TB Drugs

Question 1

What are the 4 TB drugs used for patient with active TB

Answer 1

Rifampicin, isoniazid, pyrazinamide and Ethambutol (if cannot then steptomycin)

Question 2

Are they concentration dependent or time dependent killing?

Answer 2

Concentration dependent killing

Question 3

Rifampicin class and MOA

Answer 3

It inhibits the RNA synthesis of RNA polymerase.

Question 4

Isoniazid MOA

Answer 4

It Inhibits the mycolic acid synthesis (within the cell wall).

Question 5

Ethambutol MOA

Answer 5

Inhibit cell wall synthesis

Question 5

Pyrazinamide MOA

Answer 5

Inhibit cell membrane synthesis

Question 5

Streptomycin MOA

Answer 5

Inhibits the protein synthesis by targeting the 30s ribosomal subunit.

Question 5

Rifampicin adverse effects

Answer 5

1. Skin eruptions, fever, GIT disturbances.
2. Hepatitis, hyperbilirubinemia, and transaminasaemia
3. Hepatoxicity
4. Immunologically-mediated reactions: thrombocytopenia
   flu-like syndrome (usually low doses of intermittent rifampicin)

Question 6

PTB drugs inhibitors and inducers

Answer 6

1. INH- inhibit CYP2C19,3A4,2D6, 2E1
2. RIF- induces CYP1A2,2C9, 2C19, 3A4 and P-glycoprotein.

Question 6

Rifampicin DDI

Answer 6

1. warfarin (RIF inducer of warfarin)
2. HIV protease inhibitors
3. most non-nucleoside reverse
   transcriptase inhibitors (nNRTIs)
4. oral contraceptives
5. INH or pyrazinamide (increase hepatotoxicity)
6. Methadone (opioid agonists)

Question 6

Isoniazid pK PD in indian and chinese

Answer 6

Indian- slow acetylators
Chinese-fast acetylators.

Question 6

Isoniazid Adverse Effect

Answer 6

1. Allergic skin reactions
2. Hepatotoxicity
3. Neurotoxic effects
4. Can cause pellagra
5. Haemolysis in G6PD patients

Question 7

Isoniazid DDI

Answer 7

1. phenytoin (ISH- inhibitor)
2. Carbamazepine (ISH- inhibitor)
3. rifampicin or pyrazinamide (increase risk of hepatotoxicity)
4. Alcohol intake(increase risk of hepatotoxicity)
5. Aluminium salts (reduce absorption)

Question 8

Pyrazinamide adverse effects

Answer 8

1. hepatotoxicity (1-5%) – primary adverse effect; it is dose-related, with a fatality
   rate as high as 1%.
2. GIT - nausea, vomiting
3. rashes, photosensitivity
4. arthralgia (JOINT STIFFNESS)
5. Hyperuricaemia: its metabolite, pyrazinoic acid, interferes with the tubular
   secretion of uric acid; mostly asymptomatic, but (rarely), can cause acute gouty
   arthritis.

Question 9

Pyrazinamide DDI

Answer 9

rifampicin - increase hepatotoxicity

Question 10

Ethambutol: Adverse effects

Answer 10

1. Most significant - optic neuritis, with visual abnormality (1-2%). Symptoms of
   visual toxicity: reduced visual acuity, red/green colour blindness
   Best avoided in children < 8 years who may not be able to co-operate in an eye
   test.
2. GIT – diarrhoea
3. Allergic rash
4. Asymptomatic hyperuricaemia, occasional gouty arthritis (due to inhibition of
   uric acid secretion)

Question 11

Ethambutol DDI

Answer 11

Aluminum salts (antacids) (reduce absorption)

Question 12

When to start TB treatment?

Answer 12

1. CXR suggestive of active TB
2. TB treatment can be started
   prior to sputum results
   returning
   – Public health point of view

• Baseline tests:
  – Eye: Colour vision and Visual
  acuity
  – AST/ALT/Creatinine
  – HIV,DM (f.glucose / HbA1c)

Question 13

Duration of TB treatment

Answer 13

TB meningitis: 12 months, with adjunctive steroids
* TB pericarditis: 6 months, with adjunctive steroids
* Musculoskeletal TB: 9 months
* Lymph node: 6-9 months
* Pleural TB: 6-9 months

Question 14

how to order TB drug?

Answer 14

Weigh patient!
* Rifampicin (Rif):
– 10 mg/kg. Round UP
* Isoniazid (INH) : (beware the underweight patient)
– 5 mg/kg. Round down
* Ethambutol (EMB):
– 20 mg/kg (first two months), round down.
– If need EMB beyond 2 months, dose 15mg/kg, round down
* Pyrazinamide (PZA) (omit if Age > 65)/cirrhotic):
– 25 mg/kg, round down.
* B6: 10 mg om.
* Maximum Limits (regardless of weight):
– EMB 1.6 g om
– PZA 2 g om.

Question 15

Patient education of TB drugs

Answer 15

Rifampicin 1. Imparts a harmless orange color to urine,
sweat, and tears (soft contact lenses may
be permanently stained)
2. Skin eruptions, fever and GIT disturbances
are the most common side effects.
3. Alcohol intake

Isoniazid 1. Take pyridoxine when taking INH to prevent
pellagra
2. For breastfeeding moms, INH can pass
through breastmilk
3. Reduce alcohol intake
4. Tingling sensations (neuropathy)

Pyrazinamide 1. Use sunscreen
2. Alcohol intake

Ethambutol 1. Watch for visual changes

Question 16

Hepatotoxicty in TB drugs, and how to manage

Answer 16

If latent TB: Stop treatment immediately
▪ Monitor LFTs
▪ Re-challenge with INH
when ALT improves to < 2x ULN
▪ If patient can’t tolerate INH, switch to
RIF x 4 months

Patient with symptoms of hepatitis:

If Active TB:
Stop all TB drugs and perform LFTs:
a) AST or or bilirubin ≥ 3 times upper limit of normal (ULN)or ALT>5x ULN : wait for resolution of symptoms, perform LFTs weekly and restart TB treatment when LFTs are < 3 times ULN.
b) AST, ALT and bilirubin < 3 times ULN and mild symptoms (no jaundice): restart TB treatment, closely monitor the patient and perform LFTs weekly. Continue TB treatment as long as LFTs levels remain < 3 ULN and there are no signs of worsening hepatitis.

Restart RIF
 restart INH 3-7 days later
 restart PZA 7 days later
EMB may be restarted anytime
▪ May need non-hepatotoxic regimen: EMB
+ FQ + streptomycin

If still cannot then use this 9 month regime:
For patients who are unlikely to tolerate pyrazinamide (e.g. the elderly, those with liver disease), a 9-month regimen comprising ethambutol, rifampicin and isoniazid for 2 months followed by rifampicin and isoniazid for 7 months may be used.

Question 17

Important guidelines and education for patients on TB drugs

Answer 17

The patient’s weight should be documented at each
visit and the drug dosages adjusted accordingly. Adult
patients on ethambutol must have their visual acuity
and colour vision checked at each visit. Those with
risk factors for drug-induced hepatitis must be closely
monitored