Antibacterials: Protein Synthesis Inhibitors Flashcards
What are the 6 major classes of protien synthesis inhibitors? What parts of the ribosome do they attack?
Aminoglycosides - 30S
Tetracyclines - 30S
Clindamycin - 50S
Chloremphenicol - 50S
Erythromycin (macrolides) - 50S
Linzolid - 50S
Which protein synthesis inhibitor classes are bacteriostatic? Which are bacteriocidal?
All bacteriostatic Except:
Linzolid - Variable
Aminoglycosides - Bacteriocidal
Where in protein synthesis do each of the protein synthesis inhibitors act?
Aminogycosides - Block initiation complex formation
Tetracyclines (Tet1 A site tRNA-anticodon/codon) & Chloremphenicol (Peptidyl Transferase) - Prevent transpeptidation/peptide bond formation.
Macrolides, Clindamycin - Block translocation
What are the general uses for each class of protein synthesis inhibitor? Aminoglycosides, Tetracyclines, Clindamycin, Chloremphenicol, Macrolides, Azithromycin
Aminoglycosides - Severe G- rod infections
Tetracyclines - Broad spectrum, Intracellular infections, ACNE
Clindamycin - Anaerobes above the diaphragm
Chloremphenicol - No other alternative. Developing countries (CHEAP), meningitis, bacterial conjunctivitis.
Macrolides - G+, Atypical pneumonia, Chlamydia
Azithromycin - Greater G- activity than other macrolides
Erythromycin comes in two modified forms. What are these forms, and how do they improve drug utility?
Estolate - better oral bioavailability. NOT in liver pts.
Ethyl succinate - better oral bioavailability. Flavored for peds.
What are two protein synthesis inhibitors that are metabolized by the liver’s P450 system? How does this affect dosing?
Clindamycin & Macrolides
Adjust dosing in liver pathology patients.
What are the toxicities associated with Macrolides in adults?
GI upset - Acid inactivation to ketal.
Steven-Johnson Syndrome (hypersensitivity, epidermal necrosis)
What two protein synthesis inhibotor groups are contraindicated in pregnancy or breast feeding and why?
Macrolides - pyloric stenosis
Tetracyclines - Ca2+ chelation disrupts bone and teeth growth (brown discoloration - permanent and progressive)
Why would you use clarithromycin or azithromycin rather than erythromycin?
Reduced GI upset & Better bioavailability:
Clarithromycin - C6 methoxy gp blocks ketal formation
Azithromycin - N-methylation blocks ketal formation; once a day dosing; greater G- activity.
How does resistance to macrolides develop?
- Hydrolase degradation
- Methylation or A–> G mutation of 50S (2058 site)
- Efflux pump
* *use and S. pneumoniae resistance are correlated
Which protein synthesis inhibitors are synthesized by Streptomyces?
Tetracyclines
Clindamycin
Chloremphenicol
Macrolides
Clindamycin is realted to what two other protein-synthesis inhibitors by binding site? Why is this important?
Clindamycin, Erythromycin, and chloremphenicol all bind same site on the 50S ribosomal subunit.
Important because of cross-resistance (2058 mutation) competitive binding for that site if co-administered.
What is special about the tissue distribution of Clindamycin?
Penetrates the CNS
What toxicity is associated with Clindamycin? How is this managed?
Pseudomembranous colitis from C. diff., megacolon. Treat with Metranidazole or Vancomycin.
What are two important tips for taking Tetracyclines?
- CHELATION: Don’t take with divalentcation-contatining products (Milk, Antacids, Iron) or take those 2 hrs bfore taking the medicine.
- PAIN ON INJECTION: (thrombophlebitis); insoluble calcium complex formation.
What is one use of EDTA?
Taken w/ Tetracycline to reduce PAIN ON INJECTION. Competes with Tetracycline for Ca2+ chelation. - prevents insoluble complex formation.
What are the two toxicities associated with Tetracyclines? What causes these?
