Pharmacology of Pulmonary Tuberculosis

Question 1

What is the general treatment paradigm for TB and how are drugs taken?

Answer 1

4 for 2 and 2 for 4

4 drugs for two months (RIPE)
2 drugs for four months (RI)

Drugs are take by direct observed therapy at county health to ensure adherence

Question 2

What is the mechanism of action of isoniazid (INH)?

Answer 2

It is a prodrug converted by Kat-G (Catalase in mycobacterium, think of the tiger leaping at the isolated ranger in sketchy)

Inhibits synthesis of mycolic acids (think of the fuchsia cacti on the horizon)

Question 3

What patients are at greatest risk for toxicity from isoniazid?

Answer 3

Slow acetylators - metabolism occurs in liver initially by N-acetyltranferase

Question 4

What are the two most common adverse effects of isoniazid therapy? How can these be prevented?

Answer 4

INH
Injures
Nerves - peripheral neuropathy due to increased B6 wasting -> give with pyridoxine
Hepatocytes - hepatitis is common adverse effect, must monitor liver function tests

Question 5

What is one other drug level which must be closely monitored when using isoniazid and rifampin together? Why?

Answer 5

Phenytoin - an anticonvulsant

Isoniazid is a CYP450 inhibitor, and rifampin is a CYP450 inducer

Question 6

How can hepatotoxicity caused by INH be told apart from rifampin?

Answer 6

Rifampin - causes increases in bilirubin and alkaline phosphatase

Isoniazid - causes aminotransferase elevations

Question 7

What derivative of rifampin is preferred for patients taking protease inhibitors? Why?

Answer 7

Rifabutin, induces CYP only about half as much as rifampin, which is useful in maintaining therapeutic drug concentrations

Question 8

In what patient population might Rifapentene be useful and why?

Answer 8

HIV negative patients who cannot make it to county health every day

• > Has a long-half life which allows it to be given once weekly
• > regimen is less effective than the normal regimen

Question 9

What is the mechanism of action of rifampin and its most common benign side effect?

Answer 9

Inhibits bacterial DNA-dependent RNA polymerase

Side effect - orange discoloration of body secretions such as urine, sweat, and tears

Question 10

What is the P of RIPE and what its major side effects? Mechanism of action?

Answer 10

Pyrazinamide (think pyro) - mechanism unknown

Side effects:

1. Nausea and vomiting which is significant
2. Dose dependent hepatotoxicity
3. Hyperuricemia - think of the guy knitting

Question 11

If PZA cannot be given, what must be done to the regimen? Why?

Answer 11

Continuation phase of therapy with rifampin and isoniazid must be given for an extra three months, since pyrazinamide is very effective against dormant TB, and now only rifampin would be able to kill these

Question 12

What is the name of the E drug in RIPE and its mechanism of action?

Answer 12

Ethambutol, works by inhibiting formation of bacterial cell wall via inhibition of arabinosyltransferases

Think of Ethel stopping the Arabian horse next to the wall

Question 13

What is the major toxicity of Ethambutol?

Answer 13

Eyethambutol - optic neuritis which disturbs visual acuity and red-green color vision -> think of horse with red-green goggles

Question 14

What drug was previously first line for the treatment of TB and what are its toxicities?

Answer 14

Streptomycin

-aminoglycoside toxicities include nephrotoxicity, auditory, and vestibular (ototoxicity)

Question 15

What current second-line agents are being investigated as first-line agents for TB?

Answer 15

Respiratory fluoroquinolones - Levofloxacin and moxifloxacin

Question 16

What are the side effects of concern with fluoroquinolones?

Answer 16

Tendon rupture (esp. achilles), CNS toxicities (anxiety, depression, seizures), QT prolongation (kids playing with TdP tape)

Question 17

What is the major drug interaction of FQ’s?

Answer 17

Chelation in oral formulations -> must separate with consumption of divalent cations

Question 18

Why is Linezolid only a second line agent in TB?

Answer 18

Drug courses must be so long, and the major side effects include peripheral neuropathy and bone marrow suppression (especially thrombocytopenia)

Question 19

What are the other main adverse effects of linezolid?

Answer 19

Optic neuritis, serotonin syndrome (it is a weak MAOI)

Question 20

What is the most common side effect of TB treatment and what should you do if a patient has it?

Answer 20

GI upset within the first few weeks

Check liver function tests for hepatic damage

Question 21

What is the threshold value for LFT elevation with GI upset, and what should you do if the patient is below this to make them feel better? What should be avoided?

Answer 21

<3x the upper limit of normal

For symptomatic relief: Antacids, or take drugs with a light snack (crackers). Avoid too much food or there may be poor absorption -> especially antacids with FQs as the cations may limit absorption.

Question 22

What should be done for mild and severe rashes associated with TB treatment?

Answer 22

Mild - manage symptomatically with antihistamines

Severe - Removal all medications and begin adding them back in one by one once rash resolves. Consider administering corticosteroid if rash is severe

Question 23

If the rash is petechial in nature, what drug does this make you think is causing the drug reaction?

Answer 23

Rifampin or its derivatives

-> hallmark of rifamycin hypersensitivity is associated thrombocytopenia

Question 24

At what thresholds should therapy be discontinued with liver function tests? What should be done to handle this?

Answer 24

> 5x upper limit of normal without symptoms
3x upper limit of normal with symptoms

Once patient normalizes, begin reintroducing medications one at a time (always remember, if elevated LFTs are bilirubin / alk phos, think rifampin toxicity)