Protein synthesis inhibitors Flashcards
Protein synthesis inhibitors
MOA
- MOA: Bind to and interfere w/ ribosomes
- Mostly bacteriostatic
- Bacterial ribosome (70S) differs form mammalian (80S) but closely resembles mammalian mitochondrial ribosome
Tetracyclines Glycylcyclines Aminoglycosides Macrolides Chloramphenical Clindamycin Streptogramins Linezolid Mupirocin
Tetracyclines
MOA
Doxycycline, Minocycline, Tetracycline
- Broad spectrum
- bacteriostatic
- activity against manyaerobic and anaerobic Gram +ve and Gram -ve organisms
MOA:
Binds reversibly to 30S subunit of ribosome, preventing binding of amioacyl tRNA
Tetracyclines resistance
clinical applications
- Widespread resistance (usually plasmid mediated)
- Most common use= severe acne and rosacea
- Used in empiric therapy of community-acquired pneumonia (outpatients)
- Can be used for infections of respiratory tract, sinuses, middle ear, urinary tract and intestines
- syphilis (patients allergic to penicillin)
Tetracyclines
clinical applications DOC
DOC for: Chlamydia Mycoplasma pneumoniae Lyme disease Cholera Anthrax prophylaxis Rickettsia (Rocky Mountain Spotted Fever, typhus)
Tetracyclines
clinical applications
- used in combination for
H. pylori eradication
Malaria prophylaxis and treatment
Treatment of plague, tularemia, brucellosis
tetracyclines PK
Excretion?
- Variable oral absorption (decreased by divalent and trivalent cat ions e.g Ca+2, Mg+2, Fe+2)
- 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 and skin
Excreted primarily in urine except doxycycline (primarily via bile)
TERATOGENIC-all cross placenta and are excreted into breast milk (FDA category D)
tetracyclines AE/CI
- Discoloration and hypoplasia of teeth, stunting of growth (generally avoided in pregnancy and not given in children under 8y)
- Fatal hepatotoxicity (in pregnancy, with high doses patients with hepatic insufficiency)
- PHOTOSENSITIZATION
- dizziness vertigo (esp. doxycyline and minocycline)
Glycylcyclines
Tigecycline
- structurally similar to tetracyclines
Antibacterial spectrum
- Broad-spectrum against multidrug-resistant Gram positive, some gram-negative and anaerobic organisms
Glycylcyclines clinical applications
BLACK BOX WARNING
Treatment of complicated skin, sorft tissue and intra abdominal infections.
BB warning: Increased risk of mortality has been observed with tigecycline compared with other abs when used to treat serious infections.
FDA recommends considering the use of alternative antimicrobials when treating patients w/ serious infections.
Gycylcyclines PK/AE
IV only
primarily bilary/fecal elimination
well tolerated
AE similar tetracyclines
CI: pregnancy and children
Aminoglycosides
Drugs used?
"TANGS" Amikacin, gentamicin, Tobramycin, Streptomycin, Neomycin - Bactericidal - associated with serious toxicities - Largely replaced by safer abs
Aminoglycosides MOA
Actively transported (O2-dependent) across cytoplasmic membrane
bind 30S ribosomal subunit prior to ribosome formation leading to:
- misreading of mRNA and inhibition of translocation
Aminoglycoside resistance:
3 principal mechanisms:
- plasmid associated synthesis of enzymes that modify and inactivate drug
- decreased accumulation of drug
- Receptor protein on 30S ribosomal subunit may be deleted or altered due to mutation
Aminoglycosides Pharmacodynamics
Postantibiotic effect + concentration Killing = Once daily dosing
which drug are concentration dependent?
what drugs are time dependent?
- aminoglycosides
2. Penicilins, cephalosporins
Aminoglycosides are most active against?
clinical applications?
DOC?
- Aerobic gram -ve bacteria
- anaerobes lack O2 dependent transport - Used mostly as combination
- Empiric therapy of serious infections eg, septicemia, nocosomial respiratory tract infections, complicated UTI’s, endocarditis etc
- once organism is indentified aminoglycosides are discontinued in favor of less toxic drugs.
DOC for: Infective Endocarditis incombination with either penicillin or (more commonly) vancomycin.
DOC for plague (Y. Pestis)
Streptomycin
Oral Neomycin used for?
used as adjunct in treatment for hepatic encephalopathy
Alternative to treatment options for hepatic encephalopathy?
Lactulose
Oral Vancomycin
Oral Metronidazole
Rifaximin
Lactulose
MOA
AE
Nonabsorbable disaccharide MOA: degraded by intestinal bacteria--> lactic acid + other organic acids -->acidification of gut lumen --> favors formation NH4+ from NH3 --> NH4+ is trapped in colon effectively reducing plasma ammonia concentrations. AE: - osmotic diarrhea - flatulence - abdominal cramping
Aminoglycosides PK
- Parenteral admin. only (except neomycin-topical)
- Once daily admin
- well distributed (excluding CSF, bronchial secretions)
- High level in renal cortex and inner ear*
- 99% excreted in urine (reduce dose in renal insufficiency)
Aminoglycosides AE
Both time- and concentration- dependent
- Ototoxicity
- Nephrotoxicity
- Neuromuscular blockade (myasthenia gravis=Contraindicated)
- Pregnancy unless outweighs risk- FDA category D
Macrolides
MOA
TACE Erythromycin Clarithromycin Azithromycin Telithromycin
MOA: Reversibly bind to 50S subunit inhibiting translocation.
