Pharmacology 7: Protein Synthesis Inhibitors

Question 1

What are the drugs acting at the 30s ribosomal subunit?

Answer 1

Amino glycosides

Tetracyclines

Attractive & Tantalizing

Question 2

What are the drugs acting at the ribosomal subunits?

Answer 2

Phenicols

Macrolides

Lincosamides

Panchy, Moody, & Lazy

Question 3

What does GNATS stand for in Aminoglycosides?

Answer 3

GENTAMICIN

NEOMYSIN

Amikacin
Tobramycin
Streptomycin

Question 4

What is the mechanism of action for Aminoglycosides?

Answer 4

Bactericidal!! Rapidly!!

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

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 5

What is the spectrum of activity for Post-antibiotic Effect of Aminoglycosides?

Answer 5

Gram- aerobic organisms

against Staphylococcal organisms (MRSA/MRSP)

NOT GOOD FOR:
streptococci
strict anaerobes

Question 6

What is the clinical use for Aminoglycosides?

Answer 6

** SYNERGISM SPECTRUM**

Severe gram-negative infections/sepsis
◦Pleuropneumonia, peritonitis, neonates
◦Use may be limited by adverse effects

◦Often combined with beta-lactams in these cases

Question 7

How do you choose which Aminoglycosides to use?

Answer 7

Amikacin
- more active
- less toxic
- resistance less likely
- EXPENSIVE

So if you can chose GENTAMICIN do it because it is more affordable

Question 8

What are the pharmacokinetics of Aminoglycosides?

Answer 8

Oral absorption is poor
◦Neomycin

IM absorption almost 100%

IV most common route

Question 9

Aminoglycosides

solubility?
protein binding?
volume distribution?
polar?

Answer 9

High water solubility

Low protein binding

Volume of distribution low

Highly polar

This tell you:
Stay in the plasma and extracellular fluid
◦Do not penetrate into the CNS, eye or prostate
◦Do not penetrate intracellularly
◦Example: R. equi

Question 10

What are the pharmacokinetic/ pharmacodynamic interactions of Aminoglycosides?

Answer 10

◦Concentration-dependent
◦Cmax:MIC 8-10x
◦Example
◦MIC = 2 μg/mL
◦Cmax >16-20 μg/mL

Question 11

What organ is the most common to be affected by Aminoglycosides?

Answer 11

KIDNEYS

Question 12

What are the adverse effects of Aminoglycosides?

Answer 12

1. Dose dependent nephrotoxicity
2. Nephrotoxicity
3. Renal toxicity
4. Bad for kidneys

Most clinically relevant

Risks greatly decreased with q24h dosing

Question 13

What are the benefits of once daily dosing of Aminoglycosides?

Answer 13

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 14

Nephrotoxity occurs in which Aminoglycosides most?

What are the risk increased with?
Is Toxicity reversible?

Answer 14

Gentamicin > tobramycin > amikacin

Risk increased with:
- Dehydration
- Fever
- Pre-existing renal disease

Toxicity is often reversible
- Treatment prolonged due to slow elimination of the drug from the kidney
- Administration of calcium protective

Question 15

What are adverse effects (toxicities) not as often talked about?

Answer 15

Ototoxicity
◦Drug accumulation in the perilymph and the organ of Corti
◦Deafness in horses
–>Not clinically relevant? Reversible.
◦Increased risk in cats
◦Increased risk with topical otic products; ruptured ear drum

Vestibular toxicity
◦Head tilt, ataxia, impaired righting reflexes, and cochlear toxicity

Question 16

What are other adverse effects seen less with Aminoglycosides?

Answer 16

Neuromuscular blockade
- Competitive interference with calcium transport at the motor endplate
- Should not be administered concurrently with certain anesthetics, skeletal muscle relaxants
- Should not be used in diseases of the neuromuscular junction
–>Botulism

Considered teratogenic in humans

Question 17

What are drug interactions of Aminoglycosides?

Answer 17

◦Beta-lactams

◦Bacteriostatic drugs (?)

