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ID Exam 3 D
Ramsinghani Protein Synthesis Inhibitors 50S
| Question | Answer |
|---|---|
| What are your Antimicrobials that target 50S ribosome? | Macrlides: EryTHROMYCIN, ClariTHROMYCIN, AziTHROMYCIN Lincosamides: Clindamycin Oxazolidine: LineZOLID, TediZOLID Chloramphenicol |
| Macrolides contain a: | large lactone ring, ketone group, and an amino sugar (*Neutral sugar linked either to the amino sugar or to the lactone ring |
| Ramsinghani refers to Erythromycin as the __________ macrolide | prototypical |
| What is the MOA of your Macrolides: | bind to the 23S rRNA of the 50S subunit--> blocks the polypeptide exit tunnel adjacent to peptidyl transferase |
| Macrolides have what kind of activity? Pts with ____ allergy can use this class of drugs | Bacteriostatic; PCN allergy |
| What is the MOR (mechanism of Bacterial resistance) seen in Macrolides? | 1. METHYLATION of some guanine resudes of rRNA that decrease antimicrobial binding via the "erm" gene. 2. Mutation of an adenine to guanine in 23S rRNA (decreases antimicrobial binding) 3. Drug Efflux via--> mefA, msrA, msrB (these produce your efflux proteins) |
| erm stands for? | erythromycin ribosomal methylation gene |
| The erm gene is special. This gene can cause cross-resistance with which drug classes? why is there cross-resistance? | Macrolides, Lincosamide, and Streptogramin (MLS phenotype); All of these bind to the same site (methylation rxn) |
| Macrolide activity consists of: | Broad antibacterial spectrum: Gram (+): Streptococcus gram (-): Haemophilus, Neisseria, Moraxella Atypicals: Legionella, Chlamydia, Mycoplasma, and some Mycobacterium species |
| Macrolides are particularly useful in what infections? | upper and lower respiratory |
| Clarithromycin is used for _________ _____ due to Helicobacter pylori | Gastric ulcers |
| Tell me about Erythromycin? Its water salts? | weakly basic, pKa (8); free base making it insoluble in water Water insoluble salts--> ethylsuccinate, stearate (oral) water soluble salts: lactobionate (Parenteral) |
| Acid instability can occur with which Macrolide? | Erythromycin: (Ketal formation--> the Hydroxy group (C-6) reacts with a keto group (C-9) where they cyclize |
| To prevent the ketal formation seen in erythromycin, we implement the following modifications: | 1. coated tablets (wont undergo acid mediated formation in stomach and prevent formation of ketal 2. structural modifications (**this is how we get Azithromycin and Clarithromycin) |
| Aside from the ketal formation due to acid instability, what other problem lies with Erythromycin? | unpleasant taste (to overcome this, we use water INSOLUBLE dosage forms (ethylsuccinate and stearate) help to mask the "bitter" taste and reduce the acid instability in the process. **not soluble in stomach so the acid can't do the chetal formation and prevent it completely to help reduce the GUT CRAMPS |
| What structural modifications were made to Azithromycin to prevent the ketal formation? What effect does this modification give to Azithromycin? | N-methyl group inserted into the ring b/w C-9 and C-10 known as Azalide), and the C-9 carbonyl was removed; makes it first choice macrolide and gives it POST-antibiotic effect |
| What structural modifications were made to Clarithromycin to prevent the ketal formation? | C-6-OH---> C-6-OCH3 (methoxy), this also increases its oral BA |
| This Macrolide has an oral BA of about 50% and its metabolism is Hepatic via CYP3A4 (14-OH _______ (active metabolite); Its elimination is renal unchanged + 14-OH metabolite | Clarithromycin |
| This Macrolide has an oral BA of about 25%, 3A4 metabolism (hepatic) leads to inactive metabolites and elimination is via BILE | Erythromycin |
| This Macrolide has an oral BA of 37%, Its distribution--> longer and higher tissue penetration (lungs 100x higher than plasma; Hepatic metabolism leads to inactive drug, and elimination is via bile and feces with a 1/2 life of 68 hours | Azithromycin (once daily dosing due to 1/2 life) |
| Due to Azithromycin longer and higher tissue penetration distribution, and achieving 100x in penetration to the lungs is why this drug is also used in treating _______ ______ | respiratory infections |
| Macrolides AE consist of: | -QT prolongation and ventricular arrhythmias (increased risk of CV mortality) -Hepatotoxicity (abnormal LFT, hepatitis) -GI discomfort (w/ erythromycin: diarrhea, abdominal pain, cramping (*not seen with Azithro or Clarithro) |
