Protein Synthesis Inhibitors Flashcards
Structure of tetracyclines
All have four rings, all end in “cycline”
MOA of tetracyclines
reversible binding to the 30s subunit, preventing charged tRNA from binding to acceptor site,
Susceptible bacteria concentrate the drug intracellularly, making it reach high enough levels to favor complexing with its binding site
Conversely, bacteria become resistant by pumping the drug out with efflux pumps!
Major factors in tetracycline effectiveness
Absorption is a major issue for these drugs, and it’s all about ionic displacement: metallic cations, antacids, milk or calcium-containing drugs or foods will bind to the drug and prevent its absorption.
Teratogenic: Serum drug levels in pregnant mothers reach the fetus and damages bones and teeth due to interference with calcium in those tissues with the drug being deposited instead of calcium. Thus, this drug class is teratogenic and never to be given to pregnant mothers.
For the same reason affecting bones and teeth, these drugs are not for use under 8 years of age
Metabolized and made less effective by p450 enzymes
Special effectiveness of doxycycline
Doxycycline is excreted in bile at high levels and useful for biliary tree infections
Toxicities for tetracyclines
Demeclocycline specifically inhibits action of ADH in collecting duct, and can cause iatrogenic diabetes insipidus as a result.
Take with food to decrease GI upset that is more common with this class of drugs than other antibiotics
DO NOT TAKE WITH ANY DAIRY CONTAINING FOODS, ANTACIDS, OR METAL CATIONS as it decreases absorption
Photosensitivity: excessive skin burning with sun exposure
Fatal hepatic necrosis with high doses
Inner ear toxicity with vertigo, nausea, dizziness; minocycline and doxycycline especially
TERATOGENICITY and avoidance in children, nursing mothers, pregnant mothers due to effects on bones and teeth
MOA of aminoglycosides
Inside the cell, aminoglycosides bind to specific 30S-subunit ribosomal proteins and inhibit protein synthesis 3 ways:
Interference with the initiation complex of peptide formation;
Misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide and results in a nonfunctional or toxic protein; and
Breakup of polysomes into nonfunctional monosomes.
Examples of aminoglycosides and when they’re used
Gentamycin and tobramycin
serious gram-negative infections, or gram-positive infections that require synergistic use of cell wall antibiotics like penicillins
Limitations of aminoglycosides
They depend on specific environmental factors in the human body, like availability of oxygen and alkaline pH, to be able to work well.
They enter the periplasmic space via passive diffusion via porins, then are actively transported across the cell membrane into the cytoplasm by an oxygen-dependent process and thus are a poor choice for abscesses, which tend to be an anaerobic environment.
Higher tissue pH: these antibiotics work better in an alkaline environment than an acidic environment, again demonstrating that abscesses with their acidic environment won’t be effectively treated with aminoglycosides.
Transport of these drugs is improved by cell wall-active drugs such as penicillin or vancomycin that create holes in the cell wall; this is the basis of the synergism of these antibiotics with aminoglycosides, and they are frequently used in combination in life-threatening infections that require this synergy, such as endocarditis.
WHich aminoglycoside is used for pseudomonnas
tobramycin
Mechanism of resistance to aminoglycosides
Inactivation of the drug by bacterial enzymes.
Anaerobic or acidic environment limiting entrance into cell and activation
Pharmacokinetics/dynamics/interactions for aminoglycosides
Poor GI absorption; only IV or IM for systemic infections.
Renal excretion; these drugs concentrate in the renal cortex and are only partially dialyzed, and can be very nephrotoxic even within therapeutic levels.
These drugs are both time and concentration-dependent in their killing: Once concentration breached, the time the serum level is maintained above threshold is critical.
The post-antibiotic effect with these drugs leads to dosing strategies with less frequent, larger doses, which helps ensure trough levels are low enough.
Trough levels must be monitored to prevent toxicity, especially when renal function fluctuates; clearance will be directly proportional to creatinine clearance.
Toxicities and contraindications for aminoglycosides
Toxicitiies caused by trough levels being too high – nephrotoxocity, ototoxicity
Clinical use of neomycin
Topical/enteral use only, Its use as an orally consumed agent in bowel preps in the past contributed to resistance to other aminoglycosides that are used systemically. You may also see it used in injecting infected spaces; it has a negligible effect.
Hepatic encephalopathy, decrease the gut bacteria producing byproducts of nitrogen/protein metabolism that the liver can’t detoxify
Common in skin antibiotics oitnments (neosporin)
What is the post-antibiotic effect
Occurs when low levels of antibiotics can still inhiit growth of bacteria- seen with aminoglycosides. Good to limit toxicities
Macrolides MOA
bind to 50s ribosomal subunit, preventing translocation and blocking the polypeptide exit tunnel. The protein being made in the tunnel thus can’t elongate and production shuts down.