◦Other nephrotoxic drugs

–>NSAIDs

◦Furosemide or other diuretics unless the patient is well-hydrated
–>Increased risk of nephrotoxicity, possibly due to dehydrating effects

Question 18

What are the mechanism of resistance of Aminoglycosides?

Answer 18

◦#1 is enzymatic modification (mostly plasmid mediated)
–>Aminoglycosidases
–>Amikacin least affected

◦Lesser - altered ribosome binding

◦Lesser - reduced uptake (active transport)

Question 19

Do you use Aminoglycosides in food animals?

Answer 19

NO!!!

Voluntary Ban

◦Prolonged residues in kidneys
◦US withdrawal recommendations:
–>10 days milk
–>18 months meat!

◦Canada
◦7 years for meat!!!

Question 20

Tetracyclines mechanism of action?

Answer 20

◦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 21

What are the drugs in the class of Tetracyclines?

Answer 21

◦Oxytetracycline – horses, food animals

◦Chlortetracycline – food animals

◦Minocycline – horses, dogs

◦Doxycycline – horses, dogs, cats

Question 22

What drugs are the most active that are Tetracyclines?

Answer 22

Doxycycline

Minocycline

Question 23

What are the spectrum of activity of Tetracyclines?

Answer 23

BROAD SPECTRUM
Resistance is common

Gram+ and gram- bacteria, aerobes and anaerobes

◦Chlamydia
◦Rickettsia
◦Spirochetes
◦Mycoplasma
◦L-form (cell wall deficient) bacteria
◦Some protozoa

Question 24

What are the Clinical use of Tetracyclines?

Answer 24

TICK BORNE DISEASES & INTRACELLULAR ORGANISMS

Dogs and cats
◦Ehrlichia, Rickettsia, and Mycoplasma haemofelis
◦Borrelia, Bartonella

Birds
◦Chlamydophila psittaci

Horses
◦Neorickettsia risticii, Anaplasma phagocytophilium (rickettsial diseases)
◦Lawsonia intracellularis

Question 25

What are the food animal uses of Tetracyclines?

Answer 25

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 26

How does Oral absorption work with Tetracyclines?

Answer 26

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 27

How does Tetracyclines distribution work in tissues?

Answer 27

WELL in most tissues

Question 28

What are the exceptions of distribution of Tetracyclines?

Answer 28

◦Exceptions: CNS and the eye

◦Exception: minocycline
- More lipophilic
- Doxycycline also lipophilic but has higher PPB

Question 29

What primarily eliminates Tetracyclines?

Answer 29

KIDNEYS

Exceptions:
◦Doxycycline is excreted through the bile and kidneys
◦Minocycline is primarily excreted through the bile

Question 30

What are the adverse effects that are IMPORTANT with Tetracyclines?

Answer 30

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

Question 31

Is IV administration of Doxycycline to horses work well?

Answer 31

NO, its FATAL to HORSES

Question 32

What are other adverse effects of Tetracyclines?

Answer 32

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

Question 33

What are rare adverse effects with Tetracyclines?

Answer 33

Nephrotoxicity
◦HIGH doses oxytetracycline only; formulations with propylene glycol
◦Not reported with chlor/doxy/mino

Hepatotoxicity
◦Idiosyncratic toxic hepatitis in humans, particularly pregnant women
◦Foals – doxy/rifampin

GI toxicity
◦Horses – rare around here; common in Florida

Question 34

How does resistance work in Tetracyclines?

Answer 34

Resistance is widespread among staphylococci, streptococci, and Gram- enteric bacteria

Enterococci are not susceptible

Plasmid-mediated
◦Failure of the active transport system necessary to penetrate the bacterial cell

Question 35

Tetracyclines non- antibacterial uses?

Answer 35

◦Treatment of heartworms
–>Dogs and cats
–>Wolbachia – bacterial endosymbiosis

◦Anti-inflammatory effects
–>Inhibit MMPs
–>Topical in eye for melting ulcers
–>Systemically for synovitis/laminitis in horses