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34 Cards in this Set
- Front
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sulfonamides and trimethoprim drug examples |
sulfamethoxazole sulfisoxazole trimethoprim/sulfamethoxazole sulfacetamide/topical silver sulfadiazine/topical |
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sulfonamides |
synthetic derivatives of p-aminobenzen sulfonamide - classified as anti-infectives
possess antibacterial activity that is antagonized by p-aminobenzoic acid or p-aminobenzoyl glutamic acid |
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sulfonamide MOA |
structural analogs and competitive atagonists of para-aminobenzoic acid (PABA)
prevent normal bacterial utilization of PABA for synthesis of folic acid (prevent DNA synthesis)
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what enzyme does sulfonamides block? |
dihydropteroate synthetase
block: PABA -> folate |
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what enzyme does trimethoprim block? |
dihydrofolate reductase
block: folate -> tetrahydrofolate |
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4 groups of sulfonamides |
1. absorbed and excreted rapidly with excellent antibacterial ability eg. sulfisoxazole, sulfadiazine
2. absorbed poorly when administered PO and active only in bowel lumen - used for UC and regional enteritis eg. sulfasalazine
3. mainly used topically eg. sulfacetamide, mafenide, silver sulfadiazine
4. long-acting - absorbed rapidly but excreted slowly eg. sulfadoxine |
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sulfonamide spectrum |
broad spectrum G(+) and G(-)
excert only bacteriostatic effect |
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sulfonamide indications |
1. UTI 2. nocardiosis 3. toxoplasmosis 4. use of sulfonamides for prophylaxis |
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suflonamide + trimethoprim indication |
1. UTI (upper, lower, prostatitis)
2. respiratory tract infections (bronchitis, otitis media, pneumonia)
3. pulmonary infections secondary to P. carinii (treatment and prevention)
4. gastrointestinal infections such as salmonella, shigella, traveller's diarrhea |
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uses of trimethorprim |
on its own, as effective as sulfamethoxazole/trimethoprime combo for Tx of respiratory tract or urinary tract infection
useful in pts allergic to sulfas
drug resistance is a problem |
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synergists of sulfonamides |
-sulfonamides is synergistic with trimethoprim
simultaneous administration introduces sequential blocks in pathway by which microorganisms synthesize tetrahydrofolate from precursor molecules |
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absorption of sulfonamide |
-abs rapidly from GIT -70-100% of oral dose absorbed -can be detected in urine within 30min -peak plasma levels achieved in 2-6h
small intestine is major site of absorption but some also absorbed from stomach
-pass readily through placenta and reach fetal circulation in concentrations sufficient to cause antibacterial and toxic effects to fetus |
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sulfonamide excretion |
eliminated partly as unchanged drug and partly as metabolic products (excretion higher in night)
largest fraction excreted in urine
in acidic urine, the older sulfonamides are insoluble and may precipitate, forming crystalline deposits that can cause urinary obstruction |
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ADRs to sulfonamides |
-most common: fever, skin rash, N/V/D -disturbances of urinary tract -disorders of hematopoietic system -hypersensitivity rxns due to sulfonamide ring |
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bacterial resistance to sulfonamides |
mutations that cause overproduction of PABA, cause production of a folic-acid synthesizing enzyme that has low affinity for sulfonamides, or loss of permeability to sulfonamide
dihydropteroate synthase with low sulfonamide affinity is often encoded on a plasmid that is transmissible and can disseminate rapidly and widely
sulfonamide-resistant cells may be present in susceptible bacterial populations and can emerge under selective pressure |
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sulfonamide + trimethoprim ADRs |
GI: N/V, photosensitivity
hematologic: in high doses folic acid deficiency, anemia, leukopenia, thrombocytopenia
crystalluria:
hypersensitivity: rash, angioedema, Stevens-Johnson syndrom common
kernicterus |
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crystalluria |
ADR of sulfonamide + trimethoprim
