Aminoglycosides Flashcards
What are aminoglycosides’ MOA for protein synthesis inhibition?
There are 3:
- Bind the 30s ribosome, preventing the initiation of meth-tRNA from biding to the P site
- Enhances early breakdown of the ribosomal subunit (Binds to the interface between the 30 and 50s subunit)
- Interferes with reading/distorts codons
Name the aminoglycosides (6)
Amikacin Gentamicin Kanamycin Neomycin Tobramycin Streptomycin
Why is the naming of aminoglycosides important?
- micin means it was obtained from Streptomyces griseus from soil sample
- mycin means it was obtained from Actinomycete Micromonospora
Note: Tobramycin was obtained from S. tenebrarius!
Which aminoglycosides are semisynthetic?
Kanamycin
Amikacin
What do aminoglycosides target?
Gram - bacilli
Aerobic bacteria
Are aminoglycosides bacteriostatic or bacteriocidal?
Bacteriocidal
How do aminoglycosides kill the cell?
They enter the bacteria through porins (ENERGY DEPENDENT transport), inhibit protein synthesis
Are aminoglycosides time dependent or concentration dependent?
They are CONCENTRATION dependent
Once they are in the cell, they stay there
Do NOT need to maintain certain concentrations - this makes adverse effects more likely
Also have post antibiotic effect! Still see effect when levels are low because the aminoglycosides are INSIDE the cell
How are aminoglycosides administered? Why?
Injection only (IM, IV)
Because they are ionized in body fluids and not readily absorbed
How are aminoglycoside eliminated?
Eliminated by glomerular filtration
When are aminoglycosides used in combination?
Serious infection
Sepsis
Pneumonia
Endocarditis
Aminoglycosides can be combined with _______. Why?
Beta lactams
They break down the cell wall, allow the aminoglycosides to get into the cell easier
Can decrease dose of aminoglycoside needed when we do this`
What are the major toxicity concerns with aminoglycosides?
Nephrotoxicity
Ototoxicity
Neuromuscular blockade
Hypersensitivity reactions (rare)
What is the incidence of nephrotoxicity with aminoglycoside use?
8-25%
What is the most toxic aminoglycoside? Least toxic?
Most toxic: Neomycin
Least toxic: Streptomycin
What causes nephrotoxicity with aminoglycoside use?
The aminoglycoside accumulates in the proximal tubule, inhibiting prostaglandin synthesis.
This causes damage to brush border cells
Incidence of nephrotoxicity increases with what?
Age (poor renal function?)
Total dose (increases in dose = increases in incidence)
Females at higher risk than males
Duration of treatment
Multiple daily dosing more than single dosing
When you try to maintain certain plasma levels
Nephrotoxity risk is additive with what agents?
Cisplatin
Cyclosporine
Furosemide
(and other nephrotoxins)
True or False: If you d/c aminoglycosides, hearing will come back
False - it may be permanent
Describe the ototoxicity caused by aminoglycosides
Accumulation of aminoglycosides in fluid of the cochlea can lead to both auditory and vestibular dysfunction
(Hearing and balance affected)
True or false: Ototoxicity from aminoglycosides is dose related
True
Continued loss occurs with repeated dosing
What agents can enhance ototoxicity from aminoglycosides?
Ethacrynic acid, furosemide, cisplatin, and other ototoxins
What can increase sensitivity of ototoxicity from aminoglycosides?
Genetic mutations in microsomal RNA (3 different point mutations in RNA)
What cells are most sensitive to ototoxicity?
Outer hair cells are lost before inner hair cells
What is thought to be the mechanism of hearing loss in aminoglycoside toxicity?
3 major hypotheses: Calcium hypothesis (interferes with calcium channels in hair cells) Free radical hypothesis (interact with iron to form superoxide and hydroxyl free radicals, can poke holes in membrane and damage DNA) NMDA hypothesis (Interact with NMDA receptors and glutamate to cause excitotoxicity)
Which agents have the highest incidence of auditory toxicity?
Amikacin
Kanamycin
Neomycin
Which agents have the highest incidence of vestibular toxicity?
Gentamycin
Streptomycin
Which agent has equal effect on auditory and vestibular?
Tobramycin
Recovery from aminoglycoside toxicity can take how long?
12-18 months
Some residual damage persists
Are there treatments for aminoglycoside toxicity?
No treatment except to stop drug as early as possible
What causes neuromuscular blockade with aminoglycoside use?
Blocks presynaptic release of calcium
What is the order of neuromuscular blocking potency for the aminoglycosides?
(Highest) Neomycin Kanamycin Amikacin Gentamicin Tobramicin (Lowest)
How do you treat neuromuscular blockade in aminoglycoside toxicity?
IV calcium salt
What are the contraindications for aminoglycoside use?
Myasthenia gravis
(Neuromuscular blockade can occur)
Can also enhance neuromuscular blockade in surgery
What causes aminoglycoside resistance?
Plasmid acquired aminoglycoside modifying enzymes (can increase metabolism)
Altered porins can alter transport into the bacteria
Altered ribosomes
Which aminoglycoside is used for nosocomial infections?
Amikacin
Which aminoglycoside is used for the plague?
Streptomycin
Which aminoglycoside is used for Tularemia?
Streptomycin
Which aminoglycoside is used for Tuberculosis?
Streptomycin
