DRUGS AFFECTING NUCLEIC ACID SYNTHESIS Flashcards
DRUGS AFFECTING NUCLEIC ACID SYNTHESIS
1) FLUOROQUINOLONES
2) SULFONAMIDES
3) TRIMETHOPRIM
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
DOC FOR UNCOMPLICATED UTI:
1st gen FLUOROQUINOLONES = NALIDIXIC ACID
DOC FOR TRAVELERS DIARRHEA (E. COLI)
2ND GEN FLUOROQUINOLONE: CIPROFLOXACIN
DOC FOR PSEUDOMONAS AERUGINOSA (CF PATIENTS) EVEN CHILDREN
2nd gen fluoroquinolone = CIPROFLOXACIN
PROPHYLAXIS AGAINST MENINGITIS (alternative to ceftriaxone and rifampin)
2nd Generation Fluoroquinolone: CIPROFLOXACIN
DOC FOR PROSTATITIS (E. COLI)
3rd GENERATION FLUOROQUINOLONE: LEVOFLOXACIN
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
FLUOROQUINOLONES CLINICAL APPLICATIONS TABLE
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)
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)
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
SULFONAMIDES - RESISTANCE
Plasmid transfers / random mutations that:
- Altered dihydropteroate synthase
- Decreased cellular permeability
- Enhanced PABA production
- Decreased intracellular drug accumulation
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
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)
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
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
TRIMETHOPRIM CLINICAL APPLICATIONS
1) UTI’s
2) BACTERIAL PROSTATITIS (after Ciprofloxacin)
3) BACTERIAL VAGINITIS
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
COTRIMOXAZOLE
- Combination of trimethoprim & sulfamethoxazole
- Bactericidal
Mechanism of action
• Synergistic: inhibition of sequential steps in tetrahydrofolic acid synthesis
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)
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)*
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
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)
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*
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
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)
