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Pharmacology > Anti-TB Therapeutics > Flashcards

Anti-TB Therapeutics Flashcards

1
Q

Which age group has the largest number of tuberculosis cases?

A

25-34 year olds (greater than 74 year olds)

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2
Q

What are the risk factors for tuberculosis?

A

Elderly, poverty, malnutrition, alcoholism, immunosuppression, AIDS, diabetes

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3
Q

How is tuberculosis acquired?

A

Person-to-person transmission of airborne droplets of organisms from an active case to a susceptible host

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4
Q

What occurs in a patient with a primary infection of tuberculosis?

A

Most often asymptomatic as regional lymph node spread and bacteremia
Usually controlled by the development of cellular immunity.

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5
Q

How can latent tuberculosis be detected?

A

Positive tuberculin skin test, no disease

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6
Q

How can active tuberculosis be detected?

A

Latent infection that was reactivated

Clinical signs and symptoms, radiographic evidence and bacteriological evidence

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7
Q

What are the signs and symptoms of tuberculosis?

A

Cough, fever, night sweats, pulmonary cavitation, mycobacteria dissemination, presence of bacilli in sputum (increased, at first mucoid then purulent), malaise, anorexia, extrapulmonary effects (liver, bone marrow, etc.)

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8
Q

What are the infectious agents that cause?

A

Mycobacterium tuberculosis (acid fast, high lipid content, gram negative, slow growing) and mycobacterium bovis (cows and milk, oropharyngeal and intestinal tuberculosis)

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9
Q

How can tuberculosis be reactivated?

A

Loss of balance between the immune system and bacilli, most often occurs in the lungs but can happen in lymph nodes, kidneys, gut
Symptomatic and infectious

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10
Q

What can lead to tuberculosis treatment failure and drug resistance?

A

Long duration needed for treatment and poor adherence

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11
Q

What is the standard length of treatment for tuberculosis?

A

6 months

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12
Q

What is the length of treatment for tuberculosis meningitis?

A

9-12 months

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13
Q

What are the first line drugs for tuberculosis?

A

Isoniazid, rifampin, pyrazinamide and ethambutol

Use combination therapy

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14
Q

How does isoniazid work?

A

Inhibits cell wall synthesis by inhibiting mycolic acid synthetase.
Bactericidal in extracellular area with high oxygen concentration. Important in prevention of resistance.

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15
Q

How does rifampin work?

A

Inhibits DNA-dependent RNA polymerase only in mycobacteriu, inhibiting RNA synthesis
Bactericidal in extracellular areas, including fibrotic areas.
Very important, without it treatment would last 18 months

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16
Q

What does pyrazinamide do?

A

Sterilizes semi-dormant and dormant bacteria by inhibiting mycolic acid synthesis. Active in acidic environment. Only beneficial for 2 months (while inflammation is present)

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17
Q

What does ethambutol do?

A

Inhibits arabinosyl transferase which stops arabinogalactan chain elongation and mycobacterial wall synthesis
Bacteriostatic
Prevents resistance to rifampin when primary resistance to isoniazid is present

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18
Q

When should ethambutol not be used?

A

Discontinue if the organism is sensitive to isoniazid.

Do not use in children or renal failure.

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19
Q

What occurs during the intensive phase of tuberculosis treatment? When does it occur?

A

0-8 weeks
Goal is to quickly kill the rapidly dividing organism to control disease and render the patient non-infectious and prevent the emergence of drug resistance.

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20
Q

What occurs during the continuation phase of tuberculosis treatment? When does it occur?

A

2-6 months
Sterilize the lungs by killing dormant and semi-dormant organisms to prevent relapse
Intermittent therapy allowed if directly observed therapy

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21
Q

What is the drug regime during the intensive phase of tuberculosis treatment?

A

Isoniazid, rifampin, pyrazinamide and ethambutol daily for 8 weeks
First nations use 3 times weekly after the patient has had 14 daily doses and is smear negative
Ethanmbutol can be dropped if the organism is pansensitive

22
Q

What is the drug regime during the continuation phase of tuberculosis treatment?

A

Directly observed therapy (DOT) of isoniazid and rifampin twice weekly

23
Q

How can the duration of pansensitive tuberculosis treatment change?

A

Required number of doses should be given (may have to extend duration to get them all in)
If pyrazianmide wasn’t used in first 2 months, treatment will be 9 months.
If culture is positive at 2 months, treatment is 9 months.

24
Q

What is the therapy for latent tuberculosis?

A

Isoniazid daily for 9 months or rifampin daily for 4 months.

