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PHARMACOLOGY 3 > 7 – Aminoglycosides > Flashcards

7 – Aminoglycosides Flashcards

1
Q

Aminoglycosides structure

A
  • Lots of amino groups
  • **basic molecules
    o In more acidic pH=IONIZED
    o lots of + charges=may change distribution
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2
Q

**What are the NEED to know aminoglycosides in Vet Med?

A
  • Gentamicin
  • Amikacin
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3
Q

Gentamicin examples

A
  • Gentocin
  • Otomax, Mometamaxx, Easotic
  • Topagen
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4
Q

Gentocin

A
  • Sterile injectable solution (clear)
  • IM, SC or IU (intra-uterine in mares) on label
  • *often IV off-label
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5
Q

Otomax, Mometamaxx, Easotic

A
  • Topical ointments for otitis externa
  • *antibiotic, steroid and anti-fungal all together
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6
Q

Topagen

A
  • Topical spray for dermal lesions
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7
Q

Amikacin example

A
  • Amiglyde-V
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8
Q

Amiglyde-V

A
  • Sterile ‘injectable’ solution
  • *labelled only for IU use in mares
  • **often administered IV off label
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9
Q

(Neomycin)

A
  • Used to be big in vet med
  • Various calf scour boluses
  • Skin and ear ointments
  • Antimicrobial “preservative” in many vaccines (to ensure NO infection of the vaccine itself)
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10
Q

(Apramycin)

A
  • Apralan oral solution for swine scours caused by E. coli
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11
Q

What is the mechanism of action of aminoglycosides?

A
  • Binds to bacterial ribosomal 30S sub-unit
    o Causes incorrect tRNA translation
    o Disrupts bacterial protein synthesis
    o Lead to increased bacterial membrane permeability
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12
Q

**Aminoglycosides need to penetrate bacterial cell to reach binding site: what is needed and what happens?

A
  • *need oxygen for the aminoglycosides to be taken up by the bacteria (OXYGEN DEPENDENT)
  • *if anaerobic environment=poor efficacy!
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13
Q

Local pH and aminoglycoside efficacy

A
  • Basic pH: non-ionized, easier to transport but can diffuse out
  • Acidic pH: more ionized, less transport in but, then ion-trapped
  • *unsure fully
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14
Q

Abscess and aminoglycoside efficacy

A
  • Does NOT work=cannot penetrate
    o Anaerobic!
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15
Q

What are aminoglycosides generally effective against?

A
  • *’opposite of penicillin
  • **Very good against gram NEGATIVE aerobic bacteria
    o Especially enteric bacteria
    o *Pseudomonas
  • Good against Staph
    o Including some MRSA/MRSP
  • Some activity against Enterococcus, mycobacteria and mycoplasma
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16
Q

What are aminoglycosides generally NOT or LESS effective against?

A
  • Less against Strep spp..
    o Especially amikacin
  • Intracellular pathogens
    o Salmonella
  • *anaerobes
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17
Q

Aminoglycosides: main resistance mechanism

A
  • *plasma-mediated enzymes degrade them and PREVENT BINDING to ribosome 30S subunit
    o **most significant for determining clinical susceptibility
    o Amikacin is LEAST affected by these enzymes
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18
Q

What are some other resistance mechanism against aminoglycosides?

A
  • Decrease permeability
  • Chromosomal resistance: NOT a big deal
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19
Q

Chromosomal resistance and aminoglycosides

A
  • Changes to 30S binding sites
  • Many 30S binding sites available, so these mutations don’t usually produce clinical resistance
20
Q

“First exposure adaptive resistance” - Decreased permeability and aminoglycoside resistance

A
  • Due to decreased uptake (permeability) by bacteria
  • Occurs within 1-2h of dose
  • Lasts up to 16h post-exposure
    o Then partial return of susceptibility
  • *resistance accumulates with increasing number of doses
  • IMPLICATION: use ONCE DAILY dosing with HIGH concentrations to decrease adaptive resistance effect
21
Q

Order of drugs: potency, spectrum of activity, stability against enzyme degradation (MORE to LEAST)

A
  • Amikacin: more potent spectrum against gram negative (but decrease gram positives, esp. Strep activity, DOES NOT MATTER)
  • Gentamicin
  • Neomycin
  • Streptomycin
22
Q

Oral bioavailability

A
  • Very poor
  • Historically found in calf scour boluses
  • Exception: some absorbed during enteritis or with high doses
    o Leave drug residues
23
Q

IM/SC injection bioavailability

A
  • Good absorption
  • *due to toxicity concerns=often give IV (EXTRALABEL)
24
Q

IU (label) or IMM (ELDU, cows, do NOT recommend) bioavailability

A
  • Some systemic absorption
25
Q

Local delivery: bioavailability

A
  • Hopefully MINIMAL absorption
    o Just want at the site
26
Q

Volume of distribution, elimination time and route

A
  • Low Vd
  • Rapid elimination (1-2hrs, first phase)
    o From plasma, but not ALL tissues
  • RENAL ELIMINATION
27
Q

**Renal elimination

A
  • Glomerular filtration
  • Renal disease=decreased GFR=decreased clearance
    o DOSE MODIFICATION SHOULD BE CONSIDERED
  • *binds to proximal tubule cells
28
Q

**Concentration-dependent antimicrobial

A
  • Cmax : MIC >10
  • **Increase TROUGH (rather than increase peak) plasma concentration correlates with AE
    o If trough higher=more AE
  • Long post-antibiotic effect
  • CLINICAL IMPLICATION: high dose, but only SID (or less)
29
Q

What are the AE?

