Help
Options
Didn't know it?
click below
click below
Knew it?
click below
click below
Don't Know
Remaining cards (0)
Know
retry
shuffle
restart
0:00
Embed Code - If you would like this activity on your web page, copy the script below and paste it into your web page.
Normal Size Small Size show me how
Normal Size Small Size show me how
ID Exam 3 F
Ramsinghani FQs/Sulfonamides/Trimethoprim/Miscellaneous Abx
| Question | Answer |
|---|---|
| Bacteria uses Type II Topoisomerase to aid in DNA synthesis and replication. But there are 2 types. What are they? | DNA gyrase (relieves supercoils); Topoisomerase IV (Decatenation) |
| As explained by Ramsinghani (Type II Topoisomerase) | Cuts the DNA on 1 strand (when 2 strands are separating to replicate) the protein in front get more tightly wound up so the strand tension needs to be released (DNA gyrase); Topoisomerase IV will separate the 2 DNA daughter strands called Decatenation) |
| How do FQ’s (Fluoroquinolones) have selective toxicity? | Mammalian topoisomerase II has LOWER binding affinity to FQ than bacterial Topoisomerase II |
| Give me a generalized view of FQ’s? | They are bactericidal, have broad spectrum (G+ and G-); they are synthetic abx (they are not obtained from any microbial fermentation); They are concentration dependent abx (AIC-MIC) |
| What is the MOA of FQ’s? | FQ’s inhibit DNA gyrase and topoisomerase IV, thereby inhibit DNA replication |
| The use of FQ’s in G - bacteria would primarily inhibit ___ _______ | DNA gyrase |
| The use of FQ’s in G + bacteria would primarily inhibit _________ __ | Topoisomerase IV |
| FQ use is indicated for? | Common uro-genital, respiratory, and GI infections caused by E. Coli, K, pneumoniae, C. Jejuni, P. Aeruginosa, Enterobacter, Salmonella, and Shigella sp. -also used in tuberculosis as 2nd line |
| What are the likely mechanisms of bacterial resistance to FQ’s? | Mutation in bacterial topoisomerase; insufficient accumulation of FQ in bacterial |
| Mechanism of Bacterial resistance can be: | 1. Alteration of Target by Enterobacteriacae, S. Aureus—>(DNA gyrase: mutation in gyrA and gyrB genes; topoisomerase IV: mutation in part and parE genes 2. Insufficient accumulation of drug: Reduced permeability (enterobacterales, P. Aeruginosa); Enhanced efflux (E. Coli, P. Aeruginosa) |
| FQ structure and SAR in the class: | 1. Carboxy-4 pyridone nucleus--> Pharmacophore 2. Substitution at C2 interferes w/ gyrase - DNA complexation 3. C6-F group increases abx activity (increased cell penetration due to lipophilicity **C-3 (containing CO2H) and C-4 (containing a ketone) will be where FQ bind DNA gyrase to the drug |
| SAR's to know in the FQ structures--> | Ofloxacin and Levofloxacin are isomers. Ofloxacin (racemate)--> has an equal mix of R and S isomers); Levofloxacin--> S isomer |
| What are the brand names to our FQ's: Ciprofloxacin; Levofloxacin; Moxifloxacin; Delafloxacin | Cipro; Levaquin; Avelox; Baxdela |
| Tell me about the FQ antibacterial spectrum: Ciprofloxacin and Ofloxacin? | G -, atypical; covers P. Aeruginosa |
| Tell me about the FQ antibacterial spectrum: Levofloxacin? | G +, G -, atypical; covers S. Pneumoniae, P. Aeuginosa |
| Tell me about the FQ antibacterial spectrum: Moxifloxacin? | G +, G -, atypical; Does not cover P. Aeruginosa |
| Tell me about the FQ antibacterial spectrum: Delafloxacin? | G +, G -, atypical, anaerobes *Most broad spectrum FQ; covers P. Aeruginosa, MRSA, S. Pneumoniae |
| Tell me about FQ's PK: | A: good oral absorption, Excellent BA; IV;PO; comes in ophthalmic, otic formations; D: large Vd (well distributed into all tissues and body fluids, moderate PPB; M: partially to less active compounds (**CYP enzymes generally not involved) E: mostly renal t1/2 life varies 3-12h |
