Aminoglycosides (Anti-Biotics) Flashcards
How do human and bacterial ribosome subunits differ?
Bacterial ribosomes have a 30S and 50S subunit, whereas humans have 40S and a 60S.
Even though human ribosomes differ from bacterial ones, what do humans have that closely mimic bacterial ribosomes?
Mitochondrial ribosomes resemble the 70S ribosomes somewhat, and this might explain some of the toxicities we see with ABX.
What forms the “initiation complex” of bacteria?
30S subunit of bacterial ribosome comes together with the f-met t-RNA and bind to the methionine start codon, AUG. This resulting complex is called the “initiation complex.”
What is the physiologic function of the 50S subunit?
Once the initiation complex is formed the 50S subunit comes to bind to the complex and initiate the mRNA translation.
Generally describe the “transpeptidation” step of the protein synthesis pathway.
Charged t-RNA with AA attached binds to the A (acceptor site) of the ribosome, where once attached it will form a peptide bond with the amino acid sitting adjacent to it in the P (peptidyl) site.
What is the “translocation” step of protein synthesis?
Once the peptide bond is formed between the amino acids in the P and A site, they slide over one spot so the P AA moves to the E site and the A AA moves to the P site. The t-RNA in the E site becomes uncharged and drops off leaving the AA attached, and a new AA will bind to the now empty A site. Cycle continues until a stop codon hits.
Describe the “termination” step in protein synthesis.
AA shift from the A site to the P site to the E site, attaches to a growing chain and eventually off the ribosome and this continues until they hit a stop codon where the chain elongation terminates.
Name the 6 major aminoglycosides (and the 2 slightly minor ones)
Streptomycin, Gemtamycin,Tobramycin, Amikacin,Neomycin, paramomycin. The lesser ones are Netilmicin and Kanamycin.
What’s special about the chemistry about aminoglycosides?
They are amino sugars, water soluble, very polar, more active in alkaline pH than acidic, and as a result they will not be diffuse across the cell membrances and stay in the body fluid.
Why would you want to administer aminoglycosides?
They are active against gram - aerobic organisms and are bacteriocidal. Aminoglycosides are the only protein synthesis inhibitors that are bacteriocidal as opposed to the others which are bacteriostatic.
How are aminoglycosides administered?
Not orally, through IV, IM, IT.
Vd of aminoglycosides and the ramifications of this?
High volume of distribution so patients with edema or volume overload needs dose adjustment.
CSF penetration and aminoglycosides? Placenta crossing?
Poor CSF penetration, if the drug needs to enter the CSF we need to do intrathecal administration. However, IT admin is not advised for neonates. It does cross the placenta.
Where does aminoglycosides tend to accumilate?
In the renal cortex, and in the endo/peri lymph of the inner ear.
How are aminoglycosides eliminated?
Via renal elimination (glomerular filtration) and is directly proportional to creatinine clearance (meaning they get filtered through the kidney and eliminated very quickly).
What is the half life of aminoglycosides?
Should be only 2-3 hours in normal kidney, can be 24-48 hrs in significant renal impairment.
Which kinds of patients generally get treated with aminoglycosides, and as such what do we need to consider?
Critically ill patients get aminoglycosides, and they often have renal failure, rapid renal changes, septic shock, etc, so dose adjustment might be necessary. Kidney function tests must be performed.
Even though the half lives of these drugs is relatively short (2-3 hrs) why can we get away with only 1x a day dosing?
Because it is concentration depended killing, the more drug we give the faster it kills bacteria, and further even if the drug falls below the inhibitory concentration it will continue to kill bacteria up until a certain point, hence 1x daily dosing is enough.
In terms of dosing how are aminoglycosides administered?
Its dosed at a single high loading dose and allowed to taper off rather than giving multiple drug regimens daily, this is because the drug still has antibiotic activity even after blood levels of the drug decreases.
How does aminoglycosides get into susceptable bacteria?
Gram neg bacteria have porins that allow aqueous substances to passively diffuse through (AG’s are highly polar and water soluble), and once in the cytoplasm it gets across the cytoplasmic membrane via oxygen dependent active transport. As a result, aminoglycosides will only hit gram neg aerobic organisms.
What are the things that would cause the AG’s to be not transported across the cytoplasmic membrane?
Divalent cations like Mg and Ca, acidic pH, hyperosmolarity, and anarobic conditions.
What are the 3 ways that the MOA of AG’s work?
- It blocks the initiation step by fixing the start codon.
- It blocks the translocation step to prevent protein elongation (and thus a useless protein).
- AG’s can incorporate their own amino acids into the peptide chain and thus make a non useful protein for the bacteria.
All of this eventually leads to bacterial death.
Describe the AG bacterial activity
Gram neg bacilli, like pseudomonas, and selective gram positive activity like enterococcus endocarditis if administered with other cell wall inhibitors.
Why can’t AG’s cannot cross the cell membranes of gram + bacteria, and if that is the case how come AG’s have activity against some Gram + bacteria?
Gram + have cell walls that are too thick and that do not allow for passive diffusion of aqueous molecules like the porins do for gram neg. As a result AG’s cannot normally enter, however if a cell wall inhibitor like a beta lactam is administered first, walls will be induced in the bacteria and the AG’s can slip through.
Which bacteria are intrinsically resistant to AG’s?
Gram + bacteria with intact cell walls, anerobes, facultative aerobes who are in the anarobic state.
