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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
Thiazide diuretics and potential cross-hypersensitivity
Hydrochlorothiazide
26
Loop diuretics and potential cross-hypersensitivity
Furosemide
27
Sulfonylureas and potential cross-hypersensitivity
* Chlorpropamide * Tolbutamide * Glipizide * Glyburide
28
Serotonin agonists and potential cross-hypersensitivity
Sumitriptan
29
Uricosuric drugs and potential cross-hypersensitivity
Probenecid
30
Carbonic hydrase inhibitor and potential cross-hypersensitivity
Acetazolamide
31
Selective COX-2 inhibitors and potential cross-hypersensitivity
Celecoxib
32
Sulfonamide antibiotics and potential cross-hypersensitivity
* Sulfonamide antibiotics - sulfamethoxazole
33
Trimethoprim/Sulfamethoxazole spectrum of activity
* GPC (including some MRSA) * GNR * Some anaerobes * Bacteriostatic * Concentration-dependent killing with PAE
34
Trimethoprim/Sulfamethoxazole Resistance
* Mutation * ↑PABA (para-aminobenzoic acid) * Plasmid acquired resistent enzymes (eg sulfonamide acetyltransferase)
35
PABA AKA
Para-aminobenzoic Acid
36
Bacterial Topoisomerase II inhibitors
Quinolones
37
Topoisomerase II AKA
DNA Gyrase
38
DNA gyrase inhibitors class
Quinolones
39
Topoisomerase IV inhibitors class
Quinolones
40
Quinolones MOA
* 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
Quinolones route of administration
Good oral bioavailability however, Chelated ions (cations) decreased oral uptake, cf. tetracyclines
42
Quinolones distribution
Large volume of distribution
43
Quinolones elimination
* 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
What is the basic MOA/antibiotic type of Quinolones
Bacterial topoisomerase II (DNA GyrasE) and Topoisomerase IV inhibitors
45
Quinolone not effective for UTI
Moxifloxacin is primarily metabolized and cleared in the bile so it is not effective for UTI
46
Quinolones toxicities
* GI upset (N/V) * Arthropathy * Tendon rupture * believed due to membrane metalloproteinase activation * Teratogenic * Hepatotoxicity * Polyneuropathy (sensory) * Prolonged QTc
47
Quinolones spectrum of activity
Broad * 2nd gen ciprofloxacin: GPC, GNR, atypicals (mycoplasma, Chlamydia, Legionella) and some Anaerobic coverage
48
Quinolones resistance
* Alteration in target enzymes (DNA gyrase and/or topoisomerase IV) * Impaired access to target enzymes * efflux mechanisms * Change in porin expression
49
Quinolones caution in special populations
* Pregnancy * Breastfeeding infants * Childhood
50
Quinolones and pregnancy
* Many antibiotics can cross the placenta * Fluoroquinolones are contraindicated due to teratogenicity * Other drugs are contraindicated in pregnancy including Tetracyclines and TMP/SMX
51
Quinolones and breastfeeding infants
Many antibiotics are secreted in breast milk
52
Quinolones and childhood
Fluoroquinolones, Tetracyclines, aminoglycosides, chloramphenicol are contraindicated or used with caution in neonates and young children
53
Antibiotics that can be used in pregnancy
* β-lactams * Clindamycin * Aminoglycosides
54
Question
55
Question
56
Question
57
Question
58
Question
59
Thiazide diuretics and potential cross-hypersensitivity
Hydrochlorothiazide
60
Loop diuretics and potential cross-hypersensitivity
Furosemide
61
Sulfonureas and potential cross-hypersensitivity
* Chlorpropamide * tolbutamide * glipizide * glyburide
62
Uricosuric drugs and potential cross-hypersensitivity
Probenecid
63
Carbonic hydrase inhibitors and potential cross-hypersensitivity
* Acetazolamide
64
Selective COX-2 inhibitors and potential cross-hypersensitivity
Celecoxib

Infectious Disease (82 decks)

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