Antimycobacterials: Exam 1 List Flashcards
Exam 1 List
How does Isoniazid work?
Unknown but thought to inhibit cell-wall biosynthesis by interfering with lipid and DNA synthesis
Describe the absorption of PO Isoniazid
Rapid and complete absorption orally. Food slows absorption rate. Peak plasma time 1-2 hours
Describe Isoniazid’s distribution:
Distributed to all body tissues and fluids.
Can cross into CSF
Crosses placenta & enters breast milk
Describe how Isoniazid is metabolized:
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.
How is Isoniazid eliminated?
Undergoes half-life elimination.
Urine excretion is 75-95%
Black Box Warning for Isoniazid:
Can cause severe and sometimes fatal hepatitis. Risk is related to age and increases with daily alcohol consumption
Dosing regimen for Isoniazid:
May be taken with meals or antacids if GI irritation occurs, but do not take within 1 h of aluminum-containing antacid.
What is the most common adverse reaction for Isoniazid?
Peripheral neuropathy
Which patients are at high risk for developing peripheral neuropathy when taking Isoniazid?
Malnourished
Slow acetylators
Pregnant women
Older adults
Diabetics
Patients with chronic liver disease, & those with alcohol use disorder
What medication can be given to prevent development of peripheral neuropathy in patients taking Isoniazid?
Pyridoxine (B6)
What foods/medications should be avoided when taking Isoniazid?
Alcohol, aluminum salts, oral anticoagulants, benzodiazepines, carbamazepine, cyclosporine, disulfiram, hydantoins, rifampin, theophylline, warfarin, tyramine-containing foods, histamine containing foods, ketoconazole
Providers should use Isoniazid cautiously and closely monitor patients who:
Drink alcohol daily
Have liver disease or severe renal dysfunction
Are HIV +
Are pregnant
Have preexisting peripheral neuropathy
Are older than 35 years
Describe the MOA of Rifampin
Inhibits RNA synthesis/transcription by binding to the beta subunit of RNA polymerase
Describe the PO absorption of Rifampin:
Well absorbed; food may delay or slightly reduce peak. Peak plasma time 2-4 hours
How do organisms develop resistance to Rifampin?
Point mutations that prevent binding to RNA polymerase; organisms develop this mutation rapidly when Rifampin is used as a monotherapy
How do organisms develop resistance to Isoniazid?
Through inhA gene or deletion of katG gene which encodes mycobacterium catalase
How is Rifampin metabolized?
Metabolized by the liver and undergoes enterohepatic recirculation.
Half life: 3-4 hours (prolonged in hepatic impairment)
Describe the distribution of Rifampin:
Highly lipophilic: penetrate and concentrate in most body fluids.
Crosses the blood brain barrier, as well as the placenta, and enters breast milk
How is Rifampin eliminated?
Mainly in bile
The rest in feces through enterohepatic recirculation, and a small amount in urine
Precautions & Considerations for Rifampin:
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
What drugs/medications should be avoided when taking Rifampin?
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
Patients taking Isoniazid tend to have an elevation in these labs:
Elevated serum transaminases (AST/ALT) are observed in 10% to 20% of patients
Common adverse reactions associated with Rifampin:
-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,
How does Rifampin interact with other drugs that undergo hepatic metabolism?
Rifampin is a potent inducers of the CYP enzyme system and speed the metabolism of many drugs, resulting in therapeutic failure.
Absorption & Distribution of Pyrazinamide:
Well absorbed
Widely distributed into body tissues and fluids including liver, lung, and CSF. Crosses the placenta, and enters breast milk
Metabolism & Excretion of Pyrazinamide:
Half life: 9-10 hour
70% Hydrolyzed by the liver & excreted in urine by glomerular filtration
Resistance to Pyrazinamide:
Resistance develops rapidly when used as monotherapy
Metabolically, what happens to Pyrazinamide in the presence of impaired renal or hepatic function?
Its half-life may be significantly prolonged
What comorbidity is considered high risk for patients taking Pyrazinamide?
hepatic impairment
Pyrazinamide has been known to interact with which lab tests?
Acetest and Ketostix urine tests to determine ketoacidosis
Adverse reactions for Pyrazinamide:
Dose-related hepatotoxicity
Hyperuricemia
Adverse reactions for Ethambutol:
Optic neuritis
Signs/Symptoms of optic neuritis r/t Ethambutol:
Decreased visual acuity, red–green color blindness, diminished visual fields, and sometimes loss of vision
What food/drugs should be avoided when taking Ethambutol?
Aluminum salts as they reduce the absorption of ethambutol
Metabolism & Excretion of Ethambutol:
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
What is the mechanism of action of ethambutol?
Interferes with the synthesis of arabinogalactan, an essential component of mycobacterial cell walls
Absorption & Distribution for Ethambutol:
Bioavailability ~80%
Peak plasma time 2-4 hours
Widely distributed throughout body
Crosses into CSF with inflamed meninges
ethambutol should be used cautiously in patients with:
renal impairment
Patients who are unable to appreciate or report visual changes or who have preexisting optic neuritis, cataracts, or diabetic retinopathy.
Adverse drug effects of ethambutol:
Visual disturbances, including irreversible blindness