nephrotoxicity develops as a result of crystalluria -hydration and alkalinization of urine prevent the problem (change pH of urine so crystals can dissolve) -sulfisoxazole & sulfamethoxazole more soluble at urinary pH
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kernicterus |
ADR of sulfonamide + trimethoprim
this disorder may occur in newborns, b/c sulfa drugs displace bilirubin from binding sites on serum albumin the bilirubin is then free to pass into the CNS, b/c the baby's BBB is not fully developed |
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contraindications of sulfonamide/trimethoprim |
due to danger of kernicterus, sulfa drugs should be avoided in newborns and infants < 2mth as well as in pregnant women |
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quinolones |
inhibit DNA synthesis
bactericidal and kill bacteria in concentration dependent manner |
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first generation quinolones |
used less often today
moderate G-
minimal systemic distribution |
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second generation quinolones |
expanded G- and atypical pathogen coverage
limited G+ activity
most active against aerobic G- bacilli
Ciprofloxacin is quinolone most active against Pseudomonas aeruginosa |
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third generation quinolones |
retain expanded G- and atypical intracellular activity
improved G+ coverage |
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fourth generation quinolones |
improve G+ coverage
maintain G- coverage
gain anaerobic coverage |
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quinolone MOA |
rapidly inhibit DNA synthesis by promoting cleavage of bacterial DNA in the DNA-enzyme complexes of DNA gyrase and type IV topoisomerase resulting in rapid bacterial death
gram- bacterial activity correlates with inhibition of DNA gyrase
gram+ bacterial activity correlates with inhibition of DNA type IV topoisomerase |
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therapeutic uses of quinolones |
prostatitis genitourinary infections respiratory diseases skin and soft tissue infections gastroenteritis STDs
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synergists of quinolones |
when used in combo w other antibotics such as beta-lactams and AMGs, not synergistic
ciprofloxacin and rifampin appear to be antagonistic against Staphylococcus aureus |
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absorption of quinolones |
well absorbed PO with moderate to excellent bioavailability
serum drug levels achieved after po comparable to IV (allows early transition from IV to po and reduce cost)
food does not impair abs
chelate with cations (Al, Mg, Ca, Fe, Zn) -significantly reduces abs and bioavailability, resulting in lower serum [drug] and less target-tissue penetration |
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distribution of quinilones |
widely distributed
tissue penetration higher than concentration achieved in plasma, stool, bile, prostatic tissue, and lung tissue
intracellular concentration is exceptional in neutrophils and macrophages |
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elimination of quinilones |
t1/2 varies from 1.5 to 16h -most drugs dosed q12-24h
eliminated by renal and nonrenal routes -dose adjustment in renal or hepatic impairment
majority are excreted renally; however, sparfloxacin, moxifloxacin, and trovafloxacin are excreted hepatically |
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resistance to quinolones |
quinolones inhibit 2 critically important enzymes that are required for bacterial DNA synthesis 1. DNA gyrase 2. Topoisomerase IV
resistance due to chromosomal mutation in the genes encoding these enzymes and by porin and efflux mutation
1. enzyme mutation -> changes in target regions of the drug binding site to the enzyme -> reduced drug affinity
2. mutation changes porin proteins in outer membrane -> decreased permeability of drugs -> less drug supply to target enzyme
3. mutation enhances efflux capability of organism -> increase amount of drug pumped out |
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quinolone ADRs |
GI: N/V/D, abdominal pain CNS: headache, dizziness, drowsiness, confusion, insomnia, fatigue, depression, somnolence, seizures, vertigo, restlessness, tremor dermatologic: rash, photosensitivity rxns, pruritis |
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quinolone interactions |
may increase risk of CNS stimulation and convulsions if used concomitantly with NSAIDS
may lead to hypo/hyperglycemia if used concomitantly with antidiabetic agents
probenecid
H2RAs decrease absorption |
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examples of quinolones |
nalidixic acid ciprofloxacin ofloxacin norfloxacin levofloxacin lomefloxacin sparfloxacin |
