Pharmacology 7: Protein Synthesis Inhibitors Flashcards
What are the drugs acting at the 30s ribosomal subunit?
Amino glycosides
Tetracyclines
Attractive & Tantalizing
What are the drugs acting at the ribosomal subunits?
Phenicols
Macrolides
Lincosamides
Panchy, Moody, & Lazy
What does GNATS stand for in Aminoglycosides?
GENTAMICIN
NEOMYSIN
Amikacin
Tobramycin
Streptomycin
What is the mechanism of action for Aminoglycosides?
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
What is the spectrum of activity for Post-antibiotic Effect of Aminoglycosides?
Gram- aerobic organisms
against Staphylococcal organisms (MRSA/MRSP)
NOT GOOD FOR:
streptococci
strict anaerobes
What is the clinical use for Aminoglycosides?
** 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
How do you choose which Aminoglycosides to use?
Amikacin
- more active
- less toxic
- resistance less likely
- EXPENSIVE
So if you can chose GENTAMICIN do it because it is more affordable
What are the pharmacokinetics of Aminoglycosides?
Oral absorption is poor
◦Neomycin
IM absorption almost 100%
IV most common route
Aminoglycosides
solubility?
protein binding?
volume distribution?
polar?
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
What are the pharmacokinetic/ pharmacodynamic interactions of Aminoglycosides?
◦Concentration-dependent
◦Cmax:MIC 8-10x
◦Example
◦MIC = 2 μg/mL
◦Cmax >16-20 μg/mL
What organ is the most common to be affected by Aminoglycosides?
KIDNEYS
What are the adverse effects of Aminoglycosides?
- Dose dependent nephrotoxicity
- Nephrotoxicity
- Renal toxicity
- Bad for kidneys
Most clinically relevant
Risks greatly decreased with q24h dosing
What are the benefits of once daily dosing of Aminoglycosides?
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
Nephrotoxity occurs in which Aminoglycosides most?
What are the risk increased with?
Is Toxicity reversible?
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
What are adverse effects (toxicities) not as often talked about?
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
What are other adverse effects seen less with Aminoglycosides?
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
What are drug interactions of Aminoglycosides?
◦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
What are the mechanism of resistance of Aminoglycosides?
◦#1 is enzymatic modification (mostly plasmid mediated)
–>Aminoglycosidases
–>Amikacin least affected
◦Lesser - altered ribosome binding
◦Lesser - reduced uptake (active transport)
Do you use Aminoglycosides in food animals?
NO!!!
Voluntary Ban
◦Prolonged residues in kidneys
◦US withdrawal recommendations:
–>10 days milk
–>18 months meat!
◦Canada
◦7 years for meat!!!
Tetracyclines mechanism of action?
◦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
What are the drugs in the class of Tetracyclines?
◦Oxytetracycline – horses, food animals
◦Chlortetracycline – food animals
◦Minocycline – horses, dogs
◦Doxycycline – horses, dogs, cats
What drugs are the most active that are Tetracyclines?
Doxycycline
Minocycline
What are the spectrum of activity of Tetracyclines?
BROAD SPECTRUM
Resistance is common
Gram+ and gram- bacteria, aerobes and anaerobes
◦Chlamydia
◦Rickettsia
◦Spirochetes
◦Mycoplasma
◦L-form (cell wall deficient) bacteria
◦Some protozoa
What are the Clinical use of Tetracyclines?
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
What are the food animal uses of Tetracyclines?
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.
How does Oral absorption work with Tetracyclines?
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
How does Tetracyclines distribution work in tissues?
WELL in most tissues
What are the exceptions of distribution of Tetracyclines?
◦Exceptions: CNS and the eye
◦Exception: minocycline
- More lipophilic
- Doxycycline also lipophilic but has higher PPB
What primarily eliminates Tetracyclines?
KIDNEYS
Exceptions:
◦Doxycycline is excreted through the bile and kidneys
◦Minocycline is primarily excreted through the bile
What are the adverse effects that are IMPORTANT with Tetracyclines?
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
Is IV administration of Doxycycline to horses work well?
NO, its FATAL to HORSES
What are other adverse effects of Tetracyclines?
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
What are rare adverse effects with Tetracyclines?
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
How does resistance work in Tetracyclines?
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
Tetracyclines non- antibacterial uses?
◦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