| Tell me about Moxifloxacin: | Distribution--> tissue concentration exceeds plasma concentration making it a very potent FQ; Elimination--> via Hepatic |
| What will be the NET charge on Ciprofloxacin at Physiologic pH? | NH+ (pKa 8.68) and COO- (pKa 5.76) --> Zero |
| The net zero charge on Ciprofloxacin can cause: | poor excretion of FQ leading to crystalluria. To prevent--> ensure adequate hydration and dose adjust for GFR **Ramsinghani note--> many FQ's will exist in the Zwitter ionic form therefore less soluble |
| Other PC (physiochemical properties) seen in ciprofloxacin--> | **can form chelation with di,trivalent metal ions seen at Oxole groups separate oral administration of FQ and metal ion containing meds or foods |
| ADR's to keep in mind with FQ's: | -GI (N/V/D (most common)) -Photosensitivity/Phototoxicity (Fluro groups) -Cardiotoxicity: Prolonged QT interval |
| What are the BOXED WARNINGS for FQ's? | Tendonitis, tendon rupture; peripheral neuropathy; CNS effects; Exacerbation of myasthenia gravis |
| FQ's should be avoided in pregnant, nursing mothers due to? | risk of severe metabolic acidosis, hemolyhtic anemia in 1st trimester; and erosion of load bearing joints |
| Avoid FQ's in what pt populations? | pts with myasthenia gravis |
| What Drug interactions can occur with FQ? | QT interval prolonging drugs (CI due to additive effect); Sulfonylureas/insulin (can cause dysglycemia (hypo/hyper)); Antacids, di-, trivalent metal ions; Corticosteroids |
| Key points about FQ's include: | MOA: DNA gyrase, Topo IV; selective toxicity (difference in binding affinity to target; bacterial resistance: mutation in genes (gyrA, gyrB, parC, par E); influx/efflux; Bacterial coverage--> BROAD; can cause crystalluria, chelation; ADR: Tendonitis; DI: QT-prolonging drugs |
| Tell me about the Selective toxicity of Sulfonamides: | Humans are unable to synthesize folic acid--> must obtain from diet; Bacteria MUST synthesize its own folic acid (cannot absorb from human diet) |
| The following is true of folic acid as a nutrient--> | Essential for humans, not for bacteria |
| What is the MOA of Sulfonamides? | 1. Inhibition of dihydropteroate synthase--> competitive inhibition (*no formation of Tetrahydrofolic acid in bacteria) 2. Attachment to pteridine ring--> false metabolite |
| Sulfonamide has a pKa of 10.4. Which form will predominate at urine pH of 6? | unionized form |
| Which form of sulfonamide is likely to cause crystalluria? | unionized form |
| Sulfonamides mimic what structure? | PABA |
| Sulfonamides in the presence of pH 6-8 and a pKa of 10.4--> | will not have substitution at N1 since drug is unionized |
| Sulfonamides in the presence of pH at 6-8 and a pKa of 5 (Sulfisoxazole)--> | has substitution at N1 w/ electron withdrawing group (heterocyclic ring) and stabilizes the ionic form **reduces risk of crystalluria |
| SAR of Sulfonamides--> | The sulfonamides are SYNTHETIC ANTIBACTERIAL 1. unsubstituted -NH2 group PARA to sulfonamide moiety (1.e N4) 2. alteration of benzene ring--> unfavorable 3. N1 (next to sulfone) can be substituted w/ electron withdrawing group--> increases abx activity; reduces crystalluria |
| Clinically relevant Sulfonamides--> Sulfacetamide (Sulamyd) | Therapeutic use--> management of local opthalmic infections i.e. conjunctivitis |
| Clinically relevant Sulfonamides--> Silver Sulfadiazine (Silvadene) | Therapeutic use--> Burn therapy |
| Clinically relevant Sulfonamides--> Sulfamethoxazole (Gantanol) | Therapeutic use--> **used in combination w/ Trimethoprim for tx of UTI |
| Tell me about Sulfonamides PK properties: | A: good oral absorption except sulfasalazine (IV:PO ratio is 1:1) D: well distributed in tissues and body fluids (Sulfadiazine and sulfisoxazole in CSF); all cross placenta; PPB varies; M: N4-acetylation or glucoronudation in liver (inactive metabolites) E: urine (major) unchanged + metabolites); 1/2 life varies |
