Anti- Tuberculosis Agents Flashcards
What is TB caused by?
Mycobacterium tuberculosis
(Obligate aerobic, slow-growing, acid-fast bacilli)
Name 3 Singapore Tuberculosis Elimination Programme (STEP) strategies
- Promotion of directly observed therapy (DOT) for TB pt
- Implementation of a National Treatment Surveillance Registry to monitor trx progress and outcome for all TB pts
- Contact investigations to identify recently infected close contacts of infectious TB cases, and offer preventive therapy to reduce risk of progression to active TB
Name 4 principles of TB trx
- Different rates of metabolic activity for each subpopulation of tb for active TB pt
- Prolonged trx to reduce transmission and ensure killing of these slow growing/ semi-dormant organisms to prevent relapse
- No monotherapy in active TB
- If suspected MDR, adequate number of drugd to be taken based on AST
Clinicial diagnosis of TB
Hx, RF, CLinical presentation, physical exam findings, chest x-rays,
Positive for sputum obtained for Ziehl-Neelsen strain for acid-fast bacilli
Baseline for monitoring
- LFT
- vision acuity and colour
- Weight at each visit
First line drugs for TB
2 months of daily
1. Rifampicin
2. Isoniazid
3. Pyrazinamide
4. Ethambutol
+ streptomycin
Then 4 months of daily or 3x/week of RI
How is rifampicin cleared?
Hepatic metabolism, CYP450 inducer
Can pregnant women take rifampicin?
Yes, taken with vit K to prevent postpartum haemorrhage from thrombocytopenia
ADR for rifampicin
Orange discolouration of bodily fluids
(Tears stain contact lenses, sweat and urine)
Flushing, redness, pruritus, flu-like Sx, SOB, shock, hepatitis
MOA of rifampicin
Inhibits gene transcription of mycobacteria by blocking DNA-dependent RNA polymerase, preventing mRNA and protein synthesis, causing cell death
Resistance to rifampicin occurs when…
Mutation in gene encoding for RNA polymerase beta chains
Isoniazid MOA
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
Mechanism to resistance for isoniazid
Mutations to catalase-peroxidase enzymes and regulatory genes involved in mycolic acid synthesis
Isoniazid ADME
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
Can isoniazid be taken by pregnant women?
Yes, with pyridoxine to prevent B6 def for ppl at risk of peripheral neuropathy
FDI/DDI with isoniazid
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
ADR for Isoniazid
- Peripheral neuropathy (HIV, DM, uraemic or malnourished and alc users)
- Hepatitis
- Psychosis, convulsions, haematologic rxns
Pyrazinamide MOA
Nicotinic acid derivative to be converted to active form, pyrazinoic acid by microbial enz, pyrazinamidase
Accumulation of acid decreases pH and inactivate crucial pathways
ADR of pyrazinamide
- GI Sx (NV)
- Photosensitivity
- Hepatotoxicity: dose adj
- Hyperuricemia and arthralgia: pyrazinoic acid inhibit renal tubular secretion of uric acid, resulting in gout like Sx
- Exanthema(widespread rashes) and pruritus
Ethambutol MOA
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
Excretion of Ethambutol
Renal 50%
ADR of ethambutol
- Visual toxicity (incr. In VKD and elderly)
- dose dpd
- caution in young children - Hyperuricemia/gout
- DDI: Antacids, sep by 2h
When are TB pts cured?
Negative sputum culture in last month of trx
