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Respiratory Block: Pharmacology > Treatment of TB > Flashcards

Treatment of TB Flashcards

1
Q

What are the 4 first line agents in the treatment of TB?

A
  1. Rifampicin - R
  2. Isoniazid - H
  3. Ethambutol - E
  4. Pyrazinamide - Z
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2
Q

What is considered the intensive phase of first line TB treatment?

A

Rifampicin + Isoniazid + Ethambutol + Pyrazinamide for 2 months

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3
Q

What is considered the continuation phase of first line TB treatment?

A

Isoniazid + Rifampicin for 4 months

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4
Q

What occurs during the intensive phase of treatment?

A

The intensive phase is to rapidly kill tubercle bacilli
Infectious patients become less infectious within 10-14 days
- Majority will become smear negative within 2 months

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5
Q

Who is first line TB treatment given to?

A

New patients that haven’t come into contact with resistant TB patients

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6
Q

What are the 2 main principles of TB treatment?

A
  1. Multi-drug therapy

2. Daily dosing

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7
Q

What are some of the extra-pulmonary TB types commonly seen?

A

TB meningitis, TB bones / joints, miliary TB

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8
Q

What is considered the intensive phase of extra-pulmonary TB treatment?

A

Rifampicin + Isoniazid + Ethambutol + Pyrazinamide for 2 months

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9
Q

What is considered the continuation phase of extra-pulmonary TB treatment?

A

Isoniazid + Rifampicin for 7 months

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10
Q

What is the mechanism of action of Isoniazid?

A

Inhibits cell wall synthesis - inhibits mycolic acid synthesis (mycobacterial cell wall component)

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11
Q

What is the mechanism of action of Ethambutol?

A

Inhibits cell wall synthesis - inhibits formation of mycobacterial cell wall by inhibiting arabinosyl transferase

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12
Q

What is the mechanism of action of Rifampicin?

A

Inhibits RNA synthesis - binds to the beta-unit of DNA dependent RNA polymerase

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13
Q

What is the mechanism of action of Pyrazinamide?

A

Exact target unclear (no known MOA)

  • disrupts plasma membranes
  • disrupts energy metabolism
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14
Q

How are doses calculated?

A

By weight

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15
Q

What is the main drug property of Isoniazid?

A

Bactericidal after 24 hours

- high potency: kills >90% bacilli in the first few days of treatment

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16
Q

What is the main drug property of Rifampicin?

A

Bactericidal within 1 hour

- high potency

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17
Q

What is the main drug property of Pyrazinamide?

A

Bactericidal with a low potency.

- Achieves its sterilizing action within 2-3 months

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18
Q

What is the main drug property of Ethambutol?

A

Bacteriostatic, low potency

- Minimizes the emergence of drug resistance

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19
Q

What are the target bacilli of Isoniazid?

A

Rapid and intermediate growing bacilli

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20
Q

What are the target bacilli of Rifampicin?

A

All populations including dormant bacilli

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21
Q

What are the target bacilli of Pyrazinamide?

A

Slow growing bacilli

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22
Q

What are the target bacilli of Ethambutol?

A

All bacterial populations

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23
Q

In what pH does Isoniazid work?

A

Alkaline and acid media

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24
Q

In what pH does Rifampicin work?

A

Alkaline and acid media

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25
Q

In what pH does Pyrazinamide work?

A

Acid medium

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26
Q

In what pH does Ethambutol work?

A

Alkaline and acid media

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27
Q

What is the site of action of Isoniazid?

A

Intracellular and extracellular

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28
Q

What is the site of action of Rifampicin?

A

Intracellular and extracellular

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29
Q

What is the site of action of Pyrazinamide?

A

Intracellular bacilli only macrophage

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30
Q

What is the site of action of Ethambutol?

A

Intracellular and extracellular

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31
Q

What form is Isoniazid given?

A

It is a given as a pro-drug and activated by mycobacterial KatG

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32
Q

What are the clinical uses of Isoniazid?

A
  • Mycobacterium Tuberculosis treatment
  • Non-tuberculosis mycobacteria
  • Chemoprophylaxis of TB
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33
Q

What are the pharmacokinetics of isoniazid?

A

Undergoes first pass metabolism largely by acetylation

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34
Q

What drug interactions are seen with Isoniazid?

A
  • antacids decrease absorption

- inhibits cytochrome P450 (increases plasma concentration of phenytoin / carbamazepine, warfarin)

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35
Q

How does resistance to Isoniazid develop?