| Poor metabolizers of NAT will have ________ plasma concentration of sulfonamides | increased |
| What drug interactions can occur with Sulfonamides? | Warfarin, phenytoin, oral hypoglycemic agents, methotrexate (drug effects may be increased); inhibtion of CYP2C9 and/or displacement from PPB |
| What ADR's should i be aware of with Sulfonamides? | Hypersensitivity: drug fever, rash, photosensitivity; Steven Johnson's syndrome (<1%) |
| Sulfamethoxazole can break down into Hydroxylamine and N-Nitroso metabolite. Can these cause a sulfa allergy? | These can undergo rxns that can form toxic metabolites *if the amino groups are substituted--> no formation of toxic metabolites; *If they are unsubstituted such as with a NH2 in sulfamethoxazole or a 1-sided bond to a amino group--> can get the toxic formations. |
| A sulfa allergy can take the form of: | Delayed rxn (Type IV) with s/sx of drug fever, rash, SJS, or TENS; Abx sulfonamides (about 5% of pts will experience toxic metabolites); there is an increased risk in pts that are slow acetylators; and there is a risk of cross-reactivity |
| Can a pt get a sulfa allergy from Furosemide? | It has substitution of the amino group at C4--> not able to form toxic metabolites b/c the amino group is substituted (very low risk of causing sulfa allergies) |
| Other ADR's to consider in Sulfonamides are the ________ disturbances. What are these? | Hematopoeitic; (Hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia); may provoke hemolytic rxn inG6PD-DEFICIENT pts. |
| Another serious ADR of sulfonamides in newborns is? | Kernicterus; CI in newborns (<2 months), late pregnancy, breastfeeding women |
| RBC rely on PPP to get its NADPH (cofactor). RBC use the enzyme _______________________ to get its NADPH. NADPH reduces the glutothione. why do we need it in the reduced phase? | glucose-6-phosphate dehydrogenase; need it in the reduced form to "take care of our oxidative damage." RBC would be susceptible to oxidative damage leading to hemolytic anemia |
| Sulfa drugs can displace _______, which is a byproduct of RBC when they decay | bilirubin |
| When RBC decay, they release bilirubin and that conjugates with the Plasma protein and is given out in the feces. In newborns--> | hepatic function takes 6-8 weeks to develop. in these newborns, if sulfa drugs are given, it can displace the bilirubin from the plasma proteins and can enter the brain causing serious brain damage (cerebral palsy) |
| What is the antibacterial spectrum of Sulfonamides? | G +, G -, Bacteriostatic; Poor activity against ANAEROBES |
| MOR of Sulfonamides? | Resistance is common: 1. Alteration of enzyme dihydropteroate; 2. Overproduction of PABA |
| What is the MOA of Trimethoprim? | inhibits dihydrofolate reductase (DHFR) that is necessary to convert folic acid to tetrahydrofolate |
| What is the selective toxicity of Trimethoprim? | inhibits bacterial DHFR at 100,000x lower conc. than mammalian enzyme |
| What are the PK properties of Trimethoprim? | A: good oral absorption; D: widely distributed (middle ear, prostatic fluid, vaginal fluid, bile, CSF; M: partially metabolized in liver; E: urine (60-80% unchanged); 1/2 life: 8-14h |
| Tell me about the TMP-SMX combination: | 1:5 ratio; used primarily for tx of UTI; Combination is synergistic; Minimizes bacterial resistance (UTI, otitis media, MRSA); ADR: Hyperkalemia, Rash |
| Sulfonamide attacks b/w Pteridine + PABA blocking the conversion to---> | Dihydropteroate |
| Trimethoprim attacks b/w Dihydrofolic acid blocking the conversion to ---> | Tetrahydrofolic acid |
| MOR of TMP-SMX can occur via: | -Alteration of target (Dihydropteroate synthase (causes resistance to the sulfa component); Dihydrofolate reductase (causes resistance to Trimethoprim) -Overproduction of PABA |
