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Flashcards in Protein synthesis inhibitors Deck (66):
1

Antibacterial Agents that Inhibit Protein Synthesis by interaction with bacterial ribosomes

Aminoglycosides
Tetracyclines
Chloramphenicol

2

Antibacterial Agent that Inhibit Protein Synthesis by blocking initiation

Oxazolidinones (linezolid)

3

Antibacterial Agents that Inhibit Protein Synthesis by inhibiting tRNA synthesis

Mupirocin

4

Antibacterial Agent that Inhibit Protein Synthesis by disruption of RNA processing

Aminoglycosides

5

Drug that blocks binding of aminoacyl moiety of charged tRNA molecule to acceptor site of complex

Chloramphenicol, ketolides (Direct Binding to 50S Subunit)

6

Drug prevents translocation of peptidyl tRNA from acceptor site to donor site on the 50S ribosomal subunit

Macrolides, clindamycin, streptogramins( Direct Binding to 50S Subunit)

7

Drug that blocks binding of amino acid charged tRNA to acceptor site of ribosome mRNA complex

tetracyclines (Direct Binding to 30 S Subunit)

8

Drugs that can block formation of initiation complex between ribosomes and mRNA, misread mRNA, block translocation of mRNA

aminoglycosides (Direct Binding to 30 S Subunit)

9

“-static” drugs may be “-cidal” depending on:

Drug concentration
Site of infection
Infecting organism
ie., linezolid is “–static” for enterococci and staph, but “-cidal” for strep

10

aminoglycosides: 2 effects on bacterial cell resulting in death:

Bind negative charges in outer phospholipid membrane, displacing cations that link phospholipids together  disruption of wall and leakage of contents
Irreversibly disrupt protein synthesis by blocking initiation, misreading mRNA, blocking translocation

11

3 known mechanisms of aminoglycoside resistance:

1) Modification of aminoglycoside molecule by enzymes can’t bind ribosome: Plasmids,
Amikacin has side chain that protects against deactivation by enzymes (beats this kind of resistance)
2) Binding of aminoglycosides on rRNA altered
3) Reduced uptake of aminoglycosides: mutations

12

How do you combat aminoglycoside resistance?

use agents that target cell wall in conjunction with aminoglycosides

13

What bacteria are aminoglycosides active against?

aerobic gram-negative bacilli
Klebsiella species, Enterobacter, Pseudomonas aeruginosa
little activity against anaerobes and gram-positive organisms

14

What infections are aminoglycosides used to treat?

UTI, respiratory tract, skin and soft-tissue infections

15

List aminoglycosides

streptomycin
gentamicin, tobramycin, amikacin
neomycin, kanamycin
spectinomycin

16

Streptomycin

Aminoglycoside. Useful in treating enterococcal infections

17

Gentamicin, tobramycin, amikacin

Most widely used aminoglycosides. Cross-resistance between these drugs

18

neomycin, kanamycin

aminoglycosides. limited to oral or topical due to toxicity. (nephrotoxic)

19

Spectinomycin

structurally related to aminoglycosides but lacks amino sugars and glycosidic bonds. Used as tx for gonorrhea in PCN allergic pts.

20

Adverse effects of aminoglycosides

1) Otoxicity = may be irreversible. Genetic predisposition. Cochlear toxicity=high pitched tinnitus, progressing to high pitch deafness
Vestibular toxicity=HA, N, V, vertigo
Streptomycin most ototoxic; not reported with gentamicin
2) Nephrotoxicity = usually reversible. Elevated serum creatinine, diminished concentration of urine
3) Neuromuscular blockade- aggravates muscle weakness in Parkinson's or Myesthenia Gravis patients

21

Which aminoglycoside do you want to avoid if you have sulfite allergies?

Streptomycin ONLY (because it contains metabisulfite)

22

Which aminoglycoside causes bronchospasms and hoarseness after administered via nebulizer?

Tobramycin

23

Which amino glycoside affects digoxin metabolism by altering the GI flora responsible for its metabolism?

Neomycin

24

Which aminoglycosides are "Category D" and why?

Amikacin, streptomycin, tobramycin, kanamycin

8th cranial nerve toxicity seen in fetus when these antibiotics are administered.

25

Which aminoglycosides are "Category C"?

Gentamicin, neomycin

26

What are the 3 most commonly used Tetracyclines?

Semisynthetics:
Tetracycline
Doxycycline
Minocycline

27

Which bacteria to tetracycline work against?

