Pham: protein synthesis inhibitors

Question 1

drugs acting at 30s ribosomal subunit

Answer 1

Aminoglycosides
Tetracyclines

“When in your 30s you are attractive and tantalizing”

Question 2

systemic Aminoglycosides

Answer 2

Gentamicin
Amikacin

Question 3

aminoglycosides mechanism of action

Answer 3

Bind to a specific receptor protein on the 30S ribosomal subunit
Irreversible binding
Formation of nonfunctional proteins
Aberrant proteins inserted in cell wall
Lead to altered permeability and cell death
May also affect 50S

RAPIDLY BACTERICIDAL

Post-antibiotic Effect
* Altered proteins in the cell membrane
* Increased drug permeability
* Effects last long after the drug is gone from the plasma
* Half-life < 2 hr; dosed once a day

Question 4

aminoglycosides spectrum of action

Answer 4

Gram-negative aerobic organisms!!!
Also have activity against staphylococcal organisms
Includes some MRSA/MRSP

Ineffective against streptococci
No activity against strict anaerobes!
Require oxygen for transport into cell

Question 5

aminoglycosides synergism

Answer 5

aminoglycosides= staphs, gr -
beta lactams = streps, gr +
synnergism

Question 6

How to choose gentamicin vs amikacin

Answer 6

amikacin is more active and less toxic
but gentamicin is less $$$

Question 7

aminoglycosides route of administration

Answer 7

poor oral absorbtion
IM absorption almost 100%
usually use IV

Question 8

aminoglycosides pharmokinetics

Answer 8

High water solubility
Low protein binding
Highly polar
* What does that tell you?
* Low volume of distribution
* Stay in the plasma and extracellular fluid
* Do not penetrate into the CNS, eye or prostate
* Do not penetrate intracellularly
* Example: R. equi is intracellular

Question 9

aminoglycosides excretion

Answer 9

Excreted unmetabolized by the kidney
Glomerular filtration

Question 10

aminoglycosides dosing

Answer 10

half life is short (1-2hr)
but dose 1/day
* Administer a higher dose
* Reach higher maximum concentrations (8-10x MIC)
* Active after the drug has left the plasma
* Post-antibiotic Effect
* Nephrotoxicity is dose dependent (Less likely to occur if Cmin <2-3 μg/mL)
* Requires active transport into renal tubular cells
* Saturated at higher doses

Question 11

aminoglycosides adverse effects

Answer 11

Bad for kidneys
* Risks greatly decreased with q24h dosing
* Gentamicin most nephrotoxic

risk increased with:
* Dehydration
* Fever
* Pre-existing renal disease

Toxicity is often reversible (admin Ca2+)

Others:
* Ototoxicity (dog- topical otic product w/ruptured eardrum)
* vestibular toxicity
* neuromusc blockade (dont use with some anesthetics, musc relaxants, botulism)

Question 12

aminoglycosides drug interactions

Answer 12

beta lactams: synnergism
dont mix with other nephrotoxic (NSAIDs)

Question 13

aminoglycosides Mechanisms of Resistance

Answer 13

1 is enzymatic modification (mostly plasmid mediated)

Aminoglycosidases
Amikacin least affected
Lesser - altered ribosome binding
Lesser - reduced uptake (active transport)

Question 14

aminoglycosides and food animals

Answer 14

“Voluntary Ban”
Prolonged residues in kidneys
LONG WITHDRAWL

Question 14

aminoglycosides and food animals

Answer 14

“Voluntary Ban”
Prolonged residues in kidneys
LONG WITHDRAWL

Question 15

Tetracyclines mechanism of action

Answer 15

Binds to the 30S ribosomal subunit
Blocks amino acids being added to the peptide chain
Inhibition of protein synthesis
Binding is reversible
Tetracyclines are BACTERIOSTATIC at all relevant concentrations

Question 16

tetracycline drugs

Answer 16

Oxytetracycline – horses, food animals
Chlortetracycline – food animals
Minocycline – horses, dogs
Doxycycline – horses, dogs, cats

Question 17

tetreacylines spectrum of activity

Answer 17

BROAD: Gram-positive and gram-negative bacteria, aerobes and anaerobes
but resistance is common

Question 18

Clinical uses tetracyclines

Answer 18

Tick born diseases!, Intracellular organism!

Question 19

tetracyclines in food animals

Answer 19

Injectible
Extended release
Indications:
* BRDC, severe foot rot and diphtheria, bacterial enteritis, wooden tongue, leptospirosis, wound infections, acute metritis, anaplasmosis, anthrax

Feed/water additive
* Anticoccidial
* Mycoplasma
* Etc.

Question 20

tetracyclines oral absorption

Answer 20

Oral absorption
* Good in small animals, Poor in horses, ruminants
* Still used orally, Can be erratic

Chelation
* Cations in the stomach can bind the drugs
* Should be given on an empty stomach
* Doxycycline is less affected

Question 21

tetracycline distribution

Answer 21

Distribute well to most tissues
* Exceptions: CNS and the eye
* Exception: minocycline
More lipophilic
Doxycycline also lipophilic but has higher PPB

Question 22

tetracyclines elimination

Answer 22

Primarily eliminated by the kidneys
except:
* Doxycycline is excreted through the bile and kidneys
* Minocycline is primarily excreted through the bile

Question 23

tetracyclines adverse effects

Answer 23

Esophageal strictures in cats
* Doxycycline tablets or capsules
* Direct mucosal ulceration and stricture
* Especially when broken
* 6 ml water flush or a small amount of food should always follow

Rapid IV administration of tetracyclines
* Hypotension and collapse (any species)
* Calcium chelation?
* Propylene glycol vehicles

IV administration of doxycycline to horses is fatal!!!

Skeletal effects
* Dental discoloration
* Inhibition of long bone growth
* Young animals, offspring of pregnant animals treated with tetracyclines
* Doxycycline is less likely to cause this effect

Hypersensitivity and fevers, particularly in cats
Photosensitization: Particularly with doxycycline
Others (rare): nephrotoxicity, heptatotoxicity, GI toxicity

Question 24

tetracycline resistance

Answer 24

Resistance is widespread among staphylococci, streptococci, and Gram-negative enteric bacteria
Enterococci are not susceptible
Plasmid-mediated
* Failure of the active transport system necessary to penetrate the bacterial cell