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Infectious Disease > Week 1: Nucleic Acid Synthesis inhibitors > Flashcards

Week 1: Nucleic Acid Synthesis inhibitors Flashcards

1
Q

Learning Objectives

A
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2
Q

Classes of bacterial protein synthesis inhibitors

A
  • Free-radical generators
  • Antimetabolites
  • DNA Gyrase Inhibitors
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3
Q

Free-radical generators

A

Metronidazole

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4
Q

Antimetabolites

A
  • Sulfonamides
  • Trimethoprim
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5
Q

DNA Gyrase Inhibitors

A

Fluorquinones

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6
Q

Fluoroquinolones

A
  • Ciprofloxacin
  • Levofloxacin
  • Moxifloxicin
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7
Q

Metronidazole drug class

A

Free-radical generatory bacterial protein synthesis inhibitor

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8
Q

Metronidazole MOA

A
  • Low redox potential in anaerobic systems required for reduction of the nitro group
  • Reduction of the nitro group generates reactive intermediates (eg Anion nitroso free-radicals)
  • Reactive froups disrupt nucleic acid and protein structure and function
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9
Q

Metronidazole Spectrum of activity

A
  • Active against obligate anaerobic bacteria and selected parasites, bactericidal
  • Concentration dependent killing with PAE
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10
Q

PAE AKA

A

Post-Antibiotic Effect

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11
Q

Metronidazole route of administration

A
  • Oral
  • Topical
  • Parenteral
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12
Q

Metronidazole distribution

A

Wide distribution including secretions, bone and CNS

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13
Q

Metronidazole metabolism and elimination

A

Hepatic metabolism with urinary elimination of unchanged drug and hepatic metabolites

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14
Q

Metronidazole and hepatic dysfunction

A

Dose REDUCTION is necessary in severe-hepatic dysfunction

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15
Q

Metronidazole toxicities

A
  • CNS toxicity: including ataxia, psychosis and convulsions
  • Disulfiram-like effect with alcohol - inhibits acetaldehyde dehydrogenase leading to acetaldehyde poisoning, recent evidence suggests a central serotonin-syndrome
  • Immunosuppressive and anti-inflammatory
  • Candida superinfection
  • Mutagenic, possibly carcinogenic
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16
Q

Metronidazole spectrum

A

Anaerobes:

  • C. difficile (also vancomycin, fidaxomicin)
  • Bacteroides fragilis
  • Eubacteria
  • Peptostreptococcus
  • Trichomonas vaginalis
  • Giardiasis
  • Amebiasis

Used against H. pylori in combination with other drugs (eg tetracycline, amoxicillin, clarithromycin, + proton pump inhibitor

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17
Q

Sulfonamides and Trimethoprim MOA

A
  • Sulfonamides are PABA analogs that inhibit folic acid synthesis by dihydroteroate synthetase
  • Trimethoprim is a pterdine analog that inhibits dihydrofolate reductase
  • Trimethoprim/Sulfamethoxazole produces synergistic antibacterial effects given at 1:5 resulting in optimal blood and tissue ratios ~1:20; paired for similar t1/2 (~10 hours)
  • Selectivity - sensitive bacteria synthesize folic acid in contrast to our uptake of preformed folic acid and trimethoprim is relatively selective for bacterial DHFR
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18
Q

Sulfonamides and Trimethoprim site of action

A
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19
Q

Sulfonamides and Trimethoprim absorption and distribution

A
  • Good oral availability
  • Large volume of distribution including CSF
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20
Q

Sulfonamides and Trimethoprim metabolism and excretion

A
  • Sulfonamides are eliminated by hepatic metabolism; metabolites and parent drug are eliminated in the urine
  • Trimethoprim is eliminated unchanged in the urine
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21
Q

Toxicities of sulfonamides

A
  • Allergic rxns: minor to life-threatening rash
  • Acute hemolytic anemia in G6PD deficiency
  • Crystalluria causing renal impairment
  • Kernicterus (CNS damage in newborns caused by displacing bilirubin from plasma protein binding sites
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22
Q

Sulfonamides drug interactions

A

increases warfarin or oral hypoglycemic drug levels by CYP450 inhibition

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23
Q

Toxicities of Trimethoprim

A
  • Megaloblastic anemia
  • Leukopenia
  • Inhibits tubular secretion of creatinine
  • TMP/SMX is associated with rare sudden death in patients taking ACE inhibitors or ARBs due to hyperkalemia
  • Stevens-Johnson syndrome
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24
Q

