibit arabinosyltransferase enzyme encoding by the embB gene and interferes wuth polymerization of arabinose into arabinogalactan, the principal polysaccharide on mycobacterial cell wall.

Affect integrity of cell wall and facilities entry of lipophilic Abx

Question 21

Excretion of Ethambutol

Answer 21

Renal 50%

Question 22

ADR of ethambutol

Answer 22

1. Visual toxicity (incr. In VKD and elderly)
   - dose dpd
   - caution in young children
2. Hyperuricemia/gout
3. DDI: Antacids, sep by 2h

Question 23

When are TB pts cured?

Answer 23

Negative sputum culture in last month of trx