Antimycobacterials

Question 1

How does Isoniazid work?

Answer 1

Unknown but thought to inhibit cell-wall biosynthesis by interfering with lipid and DNA synthesis

Question 2

Describe the absorption of PO Isoniazid

Answer 2

Rapid and complete absorption orally. Food slows absorption rate. Peak plasma time 1-2 hours

Question 3

Describe Isoniazid’s distribution:

Answer 3

Distributed to all body tissues and fluids.
Can cross into CSF
Crosses placenta & enters breast milk

Question 4

Describe how Isoniazid is metabolized:

Answer 4

Extensively metabolized by liver. However, metabolism is largely variable and based on genetic acetylation. (A person can be slow or fast acetylator)
The rate of acetylation does not alter effectiveness but may increase the risk for toxic reactions in slow acetylators

Ex. Fast acetylators metabolize this drug five to six times faster than slow acetylators do.

Question 5

How is Isoniazid eliminated?

Answer 5

Undergoes half-life elimination.
Urine excretion is 75-95%

Question 6

Black Box Warning for Isoniazid:

Answer 6

Can cause severe and sometimes fatal hepatitis. Risk is related to age and increases with daily alcohol consumption

Question 7

PO education for Isoniazid

Answer 7

May be taken with meals or antacids if GI irritation occurs, but do not take within 1 h of aluminum-containing antacid.

Question 8

What is the most common adverse reaction for Isoniazid?

Answer 8

Peripheral neuropathy

Question 9

Which patients are at high risk for developing peripheral neuropathy when taking Isoniazid?

Answer 9

Malnourished
Slow acetylators
Pregnant women
Older adults
Diabetics
Patients with chronic liver disease, & those with alcohol use disorder

Question 10

What medication can be given to prevent development of peripheral neuropathy in patients taking Isoniazid?

Answer 10

Pyridoxine (B6)

Question 11

What foods/medications should be avoided when taking Isoniazid?

Answer 11

Alcohol, aluminum salts, oral anticoagulants, benzodiazepines, carbamazepine, cyclosporine, disulfiram, hydantoins, rifampin, theophylline, warfarin, tyramine-containing foods, histamine containing foods, ketoconazole

Question 12

Providers should use Isoniazid cautiously and closely monitor patients who:

Answer 12

Drink alcohol daily
Have liver disease or severe renal dysfunction
Are HIV +
Are pregnant
Have preexisting peripheral neuropathy
Are older than 35 years

Question 13

Describe the MOA of Rifampin

Answer 13

Inhibits RNA synthesis/transcription by binding to the beta subunit of RNA polymerase

Question 14

Describe the PO absorption of Rifampin:

Answer 14

Well absorbed; food may delay or slightly reduce peak. Peak plasma time 2-4 hours

Question 15

How do organisms develop resistance to Rifampin?

Answer 15

Point mutations that prevent binding to RNA polymerase; organisms develop this mutation rapidly when Rifampin is used as a monotherapy

Question 16

How do organisms develop resistance to Isoniazid?

Answer 16

Through inhA gene or deletion of katG gene which encodes mycobacterium catalase

Question 17

How is Rifampin metabolized?

Answer 17

Metabolized by the liver and undergoes enterohepatic recirculation.
Half life: 3-4 hours (prolonged in hepatic impairment)

Question 18

Describe the distribution of Rifampin:

Answer 18

Highly lipophilic: penetrate and concentrate in most body fluids.
Crosses the blood brain barrier, as well as the placenta, and enters breast milk

Question 19

How is Rifampin eliminated?

Answer 19

Mainly in bile
The rest in feces through enterohepatic recirculation, and a small amount in urine

Question 20

Precautions & Considerations for Rifampin:

Answer 20

Use cautiously in hepatic impairment
Rifampin is a potent inducer of liver metabolism and can lead to sub therapeutic concentrations of other drugs metabolized by CYP enzymes

Question 21

What drugs/medications should be avoided when taking Rifampin?

Answer 21

Digoxin, Isoniazid, oral anticoagulants, azole antifungals, barbiturates, BDZs, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, digitoxin, disopyramide, efavirenz, elvitegravir, etravirine, estrogens, hydantoins, methadone, mexiletine, miraviroc, nevirapine, quinidine, sildenafil, sulfonylureas, tacrolimus, tamoxifen, theophylline, tocainide, verapamil

Question 22

Patients taking Isoniazid tend to have an elevation in these labs:

Answer 22

Elevated serum transaminases (AST/ALT) are observed in 10% to 20% of patients

Question 23

Common adverse reactions associated with Rifampin:

Answer 23

-GI: anorexia, nausea, vomiting, diarrhea, flatulence, and abdominal pain.
-Hepatotoxicity leading to hepatitis
-Transient elevations of AST/ALT in the first 8 weeks of therapy
-Orange-red discoloration of body fluids,

Question 24

How does Rifampin interact with other drugs that undergo hepatic metabolism?

Answer 24

Rifampin is a potent inducers of the CYP enzyme system and speed the metabolism of many drugs, resulting in therapeutic failure.

Question 25

Absorption & Distribution of Pyrazinamide:

Answer 25

Well absorbed
Widely distributed into body tissues and fluids including liver, lung, and CSF. Crosses the placenta, and enters breast milk

Question 26

Metabolism & Excretion of Pyrazinamide:

Answer 26

Half life: 9-10 hour
70% Hydrolyzed by the liver & excreted in urine by glomerular filtration

Question 27

Resistance to Pyrazinamide:

Answer 27

Resistance develops rapidly when used as monotherapy

Question 28

Metabolically, what happens to Pyrazinamide in the presence of impaired renal or hepatic function?

Answer 28

Its half-life may be significantly prolonged

Question 29

What comorbidity is considered high risk for patients taking Pyrazinamide?

Answer 29

hepatic impairment

Question 30

Pyrazinamide has been known to interact with which lab tests?

Answer 30

Acetest and Ketostix urine tests to determine ketoacidosis

Question 31

Adverse reactions for Pyrazinamide:

Answer 31

Dose-related hepatotoxicity
Hyperuricemia

Question 32

Adverse reactions for Ethambutol:

Answer 32

Optic neuritis

Question 33

Signs/Symptoms of optic neuritis r/t Ethambutol:

Answer 33

Decreased visual acuity, red–green color blindness, diminished visual fields, and sometimes loss of vision

Question 34

What food/drugs should be avoided when taking Ethambutol?

Answer 34

Aluminum salts as they reduce the absorption of ethambutol

Question 35

Metabolism & Excretion of Ethambutol:

Answer 35

20%-50% metabolized by oxidation in the liver
Half life: 2.5-3.6 hours
Prolonged in ESRD

50% excreted via urine as unchanged drug

Question 36

What is the mechanism of action of ethambutol?

Answer 36

Interferes with the synthesis of arabinogalactan, an essential component of mycobacterial cell walls

Question 37

Absorption & Distribution for Ethambutol:

Answer 37

Bioavailability ~80%
Peak plasma time 2-4 hours

Widely distributed throughout body
Crosses into CSF with inflamed meninges

Question 38

ethambutol should be used cautiously in patients with:

Answer 38

renal impairment
Patients who are unable to appreciate or report visual changes or who have preexisting optic neuritis, cataracts, or diabetic retinopathy.

Question 39

Adverse drug effects of ethambutol:

Answer 39

Visual disturbances, including irreversible blindness