Very broad spectrum!! Gram positive, gram negative, aerobic and anaerobes
Mycoplasma pneumoniae
Chlamydia
Pneumoniae
Trachomatis:Cervicitis, urethritis, PID, prostatitis (<35 yo), partners
Rickettsia = RMSF (spirochetes)
Borrelia burgdorferi = Lyme’s disease (spirochetes)

28

Short acting tetracyclines

Oxytetracycline, tetracycline
Frequent dosing needed

29

Intermediate-acting tetracyclines

Demeclocycline no longer used as antibiotic
Tx of SIADH (symptom of inappropriate ADH)

30

*Long-acting tetracyclines

Doxycycline and minocycline
BID dosing

31

How do tetracyclines work?

Inhibit protein synthesis by reversibly binding to the 30S subunit of RNA
Blocks the addition of amino acids to newly forming peptides
bacteriostatic (need the immune system's help)

32

What are the ADRs of tetracyclines?

Gastrointestinal: N, V, D = most common; Modified GI flora= candidiasis, C. diff
Bony structures and teeth: Binds to newly formed/forming bones and teeth. Children < 8 yo (US); < 13 yo (Canada). Fetus (Category D) and breast fed infants can be affected
Photosensitization
Vestibular reactions-dizziness, vertigo (minocycline)
Pseudotumor cerebri (idiosynchratic rxn)
Lupus-like rxn with minocycline (reversible)

33

What is unique about tetracycline absorption?

Incompletely absorbed from the GI
Further Impaired by concurrent ingestion:
Dairy products
Aluminum hydroxide
Ca++, Mg++, iron or zinc salts
Bismuth subsalicylate

34

What is unique about doxycycline elimination?

Elimination is mostly hepatic (whereas all other tetracyclines are predominantly kidney-elimination)

35

Third Generation TCN

Tigecycline (Tygacil)- Broad spectrum antimicrobial activity, including MRSA
Indicated for treatment of complicated intra-abdominal infections and complicated skin and skin structure infections in adults
Developed to overcome bacterial resistance mechanisms to TCNs (efflux and ribosomal mutations)

36

What are the indications for Chloramphenicol?

Gram (+), Gram (-)
Because of blood dyscrasias it is reserved for life-threatening infections such as typhoid fever, RMSF, and meningitis in patients allergic to PCN.

37

Is chloarmphenicol bacteriostatic or bactericidal?

Both bactericidal and bacteriostatic depending on the bacteria species.

38

Neonates can't metabolize which antibiotic due to "gray baby syndrome?"

Neonates cannot metabolize Chloramphenicol and “gray baby syndrome” ensues. Gray baby syndrome consists of pallor, abdominal distension, vomiting and collapse. Accumulation can lead to death.

39

Macrolides

1) Erythromycin
2) Clarithromycin (Biaxin)
3) Azithromycin (Zithromax—Z-pak)
(2 and 3: Semisynthetic derivatives: Derived from erythromycin; more acid stable, better tissue penetration and broader spectrum)

40

How do macrolides work?

Inhibit protein synthesis by binding to 50S ribosomal unit, blocking translocation and preventing peptide elongation
Bacteriostatic; at high concentrations or with rapid bacterial growth= bactericidal

41

erythromycin is effective against which bacteria?

Erythromycin is effective against most Gram (+) bacteria and spirochetes. Specific bacteria include: legionella pneumophila, N gonorrhoeae, N. menigitidis, H. influenzae (only in combo with sulfonamide) Poor anaerobic coverage.

42

Clarithromycin is active against which bacteria?

Clarithromycin is active against gram (+) and anaerobic bacteria, H. influenzae, H. pylori, mycobacterium avium

43

Azithromycin is active against which bacteria?

Clarithromycin is active against gram (+) and anaerobic bacteria, H. influenzae, H. pylori, mycobacterium avium PLUS anaerobic coverage

44

Bacteria resistant to PCNs also resistant to which Macrolide?

Erythromycin

45

Adverse effects of Erythromycin

1) Gastrointestinal = most common-N,V,D and cramps-Binds to motilin receptor and increases peristalsis
2) Cholestatic jaundice-Most common with estolate salt form
3)CV (more common if administered IV parenterally)
Ventricular arrhythmias-erythromycin
Palpitations, chest pain, Dizziness, HA
IV- QT prolongation

46

Clarithromycin (Biaxin)

Semisynthetic Macrolide.
Spectrum of activity = to erythromycin + enhanced coverage of atypical mycobacteria
Compared to erythromycin: Less GI upset and BID dosing
N/D, abnormal taste, dyspepsia, HA, tooth discoloration, transient anxiety and behavioral changes

47

Azithromycin (Zithromax)

Semisynthetic Macrolide: Spectrum of activity
< staph and strep coverage, > atypical mycobacterial and Haemophilus influenza coverage
Great tissue penetration and prolonged intracellular half-life
Angioedema(idiosyncratic rxn)

48

Which drugs inhibit CYP3A4?