| Nitrofurantoin (Macrobid/Macrodantin) is a _______ ____ | Miscellaneous antibiotic |
| What is the MOA of Nitrofurantoin? | likely multi-targeted (production of a reactive reduced nitrofurantoin intermediate--> making it very reactive causing interference in a lot of bacterial processes |
| Nitrofurantoin can cause interference in bacteria due to its reactive reduced intermediate. What can it interfere with? | protein synthesis; metabolism; DNA synthesis and gene expression |
| Resistance to Nitrofurantoin is ____ | rare |
| The main use of Nitrofurantoin is for the tx of: | acute uncomplicated cystitis (lower UTI) |
| PK properties about Nitrofurantoin include: | A: well absorbed, oral BA increased w/ food by 40%; D: limited; M: inactive metabolites E: urine (1/2 life 20-60 min) |
| What are the ADR's of Nitrofurantoin? | Nausea; macrocrystalline product is better tolerated; food increases absorption, decreases nausea; can cause pulmonary toxicity (acute or chronic); Drug-induced liver injury (DILI); Hemolytic anemia (G6PD) |
| What Drug interactions should I be concerned with while taking Nitrofurantoin? | avoid combination w/ Magnesium trisilicate: reduced absorption and excretion (AVOID) |
| What is the MOA of Fosfomycin (Monurol)? Can resistance occur? | inhibits cell wall synthesis; Yes: decreased influx (mut GlpT and UhpT) |
| Fosfomycin (Monurol) drug properties? | contains a phosphate; bactericidal, and has broad spectrum |
| PK properties of Fosfomycin (Monurol)? | A: oral BA: 30% D: well distributed, no PPB M: unknown E: urine + fecal t1/2 life--> 2-4h |
| Fosfomycin (Monurol) is indicated for the use of? Resistance can be seen in what species? | For acute uncomplicated cystitis (due to resistance, its mostly for limited infections; E. Coli and E. Faecalis |
| ADR of Fosfomycin (Monurol) is? | Diarrhea |
| What is the MOA of metronidazole? | disruption of DNA, RNA structure and function (inhibition of protein synthesis, cell death) |
| How is metronidazole metabolized? | -Reduction activation (becomes Hydroxyethyl oxamic acid) and -Reductive inactivation (becomes 2-Aminometronidazole) -Metabolized in host |
| How is Metronidazole metabolized in the host? | --> so instead of the CH3, you have a Hydroxylation to the Methyl hydroxy group and that is an active metabolite -by converting to 2-hydroxymethyl metronidazole metabolite (Active metabolite) |
| Resistance of Metronidazole is due to: | decreased drug influx; decreased reductive activation of drug; increase in DNA repair |
| What is Metronidazole used for? | Bacterial vaginosis (vaginal gel); amebiasis (bacterial infection) comes in: systemic (oral) and IV); activity against Bacteriodes species and C. Diff |
| PK propeties of Metronidazole consist of? | A: well absorbed D: well-distributed M: Hepatic (2-hydroxymetronidazole (active)--> 30-60%, and others; E: urine (20% unchanged + metabolites) |
| ADR's of Metronidazole consist of? What are its contraindications? | Nausea, Vaginitis, HA, metallic taste; CI: alcohol, disulfuram (this is not seen with the gel) |
| Metronidazole can cross the _______; hold breastfeeding w/oral and IV dosage forms | placenta--> low risk (but risk of cleft lip in FIRST TRIMESTER |
| Key points to remember about our Sulfonamides/Trimethoprim and our miscellaneous antibiotics: | -Sulfonamides: selective toxicity; MOA; Bacterial resistance; heterocyclic substiution on N1, Crystalluria, hemolytic anemia, sulfa allergy; displacement of other drugs from PPB; -TMP/SMX combo--> is synergistic (1:5) -Nitrofurantoin/fosfomycin: use is for acute uncomplicated cystitis -Metronidazole for bacterial vaginosis |
Created by:
Xander635
Popular Pharmacology sets