A

KatG / InhA mutations

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36
Q

What are the pharmacokinetics of Rifampicin?

A
  • highly protein bound
  • half life: 2-5 hours
  • rapid metabolism in liver (autoinduction, enterohepatic circulation)
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37
Q

What are the clinical uses of Rifampicin?

A
  • Mycobacterium tuberculosis
  • Non-tuberculosis mycobacteria
  • Leprosy, brucellosis, resistant staphylococcal infections
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38
Q

How does Rifampicin resistance develop?

A

Mutations in rpoB (beta subunit of RNA polymerase)

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39
Q

What drug interactions are seen with Rifampicin?

A

Inducer of CYTP450 enzymes: protease inhibitors, NNRTIs, warfarin, combined oral contraceptive, phenytoin, fluconazole, oral hypoglycaemics, theophylline, digoxin
= decreased efficacy of these drugs

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40
Q

What is important about the drug interactions with Rifampicin in HIV positive patients?

A

Rifampicin is a CYP450 inducer

= must exclude protease inhibitors if haven’t yet started ARVs

41
Q

What is Rifabutin?

A

Related to Rifampicin, but a less potent inducer of CYTP450

42
Q

What is Rifabutin used for?

A

Used in patients co-infected with HIV on ART regimen receiving protease inhibitors
- also used as prophylaxis in MAC

43
Q

What is ethambutol used for?

A

Only used in mycobacterial infections

- crosses BBB in meningitis

44
Q

What conversion of Pyrazinamide takes place?

A

Converted to pyrazinoic acid by mycobacterium pyrazinamidase

45
Q

What is the action of Pyrazinamide on mycobacterium?

A

Bactericidal for intracellular mycobacterium in acidic medium

46
Q

What is Pyrazinamide used for?

A

Used for the treatment of Mycobacterium infections (TB)

- distributed widely, including meninges

47
Q

What are the common adverse effects of Isoniazid?

A
  • peripheral neuropathy

- hepatitis

48
Q

How is Isoniazid peripheral neuropathy managed?

A

Give 10-25mg pyridoxine daily

49
Q

How is Isoniazid hepatitis managed?

A

Stop treatment

Do liver function tests

50
Q

What are the common adverse effects of Rifampicin?

A
  • GIT disturbances
  • Rash, hypersensitivity reactions
  • Hepatitis
  • Red / orange color of fluids - tears, urine, sweat
51
Q

How can Rifampicin GIT disturbances be managed?

A

Give anti-emetic, antacid (time antacid with isoniazid so as not to prevent absorption)

52
Q

What is the hepatotoxicity of Rifampicin?

A

Least hepatotoxic of the TB medications

- hepatotoxicity uncommon unless alcoholic or history of liver disease

53
Q

What are the common adverse effects of Ethambutol?

A
  • ocular toxicity: optic neuritis

- hyperuricaemia, joint pain

54
Q

In what condition is Ethambutol contraindicated?

A

C/I: in pre-existing optic neuritis

55
Q

What are the common adverse effects of Pyrazinamide?

A
  • Hepatotoxicity (hepatitis, liver damage)

- Hyperuricaemia, joint pain

56
Q

What is the hepatotoxicity of Pyrazinamide?

A

Most hepatotoxic

57
Q

How should Pyrazinamide hepatotoxicity be managed?

A

Stop treatment

Do liver function tests - ALT

58
Q

Which first line agents cause drug induced hepatitis?

A

Pyrazinamide, Isoniazid, Rifampicin

59
Q

Which second line agents cause drug induced hepatitis?

A

Ethionamide / prothionamide, PAS

60
Q

When should drug induced hepatitis be suspected?

A

Suspected when:
1. ALT >3 times the upper limit of normal (with symptoms)
OR
2. ALT >5 times the upper limit of normal (no symptoms)

61
Q

What should be done if drug induced hepatitis is suspected?

A
  1. Exclude other causes: viral hepatitis, alcohol consumption, other drugs
  2. Stop the hepatotoxic drugs
  3. Monitor ALT levels
62
Q

What should ALT levels be?

A

<100IU/l

63
Q

How should re-introduction of drugs be done if drugs are stopped due to drug induced hepatitis?

A

Re-introduce: Rifampicin - Isoniazid - Ethambutol - Pyrazinamide
- Monitor liver function (ALT every 3 days)

64
Q

Which of the first line TB agents is not hepatotoxic?

