L29- Protein Synthesis Inhibitors I Flashcards
list the protein synthesis inhibitors
- tetracyclines
- glycylcyclines
- aminoglycosides
- macrolides
- chloramphenicol
- clindamycin
- streptogramins
- linezolid
- mupirocin
Protein Synthesis Inhibitors:
- bacterio-(static/cidal)
- (2) MOA
- (3) MOA’s effects that are basis for AEs
1- bacteriostatic (mostly, aminoglycoside is only bacteriocidal)
2- binds bacterial ribosome (70S = 50S + 30S) —- differs from eukaryotic ribosome (80S = 60S + 40S)
3- binds mammilian mitochondrial ribosome (due to resemblance to bacterial ribosome) => AEs
______ is the only bacteriocidal protein synthesis inhibitor
aminoglycosides
list tetracyclines
- doxycycline
- minocycline
- tetracycline
Tetracycline MOA:
- enters bacteria via (1) in order to concentrate drug intracellularly
- binds (ir-/reversibly) to (3) in order to prevent (4) process
1- passive diffusion + energy dependent transport
2- reversibly
3- 30S subunit of ribosome
4- attachment of aminoacyl tRNA
______ antibiotic works by binding 30S subunit of ribosome in order to prevent tRNA attachment
tetracyclines (T for tRNA)
describe the prevalence and mechanisms of resistance to Tetracyclines
-widespread resistance (due to overuse)- usually plasmid related
1) impaired influx OR inc efflux via plasmid-encoded protein pump
2) bacterial protein production to interfere with binding to ribosomes
3) enzymatic inactivation
Tetracyclines are most commonly used to treat (1) and (2)- (3) is also a popular use of tetracyclines.
1- severe acne
2- rosacea
3- empiric therapy for CA-pneumonia
Tetracycline (monotherapy) is the drug of choice for….. (hint- 7)
- chlamydia
- Mycoplasma pneumoniae (CA-pneumonia)
- Lyme disease
- Cholera
- Anthrax prophylaxis
- Rickettsia (Rocky Mountain Spotted Fever)
Tetracycline is used in combination therapy for the following conditions….
- H. pylori
- Malaria prophylaxis and Tx (doxycycline)
- Tx of plague, tularemia, brucellosis
Tetracycline Pharmacokinetics:
- (1) describe general oral bioavailability among the tetracyclines
- accumulates in (2) tissues
- (3) main route of elimination, (4) is the exception
1- variable — doxycycline is lipid soluble, therefore parenterally admin. preferred
2- liver, kidney, spleen, skin
3- urine
4- Doxycycline –> bile
Tetracycline AEs:
- (1) common AEs
- (2) are the main contraindications due to (3) AEs
- (4) are seen with doxycycline and minocycline
- (5) via renal accumulation
- (6) via skin accumulation
1- n/v/d or superinfections
2- pregnancy, children <8y/o (crosses into placenta and breast milk — teratogen)
3- discoloration and hypoplasia of teeth (via Ca binding), stunting of growth, fatal hepatotoxicity in pregnant Pts (high doses + partial hepatic insufficiency in pregnancy)
4- dizziness, vertigo
5- exacerbation of renal dysfunction
6- photosensitive
list the glycylcyclines
tigecycline
Glycylcyclines:
- effective against (1) bacteria
- (2) describe resistance
(tigecycline)
1- broad-spectrum: MDR Gram+, some Gram- and some anaerobes
2- little resistance — efflux pumps only in Proteus and Pseudomonas spp.
describe clinical use of glycylcyclines
(tigecycline)
Last Chance Antibiotic: inc risk of mortality seen when treating serious infections
-complicated skin, soft tissue, intra-abdominal infections
Glycylcyclines:
- (1) route of administration
- (2) describe distribution
- (3) route of elimination
(tigecycline)
1- IV
2- excellent tissue and intracellular penetration
3- biliary / fecal elimination
Glycylcyclines:
- (1) AEs
- (2) contraindications
1- well tolerated — similar AEs to tetracyclines: n/v/d
2- pregnancy, children <8y/o
list the Aminoglycosides
- amikacin
- gentamicin
- tobramycin
- streptomycin
- neomycin
Aminoglycosides:
- (1) is a unique feature in comparison to the activity of all other protein synthesis inhibitors
- (2) describe general clinical use
1- bacetiocidal (all others are bacteriostatic)
2- mostly replaced by safer antibiotics — associated with serious toxicities
describe the unique feature of pharmacodynamics with Aminoglycosides (hint: time v [drug])
Postantibiotic effect + Concentration-dependent killing = once daily dose
1) concentration dependent killing = more [drug] => better killing power VS. time-dependent where duration, not drug amount, affects killing power
Aminoglycoside MOA:
- (1) entry of (2) bacteria only
- binds (ir-/reversibly) to (4) leading to inhibition of initiation complex, causing (5) and (6)
1- passively and actively (O2 dependent)
2- aerobic Gram- bacteria
3- irreversible (covalent bond)
4- 30S ribosomal subunit
5- misreading of mRNA
6- blockade of translocation
describe the mechanisms of Aminoglycoside resistance
1) plasmid-associated synthesis of enzymes –> drug modification and inactivation via acetylation, phosphorylation, adenylation
2) dec drug accumulation
3) change in receptor protein on 30S ribosomal subunit (alteration or deletion via mutation)
Aminoglycosides are the drug of choice for…..
