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ID Exam 3 C
Ramsinghani Protein Synthesis Inhibitors 30S
| Question | Answer |
|---|---|
| In bacteria, the protein synthesis occurs in the | cytoplasm |
| Ribosomes are the site for ______ ________ | protein synthesis |
| Prokaryotic ribosomes equate to 70S: what are the subunits? | 30S (paired with 16S rRNA) and 50S (23S rRNA) subunits |
| Eukaryotic ribosomes equate to 80S: what are the subunits? | 40S and 60S |
| Protein synthesis as simple as I can: | 1st AA binds at the A site and then the whole ribosomal subunit would move by 1 carbon. First tRNA AA would move to P site and the A site would be empty. Next tRNA complement another tRNA comes and binds to A site Then form peptide linkage and again move to our 3rd carbon |
| TCN's (Tetracyclines) consist of which antibiotics that target the 30S | Tetracycline, Doxycycline,and Minocyclind |
| This antibiotic is a Glycylcyclines that targets the 30S | tigecycline |
| These are considered your "New TCN's" that target the 30S ribosome--> | Eravacycline and Omadacycline |
| List off the aminoglycosides (AG) that target the 30S ribosome: | Stretomycin, Tobramycin, Gentamycin, Amikacin |
| These are considered your New AG's that target the 30S ribosome: | Plazomicin |
| Which 2 points on the TCN structure did Ramsinghani want us to note? | C4 and C6 |
| The TCN abx class are natural products of what species? | Streptomyces species |
| TCN's are ______ reduced naphthacene ring system and are HIGHLY FUNCTIONALIZED | partially |
| What is the MOA of TCN's? | Inhibition of bacterial protein synthesis: binds to 16SrRNA of 30S subunit and thereby prevents the bninding of aminoacyl tRNA to mRNA-ribosomal complex. **prevent binding at A site |
| On the south side of the TCN, we have PHENOLIC OH and Oxol groups that are either bound directly to the _____ via H-bonding to the nucleotides or bind through complexation w/ the _____ ion | 16SrRNA; magnesium |
| On the eastern side of the TCN, we see what kind of bonding? | H-bonding |
| There are no interactions on which sides of the TCN molecule? | North and West |
| Carbon 4 of the TCN contains a? | di-methyl where we see no binding to target |
| The mechanisms of bacterial resistance with TCN's are: | Alteration of bacterial target (Production of a ribosomal protection protein (TetM); Decreased accumulation using (reduced infux; INCREASED INFLUX of magneisum-chelated TCN via an energy-dependent efflux pump (tetK) |
| Mechanism of bacterial resistance: tell me about tetM? | tetM is a ribosomal protection protein that protects the A SITE and blocks TCN from binding |
| Mechanism of bacterial resistance: tell me about the reduced influx and their effect on TCN? | drug can't get inside bacteria (remember it has to reach the cytoplasm where the protein synthesis is happening so either the drug cannot get insufficent quantity inside the bacteria or there is INCREASED EFFLUX |
| Mechanism of bacterial resistance: tell me about the Increased Efflux? | this can be of the Mg2+ chelated TCN and that happens via energy dependent efflux pump produced by the gene tetK through which TCN is thrown out |
| Is there cross-resistance seen with TCN's? | Yes, resistance is fairly common. So if resistance to 1 means others won't work |
| TCNs are __________ (prevent the growth and multiplication of bacteria w/o actually killing them) | BACTERIOSTATIC |
| What is TCN's spectrum of activity? | Broad (gram + and gram - and ATYPICALS |
| TCN's are effective against many gram + and gram - bacteria, spirochetes as well as which atypicals? | MYCOPLASMA, RICKETTSIA, CHLAMYDIA, HELICOBACTER, AND ANTHRAX |
| What's so special about atypicals? what won't they produce? | they don't produce cell walls (not developed) that is why B-lactams do not work against atypical bacteria |
| TCNs have therapeutic application in cholera, ______ _______, Rocky mountain spotted fever, mycoplasma pneumonia, and MANAGEMENT OF _____ | Lyme disease; ACNE |
| PC (physio-chemical) properties of TCN consists of: | Yellow-colored (conjugated double bonds), Amphoteric, commercial preparation are HCL salts (pH of sol 1.8-2.3) |
| TCNs are administration w/ oral route may cause _________ _______. | ESOPHAGEAL ULCERATION |
