PROTEIN SYNTHESIS INHIBITORS Flashcards Preview

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1

PROTEIN SYNTHESIS INHIBITORS

• 1) Tetracyclines
• 2) Glycylcyclines
• 3) Aminoglycosides

• 4) Macrolides
• 5) Chloramphenicol

• 6) Clindamycin
• 7) Streptogramins
• 8) Linezolid
• 9) Mupirocin

Bind to and interfere with ribosomes

Bacterial ribosome (70S) differs from mammalian (80S) but closely resembles mammalian mitochondrial ribosome

• Mostly bacteriostatic

2

DOXYCYCLINE

MINOCYCLINE

TETRACYCLINE

TETRACYCLINES

"DMT" binds to the THIRTY-S subunit

-broad spectrum

-bacterioSTATIC

-activity against many aerobic and anaerobic Gram +ve and -ve organisms 

MOA: 

• Entry via passive diffusion & energy-dependent transport unique to bacterial inner cytoplasmic membrane

• Susceptible cells concentrate drug intracellularly

• Bind reversibly to 30S subunit of ribosome, preventing binding of aminoacyl tRNA

3

TETRACYCLINS - RESISTANCE

3 main mechanisms:

• Impaired influx or increased efflux by active protein pump

• Production of proteins that interfere with binding to ribosome

• Enzymatic inactivation

4

TETRACYCLINS - CLINICAL APPLICATIONS

-Most common use = severe acne & rosacea
• Used in empiric therapy of community-acquired

pneumonia (outpatients)

• Can be used for infections of respiratory tract, sinuses, middle ear, urinary tract, & intestines

Syphilis (patients allergic to penicillin)

5

TETRACYCLINE IS DOC FOR

 

DOC FOR

• Chlamydia
• Mycoplasma pneumoniae

• Lyme disease
• Cholera
• Anthrax prophylaxis

• Rickettsia (Rocky Mountain Spotted Fever, typhus)

 

Used in combination for:

• H.pylori eradication
• Malaria prophylaxis and treatment
• Treatment of plague, tularemia, brucellosis

6

TETRACYCLINE PK

 

• Variable oral absorption (decreased by divalent & trivalent cations)

Doxycycline (lipid soluble) = preferred for parenteral admin. and good choice for STD’s and prostatitis

Minocycline = reaches high concentrations in all secretions (useful for eradication of meningococcal carrier state)

• Concentrate in liver, kidney, spleen & skin

• Excreted primarily in urine except doxycycline (primarily via bile)

• TERATOGENIC – all cross placenta & are excreted into breast milk (FDA category D)

7

TETRACYCLINES - AE

• Gastric effects / superinfections (nausea, vomiting, diarrhea)

Discoloration & hypoplasia of teeth, stunting of growth (generally avoided in pregnancy & not given in children under 8y)

• Fatal hepatotoxicity (in pregnancy, with high doses,

patients with hepatic insufficiency)

• Exacerbation of existing renal dysfunction
• Photosensitization
• Dizziness, vertigo (esp. doxycycline & minocycline)

8

TIGECYCLINE

is a GLYCYLCYCLINE

-is STRUCTURALLY similar to tetracyclines

-antibacterial spectrum: Broad-spectrum against multidrug-resistant Gram- positive, some Gram-negative & anaerobic organisms

RESISTANCE: 

Little resistance

• Not subject to same resistant mechanisms as tetracyclines (exceptions = efflux pumps of Proteus & Pseudomonas species)

 

CLINICAL APPLICATIONS:

Treatment of complicated skin, soft tissue and intra- abdominal infections

 

9

GLYCYLCYCLINES - TIGECYCLINE

BLACK BOX WARNING

1) Increased risk of mortality has been observed with tigecycline compared with other antibiotics when used to treat serious infections

FDA recommends considering the use of alternative antimicrobials when treating patients with serious infections

10

GENTAMICIN

AMIKACIN

NEOMYCIN

TOBRAMYCIN

STREPTOMYCIN

"G-ANTS" - AMINOGLYCOSIDES

fight against AEROBIC gram -NEGATIVE

• Bactericidal
• Associated with serious toxicities
• Largely replaced by safer antibiotics