Erythro, clarithromycin

49

Which drug is NOT metabolized by CYP3A4

Azithromycin

50

Ketolides

“New generation” of macrolide antibiotics
Semi-synthetic derivative of erythromycin
Higher binding affinity to 50S subunit (work a little better than macrolide)
Displays greater potency against gram (+) organisms
Displays activity against macrolide-resistant strains. Does not induce bacterial methylase (mechanism of resistance). Drug able to bind 50S subunit when site is methylated (mechanism of resistance)

51

Indications for Telithromycin (Ketek)

Tx of community-acquired pneumonia, sinusitis and bronchitis caused by S. pneumoniae, H. influenzae, Chlamydia pneumoniae, M. catarrhalis, Mycoplasma pneumoniae, S. aureus
(but only use this if you have no other choice. "black box" warning. linked to liver failure/deaths)

52

Metabolism and elimination of Telithromycin (Ketek)

Hepatic metabolism with elimination in bile and urine

53

Spectrum of activity of Lincosamides: Clindamycin (Cleocin)

Gram positive = strep, staph, pneumococci
Anaerobes = gram positive and negative
Except clostridium difficile

54

Method of action of Lincosamides: Clindamycin (Cleocin)

Inhibits protein synthesis by binding to same receptor site as erythromycin (50S inhibitor)

55

Most important indication for Clindamycin (Cleocin) ?

the treatment of anaerobic or mixed (polymicrobial) infections
Perforated viscus (with agent for GNR coverage)
Mostly being replaced by metronidazole (Flagyl)
Infections of female genital tract
Inpatient PID, septic abortion, amnionitis
Decubitis, venous stasis, or arterial insufficiency ulcers
Aspiration pneumonia

56

1) What is the most common antibiotic to cause clostridium difficile toxin mediated diarrhea
Pseudomembranous Colitis
2) What is the treatment of choice?

1)Clindamycin (Cleocin)
2) Treatment of choice is metronidazole (Flagyl), (can also give Vanco PO orally)

57

Are Streptogramins: Quinupristin-Dalfopristin (Synercid) bacteriostatic or bactericidal?

Bacteriostatic

58

What are the indications for Streptogramins: Quinupristin-Dalfopristin (Synercid)?

life-threatening infections associated with vanco-resistant Enterococcus faecium (VRE) bacteremia
tx of complicated skin/structure infections by methicillin-susceptible S. aureus or S. pyrogenes

59

Quinupristin-Dalfopristin (Synercid): Metabolism and ADRs

P450 3A4 inhibitor--(Nifedipine, cyclosporin drug interactions)
IV only, limited tissue distribution, metabolized in liver to active metabolites
ADRs: phlebitis, arthralgias, myalgias, hyperbilirubinemia

60

Indications for Oxazolidinones: Linezolid (Zyvox)

Indications: vanco-resistant Enterococcus faecium (VRE); nosocomial pneumonia due to S. aureus including MRSA or S. pneumoniae; complicated/uncomplicated skin/structure infections; gram (+) community acquired pneumonia

61

What is the MOA for Oxazolidinones: Linezolid (Zyvox)?

prevents function of initiation complex. Mechanism distinct from other 50S ribosomal inhibitors  active against bacteria that is resistant to other protein synthesis inhibitors

62

Is Linezolid bacteriostatic or bactericidal, and against which organisms?

BOTH!!
Bacteriostatic against enterococci and staph;
bactericidal against strept

63

ADRs of Linezolid

GI, HA
thrombocytopenia
Linezolid = MAOI= hypertension if used with adrenergic and serotonergic drugs

64

Which drug is a tRNA inhibitor?

Mupirocin (Bactroban)

65

How does Mupirocin (Bactroban) work?

Inhibits isoleucyl RNA synthetase
Inhibits protein synthesis due to loss of critical amino acid in peptide

66

What is Mupirocin (bactroban) active against?

Active against gram (+) cocci—expect to find on the skin so good topical ointment
Used for topical treatment of skin ie., impetigo