- bind site is identical to clindamycin and chloramphenicol
- Mainly used for Gram +ve infections
- Bacteriostatic (bactericidal at high concentration)
DOC for mycoplasma pneumoniae
DOC: Macrolides
DOC for whooping cough disease (B. pertussis)
DOC: Erythromycin
Common substitue for patients with penicillin allergyy
Macrolides are common substitute for patients with penicillin allergies
Macrolides are CYP450 inhibitors except?
Azithromycin
Macrolides
AE?
CI?
GI irritation
Hepatic abnormalities (erythromycin and azithromycin)
QT prolongation (Torsade de pointes)
Severe reactions are rare (anaphylaxis, colitis)
CI: STATINs (due to cyp450 inhibiton)
Telithromycin - fatal hepatotoxicity, exacerbations of myasthenia gravies and visual disturbances –> don’t use for minor illnesses.
what macrolide can lead to fatal hepatotoxicity, exacerbations of myasthenia gravies and visual disturbances which should not used for minor illnesses.
Telithromycin
Choramphenicol:
“developing world, treats meningitis.”
- Potent inhibitor of protein synthesis
- BROAD-SPECTRUM (aerobic and anerobic Gram +ve and -ve organisms.
- Bacteriostatic (usually)
- Toxicity limits use to life-threating infections w/ no alternatives
Chloramphenicol MOA
Resistance?
- Entry via active transport
- Reversibly binds 50s ribosomes (site adjacent to site of action of macrolides and clindamycin)
- Can inhibit protein synthesis in mitochondrial ribosomes –> bone marrow suppression
Resistance: chloramphenicol tranferase (inactivates drug)
- Changes in membrane permeability
Chloramphenicol - Antibacterial spectrum
Very broad activity against: - Gram + and - - Rickettsiae - Anaerobes
Never given systemically for minor infections (due to adverse effects)
Chloramphenicol clinical applications (3rd world)
PK?
AE?
- Meningitis
- serious infections resistant to toxic drugs
- active against VRE
- Topical treatment of eye infections (mainly outside US)
- when it’s penetrations to sights is more superior to other drugs.
PK: Oral, IV or topical
- wide spread distribution (readily enters CSF)
- Inhibits hepatic oxidases (3A4 and 2C9)
AE: GRAY BABY SYNDROME (cyanosis), due to drug accumulation Bone marrow depression: - dose related reversible depression - APLASTIC ANEMIA
Clindamycin
PK?
MOA?
- Oral or IV
- MOA = same as macrolides (binds 50S subunit)
- Bacteriostatic
- Primarily used against Gram positive anaerobic bacteria.
- Also active against Bacteriodes and gram +ve aerobes
Clindamycin has cross resistance with ?
Clinical applications?
- Macrolides (bacteroides infections, abscesses, abdominal infections)
- Anaerobic infections
- skin and soft tissue infections (streptococci and staphylococci, and some MRSA)
- in combo with primaquine as an alternative in PCP
- In combo with pyrimethamine as an alternative for toxoplasmosis of brain.
- Prophylaxis of endocarditis in valvular patients allergic to penicillin.
Clindamycin AE:
- Pseudomembranous Colitis (superinfection of c. difficile)*
- GI irritation
- Skin rashes
- Neutropenia and impaired liver function
Streptogramins
- USE
Quinupristin, Dalfopristin (queen and dwarf of the Priest)
- Given as a combination (act synergistically to have bactericidal action!)
- Long postantibiotic effect***
- GRAM +VE COCCI (drug resistant Staph or VRE)***
- Multidrug resistant bacteria (streptococci, PRSP, MRSA, E. faecium)
Streptogramins
- admin?
- MOA?
Quinupristin, Dalfopristin
IV only Penetrates macs and PMNs Inhibits CYP3A4 MOA: - 50S bacterial ribosome - resistance is uncommon
Streptogramins AE
Quinupristin, Dalfopristin
Infusion related (venous irritation, arthralgia and myalgi) GI effects CNS effects (headache, pain)
Linezolid
Bacteriostatic (cidal against streptococci and clostridium perfringes)
- Most Gram positive organisms
- Tx of mulidrug resistant infections
MOA
- Binds to unique site on 23S ribosomal RNA of 50S subunit inibiting 70S initiation complex
No cross resistance
Linezolid PK
- Oral (100% bioavailable) and IV
- Widely dietributed (including CSF)
- weak reversible inhibitor of MAO
Linezolide AE
Well tolerated for short admin. ( GI, nausea, diarrhea, headaches, rash)
Long-term admin. can cause:
Reversible myelosuppression
Optic and periperal neuropathy and lactic acidosis.
Linezolide CI
reversible, nonselective inhibitor of MAO–> potential to interact with adrenergic and serotonergic drugs.
Fidaxomicin
MOA
- Narrow spectrum macrocyclic ab
- Activity against gram-positive aerobes and anaerobes especially Clostridia
- No activity against Gram-negative bacteria!
MOA:
Inhibits bacterial protein synthesis by binding to RNA polymerase.
Fidaxomicin clinical applications:
Treatment of C. difficile colitis (in adults)
“C. difficile takes the VAN to the METRO”
Fidaxomicin PK.
When administered orally, systemic absorption is negligible but fecal concentrations are high.
Mupirocin
- Antibiotic belonging to monoxycarbolic acid class
- Activitiy again most gram +ve cocci, including MRSA and most streptococci (but not enterococci)
- only topical/intranasal agent with activity against MRSA!!
- tx impetigo or secondary infected traumatic skin lesions due to S. aureus or S. pyogenes.
Mupirocin MOA
AE
Binds to bacterial Isoleucyl tranfer RNA synthetase–>inhibits protein synthesis
AE:
- resistance after prolonged use
- Mainly local and dermatologic effects (eg, burning, edema, tenderness, dry skin, pruritis).
