DRUGS AFFECTING NUCLEIC ACID SYNTHESIS Flashcards Preview

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Flashcards in DRUGS AFFECTING NUCLEIC ACID SYNTHESIS Deck (27):
1

DRUGS AFFECTING NUCLEIC ACID SYNTHESIS

1) FLUOROQUINOLONES

2) SULFONAMIDES

3) TRIMETHOPRIM

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FLUOROQUINOLONES

GENERATIONS

1st Gen = NALIDIXIC ACID (QUINOLONE)

2nd Gen = CIPROFLOXACIN --> is SYNERGISTIC with B-lactams

3rd Gen = LEVOFLOXACIN --> excellent activity against S. pneumoniae

4th Gen = GEMIFLOXACIN, MOXIFLOXACIN

 

LOWER GEN = HIGHER GRAM -VE ACTIVITY

HIGHER GEN = HIGHER GRAM +VE ACTIVITY

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DOC FOR UNCOMPLICATED UTI: 

1st gen FLUOROQUINOLONES = NALIDIXIC ACID

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DOC FOR TRAVELERS DIARRHEA (E. COLI) 

2ND GEN FLUOROQUINOLONE: CIPROFLOXACIN

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DOC FOR PSEUDOMONAS AERUGINOSA (CF PATIENTS) EVEN CHILDREN

2nd gen fluoroquinolone = CIPROFLOXACIN

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PROPHYLAXIS AGAINST MENINGITIS (alternative to ceftriaxone and rifampin) 

 

2nd Generation Fluoroquinolone: CIPROFLOXACIN

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DOC FOR PROSTATITIS (E. COLI)

3rd GENERATION FLUOROQUINOLONE: LEVOFLOXACIN

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WHEN TO USE 3RD + 4TH LINE FLUOROQUINOLONES?

Levofloxacin, moxifloxacin & gemifloxacin (excellent activity against S.pneumoniae, H.influenzae & M.catarrhalis)

Used in treatment of pneumonia when:

• First-line agents have failed
• In the presence of comorbidities

• Patient is an inpatient

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FLUOROQUINOLONES CLINICAL APPLICATIONS TABLE

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FLUOROQUINOLONES PK + AE

 

PK: 

• Good oral bioavailability
• Well distributed into all tissues and fluids (including

bones)

Iron, zinc, calcium (divalent cations) interfere with absorption, so DON'T TAKE WITH MILK OR ANTACIDS

Dosage adjustments required in renal dysfunction (except

moxifloxacin)

AE: 

• GI distress

• CNS, rash, photosensitivity

Connective tissue problems (avoid in pregnancy, nursing mother, under 18’s) – Black Box Warning!

QT prolongation (moxifloxacin, gemifloxacin, levofloxacin)

High risk of causing superinfections (C.difficile, C albicans, streptococci)

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FLUOROQUINOLONES - INTERACTIONS + CONTRAINDICATIONS 

INTERACTIONS: 

Theophylline, NSAIDs & corticosteroids = enhance toxicity of fluoroquinolones

• 3rd & 4th generation = raise serum levels of warfarin, caffeine & cyclosporine

CONTRAINDICATIONS: 

Pregnancy & nursing mothers
• Children < 18y (unless benefits outweigh risks) 

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SULFAMETHOXAZOLE

SULFADIAZINE

SULFASALAZINE

SULFONAMIDES

• Structural analogs of p-aminobenzoic acid (PABA)

• Bacteriostatic against Gram-positive & Gram-negative organisms

MOA: 

• Inhibit bacterial folic acid synthesis

• Synthetic analogs of PABA (p-amino-benzoic acid)

• Competitive inhibitors (& substrate) of dihydropteroate synthase

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SULFONAMIDES - RESISTANCE

Plasmid transfers / random mutations that:

• Altered dihydropteroate synthase
• Decreased cellular permeability
• Enhanced PABA production
• Decreased intracellular drug accumulation

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SULFONAMIDES - CLINICAL APPLICATIONS

Infrequently used as single agents (resistance)

Topical agents (ocular, burn infections)
• Oral agents (simple UTI’s)
• Sulfasalazine (oral) = ulcerative colitis, enteritis, IBD