Note- always empiric therapy and always in combination
*infective endocarditis w/ vancomycin
Aminoglycoside Pharmacokinetics:
- (1) route of administration
- (2) describe distribution
- (3) route of elimination
1- parenteral (once daily) —- except neomycin is topical
2- well-distributed everywhere: including CSF, bronchial secretions, *renal cortex and *inner ear
3- urine (reduce dose in renal insufficiency)
Aminoglycoside AEs:
- (1) are the common dangerous AEs
- (2) are the main contraindications, explain
1- ototoxicity, nephrotoxicity
2:
- Myasthenia Gravis – neuromuscular contraindication
- Pregnancy (cat. D, unless benefits outweigh risks)
Oral neomycin is used to treat (1); (2) are the alternative treatments for (1)
1- hepatic encephalopathy
2- lactulose, oral vancomycin, oral metronidazole, rifaximin
describe the MOA of Lactulose (for hepatic encephalopathy)
- non-absorbable disaccharide –> stays in GIT lumen
1) degraded by intestinal bacteria => lactic acid + other organic acids
2) gut lumen acidification
3) favors NH4+ formation (over NH3)
4) NH4+ is trapped in colon —> effectively reduces [NH3] in plasma
Lactulose:
- (1) non-MOA effects
- (2) AEs (hint- related to (1))
1- prebiotic; osmotic laxative
2- osmotic diarrhea, flatulence, abdominal cramping
list the macrolides
erythromycin
clarithromycin
azithromycin
Macrolides:
- (1) agents
- bacterio-(static/cidal)
- effective against (3) bacterial infections
1- erythromycin, clarithromycin, azithromycin
2- bacteriostatic —> bacteriocidal at high concentrations
3- Gram+
Macrolides MOA:
- (ir-reversibly) binds (2) subunit of (3) in order to block (4)
- binding site / (2) is identical or closely related to binding site of (5) drugs
1- reversibly
2- 23S RNA
3- 50S ribosomal subunit
4- translocation
5- clindamycin, chloramphenicol
describe mechanisms of resistance of Macrolides- discuss cross-resistance of agents
1) reduce membrane permeability // active efflux
2) esterase production => deactivation (enterobacteriaceae)
3) ribosomal binding site modification (chromosomal methylation or mutation)
- complete cross-resistance between all macrolides
- partial cross-resistance with clindamycin, streptogramins
______ is the macrolide with the most narrow spectrum
erythromycin (< clarithromycin, azithromycin)
Macrolides:
- all are drugs of choice for (1) treatment
- (2) is drug of choice for whooping cough
- (3) are common empiric uses
- substitute for (4)
1- atypical pneumonias (mycoplasma, chlamydia, legionella)
2- erythromycin for B. pertussis
3- CA-pneumonia, URIs, soft-tissue infections
4- penicillin in Pts w/ allergy
______ is the therapy used for N. gonorrhea
combination:
- erythromycin (macrolide)
- ceftriaxone (3rd gen. cephalosporin)
Macrolides Pharmacokinetics:
- (1) has the lowest F
- (2) is the only non-inhibitor of (3) => (4) as the main contraindication with agents that are not (2)
1- erythromycin
2- azithromycin
3- CYP P450 (erythromyin, clarithromycin are inhibitors)
4- statin use (+ if Pt is on many drugs)
Macrolides AEs:
- (1) GI effects, explain mechanism
- (2) is a risk with erythromycin or azithromycin use
- (3) is a risk with Pts with cardiac condition
- (4) reactions / complications are rare
1- irritation via dec gut flora and Motiln receptor binding => pro-kinetic
2- hepatic abnormalities
3- QT prolongation
4- hypersensitivity/anaphylaxis, colitis (superinfection)