A

Ethambutol

65
Q

What is given for TB prophylaxis?

A

Isoniazid for 6 months

66
Q

Who should Isoniazid prophylaxis be given to?

A
  • Children <5 years
  • HIV positive children
  • Adults: HIV positive and immunocompromised
67
Q

What are the ART guidelines for TB & HIV?

A

ART should be started in all TB patients living with HIV regardless of their CD4 count

  • TB treatment initiated first
  • ART within 8 weeks
  • If CD4 <50: start ART within 2 weeks
68
Q

What is an important drug interaction in TB and HIV?

A

Rifampicin interacts with protease inhibitors

69
Q

What additional prophylaxis should be given to TB & HIV patients?

A

Co-trimoxazole prophylaxis

70
Q

What should be done for TB in pregnant women?

A

Should be treated promptly with standard daily 6 month regimen

71
Q

What is the risk of TB drugs to the unborn fetus?

A

The first line drugs freely cross the placenta

Risk-benefit weigh up

72
Q

What is the risk of hepatitis in pregnant women on TB treatment?

A

Risk of Isoniazid induced hepatitis is 2.5 times higher in pregnant women than non-pregnant

73
Q

What should be done for breastfeeding mothers with TB?

A

Mothers should be encouraged to breastfeed

- if mother is infectious - use surgical masks

74
Q

What is multi-drug resistant TB?

A

Resistant to Rifampicin and Isoniazid

75
Q

What is extensively drug resistant TB?

A

MDR-TB
+ resistance to a fluoroquinolone
+ resistance to an injectable

76
Q

What are the 4 groups of second line agents used in treating resistant TB?

A
  1. Fluoroquinolones
  2. Injectables
  3. Other core 2nd line agents
  4. Add-on agents
77
Q

Which fluoroquinolone is the most commonly used in treating resistant TB?

A

Moxifloxacin

78
Q

Which fluoroquinolone is the most commonly used in treating children with resistant TB?

A

Levofloxacin

79
Q

How long is the course of treatment for MDR TB?

A

Shortened MDR TB regimen 9-12 months (vs. previously 18-24 months)

80
Q

What is the intensive phase of MDR TB treatment?

A

4-6 months:

Km-Mfx-Eto-Cfz-Z-Hh-E

81
Q

What is the continuation phase of MDR TB treatment?

A

5 months

Mfx-Cfz-Z-E

82
Q

What should be tested for in treating MDR TB?

A

Test resistance / susceptibility to Fluoroquinolones & 2nd line injectables
- If resistance: use conventional MDR-TB regimen (at least 5 drugs)

83
Q

How should MDR TB be treated in pregnancy?

A

C/I: Ethionamide / pth & injectables

84
Q

What are the two new TB drugs available?

A
  1. Bedaquiline

2. Delamanid

85
Q

Who is Bedaquiline given to?

A

Only adult patients >18 years

- MDR / Pre-XDR TB / XDR

86
Q

What is the half life of Bedaquiline?

A

Very long! = 5.5 months

- Only given for the first 24 weeks of treatment due to this

87
Q

How is Bedaquiline metabolized?

A

Hepatically

88
Q

What are the side effects of Bedaquiline?

A

QT prolongation, hepatotoxic

89
Q

What is Delamanid used to treat?

A

MDR / XDR / patients with HIV (no D/I)

>18 years of age

90
Q

What is the main adverse effect of Delamanid?

A

QT prolongation

91
Q

What is the most common related SE of Bedaquiline?

A

QT prolongation

92
Q

What is the most common related SE of Delamanid?

A
  • QT prolongation

- Peripheral neuropathy

93
Q

What is the most common related SE of Clofazimine?

A

Pink to brown discoloration of skin, cornea, retina, urine

94
Q

What is the most common related SE of Cycloserine / Terizidone?

A

Neurological & psychiatric disturbances

95
Q

What is the most common related SE of PAS?

A
  • GIT disturbance

- Hypothyroidism

96
Q

What is the most common related SE of Thioacetazone

A
  • Steven-Johnson syndrome

- Toxic epidermal necrolysis (C:I HIV)

97
Q

What is the most common related SE of Aminoglycosides?

A

Hearing loss, vestibular toxicity, nephrotoxicity, electrolyte disturbance

98
Q

What is the most common related SE of Ethionamide / prothionamide?

A

Hepatitis / hypothyroidism

Respiratory Block: Pharmacology (8 decks)

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