| What counseling points should we tell pts when taking TCN's? | Take with full glass of water Do not lay down immediately following administration Protect from heat, moisuture, and direct sunlight |
| TCNs are amphoteric: basic and acidic--> C4 contains a di-methyl amine this is ________. ON the right side of the TCN, it contains ____. This is where a pt could get the side effect of esophageal ulcerations while taking the capsule or tablet form of TCNs | basic pKa (9.4) acidic (pKa (3) |
| Why is it important to protect TCNs from sunlight? what does the color change mean? | pts will see preparation change in color from yellow to grey; Color change indicates drug DEGRADATION (can occur in months) |
| PC properties of TCN cont'd: TCNs can form ____ w/ polyvalent metal ions, complex is _______ in water. | chelation; insoluble |
| what counseling pt did Ramsinghani tell us about TCN when pt takes TCNs? | TAKE divalent and trivalent containing foods or meds 1 HOUR BEFORE OR 2 HOURS AFTER TCN |
| Why should children avoid taking TCNs? what age group? | TCN teeth; TCNs will complex with Ca2+ in teeth and bones causing stunted both formation and teeth will form yellowish complexes; Children < 12yo |
| PHOTOTOXICITY of TCN's can form _______ _______ through the many db that can absorb light producing these. | free radicals |
| What could a pt experience with the phytotoxicity? Is photo-onychoysis reversible? | Erythema on exposure to sunlight; Photo-onycholysis (nails turn blue-purple color or in extreme cases the nail separates from the nail bed; Yes, reversible once medication stops; tell pt to wear sun screen, long-sleeve clothes and hats |
| TCNs can undergo acid-catalyzed instabilities, which reaction and structures of the TCN exactly? | Dehydration rxn (loss of water molecule at C5-C6 forming a double bond b/w the 2 carbons (**once the water is lost, cannot be added back on) |
| C5-C6 dehydration rxn forms what inactive molecule? | anhydroteteracycline |
| TCNs can undergo acid-catalyzed instabilities, aside from the dehydration seen at C5-C-6, what other structure can undergo acid such as dimethyl at C4? | di-methyl group is alpha in active (TCN molecule) but can reverse its steriochemistry and in the presence of ACID, can become BETA becoming inactive |
| The transition of C4's dimethyl amine changes its steriochemistry from ALPHA to BETA, what is the name of this rxn? and what inactive molecule does it form? | Epimerization; 4-Epitectracycline (inactive) |
| Anhydrotetracycline (inactive) can also undergo epiemization changing C4 dimethyl from _______ to _______ forming which toxic molecule? | ALPHA to BETA; 4-Epianhydrotetracycline (Toxic) |
| Aside from Anhydrotetracycline converting to 4-epianhydrotetracycle via EPIMERIZATION, what other inactive molecule can convert to this toxic moelcule? via what rxn? | 4-Epitetracycline (inactive) can convert to 4- Epianhydrotetracycline via a DEHYDRATION rxn (so we see the C5-C6 water loss become the db in 4-epianhydtetracycline as well as the BETA steriochemistry |
| Why is 4-epianhydrotetracycline considered toxic? what SYNDROME can it cause? | Toxicity to the renal tubules (can have Polydipsia (poly-urea or glycosura (all of these toxic are grouped under FANCONI SYNDROME (*** so damage to renal tubules) |
| SARs of TCN: what structures or modifications are required? | Naphthalene ring system; -OH, O, ; C4 (dimethylamino group in the ALPHA orientation; Modifications can be seen at C5-C9 (so different R groups seen with different TCNs) |
| Tetracycline contains a OH at R3, but this is absent in Doxy and Mino, how does this aid their effect? | increases lipophilicity increasing oral absorption |
| Will Doxy and Minocycline form the epianydrodegradation? | No because the acid-catalysis will not be able to remove a water moelcule, since the OH is not present at R3 or C6. So no FANCONI SYNDROME :) |
| PK of TCNs--> Oral BA is variable, so its best on an empty stomach since taking with food that contains ________ decreases absorption | di/trivalent metal ions |
| Distribution of TCN: Wide distribution. Which TCN has CSF penetration? However they also cross the ________, and can enter ____ _____ which unfortunately can cause the ENAMEL of un-erupted teeth to turn yellow. | Minocycline (superior to doxy in that regard); placenta; breast milk |
