Protein Synthesis Inhibitors Flashcards
4 aminoglycosides
streptomycin, gentamicin, tobramicin & amikacin
3 tetracycines
doxycycline, tetracycline, minocycline
1 lincosamide
Clindamycin
1 oxazolidenone
Linezolid
Protein synthesis inhibitors are static or cidal
Static except aminoglycosides (cidal)
Protein synthesis inhibitors spectrum vs B-lactam
Broader than B-lactam
Protein synthesis inhibitors general mechanism
ribosomes in eukaryotic cells sufficiently different from bacterial to provide selectivity
Protein synthesis inhibotors tartgiting eleongation
Tetracyclines
Target peptide bond formation
Clindamycin
Target translocation or termination/recycline
Aminoglycosides
Target translocation
Macrolides
Action at 30S and 50S subunit of the Ribosome
Aminoglycosides
Action at 30S subunit of the Ribosome
Tetracyclines
Action at 50S subunit of the Ribosome
(i) Macrolides (ii) Clindamycin (iii) Linezolid
Aminoglycosides - streptomycin
Mechanism SE Use Resistance Kinetics
Mechanism
Binds to two receptor sites: one on 16S RNA, and one on 23S RNA; ribosomal proteins involved also
- Wrong amino acids incorporated, i.e. misreading of mRNA (miscoding/30S site)
- Block initiation (streptomycin)
- Block translocation (30S site, other)
- Inhibits recycling (50S binding site)
SE Deafness Nephrotoxicity Bone marrow suppression Muscle weakness
Use TB Anerobic GNR: Gentamicin & tobramycin GP: SYnergistic with beta lactams Anaerobes are resistant
Resistance
- Inactivating enzymes
- Membrane impermeability
- Binding site mutation
- Methylation of rRNA
Kinetics
- Parenteral administration
- renal excretion (alter)
- post antibiotic effect
- Extended interval dosing release (except in renal dysfunction)
Why are aminoglycosides cidal)
Transport into bacterial cells:
Passive diffusion through the porin channels of the outer membrane
Energy-dependent, rate-limiting transport through the plasma membrane (inhibited under anaerobic conditions)
Mech-m of cytotoxicity:
Drug-induced mutated proteins inserted into the plasma membranes enhance uptake of the drug
3 drugs with concentration dependent killing
aminoglicosides
fluoroquinolones
metronidazole
Tetracyclines
Mechanism
Resistance
Mechanism
Binds to 30S subunit & blocks amino-acyl-tRNA binding resulting in the elongation block
Resistance
- Rarely used in USA becuase of resistance
- Efflux pumps
- Reduced ribosomal 30 binding site
- Enzyme inactivation
Spectrum for tetracylines
Bacteriostatic
Mycoplasma; Chlamydia; Legionella; Rickettsia (Rocky Mtn Fever); Borellia (Lyme disease); Strep pneumonia
Outpatient > hospital
Anti-parasites: malaria prevention
Only tetracyline that is hepaticaly cleared instead of renal
Doxycycline
Well absorbed from the gut - reduced absorption with food and chelators e.g. Al(OH)3
Good tissue penetration fairly large Vd
Tetracyline SE
Gastrointestinal intolerance (N/V/D)
Hepatotoxic
Skin photosensitivity
Never use in pregnancy, neonates, children- deposits in enamel of teeth and bone
Doxycycline is the onlytetracycline that can beused in renal failure
Drug to avoid giving pregnant women, neonates or childen
Tetracycines
Macrolids
Mechanism
Resistance mechanism
Mechanism
Binds to 50s to block polypeptide release
Resistance
Selectivity and Resistance - role of 23S rRNA- nucleotide 2058
Efflux or reduced permability
Production of esterase
S. pneumoniae or S. aureus
Azithromycin (macrolides)
Use & spectrum
Bacteriostatic
Bactericidal under certain conditions (organism, site, …)
GPC, Mycoplasma, Legionella, Chlamydia, H. influenzae, Mycobacteria
Can be used in penicillin-allergic individual
Respiratory tract infections
Macrolides phamcokinets
Well absorbed from GI tract
Widely distributed, concentrated in cells
Hepatic metabolism mainly
Macrolides with shortest & longest half lives
T1/2: clarithromycin - 3-7 h azithromycin - 68 h (once daily dosing)
Macrolides SE/Toxicity
Allergy-skin rashes
hepatitis 2-5%
Gastrointestinal upsets (N/V/D)
Ototoxic-especially in elderly
Clindamycin
Class
Mechanism
Resitance
Clindamycin pharmacokinetics
Specturm
Class
A lincosamide
Mechanism
Binds to the 50S subunit on a 23S rRNA binding site and interferes with the peptide bond formation
Binding site partially overlaps with macrolides
Resistance
Mutual interference if co-prescribed with the macrolides
Resistance mechanisms same as with macrolides
Pharmacockinets
Well absorbed from the gastrointestinal tract
Good tissue penetration (large Vd) concentrated intracellularly
T1/2 2-2.5h
Hepatic metabolism
Spectrum
Bacteriostatic
Narrow spectrum
GPC (Staph. and Strep.); oral and bowel anaerobes (50% Bacillus fragilis)
Often used for deep seated infections (e.g intrabdominal infections) in combination with other agents
Used for skin and soft tissue infection + dental
SE of clindamycin
Bacteriostatic
Narrow spectrum
GPC (Staph. and Strep.); oral and bowel anaerobes (50% Bacillus fragilis)
Often used for deep seated infections (e.g intrabdominal infections) in combination with other agents
Used for skin and soft tissue infection + dental
Linezolid
Class Mechanism Resistance Spectrum Kinetics SE
Class
Oxazolidinones
Mechanism
Binds to 23S rRNA of 50S at the A site
Blocks formation of the initiation complex
Resistance
Mutation of 23S rRNA binding site
No cross-resistance with other drug classes
Pharmacodynamics and spectrum Wide range of GP organisms susceptible Bacteriostatic against staph and enterococci Bacteriocidal for most strep Used to treat VRE, VRSA and MRSA ? Potential new agent for Myco. TB
Pharmacokinetics
I/V & oral - 100% oral bioavailability
Renal (30%) and hepatic clearance (65%)
Side Effects/Toxicity Hematologic : leukopenia/thrombocytopenia & aplastic anemia Gastrointestinal intolerance: N/V/D Biochemical hepatitis Drug interactions: weak MAO-I
