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Protein Synthesis Inhibitors
Lecture 9
36
Pharmacology
Professional
02/01/2013

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Term
Do Aminoglycosides cross into CSF?
Definition
NO - not used to treat meningitis
Term
What are features of aminoglycosides?
Definition
- Renally excreted - do not use in kidney disease
- Tx for AEROBIC gram(-). Only works through porins, which are not in gram(+)
- Cidal agents
Term
What are the main side effects of aminoglycosides?
Definition
- Nephrotoxicity - most prevalent, retention in proximal tubules. Neomycin is the worst
- Ototoxicity - accumulates in otic fluid, increase permeability of hair cells, causing leakage and permanent death. Mg loss.
**Do not give in M. gravis - receptors less sensitive to Ach
Term
What is the MoA of aminoglycosides?
Definition
Hydrophobic, go through porin channels. A pump in the periplasm that uses O2 to bring in sugars brings in the the drug
**Drug binds to ribosomes at 30s, stops translation. (specifically blocking the A site of 16S)
**Block: Ca/Mg, low pH, anaerobic environment
Term
What are pleitropic effects of aminoglycosides?
Definition
Increased membrane permeability and competition for sugars/energy disturbance
Term
How does protein translation occur?
Definition
ribosomes pull mRNA apart, reading the codons. Each tRNA codes for a specific AA.
rRNA: A site, P site, E site. Bonding occurs between A and P sites.
Term
How do bacteria become resistant to aminoglycosides?
Definition
- Mutation at the 16S subunit of 30S prevents binding - doesn't happen often
- Doesn't permeate outer membrane through porins or through O2 depended pump
- Enzyme inactivation*** - via N-acetyltransferases, O-adenyltransferases, and O-phosphotransferases. Happens often.
Term
What is the spectrum of aminoglycosides?
Definition
- Aerobic gram(-): E. coli, P. aerug, Klebsiella, H. influenzae, enterobacteria, gonorrhea
- Select gram(+): synergism w/ Vanc and penicillins to treat E. faecalis or E. faecium, and Streptococci
Term
How is streptomycin used?
Definition
- Streptomycin - 1 binding domain. The first TB tx.
- Endocarditis caused by enterococci: Penicillin + Streptomycin
- Y. pestis, the black plague
**An aminoglycoside, watch kidneys
Term
How are gentamycin and tobramycin used?
Definition
- Gentamycin/Garamycin - gram(-), enterococci, Listeria (gram +). Not used alone for gram +, but a good synergist
- Tobramycin/Nebcin - Superior for P. aeruginosa. 1ST LINE: Ticarcillin + Tobramycin (T&T)
Term
What AG is incompatible IV with beta lactams?
Definition
Gentamicin, must use different bags or different arms
Term
What is amikacin?
Definition
An aminoglycoside with bulky groups to inhibit enzymatic deactivation
Broadest spectrum, used in nosocomial gram(-) infections and also TB and MAC mycobacterium infections.
**May work where gent and tobramycin have failed
Term
What is Neomycin?
Definition
A broad spectrum AGs, but P. aerug is resistant. Can be used for Enterococci. DO NOT USE IV. Used orally to wipe out gut bacteria for surgery
Term
What are properties of tetracyclines?
Definition
- Accumulate in bones and teeth
- Chelates cations - avoid w/ metals
- Given orally
- Throw away at expiration - Fanconi syndrome
Term
What is the MoA of tetracyclines?
Definition
A static agent that binds to the 30S subunit.
Water soluble, goes through porins. O2 pump to access cell. Mino and doxy are more lipophilic, get stuck in membranes
**At HIGH doses, inhibits mammalian 40S subunit. BAD. Also a teratogen.
Term
What are mechanisms of tetracycline resistance?
Definition
- Low influx, higher efflux
- Decreased access to ribosome
- Enzymatic inactivation
**Widespread resistance
Term
What are tetracyclines used for?
Definition
Specific indications only:
- Acne
- Lyme disease: B. burgdorferi
- RMSF: Rickettsia
- Chlamydia or gonorrhea
- Cholera
- Clostridium species: tetanus, C. diff, gangrene
- Add on for black plague, anthrax
