Protein Synthesis Inhibitors Flashcards
List the tetracyclines
tetracycline, doxycycline, minocycline, tigecycline*
*technically a glycylcyline
List the aminoglycosides
streptomycin, gentamycin, neomycin, amikacin
What pregnancy category do the protein synthesis inhibitors belong to?
Pregnancy Category D
Describe the mechanism of action of tetracyclines
They reversibly bind to the 30S subunit of ribosomes, blocking tRNA from binding at the A site and preventing addition of amino acids. They are bacteriostatic.
**only accumulate in bacteria, not eukaryotes
Adverse effects of tetracyclines
Modification of gut flora, superinfection, outdated meds can cause nephrotoxicity
**monocycline can cause vestibular dysfunction from CNS penetration
Indications for tetracyclines
Gram+/- bacteria.
ADME of tetracyclines
Widely distributed, particularly in bones and teeth. Absorption impaired by food and divalent metals (Mg2+, Fe2+, etc). Oral admin w/ small intestine absorption EXCEPT tigecycline (given IV). Doxy/mino have longer half-lives. Doxy/mino/tige excreted via bile so they’re safer for renal impaired patients.
Mechanisms of resistance in tetracyclines
Increased efflux/decreased influx, ribosome protection, inactivation via acetylation
Contraindications for tetracyclines
Children under 8, pregnant or breastfeeding women
Describe the mechanism of action of aminoglycosides
Bactericidal. Irreversibly binds to 30S subunit, blocking initiation of protein synthesis & elicits termination. Also incorporates incorrect amino acids. Increases permeability & leakage of cell membrane. Concentration-dependent killing.
Indications for aminoglycosides
Aerobic G- enteric bacteria
- *synergistic effect w/ B-lactams for endocarditis
- *has strong postantibiotic effect (hours) in the absence of detectable drug levels
ADME of aminoglycosides
Poorly absorbed orally, so given IV. Requires oxygen to cross cell-membranes, so does not work in anaerobic conditions. Uptake increased by cell wall inhibitors (e.g. B-lactams). Excreted via urine.
Mechanisms of resistance in aminoglycosides
*Enzymatic inactivation! Also, impaired uptake (e.g. anaerobic conditions) and mutation of ribosomal protein (usually affects streptomycin)
Adverse effects of aminoglycosides
Common. 10-25% ototoxic (can be irreversible, especially amikacin and neomycin) with vestibular and auditory damage. Also 10-25% nephrotoxic.
What drug classes are protein synthesis inhibitors?
Tetracyclines, Aminoglycosides, and Chloramphenicol
Describe the mechanism of action of chloramphenicol
Bacteriostatic. It binds to the 50S subunit of the ribosome and inhibits peptidyltransferase activity (anticodon can’t move between A and P sites).
**It can interfere with eukaryotic mitochdrial ribosomes causing cell death from inhibition of aerobic metabolism.
ADME of chloramphenicol
Absorbed rapidly after oral administration. Metabolized in the liver and inhibits some P450 enzymes so be careful. Penetrates CNS, CSF, breast milk, and placenta.
Adverse effects of chloramphenicol
Bone marrow suppression (reversible), aplastic anemia (irreversible), “Gray Baby” syndrome (infants lack UGT needed to excrete the drug)
Name the macrolides
Erythromycin, azithromycin, clarithromycin
Mechanism of action for erythromycin, azithromycin, clarithromycin, and clindamycin
Bind to the 50S ribosomal subunit inhibiting translocation and thus stopping protein synthesis.
Erythromycin is effective against
Gram + organisms, some Gram -. Good alternate for those w/ hx of penicillin/cephalosporin allergy.
Mechanism of resistance of erythromycin
Efflux, mutation at the binding site (methylase adds a methyl group to the binding site so drug can’t bind), or inactivation
ADME of erythromycin
PO or parenteral, but food interferes. Biliary excretion. Reaches fetus but not CNS. P450 inhibitor.
Adverse effects of erythromycin
Liver toxicity (acute cholestatic hepatitis), reversible hearing loss, prolonged QT w/ VTACH GI intolerance (stimulates gut motility) *sometimes given post-op for this reason
ADME of clarithromycin
Metabolized by liver, renal excretion.
Adverse effects of clarithromycin
Reversible hearing loss, Category C, drug-drug interactions (P450 inhibitor)
ADME of azithromycin
Taken up well by the tissues, which slowly leak drug back into system for long half-life. Doesn’t penetrate CNS.
***NOT a P450 inhibitor like other macrolides.
Indications for clindamycin
Very much like erythromycin, and is good for MRSA!
*Doesn’t work against Gram - aerobes b/c poor permeability of outer membrane.
ADME and adverse effects for clindamycin
Hepatic metabolism (reduce dose if hepatic dz) and urine/bile excretion. *Can cause C. diff!
Mechanisms of action and resistance of metronidazole
Disrupts DNA by forming covalent bonds once activated by nitroreductase. Resistance occurs when nitroreductase levels are reduced.
*Treats C. diff
ADME and adverse effects of metronidazole
Disulfiram-like rxn when taken w/ alcohol (lots of vomiting). Liver metabolism, P450 inhibitor. Can make urine dark red/brown and tastes metallic.
What drugs can be given in the case of vancomycin resistance?
Linezolid (protein synthesis inhibitor) and daptomycin (membrane depolarizer)
Mechanism of action of linezolid
Used for vanc-resistant infections, Gram +. Prevents formation of the initiation complex (binds 23S RNA on 50S and prevents it from attaching to 70S) so bacteria can’t synthesize protein
Adverse effects of linezolid
Myelosuppression (thrombocytopenia, leukopenia, anemia) and reversible peripheral/optic neuropathy. Mild inhibitor of monoamine oxidase (htn if taken w/ foods rich in tyramine aka “wine and cheese effect”)
Mechanism of action of daptomycin
Should be reserved for vanc-resistant Gram + infections, specifically S. aureus and VRE. Uses Ca++ to form ion-conducting pore to influx Na+ and efflux K+
ADME and adverse effects of daptomycin
Excreted via urine (adjusted dose for renal dz patients). Can cause muscle weakness/discomfort, may want to stop statins/other agents associated with rhabdomyolysis.
