Protein Synthesis Inhibitors

Question 1

List the tetracyclines

Answer 1

tetracycline, doxycycline, minocycline, tigecycline*

*technically a glycylcyline

Question 2

List the aminoglycosides

Answer 2

streptomycin, gentamycin, neomycin, amikacin

Question 3

What pregnancy category do the protein synthesis inhibitors belong to?

Answer 3

Pregnancy Category D

Question 4

Describe the mechanism of action of tetracyclines

Answer 4

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

Question 5

Adverse effects of tetracyclines

Answer 5

Modification of gut flora, superinfection, outdated meds can cause nephrotoxicity
**monocycline can cause vestibular dysfunction from CNS penetration

Question 6

Indications for tetracyclines

Answer 6

Gram+/- bacteria.

Question 7

ADME of tetracyclines

Answer 7

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.

Question 8

Mechanisms of resistance in tetracyclines

Answer 8

Increased efflux/decreased influx, ribosome protection, inactivation via acetylation

Question 9

Contraindications for tetracyclines

Answer 9

Children under 8, pregnant or breastfeeding women

Question 10

Describe the mechanism of action of aminoglycosides

Answer 10

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.

Question 11

Indications for aminoglycosides

Answer 11

Aerobic G- enteric bacteria

• *synergistic effect w/ B-lactams for endocarditis
• *has strong postantibiotic effect (hours) in the absence of detectable drug levels

Question 12

ADME of aminoglycosides

Answer 12

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.

Question 13

Mechanisms of resistance in aminoglycosides

Answer 13

*Enzymatic inactivation! Also, impaired uptake (e.g. anaerobic conditions) and mutation of ribosomal protein (usually affects streptomycin)

Question 14

Adverse effects of aminoglycosides

Answer 14

Common. 10-25% ototoxic (can be irreversible, especially amikacin and neomycin) with vestibular and auditory damage. Also 10-25% nephrotoxic.

Question 15

What drug classes are protein synthesis inhibitors?

Answer 15

Tetracyclines, Aminoglycosides, and Chloramphenicol

Question 16

Describe the mechanism of action of chloramphenicol

Answer 16

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.

Question 17

ADME of chloramphenicol

Answer 17

Absorbed rapidly after oral administration. Metabolized in the liver and inhibits some P450 enzymes so be careful. Penetrates CNS, CSF, breast milk, and placenta.

Question 18

Adverse effects of chloramphenicol

Answer 18

Bone marrow suppression (reversible), aplastic anemia (irreversible), “Gray Baby” syndrome (infants lack UGT needed to excrete the drug)

Question 19

Name the macrolides

Answer 19

Erythromycin, azithromycin, clarithromycin

Question 20

Mechanism of action for erythromycin, azithromycin, clarithromycin, and clindamycin

Answer 20

Bind to the 50S ribosomal subunit inhibiting translocation and thus stopping protein synthesis.

Question 21

Erythromycin is effective against

Answer 21

Gram + organisms, some Gram -. Good alternate for those w/ hx of penicillin/cephalosporin allergy.

Question 22

Mechanism of resistance of erythromycin

Answer 22

Efflux, mutation at the binding site (methylase adds a methyl group to the binding site so drug can’t bind), or inactivation

Question 23

ADME of erythromycin

Answer 23

PO or parenteral, but food interferes. Biliary excretion. Reaches fetus but not CNS. P450 inhibitor.

Question 24

Adverse effects of erythromycin

Answer 24

Liver toxicity (acute cholestatic hepatitis), reversible hearing loss, prolonged QT w/ VTACH
GI intolerance (stimulates gut motility)
*sometimes given post-op for this reason

Question 25

ADME of clarithromycin

Answer 25

Metabolized by liver, renal excretion.

Question 26

Adverse effects of clarithromycin

Answer 26

Reversible hearing loss, Category C, drug-drug interactions (P450 inhibitor)

Question 27

ADME of azithromycin

Answer 27

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.

Question 28

Indications for clindamycin

Answer 28

Very much like erythromycin, and is good for MRSA! | *Doesn't work against Gram - aerobes b/c poor permeability of outer membrane.

Question 29

ADME and adverse effects for clindamycin

Answer 29

``` Hepatic metabolism (reduce dose if hepatic dz) and urine/bile excretion. *Can cause C. diff! ```

Question 30

Mechanisms of action and resistance of metronidazole

Answer 30

Disrupts DNA by forming covalent bonds once activated by nitroreductase. Resistance occurs when nitroreductase levels are reduced. *Treats C. diff

Question 31

ADME and adverse effects of metronidazole

Answer 31

Disulfiram-like rxn when taken w/ alcohol (lots of vomiting). Liver metabolism, P450 inhibitor. Can make urine dark red/brown and tastes metallic.

Question 32

What drugs can be given in the case of vancomycin resistance?

Answer 32

Linezolid (protein synthesis inhibitor) and daptomycin (membrane depolarizer)

Question 33

Mechanism of action of linezolid

Answer 33

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

Question 34

Adverse effects of linezolid

Answer 34

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")

Question 35

Mechanism of action of daptomycin

Answer 35

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+

Question 36

ADME and adverse effects of daptomycin

Answer 36

Excreted via urine (adjusted dose for renal dz patients). Can cause muscle weakness/discomfort, may want to stop statins/other agents associated with rhabdomyolysis.