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SULFONAMIDE PK + AE

• Oral or topical

• Can accumulate in renal failure

• Acetylated in liver. Can precipitate at neutral or acidic pH --> kidney damage

AE: 

• GI distress, fever, rashes, photosensitivity are common

Crystalluria (nephrotoxicity)

Hypersensitivity reactions

Hematopoietic disturbances (esp. patients with G6PD deficiency)

Kernicterus (in newborns and infants <2 months)

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SULFONAMIDES - DRUG INTERACTIONS + CONTRAINDICATIONS

Warfarin, phenytoin and methotrexate can lead to increased plasma levels

CONTRAINDICATIONS: 

Newborns & infants < 2 months (kernicterus) – drugs compete with bilirubin for binding sites on albumin

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TRIMETHOPRIM

Structurally similar to folic acid

• Bacteriostatic against Gram-positive & Gram-negative organisms

MOA:

1) Potent inhibitor of bacterial dihydrofolate reductase

2) Inhibits purine, pyrimidine & amino acid synthesis

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TRIMETHOPRIM CLINICAL APPLICATIONS

1) UTI's

2) BACTERIAL PROSTATITIS (after Ciprofloxacin)

3) BACTERIAL VAGINITIS

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TRIMETHOPRIM PK + AE

 

• Mostly (80-90%) excreted unchanged through kidney
• Reaches high concentrations in prostatic & vaginal fluids

AE: 

Antifolate effects (contraindicated in pregnancy)

• Skin rash, pruritus

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COTRIMOXAZOLE

 

• Combination of trimethoprim & sulfamethoxazole

• Bactericidal

Mechanism of action

• Synergistic: inhibition of sequential steps in tetrahydrofolic acid synthesis

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COTRIMOXAZOLE CLINICAL APPLICATIONS

1) Uncomplicated UTI’s (drug of choice)

2) PCP (drug of choice)
3) Nocardiosis (drug of choice)


4) Toxoplasmosis (alternative drug)

• Respiratory, ear, sinus infections (H.influenzae, M.catarrhalis)

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COTRIMOXAZOLE AE + PK 

• Oral admin. generally (can be given IV)

• Well distributed (including CSF)

ADVERSE EFFECTS: 

• Dermatologic (common)

• GI
• Hematologic (hemolytic anemia)
• AIDS patients = higher incidence
Contraindicated in pregnancy (esp. 1st trimester)

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METRONIDAZOLE

• Antimicrobial, amebicide & antiprotozoal
• Activity against anaerobic bacteria (including bacteroides & Clostridium)

• Bactericidal

MOA: 

Anaerobic conditions are vital for optimal activity

• Undergoes reductive bioactivation of its nitro group by

ferredoxin

• Forms cytotoxic products that interfere with nucleic acid synthesis

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METRONIDAZOLE CLINICAL APPLICATIONS

1) C.difficile infections (drug of choice)
2) Anaerobic or mixed intra-abdominal infections
3) Vaginitis (trichomonas & bacterial vaginosis, G.vaginalis)

4) Brain abscesses
5) H.pylori eradication (in combination)

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METRONIDAZOLE PK + AE

• Oral, IV, rectal or topical
Wide distribution (including CSF) ****

• Elimination = hepatic metabolism

AE: 

• GI irritation, stomatitis, peripheral neuropathy (prolonged use)

Headache, dark coloration of urine

Leukopenia, dizziness, ataxia (rarer)

• Opportunistic fungal infections

-Disulfiram-like effect (avoid alcohol)

-Use generally not advised in 1st trimester

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NITROFURANTOIN

URINARY ANTISEPTIC

• Oral agents with antibacterial activity in urine but little or

no systemic effect

Use is limited to prophylaxis and treatment of lower UTI’s

• Bacteriostatic & bactericidal

• Active against many Gram-positive and Gram-negative bacteria

MOA: 

• Reduction of nitrofurantoin by bacteria in the urine leads

to formation of reactive intermediates that subsequently

damage bacterial DNA

• Slow emergence of resistance and no cross-resistance

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NITROFURANTOIN PK + AE

URINARY ANTISEPTIC

Pharmacokinetics

• Rapid elimination (only achieves adequate concentrations in urine)

Adverse Effects

• Anorexia, nausea & vomiting.

•Neuropathies, hemolytic anemia (G6PD deficient patients)