| What Drug interactions should i be concerned of when using Macrolides? | -Erythromycin and Clarithromycin are MAJOR substrate and strong inhibitors of CYP3A4; -Macrolides are CI w/many CYP3A4 metabolized drugs such as (alprazolam, colchicine, ergotamine, simvastatin); -Azithromycin: MINOR 3A4 substrate (fewer clinically significant DI); -QT prolongation: additive effect possible (avoid concurrent use with other QT prolonging drugs) |
| Tell me about Fidaxomicin (Dificid) whats special about it? MOA? PK properties? | Larger macrolide (BACTERICIDAL) MOA: inhibits RNA synthesis by inhibiting RNA polymerase; PK: A: poor oral absorption (C.Diff GI infections since the drug remains in the gut); M: hydrolysis of isobutyl ester (less active metabolite); E: fecal 1/2 life: 11h |
| So the big things to remember about Fidaxomicin are: | High Molecular weight; High lipophilicity (logP:9) (due to macrocyclic ring); low aqueous solubility |
| Tell me about Lincosamides (Clindamycin): important structure? MOA? unique groups? | Octoside (8 carbon sugar); MOA: binds to 23S rRNA of 50S ribosomal subunit; Cl group--> adds lipophilicity (oral BA: 90%) |
| What prodrugs can be formulated with Clindamycin? | Phosphate ester (parenteral) (*phosphate can ionize) Palmitate ester HCL (oral) (*C-16 fatty acid) |
| Clindamycin, our lincosamide can undergo what metabolism? | N-demethylation (leading to active metabolite) |
| What is Clindamycin's antibacterial activity? | Primarily active against (gram + bacteria; useful in PCN allergy); excellent activity against PROPIOBACTERIUM ACNES |
| What MOR can bacteria use against Clindamycin? | same as Macrolides (MLS via the "erm" gene) |
| What AE's can occur with Clindamycin? What is the BIG BOX WARNING with Clindamycin? | GI discomfort; Pseudomonas colitis (C. Diff associated diarrhea) |
| What is the name of the Oxazolidinone drug? what is the MOA and Antibacterial spectrum> | Linezolid (Zyvox)--> its a synthetic antibiotic containing an oxazolinedenome ring; MOA: binds to the 23s rRNA of 50S ribosomal subunit--> preventing the formation of the initiation complex; Gram (+) especially for VRE, MRSA; HAP, CAP, SSTI |
| What resistance can occur with Linezolid? | mutation of 23S rRNA (gram (-) --> have intrinsic resistance due to efflux pumps, and this is why we can't use Linezolid for gram (-) infections |
| What are some AE's that can occur with Linezolid? | Myelosuppresion (pt must get a weekly CBC for monitoring), headache, diarrhea, peripheral and optic neuropathy (vision changes so must be monitored |
| Linezolid has 100% BA after oral absorption making it a good conversion from: | IV to PO |
| Ramsinghani reminder of Linezolid's drug interactions are that its a ___________. | MOAI (monoamine oxidase inhibitor) ***So use caution w/ adrenergic and serotonergic drug (SSRI), and Tyramine rich foods; Exacerbation of Hypoglycemia (So use caution w/ oral hypoglycemic agents/ insulin) |
| Tyramine-rich foods contain _______ which aid in regulating BP. These are seen in aged cheese/fish/wine/chicken which can increase BP :( | Amino acids |
| Tedizolid (another Oxazolidinone): Brand name? Unique structures? MAOI? | Sivextro; prodrug containing a phospo group with 2 Na+ (this groups is removed via the plasma or intestinal phosphatase leading to Tedizolid (active); BA 90% in IV/PO; This drug is an MAOI |
| What is special about Chloramphenicol? | MOA: binds to the 50S ribosomal subunit Antibacterial activity: broad spectrum (FOR SERIOUS infections that are not treatable by other antibiotics (this is due to its serious AE) |
| Bacterial resistance to Chloramphenicol can occur via: | R-factor enzymes--> acetylation of OH |
| To counter the resistance, Chloramphenicol can be formulated as prodrugs using: | hemisuccinate (parenteral formation Palmitate (oral but this has been DISCONTINUED) |
| What are the main ADRs to know about with Chloramphenicol? | -Grey baby syndrome (babies stop feeding and respiration becomes "out of whack" and develop cyanosis and get grey color--> MORTALITY is very high; -Blood dyscrasia (poor blood cell formation) |
| Key points to know with the 50S ribosome drugs: | -50S protein synthesis inhibitors are--> 23S rRNA -Broad spectrum: Macrolides, chloramphenicol -Clindamycin, Linezolid--> gram (+) -Macrolides for URI and LRI (upper and lower respiratory infections); remember the ketal formation, MLS phenotype, QT-polongaition and DI (CYP3A4) -Clindamycin--> tx of acne (C.Diff diarrhea) -Linezolid: 100% oral BA; MAOI -Chloramphenicol: Gray baby syndrome; blood dyscrasia |
Created by:
Xander635
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