MOA: 

• Passively diffuse across membranes of Gram-negative organisms

• Actively transported (O2-dependent) across cytoplasmic membrane

--> therefore are most active against AEROBIC GRAM -VE BACTERIA

• Bind to 30S ribosomal subunit prior to ribosome formation leading to:

  • 1) misreading of mRNA, &
  • 2) inhibition of translocation

PHARMACODYNAMICS;

Postantibiotic effect + Concentration-dependent killing

Once-daily dosing

--> Concentration-dependent (aminoglycosides)

 

11

GLYCYLCYCLINES - PK/AE

 

IV only
• Excellent tissue & intracellular penetration • Primarily biliary/fecal elimination

Adverse effects
• Well tolerated
• AE similar to tetracyclines

Contraindications

Pregnancy & children <8y

12

AMINOGLYCOSIDES - RESISTANCE

3 principal mechanisms:
1) Plasmid-associated synthesis of enzymes that

modify and inactivate drug

2) Decreased accumulation of drug

3) Receptor protein on 30S ribosomal subunit may be deleted or altered due to mutation

13

CONCENTRATION DEPENDENT VS TIME-DEPENDENT KILLING

• Concentration-dependent (aminoglycosides)

• Time-dependent (penicillins, cephalosporins)

14

AMINOGLYCOSIDES - CLINICAL APPLICATIONS 

-Used mostly in COMBINATION

Empiric therapy of serious infections eg, septicemia, nocosomial respiratory tract infections, complicated UTI’s, endocarditis etc

• Once organism is identified aminoglycosides are normally

discontinued in favor of less toxic drugs

DOC: 

1) Empiric therapy of infective endocarditis in combination with either a penicillin or (more commonly) vancomycin

2) Streptomycin is the drug of choice for Plague (Y.Pestis)

15

TREATEMENT FOR THE PLAGUE

-the plague (yersinia pestis) is treated with STREPTOMYCIN

16

ORAL NEOMYCIN

AMINOGLYCOSIDE

• Used as adjunct in treatment for hepatic encephalopathy

Alternative treatment options for hepatic encephalopathy:

1) Lactulose
2) Oral vancomycin
3) Oral metronidazole

4) Rifaximin

17

HEPATIC ENCEPHALOPATHY

-treated with ORAL NEOMYCIN 

Alternative treatment options for hepatic encephalopathy:

Lactulose
• Oral vancomycin
• Oral metronidazole

• Rifaximin

 

18

LACTULOSE

-Nonabsorbable disaccharide

MOA

• Degraded by intestinal bacteria  lactic acid + other organic acids

--> acidification of gut lumen

--> favors formation of NH4+ from NH3

--> NH4+ is trapped in colon effectively reducing plasma ammonia concentrations

Other Effects

• Prebiotic (suppression of urase producing organisms)

• Osmotically active laxative

Adverse Effects

• Osmotic diarrhea
• Flatulence
• Abdominal cramping

19

AMINOGLYCOSIDES PK + AE

Like sticking the "sai" from sketchy into your EAR as well as KIDNEY

 

PK: 

Parenteral admin. only (except neomycin - topical)
Once-daily admin.
• Well distributed (excluding CSF, bronchial secretions)
High levels in renal cortex & inner ear
• 99% excreted in urine (reduce dose in renal insufficiency)

AE: 

Both time- and concentration-dependent

• Ototoxicity

• Nephrotoxicity

• Neuromuscular blockade (myasthenia gravis =

contraindicated)

• Pregnancy (contraindicated unless benefits outweigh risks – FDA Category D)

20

ERYTHROMYCIN

CLARITHROMYCIN

AZITHROMYCIN

TELITHROMYCIN

 

Mainly used to treat Gram-positive infections

Bacteriostatic (bactericidal at high conc.)