A
  1. Nephrotoxicity
  2. Ototoxicity
  3. Neuromuscular blockade: rare
  4. Drug interactions
30
Q

Nephrotoxicity (acute tubular necrosis): mechanism of AE

A
  • Most common
  • *uptake and accumulation of AG into renal proximal tubule cells
    o AG binds to charged phosphotidylinositol on tubular cells
    o AG enters cell via carrier-mediated pinocytosis
    o AG sequestered in lysosomes=eventually ruptures
    o Causes cell death
31
Q

What are some protective conditions to ‘avoid’ nephrotoxicity?

A
  • *anything that can decrease contact of AG in filtrate with proximal tubule cells
    1. Increase GFR
    1. SID, high doses
    1. High calcium or protein in diet
32
Q

Protective conditions: increase GFR

A
  • FLUID THERAPY (hydration)
  • High protein in diet: not clinically useful
33
Q

Protective conditions: SID, high dosing

A
  • Rapid elimination in filtrate, so decrease overall contact
34
Q

Protective conditions: high calcium or protein in diet

A
  • Cations compete with + charges on AG for tubule cell binding
  • *likely not relevant due to feeding time required
35
Q

Ototoxicity (ear): AE mechanism

A
  • same as nephrotoxicity
  • Likely not to notice this: but more of a problem LONG term
36
Q

Why are nephron and ototoxicity exacerbated by diuretics?

A
  • Good for getting things out of kidney, but then animal is losing urine and may be DEHYDRATED for a period of time afterwards
  • Want to use a FLUID BAG
37
Q

Neuromuscular blockade: AE

A
  • Rare
  • Related to blockade of ACh at motor end plate
  • Treat with calcium
38
Q

Drug interactions: AE

A
  • pH incompatibilities (mixed together in syringe)
    o NOT usually mixing things in same syringe=NOT a problem
    o ONE drug, ONE syringe
  • “synergy” with beta-lactams (but IN VITRO only)
  • Avoid using with other nephrotoxic drugs
39
Q

Beta-lactam and AG ‘synergism’

A
  • Only IN VITRO
  • *complementary spectrum but not because they make each other work better
  • *humans: higher incidences of AE (nephrotoxicity)
  • *more if you have a severe condition and not sure what is happening=combo or broad spectrum is justifiable
40
Q

AG use and food animals

A
  • Drug residues can occur
  • Extremely SLOW depletion from the kidney (pretty much the rest of their life)
  • Neomycin and Gentamicin residue violations are COMMON
    o Not as much a problem now, as they are used as much anymore in food animals
  • Plasma: 1 day
  • Urine: 100 days
  • Kidneys: high even 1 year later
  • *do NOT use extra label use in food animals
41
Q

Therapeutic drug monitoring: when worried about dosing regimen

A
  • Need a human lab with an assay (need peak and trough plasma concentrations)
  • Increase urine gamma glutamyl transferase (GGT) enzyme and urine [GTT:creatinine] ratio
  • Proteinuria
  • Increase in serum urea nitrogen and serum creatinine
42
Q

Look at urine enzyme levels and compare to urine creatinine levels (GGT:creatinine ratio)

A
  • Creatinine: base line marker of FILTRATION
  • UGGT : UCr may go up 2-3x baseline within three days of a nephrotoxic dose
  • *most SENSITIVE: can find in a couple of days
43
Q

Proteinuria for therapeutic drug monitoring

A
  • Disadvantages
    o Lots of things cause it
    o Takes time for it to occur=likely TOO late and probably already finished therapy
44
Q

What about serum urea nitrogen and serum creatinine?

A
  • NOT seen for 7 days
    o Damage is already done!
45
Q

**What can you do when doing IV AGs to prevent toxicity and increase effectiveness?

A
  • FLUIDS: safety
  • HIGH DOSE not very often (once a day)
46
Q

Local drug therapy

A
  • Regional perfusion
    o IVRP or intra-osseous
    o Intra-articular (joint injections: gentamycin)
    o *hopefully have exposed the site to high doses
  • Antimicrobial-impregnated beads (polymethylmetacrylate, PMMA)
    o ‘double-edged’ sword: high concentration at injection site, but slowly leaks out=prolonged exposure

PHARMACOLOGY 3 (15 decks)

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