**Not used for enterobacteria, gram(+)
Term
What are AEs of tetracyclines?
Definition
- Category D in pregnancy
- Deposition to bone
- Hepatotoxicity
- Superinfections: C. albicans and C. diff
Term
What drugs are tetracyclines?
Definition
- Tetracycline/Sumycin - 2nd choice for gonorrhea in a pen allergy. Most effective for H. pylori
- Minocycline/Minocin
- Doxycycline/Vibramycin
- Tigecycline/Tygacil - Affects CRE! Also Bacteroides, Staph, Strep. Overcomes resistance to other TETs
Term
What is Rocky Mountain Spotted Fever?
Definition
Rickettsia rickettsii - tick bite transmission causes fever, HA, rash that can be fatal. Do not delay Tx
**Only alternate is chloramphenicol
Term
What is Cholera?
Definition
A diarrheal disease caused by Vibrio cholerae - can lead to shock and death. Drinking water and eating shellfish
**B component of toxin binds to cells while A component enters cells. Binds to Gs, locking it into active. cAMP always on = efflux of water.
Term
What is the MoA of macrolides?
Definition
A lipophilic static agent that binds to the 23S P site of 50S, blocking extension of the tRNA.
Term
How do bacteria become resistant to macrolides?
Definition
- Efflux by active pump, a common mechanism
- Methylation of the ribosome, preventing binding of the macrolide
- mutation of 23S subunit
**gram(-) intrinsically resistant due to lipophilicity.
Term
What are AEs of macrolides?
Definition
MANY drug interactions - 3A4 substrates. longer half life and toxicity for both drugs: Statins, CCBs, oral contraceptives
Term
What is the spectrum of the macrolides?
Definition
- Primarily gram (+) organisms: NOT MRSA, Strep and Staph, S. perfringens, Listeria, B. anthracis
- 4 gram(-): H. influenzae, gonorrea, H. pylori***, Legionella, chlamydia
**drug of choice in H. pylori and legionella
Term
What are the different types of erythromycin?
Definition
Erythromycin/E-mycin
Erythromycin Estolate/Ilosone
Erythromycin Ethylsuccinate/Eryped/EES
Deactivates in acidic environments, food reduces absorption. Prodrugs mask bitter taste
Term
How is Clarithromycin/Biaxin used?
Definition
Structure increases lipophilicity and decreases ketal formation - Increased potency for H. influenzae.
**The drug of choice for H. pylori and M. pneumoniae
Term
How does H. pylori cause ulcers?
Definition
- Secretion of urease creates a base cloud around the bacteria
- Evades host defenses
- VacA - vacuolation of luminal cells
**Decrease in somatostatin --> increase in gastrin
Term
What are the standard therapies for H. pylori?
Definition
- Triple: PPI + Clarithromycin + Amoxicillin
- Quad: PPI + bismuth + Metronidazole + Tetracycyline
Term
How does a Z-pack work?
Definition
Has a long half life and very lipophilic
SYNERGISM w/ cephalosporins vs: Gonorrhea and M. pnemoniae.
**Less 3A4 side effects
Term
What macrolide is a 'ketolide'?
Definition
Telithromycin/Ketek
ONLY used for multi-drug resistant S. Pneumoniae
**Many black box warnings
Term
Which macrolid is approved to treat C. diff?
Definition
Fidaxomicin/Dificid
Actually inhibits bacterial RNA polymerase
**Less recurrence than with vancomycin
Term
What are features of clindamycin?
Definition
- Binds to 50S subunit
- Used for Strep including agalactiae, MSSA, Bacteroides, ACNE, clostridium
- POTENT cause of C. diff
Term
What does Linezolid/Zyvox cover?
Definition
Only gram(+) but resistant strains: MRSA, VISA, VRSA, VRE, Listeria, M. tuberculosis
**Inhibits binding of tRNA to 70S, displacement of ternary complex
Term
What is Chloramphenicol used for?
Definition

- Very wide spectrum - Inhibits binding to A site, can also work on mammalian cells. TOXIC - aplastic anemia

- Alternate treatment for RMSF - Ricketsia

Term
What is Synercid used to treat?
Definition
Quinupristin/Dalfopristin or Synercid - only used to treat MDR/Vanc resistant E. faecium, NOT E. faecalis
**IV only, resistance by hydrolysis and efflux. Quin blocks P site, Dalf binds A site --> inhibits translation
**3A4 effects
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