| Minocycline and Doxycycline's half-life is 16-18 hours meaning their dosing is: | once-daily |
| What are some AE's of TCN? | GI DISCOMFORT--> N/V/D; photosensitivity, onycholysis and pigmentation of nails; discoloration of teeth in children (avoid in <12 yo); depressed bone growth in neonates (hence we don't give to pregnant women); Hypersensitivity rxn (rash) |
| TCN has an adverse effect of superinfection, what is this exactly? | superinfection (pseudomembranous colitis--> C. Diff associated diarrhea (more harmful bacteria will get a chance to grow) we're disrupting the natural flora) |
| Pts can also experience this other severe TCN AE which is? | intracranial HTN (pseudotumor cerebri) (**Increased pressure in the skull) |
| What drug interactions can occur with TCNs? | Antacids, Iron, Zn, Bismuth salts: which decrease TCN levels; Retinoic acids--> avoid combo since it could lead to benign psedotumor cerebri) |
| Why can't PCNs be used with TCNs? | taking the 2 together decreases PCN bactericidal effect; since TCNs prevent the growth and multiplcation of the bacteria and your ARRESTING the bacteria growth--> PCNs need actively dividing bacteria. |
| This group is related to TCNs since they share the common feature of the naphthalene ring system | Glycylcycline-->main drug (Tigecycline) |
| Tigecycline contains what structure at C9? How does this structure help the drug's activity? | T-Butylglycylamido substitution; Its polar and basic, and not only has good activity agains gram + and gram - but also active against MDR strains that were resistant to the first-line treatment. |
| Give an example of an MDR(multi-drug resistant) strain where the bacteria became resistant to the first-line option? | Tuberculosis (TB bacterium resistant to rifampin/Isoniazid) |
| MOR seen with the Glycylcycline (Tigercycline) is rare. How does it avoid TCN resistance? | Enhanced affinity to binding site (avoids the ribosomal protection of the tetK and tetM genes); and can cause steric hinderance to efflux proteins due to its C-9 substitution where the drug can't be effluxed out |
| The MOA of the Glycylcylcine (Tigercycline) is? | binds to 30S ribosome (inhibiting bacterial protein synthesis |
| What is the therapeutic use of Glycylcylcine (Tigercycline)? | Treatment of complicated skin/skin structure infections and intra-abdominal infections |
| How is the Glycylcylcine (Tigercycline) administered? | IV (not PO due to BASIC structures) |
| What AE can occur when using Glycylcylcine (Tigercycline)? | Injection site pain and thrombophlebitis |
| What are your new TCNs? | Eravacycline (Xerava) Omadacycline (Nuzyra) |
| What is Eravacycline (Xerava) and Omadacycline (Nuzyra)'s antibacterial activity? | similar to tigercycline; Basic, polar group substitution at C-9 which allows it to avoid the TCN resistance. |
| Ramsinghani test question: What part of the molecule allows the drug to avoid the TCN reistance? | substitution at C-9** |
| Aminoglycosides are natural products obtained from which species? | Streptomyces and Micromonospora |
| Which of your Aminoglycosides are derived from Streptomyces? | StreptoMYCIN, NeoMYCIN, TobraMYCIN |
| Which of your Aminoglycosides are derived from Micromonospora? | GentaMICIN |
| Aminoglycosides are linked via ________ bonds | glycosidic |
| All Aminoglycosides have at least ONE __________ sugar and a highly substituted _____ ________________ ring (aminocyclitol) | aminohexose; 1,3-diaminocyclohexane |
| Streptomycin contains a _____ group making it very basic | guanidino |
| Aminoglycosides are _________. | bactericidal |
| What is the MOA of Aminoglycosides? | inhibition of bacterial protein synthesis (Aminoglycosides bind to the 16S rRNA of the 30S subunit of the ribosome **(bind to the A site or they block further down and stop protein synthesis and cause pre-termination or incorporation of incorrect AA |
| Aminoglycosides can: | 1. Block initiation of protein synthesis 2. blocks further translation and elicits premature termination 3. incorporation of incorrect amino acids |
| What is the Aminoglycosides antibacterial activity? | Aminoglycosides are effective ONLY AGAINST AEROBIC MICROORGANISMS; effective against G + and G - bacteria; RESERVED for MORE SERIOUS G- infections **(only aerobic) |
