PROTEIN SYNTHESIS INHIBITORS Flashcards
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
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
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
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)
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
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)
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)
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
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
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)
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
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
CONCENTRATION DEPENDENT VS TIME-DEPENDENT KILLING
- Concentration-dependent (aminoglycosides)
- Time-dependent (penicillins, cephalosporins)
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)
TREATEMENT FOR THE PLAGUE
-the plague (yersinia pestis) is treated with STREPTOMYCIN
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
HEPATIC ENCEPHALOPATHY
-treated with ORAL NEOMYCIN
Alternative treatment options for hepatic encephalopathy:
- Lactulose
- Oral vancomycin
- Oral metronidazole
• Rifaximin
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
