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Sulfonamides, trimethoprim and Quinolones
By S. Bohlooli, PhD
School of Medicine, Ardabil University of Medical Sciences
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Antifolate drugs
Sulfonamides Trimethoprim Trimethoprim & Sulfamethoxazole
mixture
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Sulfonamides: chemistry
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Sulfonamides: mechanism of action Inhibition of
dihydropetroate synthase
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Sulfonamides: antimicrobial activity
Gram positive and negative bacteria
Nocardia, chlamydia trachomatis Some protoza Some enteric bacteria Rickettisiae stimulated!
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Sulfonamides: resistance
Overproduction of PABA Low affinity dihydropetroate
synthase Loss of permeability to
sulfonamides
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Sulfonamides: pharmacokinetics
Oral absorbable Short Medium Long
Oral, nonabsorbable
topical
Serum protein bind 20 ~ 90%
Excreted into urine
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Pharmacokinetic Properties of Some Sulfonamides and Trimethoprim
Drug Half-Life Oral Absorption
Sulfonamides
Sulfacytine Short Prompt (peak levels in 1–4 hours)
Sulfisoxazole Short (6 hours) Prompt
Sulfamethizole Short (9 hours) Prompt
Sulfadiazine Intermediate (10–17 hours) Slow (peak levels in 4–8 hours)
Sulfamethoxazole Intermediate (10–12 hours) Slow
Sulfapyridine Intermediate (17 hours) Slow
Sulfadoxine Long (7–9 days) Intermediate
Pyrimidines
Trimethoprim Intermediate (11 hours) Prompt
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Sulfonamides: clinical uses Oral absorbable agents
Sulfisoxazole, sulfamethoxazole To treat urinary tract infection
Sulfadiazine: toxoplasmosis Sulfadoxine: long acting, in a combination for
treatment of malaria Oral nonabsorbable agents
Ulcerative colitis, enteritis, other inflammatory bowel disease
Topical agents Sulfacetamide: ophthalemic Mafenide & silver sulfadiazine: topically
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Sulfonamides: adverse reactions Cross allergenic sulfonamide drugs:
Thiazide, furosemide, diazoxide, sulfonylurea hypoglycemic agents, and others
Fever, skin rashes, exfoliative dermatitis,photosensivity, urticaria, nausea, vomiting, diarrhea
Stevens-Johnson syndrom Urinary tract disturbances
Crystalluria, hemturia, obstruction Hematopoietic disturbance
Hemolytic or aplastic anemia Granulocytopenia, thrombocytopenia, leukmoid
reaction Hemolysis in G-6PDH deficient patients Kernicterus in newborn of mothers have taken near
the end of pergnancy
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Trimethoprim: chemistry
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Trimethoprim: resistance
Reduced cell permeability Overproduction of DHF reductase Altered affinity of reductase
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Trimethoprim: pharmacokinetics
Usually given orally alone or in combination with sulfamethoxazole
Mainly excreted into urine More antibacterial activity in
prostatic and vaginal fluids
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Clinical use Oral trimethoprim
Acute urinary infection Oral trimethoprim-sulfamethoxazole
P jiroveci pneumonia, shigellosis, systemic salmonella infection, complicated urinary tract infection,
Active against many respiratory pathogens Intravenous trimethoprim-sulfamethoxazole
Gram negative sepsis, pneumocystis pneumonia Shigllosis, typhoid fever
Oral pryrimethamine with sulfanamide With sulfadiazine in Leishmaniasis, toxoplasmosis With sulfadoxine in malaria
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Adverse effects
Megaloblastic anemia Leukopenia, granulocytopenia Can be prevented by folinic acid The AIDS patients have high
frequency of unwanted reactions
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DNA gyrase inhibitors
Fluoroquinolones Nalidixic acid and cinoxacin
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Fluoroquinolones: chemistry
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Fluoroquinolones: chemistry-2
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Fluoroquinolones: antibacterial activity
Block of bacterial DNA synthesis by Inhibiting topoisomerase II, IV
Gram positive & negative bacteria Mycoplasma & clamydia, legionella Some mycobacteria Anaerobic bacteria
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Fluoroquinolones: resistance
Change in permeability Loss of affinity
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Fluoroquinolones: pharmacokinetics
Well absorbed after oral administration
Good distribution Divalent cations impair absorption
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Pharmacokinetic Properties of Fluoroquinolones
Drug Half-Life (h)
Oral Bioavailability (%)
Peak Serum Concentration (mcg/mL)
Oral Dose (mg)
Primary Route of Excretion
Ciprofloxacin 3–5 70 2.4 500 Renal
Gatifloxacin 8 98 3.4 400 Renal
Gemifloxacin 8 70 1.6 320 Renal & nonrenal
Levofloxacin 5–7 95 5.7 500 Renal
Lomefloxacin 8 95 2.8 400 Renal
Moxifloxacin 9–10 > 85 3.1 400 Nonrenal
Norfloxacin 3.5–5 80 1.5 400 Renal
Ofloxacin 5–7 95 2.9 400 Renal
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Fluoroquinolones: clinical uses Urinary tract infection
Even with multi-drug resistant organisms Bacterial diarrhea
Shigella, salmonella, toxigenic E. coli Infections of soft tissues, bones and joints Intra-abdominal and respiratory tract infections Gonococcal infection Chlamydial urethritis and cervicitis Legionellosis Tuberclusis and atypical mycobacterial
infections
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Fluoroquinolones: adverse effects Nausea, vomiting & diarrhea Headache, dizziness, insomnia, skin rash,
abnormal liver test Acute hepatitis & hepatic failure:
trovafloxacin Photosensivity: lomefloxacin, pefloxacin QT prolongation: sparfloxacin Hyperglycemia or hypoglycemia May damage growing cartilage:
arthropathy Tendinitis
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Nalidixic acid & cinoxacin
Excreted too rapidly Useful for urinary tract infections