Protein Synthesis Inhibitors I Flashcards
The bacterial ribosome is ___S.
70
Bacterial ribosome subunits.
50 and 30s
Drugs that are inhibitors of protein synthesis.
Tetracyclines
Chloramphenicol
Macrolides
These protein synthesis inhibitors inhibit the 30s subunit of the bacterial ribosome.
Tetracyclines
These protein synthesis inhibitors inhibit the 50s bacterial ribosomal subunit.
Chloramphenicol
Macrolides
These protein synthesis inhibitors prevent aminoacyl tRNA from bringing over an amino acid.
Tetracyclines
Tetracyclines bacteriocidal or static?
Static
Tetracycline MOA
Prevents aminoacyl-tRNA from binding to its acceptor site on the ribosome.
How do tetracyclines penetrate the microorganism?
Active and Passive diffusion
Mechanism of resistance for tetracycline.
1) Decreased drug penetration into the microorganism.
2) Increased drug efflux from the microorganism.
3) Decreased affinity for the 30s ribosome.
4) Cross-resistance among all Tetracyclines.
Cross-resistance
Resistance to a substance bc of exposure to a similarly-acting substance.
T/F: if patient is resistant to one tetracycline, they may not be resistant to all the tetracyclines.
False.
Which organ eliminates most Tetracyclines from the body?
Kidney
Which organ eliminates tetracyclines with a low renal clearance?
Gall bladder
These tetracyclines are eliminated through the gall bladder.
Doxy and Minocycline
What is Arestin AKA?
Minocycline
Clinical uses of Tetracyclines
1) GI and GU infections (but most bacteria causing these infections are resistant, so we try to use different drugs).
2) Local administration in periodontitis (Minocycline/Arrestin).
Adverse effects of Tetracycline use.
1) Tooth discoloration
2) Headaches and nausea
3) Photosensitivity
4) Liver damage
5) Superinfection
What is superinfection?
When you get another infection while treating an infection you currently have.
The new organism will be resistant to the antibiotic you used to treat the primary infection.
Organisms that cause superinfections.
1) Staph aureus
2) Candida albicans
3) C. difficile
Risk factors for superinfections.
1) In-hospital stays for more than 6 days.
2) Use of a broad spectrum antibiotic.
These tetracyclines do NOT accumulate in the body with kidney dysfunction bc they’re eliminated by the liver.
Doxy and Minocycline
Tetracycline drug interactions:
1) Bony structures and teeth.
2) Can cause Nitrogen retention when used with diuretics.
This protein synthesis inhibitor does NOT bind to mammalian ribosomes.
Chloramphenicol
This protein synthesis inhibitor is:
Broad-spectrum
Inexpensive
Orally administered
Chloramphenicol
Reversibly binds to the 50s subunit of bacteria to inhibit protein synthesis, and does not affect mammalian ribosomes.
Chloramphenicol
Chloramphenicol specificity
More specific at inhibiting gram-negative organisms.
Microbes inhibited by Chloramphenicol
H. influenzae
Neisseria meningitidis
This is made by plasmids to inactivate chloramphenicol .
Chloramphenicol acetyltranferase
Chloramphenicol resistance
1) Presence of mutants that are less permeable to chloramphenicol.
2) Plasmids make Chloramphenicol acetyltransferase to acetylate chloramphenicol, this inactivating it.
How is chloramphenicol inactivated?
Acetylation and by conjugation with glucuronic acid (glucuronidation).
Very important adverse effect of Chloramphenicol.
Inhibits CYP450, so Warfarin and Phenytoin levels increase in the body.
These drugs cause Chloramphenicol metabolism.
So more chloramphenicol is needed to have a therapeutic effect when the person is taking these drugs.
Rifampin and Phenobarbital
Chloramphenicol distribution in the body.
Concentration in CNS = that in serum
How is Chloramphenicol inactivated?
Glucuronidation and acetylation.
How does the dose affect Chloramphenicol in cases of renal insufficiency?
It doesn’t!
Because the liver breaks down Chloramphenicol.
This organ breaks down Chloramphenicol.
Liver
How is the dose of Chloramphenicol affected in cases of hepatic failure?
Need to lower the dose bc the liver can’t properly break it down.
How is dose of Chloramphenicol affected by newborns?
Has to be reduced bc babies don’t have the means to glucuronidate, and thus, breakdown Chloramphenicol.
Too high a dose of Chloramphenicol in babies causes this.
Gray Baby Syndrome:
Vomiting, flaccidity Hypothermia Gray color Shock Vascular collapse
Large protein synthesis inhibitors derived from Streptomyces.
Macrolides
Prototype for the macrolides.
Erythromycin
Clinical use of Erythromycin Macrolide
1) Penicillin substitute for those allergic to Penicillin with strep or pneumococci infections.
2) Starred: As prophy against bacterial endocarditis during dental procedures in people with valvular heart disease.
This antibiotic is beginning to replace Erythromycin.
Clindamycin
Macrolides MOA
Inhibit formation of the 50s subunit, and prevent protein elongation in the 50s subunit.
Optimal pH for Erythromycin to work.
Basic (so it needs a protective coating for when we take it orally and it goes into the acidic stomach).
These protein synthesis inhibitors do not affect mammalian ribosomes.
Chloramphenicol
Macrolides
4 Types of resistance to Erythromycin
1) Reduced permeability of the cell membrane (so the antibiotic can’t get into the bacterial cell).
2) Increased efflux out of the cell.
3) Production of esterases that break down macrolides.
4) Methylation of rRNA
Cross resistance is seen in which protein synthesis inhibitor antibiotics?
Tetracyclines and Macrolides
Why do patients with renal failure not need to reduce their dose of Erythromycin?
BC it’s excreted in the liver.
What does dosing of macrolides depend on?
Lipid solubility.
Dosing:
Erythromycin
Clarithromycin
Azithromycin
Erythromycin 4x/day
Clarithromycin 2x/day
Azithromycin 1x/day
Erythromycin adverse reactions.
Anorexia, N,V,D
GI intolerance
Erythromycin inhibits CYP 450 (like Chloramphenicol!).
Leads to increased serum concentration of drugs that undergo metabolism thru CYP450 enzymes:
Warfarin
Cyclosporine
Possible QT prolongation
This macrolide dosage is 4 times a day, so patient compliance is low.
Erythromycin
This macrolide has to be taken once a day, so it has high patient compliance.
Azithromycin
A = first letter of the alphabet = 1 time a day
These protein synthesis inhibitors inhibit CYP450 enzymes, so Warfarin and Phenytoin levels increase.
Chloramphenicol and Erythromycin
