Sulfonamides, trimethoprim and Quinolones

By S. Bohlooli, PhD

School of Medicine, Ardabil University of Medical Sciences

Antifolate drugs

Sulfonamides Trimethoprim Trimethoprim & Sulfamethoxazole

mixture

Sulfonamides: chemistry

Sulfonamides: mechanism of action Inhibition of

dihydropetroate synthase

Sulfonamides: antimicrobial activity

Gram positive and negative bacteria

Nocardia, chlamydia trachomatis Some protoza Some enteric bacteria Rickettisiae stimulated!

Sulfonamides: resistance

Overproduction of PABA Low affinity dihydropetroate

synthase Loss of permeability to

sulfonamides

Sulfonamides: pharmacokinetics

Oral absorbable Short Medium Long

Oral, nonabsorbable

topical

Serum protein bind 20 ~ 90%

Excreted into urine

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

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

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

Trimethoprim: chemistry

Trimethoprim: resistance

Reduced cell permeability Overproduction of DHF reductase Altered affinity of reductase

Trimethoprim: pharmacokinetics

Usually given orally alone or in combination with sulfamethoxazole

Mainly excreted into urine More antibacterial activity in

prostatic and vaginal fluids

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

Adverse effects

Megaloblastic anemia Leukopenia, granulocytopenia Can be prevented by folinic acid The AIDS patients have high

frequency of unwanted reactions

DNA gyrase inhibitors

Fluoroquinolones Nalidixic acid and cinoxacin

Fluoroquinolones: chemistry

Fluoroquinolones: chemistry-2

Fluoroquinolones: antibacterial activity

Block of bacterial DNA synthesis by Inhibiting topoisomerase II, IV

Gram positive & negative bacteria Mycoplasma & clamydia, legionella Some mycobacteria Anaerobic bacteria

Fluoroquinolones: resistance

Change in permeability Loss of affinity

Fluoroquinolones: pharmacokinetics

Well absorbed after oral administration

Good distribution Divalent cations impair absorption

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

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

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

Nalidixic acid & cinoxacin

Excreted too rapidly Useful for urinary tract infections