Sulfonamide antibiotics cross-hypersensitivity

A

Sulfamethoxazole

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25
Q

Thiazide diuretics and potential cross-hypersensitivity

A

Hydrochlorothiazide

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26
Q

Loop diuretics and potential cross-hypersensitivity

A

Furosemide

27
Q

Sulfonylureas and potential cross-hypersensitivity

A
  • Chlorpropamide
  • Tolbutamide
  • Glipizide
  • Glyburide
28
Q

Serotonin agonists and potential cross-hypersensitivity

A

Sumitriptan

29
Q

Uricosuric drugs and potential cross-hypersensitivity

A

Probenecid

30
Q

Carbonic hydrase inhibitor and potential cross-hypersensitivity

A

Acetazolamide

31
Q

Selective COX-2 inhibitors and potential cross-hypersensitivity

A

Celecoxib

32
Q

Sulfonamide antibiotics and potential cross-hypersensitivity

A
  • Sulfonamide antibiotics - sulfamethoxazole
33
Q

Trimethoprim/Sulfamethoxazole spectrum of activity

A
  • GPC (including some MRSA)
  • GNR
  • Some anaerobes
  • Bacteriostatic
  • Concentration-dependent killing with PAE
34
Q

Trimethoprim/Sulfamethoxazole Resistance

A
  • Mutation
  • ↑PABA (para-aminobenzoic acid)
  • Plasmid acquired resistent enzymes (eg sulfonamide acetyltransferase)
35
Q

PABA AKA

A

Para-aminobenzoic Acid

36
Q

Bacterial Topoisomerase II inhibitors

A

Quinolones

37
Q

Topoisomerase II AKA

A

DNA Gyrase

38
Q

DNA gyrase inhibitors class

A

Quinolones

39
Q

Topoisomerase IV inhibitors class

A

Quinolones

40
Q

Quinolones MOA

A
  • Prevent the negative supercoiling of DNA and cause DNA strand breakage (Topt II AKA DNA gyrase; GN)
  • PRevent daughter cell chromatid separation (Topo IV; GP)
  • Selective because analogous eukaryotic topoisomerase-II is not inhibited until 5x104
  • Bactericidal
  • Concentration-dependent killing with PAE
41
Q

Quinolones route of administration

A

Good oral bioavailability however, Chelated ions (cations) decreased oral uptake, cf. tetracyclines

42
Q

Quinolones distribution

A

Large volume of distribution

43
Q

Quinolones elimination

A
  • Ciprofloxacin and levofloxacin are primarily cleared by the kidneys but also partially metabolized by hepatic CYP450 with drug-interactions
  • Moxifloxacin is primarily metabolized and cleared in the bile so it is not effective for UTI
44
Q

What is the basic MOA/antibiotic type of Quinolones

A

Bacterial topoisomerase II (DNA GyrasE) and Topoisomerase IV inhibitors

45
Q

Quinolone not effective for UTI

A

Moxifloxacin is primarily metabolized and cleared in the bile so it is not effective for UTI

46
Q

Quinolones toxicities

A
  • GI upset (N/V)
  • Arthropathy
  • Tendon rupture
    • believed due to membrane metalloproteinase activation
    • Teratogenic
  • Hepatotoxicity
  • Polyneuropathy (sensory)
  • Prolonged QTc
47
Q

Quinolones spectrum of activity

A

Broad

  • 2nd gen ciprofloxacin: GPC, GNR, atypicals (mycoplasma, Chlamydia, Legionella) and some Anaerobic coverage
48
Q

Quinolones resistance

A
  • Alteration in target enzymes (DNA gyrase and/or topoisomerase IV)
  • Impaired access to target enzymes
    • efflux mechanisms
    • Change in porin expression
49
Q

Quinolones caution in special populations

A
  • Pregnancy
  • Breastfeeding infants
  • Childhood
50
Q

Quinolones and pregnancy

A
  • Many antibiotics can cross the placenta
  • Fluoroquinolones are contraindicated due to teratogenicity
  • Other drugs are contraindicated in pregnancy including Tetracyclines and TMP/SMX
51
Q

Quinolones and breastfeeding infants

A

Many antibiotics are secreted in breast milk

52
Q

Quinolones and childhood

A

Fluoroquinolones, Tetracyclines, aminoglycosides, chloramphenicol are contraindicated or used with caution in neonates and young children

53
Q

Antibiotics that can be used in pregnancy

A
  • β-lactams
  • Clindamycin
  • Aminoglycosides
54
Q

Question

A
55
Q

Question

A
56
Q

Question

A
57
Q

Question

A
58
Q

Question

A
59
Q

Thiazide diuretics and potential cross-hypersensitivity

A

Hydrochlorothiazide

60
Q

Loop diuretics and potential cross-hypersensitivity

A

Furosemide

61
Q

Sulfonureas and potential cross-hypersensitivity

A
  • Chlorpropamide
  • tolbutamide
  • glipizide
  • glyburide
62
Q

Uricosuric drugs and potential cross-hypersensitivity

A

Probenecid

63
Q

Carbonic hydrase inhibitors and potential cross-hypersensitivity

A
  • Acetazolamide
64
Q

Selective COX-2 inhibitors and potential cross-hypersensitivity

A

Celecoxib

Infectious Disease (82 decks)

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