| Aminoglycosides antibacterial activity is _______- dependent killing. They also have _____- antibiotic effect | concentration; maintain above the MIC for the drug to be effective; POST |
| Streptomycin is most effective against? | tuberculosis, brucellosis, and tularemia |
| MOR can occur with Aminoglycosides through which modifications? | Alteration of Drug--> using modifying enzymes (N-acetylation, O-phosphorylation, O-adenylation. All leads to inactivation of Aminoglycosides |
| Tell me about the Alterations of drug modifying enzymes: 1. N-acetylation; 2. O-phosphorylation; 3. O-adenylation | 1. amino groups in gentamicin won't bind 2. happens at different -OH groups (such as Tobramycin's top Carbon (CH2OH) 3. addition of an adenine ring (seen with gentamicin at the -OH) |
| These 3 alteration of drugs can occur with which species of bacteria? | S. aureus, P. Aeruginosa, Enterococci, Enterobacteriaceae |
| Bacteria that are resistant to other Aminoglycosides may be susceptible to _______. Why is that? | Amikacin; Amikacin is a semi-synthetic Aminoglycoside and was made with a modification HABA where bacteria aren't able to modify it |
| HABA seen in Amikacin has what effect for the drug? | Inhibits binding of modifying enzymes that affect other aminoglycosides |
| Another MOR for bacteria's fight against Aminoglycosides aside from the Alteration of Drug through modification is: | Mutation of drug target--> RIBOSOME; **30S gets mutated and drug won't bind effectively *Point mutation of ribosomal A site (tRNA gets mutated and drug may not be able to bind) |
| Aminoglycosides are strongly _______. What can they form? | basic; they can form water soluble salts with inorganic acids such as gentamicin sulfate |
| PK properties of Aminoglycosides: | A: poorly absorbed after oral admin (given parenterally for tx systemic infections) D: low distribution into tissues and secretions (low PPB) M: none E: urine (glomerular filtration with a half-life 2-3h |
| What is Neomycin's Boxed warning? | Its an ointment and when applied to in-tact skin won't be absorbed systemically; However when applied to "denuded-area" or a burn with broken skin--> can be absorbed and enter the systemic circulation and be VERY TOXIC |
| What are the main AE's of Aminoglycosides? | Nephrotoxicity--> Acute kidney injury (cationic AG bind to anionic phospholipids in the PROXIMAL tubule cell membranes Ototoxicity--> vestibular and cochlear toxicity (high AG conc. in endolymph and perilymph of inner ear |
| The higher the number of amino groups, the ______ the toxicity | greater |
| Rank the Aminoglycosides in order of least to most NEPHROTOXIC | 1. Neomycin (contains 6 amino groups) 2. Genatmicin (contains 5 amnio groups) 3. Streptomycin (contains 3 amnio groups) |
| What drug interactions should i be concerned with when using Aminoglycosides? | -increased risk of nephrotoxicity, ototoxicity w/vancomycin, AmpB; -Synergisim w/ B-Lactams -Neuromuscular blockers (depolarizing and non-depolarizing): Neuromuscular blocking effect enhanced by AG but respiratory depression may occur |
| AG and PCN--> Aminoglycosides and B-lactam antibiotics are _______ however ________ incompatible | synergisitc; chemically |
| Our new Aminoglycosides (Plazomicin) contains what structures? How do they help the drug? | HABA (hydroxyaminobutyric acid) AND hydroxyethyl groups; both help to evade AG-modifying enzymes (**help prevent inactivation of drug) |
| What MOR do we see with Plazomicin? What indication does Plazomicin have? | Efflux, and Alteration of ribosome; used for cUTI (**complicated UTI) |
| PCN and AG (2 things) | should not be mixed together (not in the same IV bag) can be used together (remember the synergisitic effect, they are both bactericidal) |
| Key points of 30S protein synthesis inhibitors consist of: | Selective toxicity due to difference in bacterial and host ribosome Use: TCN have a variety of indications; AG-AEROBIC G (-) Admin: TCN (mostly oral); AG (mostly parenteral) TCN: Chelation/photosensitivity/pH related instability (fanconi) AG: Chemical rxn w/ PCN MOR: TCN (tetK and tetM) ribosome protection and effux; AG: covalent modification of AG (N-acetyl, O-phospo, N-adenyl Effect of PCN: TCN (antagonism); AG (synergism) |
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Xander635
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