Dehydration and epimerization of drug in acid or old meds
Fanconi syndrome - failure to reabsorb in the PCT
GI upset
How can the toxicities associated with Tetracyclines be avoided?
Use lower doses if possible. DON’T administer old meds. Med monitoring for epimerization.
Other than tetracycline, what are 4 other tetracyclines, and why would you use them as opposed to tetracycline?
- Democycline - for SIADH; Demethylated C6 = secondary carbocation = slower dehydration and epimerization
- Minocycline - NO hydration or epimerization - Lacks C6 OH
- Doxycycline - NO hydration or epimerization - Lacks C6 OH, Fecally excreted, and once-a-day dosing.
- Oxytetracycline
Chloremphenicol is often only used in developing countries because it is a cheap drug. However, it has serious side effects. What toxicities are associated with chloremphenicol?
Aplastic anemia - Rare and Fatal
Bone marrow suppression - reversible
Gray Baby Syndrome
What is Gray Baby Syndrome? What causes it and why?
Babies are gray ashen color, limp, and hypotensive. Cuased by Chloremphenicol. Neonates have underdeveloped UDP-glucuronyl transferases in their livers and can’t metabolize chloremphenicol.
How is resistance to chloramphenicol developed?
Acetyltransferase enhancement - acetylation inactivates the drug.
Name 7 Aminoglycosides. What is the general use for aminoglycosides? Any special uses for the 7 named?
AMINOGLYCOSIDES: Severe G- rod infections Gentamicin - UTI, burns, osteomyelitis/septic arthritis Tobramicin Neomycin - Bowel surgery prophylaxis Amikacin - Nosocomial Kanamycin Spectinomycin - N. gonorrhea Streptomycin
What is the mechanism(s) of action of aminoglycosides?
- Inhibit formation of initiation complex
- Block translocation from A–>P site
- Cause misreading of mRNA (impairs proofreading function –> wring AA in proteins –> cell membrane damage –> enhances permeability to more drug)
What are aminoglycosides often paired with? What are the conditions of useing these agents together and why?
Paired with beta-lactam/penicillin - Synergism. Enhances cell uptake of aminoglycoside b/c of damaged cell wall. Don’t use in same solution or at same injection site - the combo of drugs will inactivate each other.
What toxicities are associated with Aminoglycosides, and what do you do to treat the toxicities?
Ototoxicity/Vestibulartoxicity - Permanent, Discontinue or lower dose Nephrotoxicity - Discontinue or lower dose Neuromuscular blocade (curare-like effect) - Neostigmine, Calcium gluconate
How has resistance developed to Aminoglycosides?
Bacterial transferase enzymes that inactivate by acetylation, phosphorylation, and adenylation.
What are the three streptogramins and which are bacteriostatic vs. bacteriocidal?
Quinupristin - Bacteriostatic
Dalfopristin - Bacteriostatic
Synercid - 30% Quinu, 70% Dalfo - BACTERIOCIDAL
What are two antibiotics that are effective against VanR E. faecium and MRSA?
Synercid (Streptogramin), Linezolid (Oxazolindinones)
What is one contraindication for giving a streptogramin?
Taking other meds metabolized by CYP3A4 - streptoramins inhibit CYP3A4.
What are the mechanisms of Quinupristin and Dalfopristin?
Quinupristin - Blocks peptide exit tunnel in ribosome
Dalfopristin - Blocks peptidyl transferase/peptide bond formation. (Same as chloremphenicol)
Resistance to quinupristin has developed how?
quinupristin binds in same site as erythromycin and clincamycin = same 2058 ribosomal 50S mutation confers resistance.
What are toxicities associated with linezolid?
Thrombocytopenia, myelosuppresion, anemia -> Candida infections. Lactic acidosis.
What should not be consumed or taken with linezolid and why?
Linezolid = MAO inhibitor
Serotonin syndrome if taken with:
Serotonergic or adrenergic agents, Tyramine
How has resistance to linezolid developed?
2576 mutation of site in 50S subunit where linezolid binds.