MOA: 

• Reversibly bind to 50S subunit inhibiting translocation

• Binding site is identical or close to that for clindamycin & chloramphenicol

ANTIBACTERIAL SPECTRUM: 

Most active against Gram-positive bacteria (some activity against Gram-negatives)

• Spectrum is slightly wider than that of penicillins

• Azithromycin, clarithromycin & telithromycin have broader spectrum than erythromycin

21

MACROLIDES - RESISTANCE

 

3 main mechanisms (usually plasmid encoded):

  1. • Reduced membrane permeability or active efflux
  2. • Production of esterase that hydrolyze drugs (by enterobacteriaceae)
  3. • Modification of ribosomal binding site (by chromosomal mutation or by a methylase)

• Complete cross-resistance between erythromycin, azithromycin, & clarithromycin

• Partial cross-resistance with clindamycin & streptogramins

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MACROLIDES - CLINICAL APPLICATION

• Used in empiric therapy of community-acquired pneumonia (outpatient & in combination with B-lactam for inpatients)

• DOC for Mycoplasma pneumoniae

• Treatment of upper respiratory tract & soft-tissue infections (eg, Staph, H.influenzae, S.pneumoniae, enterococci)

• Erythromycin = DOC for whooping cough (B.pertussis)

 

Is a common substitute for patients with penicillin allergy

23

WHOOPING COUGH TREATMENT

ERYTHROMYCIN (macrolide) 

24

Mycoplasma Pneumonia treatment

macrolide

25

MACROLIDES PK + AE

 

PK: 

• Clarithromycin, azithromycin, telithromycin = improved oral absorption, longer t1/2, increased bioavailability compared to erythromycin

• Azithromycin & telithromycin = greater tissue penetration compared to other macrolides

• Erythromycin, clarithromycin & telithromycin = CYP P450 inhibition (NOT azithromycin)****

AE:

• GI irritation
• Hepatic abnormalities (erythromycin & azithromycin) • QT prolongation
• Severe reactions are rare (anaphylaxis, colitis)

 

26

MACROLIDE CONTRAINDICATIONS 

Macrolides always standing on the static (statins) telephone poles (TELI) --> fatal hepatotoxicity, exacerbation of myasthenia gravis  

 

CONTRAINDICATIONS:

1) Statins (due to macrolides inhibiting CYP P450)

2) Telithromycinfatal hepatotoxicity, exacerbations of myasthenia gravis, & visual disturbances --> don’t use for minor illnesses

27

CHLORAMPHENICOL

Potent inhibitor of protein synthesis
• VERY Broad-spectrum (aerobic & anaerobic Gram-positive & -

negative organisms)

• Bacteriostatic (usually)

Toxicity limits use to life-threatening infections with no alternatives

MOA: 

Enters cells via ACTIVE TRANSPORT process
Binds reversibly to 50S ribosomal subunit (site adjacent

to site of action of macrolides & clindamycin)

• Can inhibit protein synthesis in mitochondrial ribosomes

ADVERSE EFFECTS 

--> bone marrow toxicity --> reversible or APLASTIC ANEMIA

 

28

CHLORAMPHENICOL ANTIBACTERIAL SPECTRUM + CLINICAL APPLICATIONS

Very broad spectrum
• Activity against Gram-positive and negative bacteria, including Rickettisae & anaerobes
N.meningitidis, H.influenzae, Salmonella & bacteroides = highly susceptible

• Never given systemically for minor infections (due to adverse effects)

CLINICAL APPLICATIONS: 

1) Serious infections resistant to less toxic drugs

2) When chloramphenicols penetrability to site of

infection is clinically superior to other drugs

3) Active against many VRE

4) Topical treatment of eye infections (mainly outside US)

29

CHLORAMPHENICAL PK + AE

 

Chloram"chemical" --> inhibits hepatic oxidases, and does BONE MARROW DEPRESSION b/c is such a strong chlorine chemical, also TURNS YOU GREY!!! 

• Oral, IV or topical
• Wide distribution (readily enters CSF)
• Inhibits hepatic oxidases (3A4 & 2C9)

AE: 

• GI distress
Bone marrow depression

  • dose-related reversible depression
  • severe irreversible aplastic anemia

Gray baby syndrome (cyanosis), due to drug accumulation

30

CLINDAMYCIN

"give it to 50 (for 50S subunit)  y/o's and then they get C diff 

--> used for gut anaerobic bact

 

MOA = same as macrolides (binds to 50S subunit)

• Mainly bacteriostatic

• Primarily used against Gram-positive anaerobic bacteria. Also active against bacteroides