25
Q

What are some adverse effects of isoniazid?

A

Peripheral neuropathy due to interference with pyridoxine metabolism (occurs in B6 deficiency)
Seizures, rash, hepatic toxicity (hepatitis, increase in LFTs), drug interactions

26
Q

How can resistance to isoniazid occur?

A

Due to decreased drug uptake

27
Q

How can resistance to rifampin occur?

A

Rapid resistance due to alteration in DNA-dependent RNA polymerase structure causing decreased drug binding

28
Q

What are some adverse effects of rifampin?

A

Uncommon
Hepatotoxiity, discolouration of urine/sweat, rash, oral pain, “flu-like”, thrombocytopenia, dose dependent interference with bilirubin uptake causing unconjugated hyperbilirubinemia or jaundice

29
Q

What are some drug interactions with rifampin?

A

Concentration of rifampin is decreased by HIV protease inhibitors
Decreased efavirenz
Decreased raltegravir
All HIV drugs

30
Q

What are some adverse effects of pyrazinamide?

A

Hepatotoxicity, hyperuriaenemia which could cause gout. arthralgias, GI effects, rash

31
Q

How can resistance against pyrazinamide occur?

A

Due to loss of pyrazinamidase which decreases the conversion to pyrazinoic acid

32
Q

What are the adverse effects of ethambutol?

A

Loss of visual acuity, loss of colour discrimination (green), GI upset

33
Q

How do we monitor the microbiological response to TB therapy?

A

Sputum at 2 months and sputum at completion of therapy

34
Q

How do we monitor the laboratory response to TB therapy?

A

Check AST, ALT, bilirubin and CBC

Twice weekly in the first 2 weeks then monthly at 1 month

35
Q

How can pregnancy change tuberculosis therapy?

A

Can continue therapy as usual. First line drugs are safe in pregnancy and lactation

36
Q

What are the abnormal LFTs that a patient may develop while on TB therapy?

A

AST/ALT is 5x the upper limit of normal asymptomatic or AST/ALT is 3x the upper limit of normal, symptomatic or jaundice

37
Q

What should be done if a patient develops abnormal LFTs on tuberculosis therapy?

A

Hold TB meds until ALT returns to

38
Q

How does TB treatment change in patients with pre-existing liver disease?

A

Be aware that treatment may elevate AST/ALT

If ALT is more than 3x the upper limit of normal is not related to TB, avoid pyrazinamide

39
Q

How does TB treatment change in patients with cirrhosis?

A

Rifampin, ethambutol and fluoroquinolone

40
Q

How does TB treatment change in patients with renal insufficiency?

A

Dose adjust pyrazinamide and ethambutol if creatine levels are

41
Q

How does multi-drug resistant tuberculosis (MDR-TB) emerge?

A

Course of antibiotics is interrupted or the levels of drug are insufficient to kill bacteria

42
Q

What is multi-drug resistant tuberculosis (MDR-TB)?

A

Patients (4%) who are resistant to refampin and isoniazid and potentially other drugs.

43
Q

Who is more likely to develop MDR-TB?

A

Patients with weakened immune systems (HIV, immunosuppressant drugs), areas poverty and lack of healthcare

44
Q

What is extensively drug resistant tuberculosis?

A

A form of MDR-TB that is resistant to ridampin and isoniazid, any quinolone and any injectable 2nd line agent
Makes TB untreatable

45
Q

What are some alternative treatment regimes for a patient who is isoniazid resistant?

A

Rifampin and pyrazinamide and ethambutol or streptokinase for 6-9 months
Rifampin and ethambutol for 12 months
Fluoroquinolone or aminoglycosides may be added

46
Q

How is MDR-TB treated?

A

Combinations of 5-7 drugs
Isoniazid, rifampin, pyrazinamide, ethambutol, an aminoglycoside, a fluoroquinolone and one of: cycloserine, ethionamide or aminosalicylic acid

47
Q

What is the MDR-TB therapy regime?

A

An injectable is used daily for the first 2-6 months then stepped down to 3 times a week, ideally for 8 months. Must have daily directly observed therapy
Duration of therapy is total 20 months.

48
Q

How are MDR-TB drug regime decided?

A

Individual regimes are guided by Drug Susceptibility Testing (DST)

49
Q

How does bedaquiline work?

A

New MDR-TB drug
Inhibits mycobacterium ATP synthase
Used in combination with rifampicin and pyrazinamide

50
Q

What are the safety issues with bedaquiline?

A

Liver toxicity, prolonged QT, chest pain, hemoptysis and nausea/headache

Pharmacology (11 decks)

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