What causes resistance to macrolides
Resistance to macrolides is carried on plasmids and spread via conjugation, the most testable form of resistance is modification of the ribosomal binding site by a macrolide-inducible methylase that also affects other drug classes. The bacteria will appear susceptible initially in the lab but resistance emerges during therapy
What is the D-Test
Azithromycin pharmacodynamics
Azithromycin is absorbed and then extensively distributed to tissue. S.l.o.w.l.y…the drug comes back out of tissue and into bloodstream, with a T1/2= 3 days, due to its extremely large volume of distribution! Some things that are great about this drug compared to the other macrolides when used properly: it can treat chlamydia in a single dose in the ER in adolescent patients that are not likely to follow up or take meds!
Erythromycin pharmacodynamics and toxicities (what cytochrome does it target)
Drug interactions are a major problem since erythromycin inhibits CYP3A4, meaning patients on erythromycin are at risk for toxicity from theophylline, warfarin, cyclosporine, and methylprednisolone
Erythromycin increases the absorption of oral digoxin, increasing risk of toxicity.
Macrolides adverse effects
Acute hepatitis and cholestasis; this indicates a person who is more sensitive to the p45- inhibition effect and who should not take these drugs again
Macrolide class toxicity that is very dangerous to fatal: in patients who already have QT prolongation, the addition of these drugs can cause unstable ventricular arrhythmias and sudden death without warning, particularly in combination with other QT prolonging meds.
What are ketolides and toxicities
This class has the same MOA as macrolides, and bacteria have not evolved efflux pumps or methylases yet so less resistance. It is a reversible cyt p450 inhibitor, and carries the toxicity of drug-induced hepatitis.
Example of Lincosamide
Clindamycin
MOA of lincosamides. What are they good for
It has the same mechanism of action and binding site as the macrolides, 50s
It SHINES and should stick in your memory for coverage of anaerobic bacteria
It also covers most community-acquired methicillin-resistant staph aureus (MRSA)
It also has GREAT penetration into abscesses/pus, because it is concentrated by phagocytic cells that are chemotactically attracted by c3a and c5a to abscesses!
Mechanism of climdamycin resistance
inducible methylases, same as macrolides
Have to check on a D test
MOA of streptogramins
Quinupristin-dalfopristin, aka Synercid; 2 streptogramins complexed together for synergistic action.
Quinupristin binds to the 23s subunit of the 50s ribosome, altering its conformation and increasing its affinity for dalfopristin by 100x while also blocking translocation.
Dalfopristin binds the 50s ribosome and blocks the transpeptidase enzyme.
Gram-positive coverage only due to porin size, used for penicillin-resistant pathogens
Pharmacodynamics of streptogramins
This drug inhibits CYP3A4 just like erythromycin. Increased levels of warfarin, diazepam, NNRTIs, and cyclosporine are all seen.
Main toxicities of streptogramins
Arthralgia/myalgia syndromes are its main toxicity: painful or inflamed joints and muscles.
MOA for chloramphenicol
Chloramphenicol binds to the 50s subunit and inhibits peptide formation.
Chloramphenicol interactions and toxicities
Chloramphenicol is a potent inhibitor of protein synthesis that is inactivated in liver by activity of glucuronyl transferase. Remember from your prior study of the biochemistry of neonatal jaundice that newborn babies are relatively deficient in this enzyme. Giving this drug resulting in “gray baby syndrome” = vomiting, flaccidity, hypothermia, gray color, shock, and vascular collapse when given usual doses of drug. This toxicity is one of the major issues you will see on exam questions.
Chloramphenicol also inhibits metabolism of phenytoin, tolbutamide, chlorpropamide, and warfarin, and will increase levels of those drugs to possibly toxic levels.
Chloramphenicol toxicities
Irreversible anaplastic anemia
Primary drug for Oxazolidinones
Linezolid
MOA of oxazolidnones
prevents formation of the entire ribosome complex that initiates protein synthesis.
Major use of linezolid
It is one of the few options left for vancomycin-resistant enterococcus (VRE.)
Toxicities and contraindications of oxazolidnones
Thrombocytopenia is the most common, but anemia and neutropenia can also occur
optic and peripheral neuropathy and lactic acidosis have been reported with prolonged courses of linezolid. These side effects are thought to be related to linezolid-induced inhibition of mammalian mitochondrial protein synthesis.
Serotonin syndrome occurring when linezolid is coadministered with serotonergic drugs, most frequently selective serotonin reuptake inhibitor antidepressants. Kind of like sympathetic overdrive
