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PR3151 CA1: Antibiotics (NUS Pharmacy) > Anti-TB Agents > Flashcards

Anti-TB Agents Flashcards

1
Q

What kind of bacilli is Mycobacterium tuberculosis?

A

Obligate aerobe, acid-fast bacilli

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2
Q

When is the highest risk of progression to active TB?

A

In the first 2 years after initial infection

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3
Q

Which population is most susceptible to progression to active TB?

A

Immunocompromised patients, elderly, HIV positive patients

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4
Q

What is STEP and their strategies to control TB?

A

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

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5
Q

First line Anti-TB agents

A

Rifampicin, Isoniazid, Pyrazinamide, Ethambutol, Streptomycin

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6
Q

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

A

Reduce transmission

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

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7
Q

Clinical diagnosis that prompts treatment initiation

A

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

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8
Q

What to check before initiating TB treatment?

A
  1. Baseline liver enzymes
  2. Visual acuity & color vision (for ethambutol)
  3. Weight loss and dose adjustments
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9
Q

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

A

6 Month Regimen

  • 2 month Intensive Phase (RIPE) daily
    »> Majority elimination
  • 4 month Continuous Phase (RI) 3x/wk to daily
    »> Cure
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10
Q

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

A

All first-line TB drugs

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11
Q

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

A

Rifampicin, Isoniazid, Pyrazinamide

after light meals or before bedtime

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12
Q

Rifampicin: Administration? MOA?

A

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

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13
Q

Rifampicin Resistance mechanism

A

Mutation in gene coding for RNA polymerase beta chain

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14
Q

Rifampicin clinical indications

A

Active and latent TB; Leprosy (Mycobacterium leprae)

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15
Q

Rifampicin is cleared by?

A

Hepatic metabolism and Biliary excretion

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16
Q

Rifampicin should be used with caution in which patients?

A

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

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17
Q

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

A

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

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18
Q

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

A

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

Hepatotoxicity potential increased
- Isoniazid

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19
Q

5 ADRs of Rifampicin

A
  1. Cutaneous Syndrome (Flush, pruritus)
  2. Hepatitis
  3. Flu-like Syndrome (Fever, chills)
  4. Respiratory Syndrome (SOB)
  5. Immune reactions (Thrombocytopenia)
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20
Q

Patient counselling point for rifampicin ADR

A

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

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21
Q

Isoniazid: Administration? MOA?

A

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

22
Q

Isoniazid Resistance mechanism

A

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

23
Q

Isoniazid is clinically indicated in ________

A

Active/Latent TB and Prophylaxis

24
Q

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

A

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

25
Q

Isoniazid should be used with caution in _______________________ and why?

A

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

26
Q

What should be given with isoniazid and why?

A

Pyridoxine; Avoid vitamin B6 deficiency leading to peripheral neuropathy

27
Q

How does isoniazid cause vitamin B6 deficiency?

A

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

28
Q

How is pyridoxine used by the body?

A

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

29
Q

Isoniazid food interactions?

A

Carbohydrates decrease absorption

Tyramine and histamine rich food (MAO and histaminase inhibition by isoniazid)

Antacids increase pH, reduce absorption

30
Q

Isoniazid affects CYP450 by acting as a ________

A

Inhibitor that increases phenytoin anticonvulsant and anticoagulant concentrations

31
Q

Isoniazid ADRs?

A
  1. Hypersensitivity (Rare) - Lupus-like syndrome, psychosis, hematologic reactions
  2. Hepatitis
  3. Peripheral Neuropathy
32
Q

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

A

Persistent bacilli; Pyrazinamide

33
Q

Comment on Pyrazinamide molecular structure and derivative

A

Similar to isoniazid; Nicotinic acid derivative

But no cross-resistance to isoniazid

34
Q

Comment on the effect of pyrazinamide action on bacteria and macrophages

A
  1. Bactericidal
  2. Potent sterilizing effect
  3. In acid medium within macrophages and at site of acute inflammation
35
Q

Pyrazinamide: Administration? MOA?

A

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

36
Q

Pyrazinamide Resistance Mechanism?

A

Mutation in gene coding for pyrazinamidase

37
Q

Pyrazinamide is clinically indicated for ________

A

Active TB

38
Q

Can TB drugs penetrate CSF fluid?

A

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

39
Q

Are all TB drugs safe in pregnancy? What category?

A

Cat C

Rifampicin - Give with Vitamin K (Hemorrhage)

Isoniazid - Give with Pyridoxine (Peripheral Neuropathy)

Pyrazinamide - Safe

Ethambutol - Not teratogenic

40
Q

Pyrazinamide cautions in which patients?

A

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

41
Q

Pyrazinamide DDI with _________

A

Probenecid, Rifampicin, Isoniazid

42
Q

Pyrazinamide ADR

A
  1. GI effect N/V
  2. Hepatotoxicity
  3. Photosensitivity
  4. Hyperuricemia & Arthralgia (Gout-like symptoms)
  5. Exanthema (Rash) & Pruritus
43
Q

How does pyrazinamide cause gout-like symptoms?

A

Pyrazinoic acid inhibits renal tubular secretion of uric acid

44
Q

Ethambutol effect on bacilli and what bacilli?

A

Bacteriostatic, Rapid growing bacilli

45
Q

Ethambutol Administration, MOA?

A

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)

46
Q

Ethambutol Resistance Mechanism

A

Mutation in embB gene encoding arabinosyltransferase

47
Q

Ethambutol is cleared by?

A

Urine excreted unchanged (50%)

Liver metabolism (25%)

Feces unchanged (25%)

48
Q

Ethambutol ADRs?

A
  1. Visual toxicity (Acuity, color, blurring)
  2. Hyperuricemia/Gout (Less than pyrazinamide)
49
Q

Who has greater risk of visual toxicity taking ethambutol?

A

Kidney failure, elderly, prolonged treatment (> 2 months)

Caution in young children

50
Q

What drug can replace ethambutol in the intensive phase?

A

Streptomycin

PR3151 CA1: Antibiotics (NUS Pharmacy) (11 decks)

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