Antimycobacterial drugs Flashcards
(47 cards)
Why are mycobacteria so difficult to kill
Primary TB drugs and course (time)
Isoniazid, Rifampin, Ethambutol, Pyrazinamide, Streptomycin, “RIPES”
3-4 drugs for 6 months
What are the rifamycins
rifampin, rifapentine, rifabutin
Rifamycins MOA
They enter the acid-fast bacillus (AFB) in a concentration-dependent manner, reaching steady state within about 15 minutes.
They act by binding the beta-subunit of DNA-dependent RNA polymerase and form a stable complex that blocks chain formation in RNA synthesis.
Dosing strategy for rifampin
Rifampin has a strong post antibiotic effect; goal is thus usually to increase peak plasma concentration rather than time above MIC
Rifampin interactions
Absorption can be prevented with food and other medications, so it must be taken on empty stomach.
It has very complex pharmacokinetics, including the ability to induce its own metabolizing enzymes in the p450 system, and thus Rifampin interacts with many drugs.
Poor CNS absorption
Rifampin adverse effects
Orange discoloration of skin, urine, feces, saliva, tears, contact lenses
-Severe hepatic problems if preexisting liver disease, liver enzymes must be monitored on this medication
-Hypersensitivity reactions, including autoimmune reactions
-Major player in drug interactions;
Therapeutic failure of other drug as metabolism of other drugs is induced
Induction favors secondary pathways that cause increased production of toxic metabolites with some drugs
Who should get isoniazid
Isoniazid (INH) is a primary TB drug; this means that all patients who have susceptible M. tuberculosis should get this drug unless they have a direct contraindication or allergy.
Isoniazid chemistry
The prodrug isoniazid is metabolized in humans by NAT2 isoforms to its principal metabolite, N-acetyl isoniazid, which is excreted by the kidney.
100% bioavailability with good CNS penetration
Isoniazid MOA
Isoniazid diffuses into mycobacteria where it is “activated” by KatG (oxidase/peroxidase) to the nicotinoyl radical, which reacts spontaneously with NAD+ or NADP+ to produce adducts that inhibit important enzymes in mycolic acid and nucleic acid synthesis.
Isoniazid and B6
INH is chemically very similar to vitamin B6, pyridoxine, and inhibits enzymes and reactions requiring B6 in mammalian cells as a result, which is a major source of toxicity. This toxicity can be usually prevented by giving pyridoxine (B6) with the drug.
Isoniazid resitance mechanism
Resistance due to mutations or deletions in KatG gene (most important) or efflux pumps, and there is evidence that development of one leads to development of the other form of resistance.
Isoniazid metabolism
It is metabolized via acetylation (NAT2 enzyme), different genes (autosomal dominant) determine how fast or slow it will be acetylyzed and removed.
This is the most important characteristic that determines efficacy of treatment (in vivo efficacy) with INH for TB that demonstrates sensitivity in lab cultures to the drug
Isoniazid toxicities
- Isoniazid hepatitis (have to monitor liver enzymes)
- ANCA+ vasculitis, arthritis, or other hypersensitivity syndromes
- methemoglobinemia
- Peripheral neuritis and neurotoxicity due to dihydrofolate reductase inhibition in mammalian cells and resulting B6 (pyridoxine) deficiency. Neurotoxicity manifests as seizures, encephalopathy, and psychosis; all are preventable if the patient is given supplemental B6.
INH toxicity relationship to metabolism
What is INH overdose syndrome
Ethambutol MOA
It inhibits arabinosyl transferase III, an enzyme in the pathway for cell wall synthesis specific to mycobacteria only (due to the manufacture of glucans in cell wall.
Ethambutol dosing
Ethambutol is 80% bioavailable and redistributes so that rate of decline in serum concentration is much faster soon after the dose is taken than subsequently. Dosing strategies of higher, intermittent doses are thus used.
Ethambutol metabolism
This drug is metabolized by the alcohol dehydrogenase group of enzymes
Ethambutol adverse effects
It has the unique adverse effect of loss of red/green vision, particularly at higher doses and with longer therapy, so you must test with vision cards during treatment and discontinue drug if this occurs. You must also test prior to treatment as this finding also occurs naturally in 6-8% of natal males as a genetic trait
Pyrazinamide MOA
This little bitty molecule is “activated” by acidic conditions within edges of TB cavities and is also a first line TB drug.
First, the bacillus deaminates the drug PZA to the molecule POA- and transports it out of bacillus; resistance to drug is thus caused by alterations in deamination enzyme, pyrazinamidase.
Then, the molecule POA- is protonated in the acidic environment of the TB cavity edge to POAH,
Which is then is lipid-soluble and reenters bacillus and is able to kill the bacillus somehow.
Pyrazinamide Mechanism of killing
- Inhibition of mycolic acid synthesis in POA- form
- Reduction of intracellular pH from H+ liberated in POA- form
- Disruption of membrane transporters in POAH form
Pyrazinamide absorption and metabolism
This drug has good oral absorption and 20-fold accumulation in lung epithelial lining fluid, making it one of those special cases where specific tissue concentration is much higher than measured serum concentration. Kind of uniquely, there are “slow absorbers” and “fast absorbers
Pyrazinamide adverse effects
Liver injury is the most serious side effect and most prevalent with higher doses than currently used. Must monitor AST and ALT on this drug and stop the drug if they rise. This drug should be avoided altogether in liver impairment.
This drug does causes hyperuricemia; may precipitate gout attacks in folks who are susceptible.
